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K. Park
Moderator of
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MINI 30 - New Kinase Targets (ID 157)
- Event: WCLC 2015
- Type: Mini Oral
- Track: Treatment of Advanced Diseases - NSCLC
- Presentations: 15
- Moderators:K. Park, M. Villalona
- Coordinates: 9/09/2015, 18:30 - 20:00, Four Seasons Ballroom F3+F4
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MINI30.01 - Oncolytic Reovirus in Combination with Paclitaxel/Carboplatin in NSCLC Patients with Ras Activated Malignancies, Long Term Results (ID 500)
18:30 - 18:35 | Author(s): M. Villalona, E. Lam, G. Otterson, W. Zhao, M. Timmons, D. Subramaniam, E. Hade, E. Bertino, B. Chao, G. Selvaggi, M. Knopp, G.M. Gill
- Abstract
- Presentation
Background:
Reovirus is a naturally occurring virus which preferentially infects and causes oncolysis in tumor cells with a Ras-activated pathway. Cells that express high levels of EGFR are also susceptible to reovirus infection. In preclinical studies, reovirus induces host immunity and cell cycle arrest, acting synergistically with standard cytotoxic agents. Its adverse effects are mild to moderate flu-like symptoms. We have hypothesized those patients with EGFR-mutated, EGFR-amplified, or Kras-mutated NSCLC through a common downstream activated Ras pathway should be susceptible to treatment with reovirus
Methods:
We designed a Fleming, single-arm, phase II study to evaluate the objective response rate (CR + PR RECIST, or >40% PET SUV decrease) of reovirus in combination with paclitaxel-carboplatin as first-line therapy in patients with metastatic NSCLC. Secondary endpoints included progression free and overall survival. Eligible patients had ECOG PS 0-2, adequate organ function, no prior systemic chemotherapy for metastatic disease, and tumors with the specified genotype, as per CLIA certified testing. Adjuvant chemotherapy, or erlotinib/gefitinib for pts with EGFR mutant tumors was permitted.
Results:
Thirty-seven patients were enrolled. Molecular tumor demographics included 20 pts with Kras mutations; 10 with EGFR amplification alone; 3 patients with EGFR mutations and four patients with BRAF V600E mutations. Overall, 258 cycles (median 4, range 1-47) were administered. Initial doses used were C AUC 6 on day 1, and P 200 mg/m[2],on day 1 of each 21-day cycle. Due to unacceptable toxicities (grade 3 diarrhea and febrile neutropenia [1 each]) in the first two patients, doses were reduced to P 175 mg/m-m[2] and C AUC 5.. Common toxicities considered at least possibly related to the therapy included fatigue (30 pts); diarrhea (21 pts); nausea (19 pts); arthralgia-myalgia (15 pts); and anorexia (9 pts). Grade 3-4 adverse events included neutropenia (7 Gr3, 1 Gr4), anemia (2 Gr3), fatigue (9 Gr3), diarrhea (3 Gr3), nausea/vomiting (3 Gr3) and a single case of sepsis. Response evaluation showed 11 PR (5 Kras mutant), 20 SD, 4 PD and 2 NE patients by RECIST (ORR: 31%, 90% one-sided lower CI: 21%). Four of the SD patients had >40% PET SUV reductions after two cycles. Three patients opted to switch to pemetrexed maintenance after 4 cycles without disease progression or moderate/severe toxicity. Median PFS, OS and 12 month overall survival rates were: 4 months (95% CI: 2.9-6.1), 13.1 months (95% CI: 9.2-21.6) and 57% (95% CI: 39-72%), respectively. Seven patients are alive after a median follow up of 34.2 months (range: 26.9-71.5), including two patients with no evidence of disease progression to date (50 and 37 months).
Conclusion:
Oncolytic reovirus administration in combination with paclitaxel and carboplatin was well tolerated. The RECIST response rate (11/35 [31%]; 28% of Kras mutants)(15/35; 43% if PET is considered) is not conclusive, nor excludes additional benefit of the reovirus to chemotherapy. However, the number of patients surviving longer than 2 years (11; 30%) is substantial, suggesting either effect of second/third line post paclitaxel/carboplatin/reolysin treatment or perhaps the triggering of an immune response following tumor reovirus infiltration. The latter concept merits further investigation.
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MINI30.02 - Phase II Study of Defactinib, VS-6063, a Focal Adhesion Kinase (FAK) Inhibitor, in Patients with KRAS Mutant Non-Small Cell Lung Cancer (NSCLC) (ID 2875)
18:35 - 18:40 | Author(s): D.E. Gerber, R. Camidge, D. Morgensztern, J. Cetnar, R. Kelly, S.S. Ramalingam, D.R. Spigel, W. Jeong, P. Scaglioni, M. Li, M. Keegan, J. Horobin, T.F. Burns
- Abstract
- Presentation
Background:
KRAS mutations, which occur in approximately 30% of lung adenocarcinoma cases, represent a major unmet clinical need in thoracic oncology. Preclinical studies have demonstrated that KRAS mutant NSCLC cell lines and xenografts with additional alterations in either p53 or INK4a/Arf (CDKN2A) are sensitive to FAK inhibition. Defactinib (VS-6063) is a selective oral inhibitor of FAK. This trial examined the effect of FAK inhibition in patients with KRAS mutant NSCLC and various permutations of p53 and CDKN2A alterations.
Methods:
This multi-center, non-randomized, open-label, multi-cohort trial enrolled patients with advanced KRAS mutant NSCLC who had received at least one prior (platinum-based chemotherapy doublet) line of therapy. The primary endpoint was progression-free survival (PFS) at 12 weeks. Patients were enrolled into one of four cohorts defined by INK4a/Arf and p53 status. In all cohorts, patients received defactinib 400 mg orally BID until disease progression.
Results:
Fifty-three patients with KRAS mutant NSCLC were enrolled across 9 US sites as of the data cut-off date (13-Mar-2015). Forty-seven patients were enrolled to one of the four molecularly defined cohorts. The median age was 62 years (range 33-80); 48% were female. The median number of prior lines of therapy was 3 (range 1-8) 15 (28%) pts met the 12 week PFS endpoint, with one patient achieving a PR. Median PFS was 46 days (range 12-205 days). Eight patients remained on study as of the data cut-off date. Clinical efficacy did not correlate with secondary mutation status across this KRAS mutant population. Adverse events considered at least possibly related to defactinib were experienced by 35 pts (76%). The majority of these were grade 1 or 2. 11 patients (24%) experienced at least possibly related grade 3-5 events, including 2 grade 5 respiratory failure events. Underlying disease was a confounding factor in many pts. The most commonly reported treatment emergent adverse events of any grade were fatigue (24%) and increased bilirubin (24%).
Conclusion:
In pretreated pts with KRAS mutant NSCLC defactinib demonstrates promising clinical activity with disease control rates comparable to other molecularly targeted agents for this pt population. Defactinib was generally well tolerated. Further development is warranted. Clinical trial: NCT01778803.
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MINI30.03 - Smoking Predicts Sensitivity to PARP Inhibitor, Veliparib, in Advanced NSCLC Patients (ID 1279)
18:40 - 18:45 | Author(s): N. Blais, S.S. Ramalingam, J. Mazières, M. Reck, C.M. Jones, E. Juhasz, L. Urban, S. Orlov, F. Barlesi, E. Kio, U. Keilholz, J. Qian, Q. Qin, M. Dunbar, H. Xiong, R. Mittapalli, P. Ansell, M.D. McKee, V. Giranda, V. Gorbunova
- Abstract
- Presentation
Background:
Tobacco-related non-small cell lung cancer (NSCLC) is associated with reduced survival and greater genomic instability. Veliparib (V) is a PARP inhibitor that augments platinum-induced DNA damage in preclinical studies, and a recent Phase 2 trial of advanced NSCLC trended to improved survival (HR 0.80; CI 0.54–1.18) when V was added to carboplatin (C) and paclitaxel (P). Here we report outcomes based on smoking status from this randomized Phase 2 study of CP with either V or placebo in advanced NSCLC.
Methods:
Patients with previously untreated advanced/metastatic NSCLC were randomized 2:1 to CP with either V at 120mg BID or placebo (randomization stratified by histology and smoking history). Cotinine was measured in patients’ plasma samples as an index of recent tobacco use.
Results:
Of 158 patients, 68% were male, and 49% had squamous NSCLC. At study entry, 60% pts were self-reported current smokers, 27% former smokers, and 13% never smoked. There were no significant differences in veliparib pharmacokinetic parameters between cotinine-high and low. Grade 3/4 AEs were elevated in current-smokers treated with VCP vs CP (66% vs. 40%, p=0.026); all-grade AEs and SAEs were similar between the two groups. The most common AEs in current-smokers were neutropenia (41% VCP; 27% CP), alopecia (36%; 33%), and anemia (31%; 40%). Figure 1 A sensitivity analysis of heavy vs light-smokers (≥ vs <39 pack-years, current or former smokers) showed advantage of veliparib in heavy-smokers: median PFS [HR(95% CI)] for VCP/CP was 7.0 vs 3.5 [0.43(0.20–0.94)] for heavy-smokers and 4.4 vs 4.2 [0.97(0.49–1.92)] for light-smokers; median OS was 12.6 vs 8.8 [0.52 (0.27–1.02)] for heavy-smokers and 9.9 vs 8.8 [0.92(0.53–1.61)] for light-smokers. A cotinine sensitivity analysis found that outcomes in cotinine-high were similar to current-smokers: PFS, cotinine-high HR was 0.38 (0.19–0.73) and cotinine-low was 0.97 (0.51–1.87); OS, cotinine-high HR was 0.52 (0.29–0.92) and cotinine-low was 1.07 (0.63–1.81). In univariate analyses assessing the influence of baseline characteristics and treatment on outcomes, smoking status and treatment had a significant interaction (p=0.0301 PFS, p=0.0118 OS). Additionally, multivariate analysis including all factors also identified current smoking as predictive of improved outcomes with VCP.
Conclusion:
Smoking status was a strong predictor of efficacy for veliparib-chemotherapy combination in advanced NSCLC. No differences in pharmacokinetics of V were seen based on plasma cotinine; toxicity of VCP was acceptable regardless of smoking history. A Phase 3 study has been initiated in patients with smoking history (M14-359).
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MINI30.04 - A Randomized Phase 2 Trial of Cabozantinib, Erlotinib or the Combination as 2nd or 3rd Line Therapy in EGFR Wild-Type NSCLC: ECOG-ACRIN E1512 (ID 404)
18:45 - 18:50 | Author(s): J.W. Neal, S.E. Dahlberg, H.A. Wakelee, S.C. Aisner, M. Bowden, D.P. Carbone, S.S. Ramalingam
- Abstract
Background:
Cabozantinib (C) is a small molecule inhibitor of multiple receptor tyrosine kinases, including MET, VEGFR2 & RET. MET is involved in tumor differentiation & VEGFR2 is a mediator of angiogenesis. Erlotinib (E) is FDA approved for the treatment of NSCLC.
Methods:
The primary objective of this randomized phase 2 study was to compare progression-free survival (PFS) of pts treated with E vs. C, & E vs E+C; each comparison had 91% power to detect a PFS hazard ratio (HR) of 0.5 with a 1-sided 0.10-level test stratified on prior number of therapies & ECOG PS. Secondary objectives included overall survival (OS), RECIST 1.1 response & CTCAE v4 toxicity. Pts were selected with previously treated (1-2 regimens) metastatic non-squamous EGFR wt NSCLC. Submission of archival tissue for central MET IHC testing was required. Oral daily dosing was: E-150 mg; C-60 mg; E+C-150 mg E, 40 mg C. Imaging was performed every 8 weeks. Pts optionally crossed over to E+C following progression on E or C.
Results:
125 pts were enrolled, of which 115 were eligible & treated (E, n=39; C, n=39; E+C, n=37). Pt characteristics were balanced between arms except for lower rate of brain mets history on E (p=0.02). Median follow up is 8.5 m. Compared with E (median 1.9 m), PFS was significantly improved on C (3.9 m, HR 0.33, p=0.0002, 80% CI 0.22-0.49) & E+C (4.1 m, HR 0.31, p=0.0002, 80% CI 0.21-0.46). Similarly, compared with E (median 4.0 m), OS was significantly improved on C (HR 0.52, p=0.02) & E+C arm HR 0.50, p=0.02). Grade 3-4 treatment-related hypertension & mucositis were higher on C and grade 3-4 diarrhea was higher on E+C. Overall worst grade toxicities were also significantly higher on C and E+C. MET IHC results were available on 88 patients from the primary analysis & 85% were positive (1-3+ membrane or cytoplasm staining with MET4 antibody). There was no correlation between MET status and PFS.
Conclusion:
C & C+E significantly improved PFS over E alone in pts with EGFR wt NSCLC. Cabozantinib-based regimens are promising for further investigation in this patient population. Funded by ECOG-ACRIN and NCI Contract No. HHSN261200800001E.
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MINI30.05 - Discussant for MINI30.01, MINI30.02, MINI30.03, MINI30.04 (ID 3388)
18:50 - 19:00 | Author(s): N. Pennell
- Abstract
- Presentation
Abstract not provided
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MINI30.06 - Activity of AUY922 in NSCLC Patients With EGFR Exon 20 Insertions (ID 1744)
19:00 - 19:05 | Author(s): Z. Piotrowska, E. Smit, D.B. Costa, M.S. Huberman, G.R. Oxnard, J.F. Gainor, R. Heist, A. Muzikansky, C.G. Azzoli, A. Shaw, C. Lin, W. Liao, C. Ho, M.J. Niederst, L. Fulton, J.A. Engelman, L.V. Sequist, J.C. Yang
- Abstract
- Presentation
Background:
EGFR exon 20 insertions (ins20) represent a rare subtype (4%) of EGFR mutations and are refractory to EGFR-specific tyrosine kinase inhibitors (TKIs). No effective targeted therapies exist for patients (pts) with ins20; median PFS on the irreversible EGFR TKI Afatinib is 2.8 months (mos). Based on a durable RECIST partial response (PR) to AUY922, a Heat Shock Protein 90 (Hsp90) inhibitor, observed in an EGFR ins20 patient in a previous study (NCT01124864), we designed a phase II investigator-initiated trial to assess the activity of AUY922 in NSCLC pts with EGFR ins20. Since pts with these mutations are rare, we identified other international investigators who have treated ins20 patients with AUY922. Here, we present the results of a pooled international experience of 21 patients with EGFR ins20 treated with AUY922 in the United States, Taiwan and the Netherlands.
Methods:
A total of 21 patients with EGFR in20 are included in this analysis. 14 were treated on a single-arm, multi-center, open-label study of AUY922 in advanced NSCLC pts with EGFR ins20 mutations in the US (NCT01854034). Five were treated on a multicenter Taiwanese trial of AUY922 across a variety of molecular NSCLC subtypes (NCT01922583) and two were treated on a compassionate-use basis in the Netherlands. The starting dose of AUY922 was 70mg/m2 IV weekly for all patients.
Results:
21 pts, including 14 females and 7 males, average age 55 (range, 27-75) were included in this analysis. The median number of prior therapies was 2 (range, 1-6.) 6 pts received a prior EGFR TKI; none responded to TKI monotherapy. The most common AUY922-related toxicities were grade 1-2 visual changes (18/21; 86%) diarrhea (18/21; 86%) and fatigue (15/21; 71%). The only treatment-related grade 3 toxicities was hypertension (2/21; 1%) and AST elevation (1/21; 0.5%). There was one death on study, related to pre-existing comorbidity/unrelated to AUY922. Among the 21 patients treated, 5 achieved a partial response by RECIST 1.1 (ORR 24%) (Figure 1.) The median PFS estimate is 3.9 mos (95% CI, 2.9 to 10.7.) 6 patients remain on treatment at the time of abstract submission. Updated results and correlation with specific ins20 mutations will be presented. Figure 1
Conclusion:
This international experience suggests that AUY922 may be an active therapy for advanced NSCLC pts with EGFR ins20 mutations with an ORR 24% and median PFS 3.9 mo. AUY922 is generally well-tolerated, though reversible low-grade ocular toxicity is common. Further study of AUY922 in this population is warranted.
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MINI30.07 - Crizotinib in Patients with ROS1 NSCLC. Preliminary Results of the AcSé Trial (ID 2426)
19:05 - 19:10 | Author(s): D. Moro-Sibilot, L. Faivre, G. Zalcman, M. Perol, J. Mazières, F. Barlesi, J. Otto, I. Monnet, A. Cortot, M. Wislez, H. Léna, P.J. Souquet, S. Lantuejoul, I. Rouquette, A. McLeer-Florin, G. Ferretti, N. Hoog-Labouret, F. Nowak, M. Jimenez, G. Vassal
- Abstract
- Presentation
Background:
To avoid uncontrolled off-label use and allow for a nationwide safe access to crizotinib (crz) for patients (pts) with an ALK, MET or ROS1 positive (+) tumor, the French National Cancer Institute (INCa) launched the AcSé program, funding both access to tumor molecular diagnosis and an exploratory multi-tumor 2-stage design phase II trial. We report the preliminary results of the ROS1+ NSCLC cohort.
Methods:
ROS1 status was assessed in 28 regional INCa molecular genetic centers by break-apart FISH assays in tumor samples showing an IHC score of ≥1+. Pts with ROS1 rearrangements, progressing after at least one standard treatment (including a platinum-based doublet, unless pts were considered as unfit for chemotherapy) were proposed to receive crz 250 mg BID. Responses were centrally assessed using RECIST v1.1. The objective response rate (ORR) and disease control rate (DCR) were assessed every 8 weeks.
Results:
From Aug. 5, 2013 to Mar. 1, 2015, 39 pts with ROS1+ NSCLC were enrolled. 37 pts had received crz, leading to 37 pts with clinical information. Median age: 62 years (range 33–81), 70% females, 95% non-squamous histology, and 94% metastatic disease at study entry. Median number of prior treatments: 2 (range 1 –7). Twenty four pts were still on treatment at the cut-off date, 13 have stopped crz (8 PD, 3 adverse events (AEs), 2 deaths). Among the 27 pts evaluable for response at 8 weeks, we observed 16 PR, 7 SD and 4 PD, leading to ORR=59% [95% CI:39-78], and DCR=85% [66-96]. DCR at 6 months was 57% (disease control was achieved in 12/21 evaluable pts). Crz was well tolerated with only 4 grade ≥3 (1 AE + 3 SAEs) and 9 grade 1-2 SAEs. Most common AEs, mainly grade 1, were visual disorders (54% of pts), peripheral edema (51%), diarrhea (48%), nausea (46%), and elevated transaminases (43%).
Conclusion:
Crz was well tolerated and achieved a robust treatment response rate in ROS1+ NSCLC. These results underline the interest of integrating ROS1 in biomarkers routine screening. Survival data and duration of response will be presented.
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MINI30.08 - ROS1 Resistance to Crizotinib Is Mediated by an Activating Mutation in c-KIT (ID 2244)
19:10 - 19:15 | Author(s): R. Dziadziuszko, A.T. Le, D.L. Aisner, A. Wrona, R.C. Doebele
- Abstract
- Presentation
Background:
Non-small cell lung cancer (NSCLC) patients with ROS1 chromosomal rearrangement benefit from treatment with the ROS1 inhibitor crizotinib with remarkable response rates and durable disease control. Similar to ALK and EGFR mutant NSCLC treated with targeted kinase inhibitors, disease progression inevitably occurs due to acquired resistance either by mutation within the kinase domain of ROS1 or via bypass signaling. However, limited data exists on the spectrum of resistance mechanisms in ROS1+ NSCLC. Here report on a novel bypass mechanism for ROS1 resistance discovered in a ROS1+ tumor sample from patient with acquired resistance to crizotinib in which an activating mutation in the KIT receptor (p.D816G) desensitize ROS1 cells to crizotinib inhibition.
Methods:
Patients with ROS1+ NSCLC treated with crizotinib who developed acquired resistance underwent biopsy of a progressing tumor. Tumor samples were analyzed for potential resistance mechanisms. Assessment of mutations within the ROS1 kinase domain was accomplished by direct sequencing of exons 35 thru exon 42 of ROS1 from genomic DNA isolated from FFPE tissue. The SNaPshot® Multiplex System was used to profile additional tumor related genes for mutations. The ROS1 rearranged cell lines, HCC78 and CUTO-2, were transduced with lentivirus to generate ectopic expression of the KIT[D816G] cDNA. Cell proliferation was assessed by an MTS assay and cellular signaling was measured by western blot analysis.
Results:
Sequencing of the patient’s post crizotinib sample showed no mutation in the ROS1 kinase domain. Additional mutational profiling by SNaPshot® revealed the acquisition of a KIT[D816G] mutation in the post-crizotinib sample that was not present in the pre-crizotinib tumor sample. HCC78 and CUTO-2 ROS1+ cell lines expressing the KIT[D816G] mutation were refractory to crizotinib by both cell proliferation assays and analysis of downstream signaling pathways. Both ROS1 and KIT activity had to be inhibited in order to suppress downstream signaling and proliferation in these cells.
Conclusion:
Activation of KIT by a gain-of-function mutation is a novel mechanism of resistance to crizotinib in ROS1 rearranged NSCLC. This bypass-signaling pathway serves as a ROS1 independent mechanism of progression, similarly to previously identified EGFR or RAS signaling pathways, and can potentially be targeted by KIT inhibitors.
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MINI30.09 - Clinical Response to Entrectinib in a Patient with NTRK1-Rearranged Non-Small Cell Lung Cancer (NSCLC) (ID 2913)
19:15 - 19:20 | Author(s): A.F. Farago, M. Patel, T. Bauer, S.V. Liu, A. Drilon, J. Wheler, S.I. Ou, D.M. Jackman, D.B. Costa, P. Multani, Z. Hornby, D. Luo, J.E. Lim, A.J. Iafrate, A. Shaw
- Abstract
- Presentation
Background:
Chromosomal rearrangements involving neurotrophic tyrosine kinase 1 (NTRK1) occur in less than 1% of NSCLCs. Cell-based assays have demonstrated that NTRK1 rearrangement leads to expression of an oncogenic TrkA fusion protein. While inhibition of TrkA in preclinical models reduces TrkA auto-phosphorylation and cell proliferation, the clinical activity of TrkA inhibitors in NSCLCs harboring an NTRK1 fusion is not known. Entrectinib (RXDX-101) is an orally available tyrosine kinase inhibitor of TrkA, TrkB, TrkC, ROS1, and ALK, with IC50 values for kinase inhibition ≤ 2 nM.
Methods:
We used an anchored multiplex polymerase chain reaction (AMP) assay to screen for NTRK1 rearrangements (Zheng et al., Nature Medicine 2014). Among over 663 NSCLC cases screened, we identified one positive case in which the 3’ end of SQSTM1 exon 6 was fused to the 5’ end of NTRK1 exon 10, leading to an SQSTM1-NTRK1 fusion transcript. We enrolled the patient onto the Phase 1 dose escalation study of entrectinib in adult patients with locally advanced or metastatic tumors (NCT02097810). The dose of entrectinib was 400 mg/m[2] (750 mg) once daily. We assessed safety of entrectinib and response to treatment using RECIST 1.1.
Results:
The patient is a 46 yo male with a 30 pack year smoking history who was first diagnosed with metastatic NSCLC in November 2013. Prior therapies included carboplatin/pemetrexed, pembrolizumab, docetaxel, and vinorelbine. At the time of study enrollment, the patient had an ECOG performance status of 2 and required supplemental oxygen at a rate of 3 liters per minute by nasal cannula. He reported significant pain and dyspnea due to widely metastatic disease, including a large left hilar mass narrowing the left upper lobe bronchus and obstructing the left lower lobe bronchus, extensive and palpable neck and chest lymphadenopathy, and a palpable expansile left chest wall mass. Staging head CT also revealed numerous (15 to 20) asymptomatic brain metastases measuring up to 1.7 cm that had not been previously treated. The patient was started on entrectinib and tolerated the study medication well, with one adverse event of grade 1 dysgeusia, which resolved after two weeks. Within three weeks of starting treatment, the patient reported resolution of dyspnea and pain, and improvement in energy and appetite. He no longer required supplemental oxygen and all sites of palpable disease had improved or resolved. At four weeks of treatment, restaging CT scans demonstrated a partial response by RECIST of -47%, with significant regression or resolution of lymphadenopathy, reduction in size of the chest wall mass, and marked reexpansion of the left lung. Restaging of the CNS by head CT demonstrated near complete resolution of previously visualized brain metastases.
Conclusion:
In a heavily pre-treated patient with NSCLC harboring an NTRK1 gene fusion, entrectinib therapy resulted in rapid clinical improvement and a radiologic partial response at 4 weeks with minimal toxicity. This preliminary report suggests that entrectinib may be an effective therapy for patients with NTRK1-rearranged NSCLC.
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MINI30.10 - Discussant for MINI30.06, MINI30.07, MINI30.08, MINI30.09 (ID 3409)
19:20 - 19:30 | Author(s): D.S. Tan
- Abstract
- Presentation
Abstract not provided
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- Abstract
- Presentation
Background:
FGFR1 amplification is one of the most common potential driving oncogenes in squamous cell carcinoma (SCC), which accounts for 20% of non-small cell lung cancer (NSCLC) squamous cell carcinoma. This phase II study evaluated the efficacy and toxicity profile of dovitinib, an orally active FGFR (fibroblast growth factor receptor) inhibitor, in advanced SCC patients.
Methods:
Patients with histological confirmed advanced squamous cell NSCLC and previously treated with at least one cytotoxic chemotherapy were enrolled from April 2013 to December 2014. All patients had FGFR1 gene amplification more than 5 copies by fluorescent in situ hybridization (FISH). Each 7-day treatment cycle consisted of dovitinib 500mg orally administration on days 1 to 5 and 2 days off. Primary endpoint was overall response rate and secondary endpoints included PFS, OS and toxicity.
Results:
All 26 patients were male with the median age of 68 years (range, 52 – 80). Most patients were ever smokers (96%) and had good ECOG (0-1) performance status (85%). The median number of dovitinib treatment cycles administered was 2.5 (range, 1-12). The overall response rate (ORR) was 11.5% (95% CI, 0.8 – 23.8) and disease control rate (DCR) was 50% (95% CI, 30.8 – 69.2). There were three partial responses (PR) and ten stable diseases (SD). Duration of response in 3 patients who achieved PR was 4.5+, 5.1+ and 6.1months. After the median follow-up duration of 15.7 months (range, 5.8 – 25.6 ), the median overall survival (OS) was 5.0 months (95% Confidential Interval, 3.61 – 6.39) and progression-free survival (PFS) was 2.9 months (95% CI, 1.54 – 4.26). Grade 1/2 fatigue (69%) and anorexia (85%) were most commonly reported adverse events and 12 patients (46%) required dose reduction of dovitinib.
Conclusion:
Dovitinib treatment a showed modest efficacy in advanced squamous cell lung cancer patients with FGFR1 amplification. Further studies to evaluate other biomarkers correlated with the efficacy of dovitinib in SCC should be warranted.
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MINI30.12 - A Phase II Trial of Pictilisib with Chemotherapy in First-Line Non-Squamous NSCLC (ID 1432)
19:35 - 19:40 | Author(s): B. Besse, A.V. Luft, N. Fadeeva, J. Mezger, T. Beck, P. Bidoli, F. Denis, E. Paschold, G. Robinet, H. Groen, J. Von Pawel, M. Lackner, S. Gendreau, J. Spoerke, K. Bassett, H. Koeppen, H. Gilbert, H. Jin, G. Shankar, W. Lin, E. Felip
- Abstract
- Presentation
Background:
In non-squamous non-small cell lung cancer (NSCLC), PI3-kinase (PI3K) pathway activation, including downregulation of phosphatase and tensin homolog (PTEN) expression, may promote cell survival and enhance chemotherapy resistance. Additionally, mutations in KRAS have been shown preclinically to confer resistance to PI3K inhibition. The pan-PI3K inhibitor pictilisib potentiates the activity of taxanes, platinum agents, and antivascular endothelial growth factor therapy in preclinical models of NSCLC. This phase II hypothesis-generating study (NCT01493843) evaluated the safety and efficacy of pictilisib in combination with carboplatin, paclitaxel, and bevacizumab in patients not treated for advanced or recurrent non-squamous NSCLC.
Methods:
Overall, 158 patients were randomized to receive carboplatin (area under the curve [AUC] = 6 mg/ml/min), paclitaxel (200 mg/m[2]), and bevacizumab (15 mg/kg) every 3 weeks (q3w) with 340 mg oral pictilisib (n=79) or placebo (n=79) daily in the first 2 weeks of each cycle for a total of 4 cycles. Bevacizumab q3w with daily pictilisib or placebo was continued until disease progression or unacceptable toxicity. Stratification factors included Eastern Cooperative Oncology Group performance status and smoking status. The primary endpoint was progression-free survival (PFS) in the intention-to-treat (ITT) population and in patients with PTEN null/low expression (assessed by immunohistochemistry). Overall survival (OS), objective response rate (ORR), and safety were secondary endpoints. Pre-planned exploratory analyses included efficacy in the KRAS-wildtype subgroup. Tumor assessment was based on RECIST v1.1. Safety analyses were performed on patients who received at least one dose of study drug.
Results:
Median PFS in the ITT population was 6.9 months in the pictilisib arm and 5.9 months in the placebo arm (HR 0.82; 90% CI 0.59–1.13), while median OS was 13.6 months (pictilisib arm) versus 16.1 months (placebo arm) (HR 1.12; 90% CI 0.79–1.59). In patients with PTEN null/low expression, median PFS was 5.9 months (pictilisib arm) and 5.7 months (placebo arm) (HR 0.74; 90% CI 0.41–1.32). In the KRAS-wildtype subgroup, median PFS was 9.7 months (pictilisib arm) versus 5.7 months (placebo arm) (HR 0.70; 90% CI 0.45–1.09); median OS was 14.5 months in both arms. ORR in the ITT population was 37% (pictilisib arm) versus 29% (placebo arm). In the pictilisib arm, common grade ≥3 adverse events (AEs) included neutropenia (23%), rash (20%), thrombocytopenia (8%), febrile neutropenia (5%), and hyperglycemia (5%). AEs led to higher rates of discontinuation in the pictilisib arm (26% versus 16% in the placebo arm), particularly during the first 4 cycles. However, the proportion of AE-related deaths was higher in the placebo arm (9 [12%] versus 5 [6%] in the pictilisib arm).
Conclusion:
This phase II trial of first-line pictilisib plus chemotherapy and bevacizumab in patients with non-squamous NSCLC showed a modest trend for improved PFS, with additional toxicity and no OS benefit. The safety profile was consistent with other pictilisib trials. PTEN null/low expression was not a predictive biomarker, although its prognostic value cannot be excluded. A trend for improved PFS, but not OS, was observed in the KRAS-wildtype subgroup, especially during the maintenance phase of treatment.
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MINI30.13 - A Phase II Trial of Pictilisib with Chemotherapy in First-Line Squamous NSCLC (ID 1653)
19:40 - 19:45 | Author(s): D.R. Spigel, A. Luft, I. Vynnychenko, N. Fadeeva, Z. Mark, S. Ponce, M. Matrosova, J. Goldschmidt, B. Szima, M. Saleh, M. Lackner, S. Gendreau, K. Bassett, J. Spoerke, H. Koeppen, H. Gilbert, H. Jin, G. Shankar, W. Lin, F. Denis
- Abstract
- Presentation
Background:
In squamous non-small cell lung cancer (NSCLC), the PI3-kinase (PI3K) pathway may be activated via several mechanisms including PIK3CA amplification and downregulation of phosphatase and tensin homolog (PTEN) expression; activation of this pathway can promote cell survival and enhance chemotherapy resistance. Pictilisib, a pan-PI3K inhibitor, potentiates the activity of taxanes and platinum agents in preclinical NSCLC models. This phase II, hypothesis-generating study (NCT01493843) evaluated the safety and efficacy of pictilisib in combination with carboplatin and paclitaxel in patients with advanced or recurrent squamous NSCLC.
Methods:
Overall, 160 patients were randomized to receive carboplatin (target area under the curve [AUC] = 6 mg/ml/min) and paclitaxel (200 mg/m[2]) every 3 weeks with 340 mg oral pictilisib (n=81) or placebo (n=79) daily in the first 2 weeks of each cycle for a total of 4 cycles. Pictilisib or placebo was continued daily until disease progression or intolerable toxicity. Stratification factors included Eastern Cooperative Oncology Group performance status and smoking status. The primary endpoint was progression-free survival (PFS) in the intention-to-treat (ITT) population and in patients with PIK3CA amplification (assessed by chromogenic in situ hybridization [CISH]). Overall survival (OS), objective response rate (ORR), safety, and PFS in the PTEN null/low subgroup were secondary endpoints. Tumor assessment was based on RECIST v1.1. Safety analyses were performed on patients who received at least one dose of study drug.
Results:
Median PFS in the ITT population was 5.6 months in the pictilisib arm and 5.5 months in the placebo arm (HR 0.82; 90% CI 0.60–1.12). Median OS was 11.7 months in the pictilisib arm and 12.2 months in the placebo arm (HR 1.10; 90% CI 0.77–1.57). PFS and OS analyses in patients with PIK3CA amplification will be presented. Median PFS for the PTEN null/low subgroup was 6.7 months in the pictilisib arm and 5.5 months in the placebo arm (HR 0.69; 90% CI 0.42–1.13). ORR in the ITT population was 28% in the pictilisib arm and 34% in the placebo arm. Common grade ≥3 adverse events (AEs) included neutropenia (18%), rash (8%), and thrombocytopenia (7%). AEs led to higher proportion of discontinuations (22% in the pictilisib arm vs. 15% in the placebo arm) and AE-related deaths in the pictilisib arm (12 [14%] vs. 2 [3%] in the placebo arm). Deaths were due to disease progression or AEs typically reported in lung cancer. No unexpected safety signals were identified for pictilisib.
Conclusion:
In this first phase II trial of a PI3K inhibitor in first-line squamous NSCLC, the combination of pictilisib with chemotherapy introduced additional toxicity with a minimal PFS improvement and no OS benefit in the ITT population. The safety profile was consistent with other pictilisib trials. PTEN null/low expression did not identify a subgroup with significantly improved efficacy, although the prognostic value of PTEN as a biomarker in squamous NSCLC cannot be excluded. Efficacy analysis in the PIK3CA amplification subgroup is ongoing and will be presented at the conference.
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MINI30.14 - Evaluation of the MET/AXL Receptor Tyrosine Kinase (RTK) Inhibitor MGCD265 in a Patient with Metastatic Non-Small Cell Lung Cancer (NSCLC) Harboring AXL Amplification (ID 3611)
19:45 - 19:50 | Author(s): K.T. Do, L. MacConaill, A. Dubuc, I. Chen, R. Chao, V. Tassell, J. Christensen, G.I. Shapiro, L.M. Sholl
- Abstract
- Presentation
Background:
This abstract is under embargo until September 9, 2015 and will be distributed onsite on September 9 in a Late Breaking Abstract Supplement.
Methods:
Results:
Conclusion:
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MINI30.15 - Discussant for MINI30.11, MINI30.12, MINI30.13, MINI30.14 (ID 3552)
19:50 - 20:00 | Author(s): J.V. Heymach
- Abstract
- Presentation
Abstract not provided
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Author of
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ED 13 - The EGF Receptor and Targeting T790M (ID 13)
- Event: WCLC 2015
- Type: Education Session
- Track: Treatment of Advanced Diseases - NSCLC
- Presentations: 1
- Moderators:M. Boyer, M.A. Gubens
- Coordinates: 9/09/2015, 14:15 - 15:45, Mile High Ballroom 1a-1f
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ED13.04 - 3rd Generation EGFR TKI (ID 1827)
15:20 - 15:40 | Author(s): K. Park
- Abstract
- Presentation
Abstract:
The introduction of EGFR TKIs has dramatically changed the natural history of advanced and/or metastatic NSCLC. The objective response rates of 50 to 70% are achieved and overall survival has improved from 4-5 months to over 30 months in EGFRm(+) NSCLC patients. However, unfortunately the patients are not cured of the disease and after a median PFS of 9 to 13 months, the disease comes back eventually with the emergence of acquired resistance(AR) to EGFR TKIs. Mechanisms of AR include target gene modification, activation of bypass tracks or histologic transformation, etc. In approximately 60% of patients, the mechanism of resistance is due to the acquisition of a gatekeeper T790M EGFR mutation. This T790M mutation leads to an enhanced affinity for ATP, thus reducing the ability of ATP-competitive reversible EGFR tyrosine kinase inhibitors, including gefitinib and erlotinib, to bind to the tyrosine kinase domain of EGFR. One strategy to overcome this mechanism of resistance mediated by target gene modification is through the use of more potent, novel, next-generation inhibitors. The ‘2[nd]-generation’ irreversible EGFR inhibitors such as afatinib and dacomitinib, covalent inhibitors of HER family kinases, showed preclinical activity against T790M in vitro. Both agents demonstrated excellent clinical activities in EGFR TKI-naïve patients with EGFR-mutant NSCLC in terms of response rate and progression-free survival as compared to cytotoxic chemotherapy. However, the results of treatment in patients with EGFR-mutant lung cancer who progress on an EGFR TKI are quite disappointing. Studies of afatinib monotherapy among patients with acquired resistance to erlotinib or gefitinib showed a response rate of only 7-8% and a progression-free survival of 3 to 4 months. This result may be due to the fact that physiologic doses of current generation irreversible EGFR TKIs do not fully inhibit EGFR T790M and dose escalation of 2[nd]-generation EGFR inhibitors is limited by on-target inhibition of wild-type EGFR, which leads to EGFR-mediated toxicity (skin rash and diarrhea). The so-called ‘3[rd]-generation’ EGFR TKIs are pyrimidine-based irreversible inhibitors and has mutant-specific activity including T790M mutation while sparing wild-type EGFR. There are several 3[rd]-generation EGFR TKIs under development, e.g., AZD 9291, CO-1686(Rociletinib), HM61713, ASP8273, EGF816, to name a few. The early clinical trials of the 3[rd]-generation EGFR TKIs have demonstrated a promising efficacy in patients with advanced EGFR-mutated NSCLC who have progressed on prior EGFR TKI therapy, including cohorts of patients with EGFR T790M-mutated NSCLC. For CO-1686, the reported overall response rate in the phase 1 study was 59%(27/46) in patients with centrally confirmed EGFR T790M-containing tumors. Median progression-free survival was 13.1 months. Likewise, initial results from the phase I trial of AZD9291 demonstrated a response rate of 61%(78/127) in patients with EGFR T790M positive tumors with median PFS of 9.6 months. Both AZD9291 and CO-1686 have recently been granted Breakthrough Therapy designation by the US FDA based upon results from early clinical studies. Early phase I/II results of HM61713 also showed encouraging anti-tumor activity with objective response rate of 55%(34/62) in T790M positive Korean NSCLC patients and global phase II trial is planned to launch. The early results of EGF816 and ASP8273, another irreversible 3[rd]-generation EGFR TKIs under clinical development, were recently reported and both agents demonstrated encouraging response rates of 50-60% in T790M(+) NSCLC patients after progression on a 1[st] or 2[nd] generation EGFR TKIs. Further studies are ongoing and mature results are awaited. In brief, many of the 3[rd] generation EGFR TKIs currently at various stages of development look so promising with encouraging clinical activities for T790M(+) NSCLC patients esp. in terms of response rate. In general these newer generation EGFR TKIs also have much better toxicity profiles as they spare the wild-type EGFR, e.g., less skin rash, diarrhea or paronychia compared with the 1[st]- or 2[nd]-generation EGFR TKIs though the toxicity profiles are slightly differerent one from another at some aspects. Since the follow-up is rather short we need longer follow up to confirm survival benefits. We certainly have made a significant progress in the management of advanced NSCLC with AR to EGFR TKIs, however, there are still several issues to be investigated to further improve the treatment outcomes, e.g., optimal timing and/or sequence of the 3[rd] generation EGFR TKIs, how to delay or prevent the emergence of resistance to 3[rd] generation agents, CNS progression, management of non-T790M-dependent AR to EGFR TKIs, etc. References Cong CR and Jänne PA. The quest to overcome esistance to EGFR-targeted therapies in cancer. Nat Med. 2013;19(11):1389-1400 Lovly CM and Shaw AT. Molecular Pathways: Resistance to Kinase Inhibitors and Implications for Therapeutic Strategies. Clin Cancer Res. 2014;20(9):2249–56. Jänne PA et al. AZD9291 in EGFR Inhibitor–Resistant Non–Small-Cell Lung Cancer, N Engl J Med. 2015 Apr 30;372(18):1689-99. Sequist LV et al. Rociletinib in EGFR-Mutated Non–Small-Cell Lung Cancer, N Engl J Med. 2015 Apr 30;372(18):1700-9. Park K et al. Updated safety and efficacy results from phase I/II study of HM61713 in patients (pts) with EGFR mutation positive non-small cell lung cancer (NSCLC) who failed previous EGFR-tyrosine kinase inhibitor (TKI). PASCO 2015 #8084 Tan D S-W et al. First-in-human phase I study of EGF816, a third generation, mutant-selective EGFR tyrosine kinase inhibitor, in advanced non-small cell lung cancer (NSCLC) harboring T790M. PASCO 2015 #8013 Goto Y et al. ASP8273, a mutant-selective irreversible EGFR inhibitor in patients (pts) with NSCLC harboring EGFR activating mutations: Preliminary results of first-in-human phase I study in Japan. PASCO 2015 #8014T
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MINI 05 - EGFR Mutant Lung Cancer 1 (ID 103)
- Event: WCLC 2015
- Type: Mini Oral
- Track: Treatment of Advanced Diseases - NSCLC
- Presentations: 2
- Moderators:Y. Yatabe, R. Perez-Soler
- Coordinates: 9/07/2015, 16:45 - 18:15, Mile High Ballroom 2a-3b
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MINI05.04 - Survival Outcome Assessed According to Tumor Burden & Progression Patterns in Patients with EGFR Mutant NSCLC Undergoing EGFR-TKIs (ID 886)
17:00 - 17:05 | Author(s): K. Park
- Abstract
- Presentation
Background:
Mutations in the epidermal growth factor receptor (EGFR) are associated with a marked therapeutic response to EGFR-tyrosine kinase inhibitors (TKIs) in patients with advanced non-small cell lung cancer (NSCLC). However, clinical predictors of the survival benefit of EGFR-TKI treatment in NSCLC with EGFR activating mutations have not been well elucidated. Therefore, this study evaluated clinical predictors of survival outcome in patients with EGFR mutant NSCLC who were treated with EGFR-TKIs. Mutations in the epidermal growth factor receptor (EGFR) are associated with a marked therapeutic response to EGFR-tyrosine kinase inhibitors (TKIs) in patients with advanced non-small cell lung cancer (NSCLC). However, clinical predictors of the survival benefit of EGFR-TKI treatment in NSCLC with EGFR activating mutations have not been well elucidated. Therefore, this study evaluated clinical predictors of survival outcome in patients with EGFR mutant NSCLC who were treated with EGFR-TKIs.
Methods:
A total of 224 patients with EGFR-mutant lung adenocarcinomas that were treated with EGFR-TKIs were retrospectively reviewed. Treatment outcomes were evaluated based on clinical factors, number of metastasis site and progression patterns.
Results:
The clinical factors associated with reduced progression-free survival (PFS) and overall survival (OS) by univariate analysis were ECOG performance status (PS) ≥ 2, intra- and extrathoracic metastasis, presence of extrathoracic metastasis, high number of metastasis sites, metastasis to liver or adrenal gland at baseline, and rapid progression of primary tumor at the time of progressive disease (PD). In multivariate analysis, factors that remained significantly associated with shorter PFS were ECOG PS ≥ 2 (Odds ratio [OR] 2.189 [95% CI, 1.374 – 3.437]; P < 0.001) and rapid progression of primary tumor at PD (OR 1.800 [95% CI, 1.059 – 3.058]; P = 0.030).
Conclusion:
Thus, tumor burden, expressed as the number of metastasis sites at the time of EGFR-TKI treatment, and rapid progression of primary tumor at PD are predictive of inferior survival in patients with lung adenocarcinoma with activating EGFR mutations.
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MINI05.06 - A Phase Ib/II Study of Afainib plus Nimotuzumab in Non-Small Cell Lung Cancer Patients with Acquired Resistance to Gefitinib or Erlotinib (ID 667)
17:15 - 17:20 | Author(s): K. Park
- Abstract
- Presentation
Background:
Afatinib (A) is a potent irreversible EGFR TKI and nimotuzumab (N) is a humanized anti-EGFR mAb. In this phase Ib/II study, we aimed to assess the safety and activity of A plus N in advanced NSCLC patients with acquired resistance to gefitinib or erlotinib.
Methods:
Major inclusion criteria were advanced NSCLC with activating EGFR mutation or disease control for at least six months with previous gefitinib or erlotinib therapy. In the phase Ib study using classic 3+3 dose escalation method, patients were treated with A 40mg/d or 30mg/d in combination with N 100mg/w or 200mg/w. One cycle was composed of 4 weeks of treatment. In the phase II study, patients were treated with A plus N in the level of RP2D defined in the phase Ib study.
Results:
Overall, fifty pts were enrolled and treated: 13 in phase Ib and 37 in phase II. At the starting dose level (A 40mg/d + N 100mg/w), one out of 6 pts experienced end-of-cycle 1 DLT (G3 diarrhea), and the dose was up to the next level of A 40mg/d + N 200mg/w. Out of 6 pts at this level, 2 pts experienced DLTs (G3 diarrhea and G3 neutropenia, respectively), and RP2D was accordingly determined as A 40mg/d + N 100mg/w. In the whole treatment duration of the phase II, there was no treatment related death and 10 pts (20%) experienced any grade 3 adverse event, including diarrhea and skin rash. Out of evaluable 50 pts in the phase Ib/II study, the response rate was 36% (18 achieved partial response out of 50) and the median PFS was 4.4 months (95% CI:3.2-5.5 months).
Conclusion:
A and N showed an acceptable safety profile and promising antitumor activity in advanced NSCLC patients with acquired resistance to gefitinib or erlotinib.
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MINI 17 - WT EGFR, Angiogenesis and OMD (ID 131)
- Event: WCLC 2015
- Type: Mini Oral
- Track: Treatment of Advanced Diseases - NSCLC
- Presentations: 1
- Moderators:R. Feld, R. Dziadziuszko
- Coordinates: 9/08/2015, 16:45 - 18:15, Mile High Ballroom 4a-4f
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MINI17.06 - Subgroup Analysis of East Asian Patients in the Phase III REVEL Trial (ID 729)
17:20 - 17:25 | Author(s): K. Park
- Abstract
- Presentation
Background:
The REVEL trial demonstrated that second-line treatment with ramucirumab (RAM) plus docetaxel (DOC) significantly improved overall survival (OS) compared to placebo (PBO) plus DOC in the intent-to-treat (ITT) population (N=1253) of patients with stage IV non-small cell lung cancer. The REVEL trial also significantly improved progression-free survival (PFS) and objective response rates (ORRs). Results from the East Asia (EA) subgroup (Taiwan and Korea) analysis are presented.
Methods:
Subgroup analyses were performed in the EA ITT population, which consisted of all patients who were randomized in Taiwan (n=27) and Korea (n=62). Endpoints evaluated in the EA subgroup were OS, PFS, ORR, and safety. OS and PFS were analyzed using the Kaplan-Meier method and Cox proportional hazard model. Response was compared using the Cochran-Mantel-Haenszel test. ClinicalTrials.gov number NCT01168973.
Results:
In the 89 ITT EA patients, median OS was 15.44 months for the RAM plus DOC arm (n=43) and 10.17 months for PBO plus DOC arm (n=46) (HR: 0.762, 95% CI: 0.444–1.307). Median PFS was 4.88 months for the RAM plus DOC arm and 2.79 months for the PBO plus DOC arm (HR: 0.658, 95% CI: 0.408–1.060). The ORRs were 25.6% (95% CI: 13.5–41.2) in the RAM plus DOC arm and 9% (95% CI: 2.4–20.8) in the PBO plus DOC arm. Approximately two years after the enrollment of the first patient, in May 2012, the independent data monitoring committee recommended a reduction in the dose of DOC from 75 mg/m[2] to 60 mg/m[2] for newly enrolled EA patients, based on a higher incidence of neutropenia and febrile neutropenia associated with 75 mg/m[2] in EA patients compared to non-EA patients. This amendment resulted in a reduction in the toxicity associated with the original treatment regimen (Table). Table: Select grade ≥3 treatment-emergent adverse events, regardless of causality, by treatment arm and DOC dose in EA patients
Data are n (%). *Consolidated term.Preferred term RAM plus DOC (75 mg/m[2]) (n = 32) PBO plus DOC (75 mg/m[2]) (n = 33) RAM plus DOC (60 mg/m[2]) (n = 11) PBO plus DOC (60 mg/m[2]) (n = 13) Any 31 (96.9) 26 (78.8) 6 (54.5) 7 (53.8) Neutropenia* 26 (81.3) 24 (72.7) 6 (54.5) 5 (38.5) Febrile neutropenia 14 (43.8) 4 (12.1) 0 1 (7.7)
Conclusion:
Although not statistically powered to demonstrate significant improvement, the improved OS, PFS, and ORR observed in the EA subgroup treated with RAM plus DOC is consistent with the treatment effect observed in the overall ITT population in the REVEL trial. A dose reduction in DOC from 75 mg/m[2] to 60 mg/m[2] was associated with an improved safety profile and a reduction in the incidence of febrile neutropenia in the EA subgroup.
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MINI 26 - Circulating Tumor Markers (ID 148)
- Event: WCLC 2015
- Type: Mini Oral
- Track: Biology, Pathology, and Molecular Testing
- Presentations: 1
- Moderators:M. Macmanus, C. Aggarwal
- Coordinates: 9/09/2015, 16:45 - 18:15, 205+207
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MINI26.11 - Longitudinal Monitoring of EGFR Mutations in Plasma of EGFR Mutant NSCLC Patients Treated with EGFR TKIs: Korean Lung Cancer Consortium (ID 1130)
17:40 - 17:45 | Author(s): K. Park
- Abstract
- Presentation
Background:
Detection of epidermal growth factor receptor (EGFR) mutation in non-small cell lung cancer (NSCLC) patients is mainly based on tissue biopsy, which is invasive and time consuming. Furthermore, there is still a need for serial monitoring of EGFR mutations and detection of EGFR tyrosine kinase inhibitors (TKIs) resistance. We hypothesized that plasma-based EGFR mutation analysis may be feasible for monitoring response to EGFR TKIs and could be used to predict the resistance.
Methods:
From January 2012 to October 2014, 200 EGFR mutant NSCLC patients were enrolled and treated with EGFR TKIs (141 patients for gefitinib, 46 patients for erlotinib, and 13 patients for afatinib). Plasma samples were prospectively obtained every 2 months from baseline until disease progression. The longitudinally collected plasma samples (n = 368) from 81 patients who progressed were analyzed using droplet digital PCR (ddPCR). We identified an association between serial EGFR mutant titers in plasma cell-free DNA (cfDNA) samples and the patient’s clinical response to EGFR TKIs.
Results:
Of a total 58 baseline cfDNA samples available for ddPCR, 43 (74%) samples demonstrated same mutation in the matched tumors (i.e. sensitivity: 70.8% (17/24) for L858R vs 76.5% (26/34) for exon 19 deletions). The concordance rate of plasma with tissue results of EGFR mutation was 88% for L858R and 86% for exon 19 deletion, respectively. Of the 54 patients with both before and after treatment plasma samples, 40 patients showed a dramatic decrease of mutant copies (greater than 50%) in blood in the first 2 months after treatment. We also found the secondary mutation (T790M) emerged in 28 patients around 3~13 months after treatment and in 4 patients before the treatment. Elevated circulating mutations (L858R/ex19/T790M) can be detected in 5 patients before disease progression as determined by CT scan.
Conclusion:
These results suggest that ddPCR is an appropriate method for determining plasma-based EGFR mutation status and may aid in monitoring response to EGFR TKIs and early detection of EGFR TKIs resistance.
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MINI 30 - New Kinase Targets (ID 157)
- Event: WCLC 2015
- Type: Mini Oral
- Track: Treatment of Advanced Diseases - NSCLC
- Presentations: 1
- Moderators:K. Park, M. Villalona
- Coordinates: 9/09/2015, 18:30 - 20:00, Four Seasons Ballroom F3+F4
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MINI30.11 - Efficacy and Safety of Dovitinib in Advanced Squamous Cell Lung Cancer with FGFR1 Amplification: A Single-Arm, Phase II Study (ID 666)
19:30 - 19:35 | Author(s): K. Park
- Abstract
- Presentation
Background:
FGFR1 amplification is one of the most common potential driving oncogenes in squamous cell carcinoma (SCC), which accounts for 20% of non-small cell lung cancer (NSCLC) squamous cell carcinoma. This phase II study evaluated the efficacy and toxicity profile of dovitinib, an orally active FGFR (fibroblast growth factor receptor) inhibitor, in advanced SCC patients.
Methods:
Patients with histological confirmed advanced squamous cell NSCLC and previously treated with at least one cytotoxic chemotherapy were enrolled from April 2013 to December 2014. All patients had FGFR1 gene amplification more than 5 copies by fluorescent in situ hybridization (FISH). Each 7-day treatment cycle consisted of dovitinib 500mg orally administration on days 1 to 5 and 2 days off. Primary endpoint was overall response rate and secondary endpoints included PFS, OS and toxicity.
Results:
All 26 patients were male with the median age of 68 years (range, 52 – 80). Most patients were ever smokers (96%) and had good ECOG (0-1) performance status (85%). The median number of dovitinib treatment cycles administered was 2.5 (range, 1-12). The overall response rate (ORR) was 11.5% (95% CI, 0.8 – 23.8) and disease control rate (DCR) was 50% (95% CI, 30.8 – 69.2). There were three partial responses (PR) and ten stable diseases (SD). Duration of response in 3 patients who achieved PR was 4.5+, 5.1+ and 6.1months. After the median follow-up duration of 15.7 months (range, 5.8 – 25.6 ), the median overall survival (OS) was 5.0 months (95% Confidential Interval, 3.61 – 6.39) and progression-free survival (PFS) was 2.9 months (95% CI, 1.54 – 4.26). Grade 1/2 fatigue (69%) and anorexia (85%) were most commonly reported adverse events and 12 patients (46%) required dose reduction of dovitinib.
Conclusion:
Dovitinib treatment a showed modest efficacy in advanced squamous cell lung cancer patients with FGFR1 amplification. Further studies to evaluate other biomarkers correlated with the efficacy of dovitinib in SCC should be warranted.
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MINI 31 - ALK (ID 158)
- Event: WCLC 2015
- Type: Mini Oral
- Track: Treatment of Advanced Diseases - NSCLC
- Presentations: 2
- Moderators:S. Malik, I. Ou
- Coordinates: 9/09/2015, 18:30 - 20:00, Mile High Ballroom 1a-1f
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MINI31.02 - Real-World Characteristics and Outcomes for ALK+ NSCLC in Korea (ID 535)
18:35 - 18:40 | Author(s): K. Park
- Abstract
- Presentation
Background:
Clinical trials have shown superior efficacy of ALK inhibitors compared with chemotherapies for patients diagnosed with ALK+ non-small cell lung cancer (NSCLC). In Korea, crizotinib was approved for ALK+ NSCLC in 2011 but is not yet reimbursed. The objective of this study was to describe real-world patient characteristics, ALK testing and treatment patterns, and survival among Korean patients diagnosed with locally-advanced or metastatic ALK+ NSCLC.
Methods:
A retrospective patient chart review was conducted in two major cancer centers in Korea. Participating physicians (N=4) reviewed patient charts and reported patient characteristics, ALK testing and treatment patterns, and survival of patients diagnosed with ALK+ locally-advanced or metastatic NSCLC. ALK inhibitor treatment duration and overall survival (OS) were estimated using Kaplan-Meier analyses.
Results:
In late 2014, 55 ALK+ NSCLC patients were identified for this study. The median follow-up time among these patients was 24.8 months. The median age at locally advanced or metastatic NSCLC diagnosis was 60 years (interquartile range: 52 - 67); 53% of patients were female, 51% were never-smokers, 2% were former smokers, 33% were current smokers, 15% had unknown smoking status, and 98% were diagnosed with adenocarcinoma. At primary diagnosis, 67% of patients had metastatic disease. ALK rearrangement was confirmed by fluorescent in situ hybridization (78%) or immunohistochemistry (22%). 27% of patients had their ALK rearrangement detected more than three months after their locally-advanced or metastatic diagnosis. The majority of patients received initial systemic chemotherapy; only 13% received an ALK inhibitor in the first-line, and 62% received an ALK inhibitor by the end of follow-up. Out of 30 patients who received crizotinib, 83% discontinued (median duration of 6.3 months) and 13% died while still on crizotinib. Of those who discontinued, 32% switched to chemotherapy, 16% switched to a different ALK inhibitor, and 52% received no further antineoplastic therapy. After discontinuing crizotinib, the median OS was 4.3 months.
Conclusion:
In this study of locally-advanced or metastatic ALK+ NSCLC patients in Korea, OS was poor following discontinuation of crizotinib with a median survival of 4.3 months. Additionally, many patients had delays in receiving ALK testing. Among patients who failed crizotinib treatment, over half received no further antineoplastic therapy. These findings suggest the need to provide timely access to ALK testing and effective treatments following crizotinib discontinuation for ALK+ NSCLC patients in Korea.
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MINI31.14 - PROs with Ceritinib in ALKi-Naive ALK+ NSCLC Patients with and without Brain Metastases (ID 1528)
19:45 - 19:50 | Author(s): K. Park
- Abstract
Background:
In the pivotal ASCEND-1 study, ceritinib, an anaplastic lymphoma kinase inhibitor (ALKi), demonstrated sustained clinical activity in ALKi-naive patients with ALK-rearranged (ALK+) non-small cell lung cancer (NSCLC), including in patients with brain metastases (BrM). ASCEND-3 (NCT01685138) evaluated patient-reported outcomes (PROs) as well as clinical outcomes with ceritinib, in ALKi-naive ALK+ NSCLC patients with and without baseline BrM.
Methods:
Adult patients with ALK+ NSCLC previously treated with up to 3 lines of cytotoxic therapy received oral ceritinib 750 mg daily. PROs were assessed using Lung Cancer Symptom Scale (LCSS) and EORTC (QLQ-C30, QLQ-LC13) quality of life and lung cancer surveys at baseline and Day 1 of treatment cycles 2, 3, and every two cycles thereafter (1 cycle=28 days). Data were analyzed by presence/absence of baseline BrM. Data beyond cycle 9 are not reported due to small sample sizes.
Results:
Of 124 enrolled patients (median age [range] 56 [27–82] years; 40.3% male), 50 (40.3%) had BrM at baseline. At data cutoff (27 June 2014), median follow-up was 8.3 months. Up to cycle 9, PRO questionnaire compliance was at least 97.0%. In the overall patient population, investigator-assessed disease control rate (DCR) was 89.5% and median duration of response (DOR) 9.3 months. Investigator-assessed whole-body DCR [95% confidence interval (CI)] in patients with and without baseline BrM was 86.0% [73.3, 94.2] and 91.9% [83.2, 97.0], respectively, while DOR [95% CI] was 9.1 [7.5, Not Estimable] and 10.8 [9.3, 10.8] months, respectively. Mean change from baseline in patients’ total LCSS score ranged from -3.4 to -11.4 while receiving ceritinib, with 82.1% of patients experiencing symptom improvement; symptoms improved in patients with and without baseline BrM (Figure). QLQ-LC13 outcomes were broadly consistent with those of LCSS in the full patient population and in the subgroups of patients with and without baseline BrM. In general, mean global quality of life (QLQ-C30) was maintained on treatment for all patients. Patients reported diarrhea and nausea and vomiting symptoms were worse than baseline, however, nausea and vomiting symptoms did reduce over time. Figure 1
Conclusion:
In ALKi-naive patients with ALK+ NSCLC, treatment with ceritinib demonstrated clinical efficacy and improved cancer symptoms, with health-related quality of life generally maintained regardless of baseline BrM status. Improvements were greatest for the lung-related symptoms, cough and pain.
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ORAL 11 - Clinical Trials 1 (ID 100)
- Event: WCLC 2015
- Type: Oral Session
- Track: Thymoma, Mesothelioma and Other Thoracic Malignancies
- Presentations: 1
- Moderators:A.K. Nowak, F. Detterbeck
- Coordinates: 9/07/2015, 10:45 - 12:15, 702+704+706
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ORAL11.06 - A Prospective Phase II Study of Cisplatin and Cremorphor EL-Free Paclitaxel (Genexol-PM) in Patients with Unresectable Thymic Epithelial Tumors: Can 18F-FDG PET/CT Play a Role? (ID 2221)
11:39 - 11:50 | Author(s): K. Park
- Abstract
- Presentation
Background:
We conducted a prospective phase II study of cisplatin plus Cremorphor EL-free paclitaxel (Genexol-PM) in patients with unresectable thymic epithelial tumors (TETs) in order to determine the efficacy and tolerability of the combination.
Methods:
Patients were treated with cisplatin (70 mg/m[2]) and Genexol-PM (230 mg/m[2]) every three weeks for a maximum of six cycles. The primary end point of this study was objective response rate (ORR), and secondary end points included toxicity, progression-free survival (PFS), overall survival (OS), correlation between early [18]F-FDG PET/CT response and PFS, and correlation between baseline FDG uptake and histology.
Results:
Forty-two patients with unresectable thymoma (n=14) or thymic carcinoma (n=28) were enrolled. The median age was 59 years (range, 25-77) and 30 (71%) patients were male, and 39 (93%) had an ECOG PS of 1. The median number of treatment cycles was six (range 1-6). For 40 assessable patients, the ORR was 62.5% (95% confidence interval [CI] 47.6-77.4) with rates of 46% (95% CI 23.3-76.9) for advanced thymoma (n=13) and 70% (95% CI 52.0-82.1) for thymic carcinoma (n=27). With a median follow-up of 15.5 months, the median PFS was 9.8 months (11.4 months for thymoma vs. 8.1 months for thymic carcinoma, with median follow-ups of 16.1 vs. 15.5 months, respectively). The two-year OS was 77.9% for thymoma and 65.9% for thymic carcinoma. There were no treatment-related deaths. The most common grade 3 and 4 treatment-related adverse event was neutropenia in 11 patients (26%). Sixteen (38%) patients experienced grade 2 hypersensitivity reactions. There was no correlation between early PET response and PFS, but tumor histology (thymoma vs. thymic carcinoma) was correlated with SUV~max~ before chemotherapy.
Conclusion:
These data suggest that the combination of cisplatin and Genexol-PM is highly effective and tolerable for the treatment of unresectable TETs, especially in patients with thymic carcinoma.
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ORAL 34 - Quality/Survival/Prognosis in Localized Lung Cancer (ID 153)
- Event: WCLC 2015
- Type: Oral Session
- Track: Treatment of Localized Disease - NSCLC
- Presentations: 1
- Moderators:B.C. Cho, R.L. Keith
- Coordinates: 9/09/2015, 16:45 - 18:15, 201+203
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ORAL34.03 - Prognostic Factors in Early Stage NSCLC: Analysis of the Placebo Group in the MAGRIT Study (ID 24)
17:07 - 17:18 | Author(s): K. Park
- Abstract
- Presentation
Background:
The MAGRIT study was a worldwide, multicenter, phase-3 double-blind, randomized trial evaluating efficacy of the MAGE-A3 Cancer Immunotherapeutic in resected non-small cell lung cancer (NSCLC) (www.clinicaltrials.gov NCT00480025). We examined baseline patient and disease characteristics associated with overall survival (OS) and disease-free survival (DFS) among patients assigned to placebo.
Methods:
Study participants were ≥18 years, with histologically proven, MAGE-A3-positive stage IB, II or IIIA NSCLC (AJCC 6.0). Participants had undergone complete anatomical resection of the tumor (lobectomy or pneumectomy) with mediastinal lymph node (LN) dissection or sampling according to standard of care. Up to four cycles of platinum-based adjuvant chemotherapy were allowed. Cox regression models were used to explore characteristics that could predict DFS and OS. Factors statistically significant in univariate analysis (p<0.05) were included in multivariate models using a stepwise approach (p<0.05 to enter/remain in the model).
Results:
There were 757 placebo patients in the total treated population; median age 63 years, 76% male, 53% with squamous cell carcinoma (SCC), 34% with adenocarcinoma, 98% with performance status 0-1, 52% had received adjuvant chemotherapy.In univariate analyses, SCC, lower N-category and earlier disease stage were associated with improved DFS. Lower N-category, earlier stage and smaller tumor size were associated with improved OS. In multivariate analysis, N-category (HR 1.34, 95%CI [1.16-1.55]) and histological type (HR for SCC vs non-SCC 0.64, 95%CI [0.51-0.81]) remained significant for DFS. N-category (HR 1.47, 95%CI [1.21-1.79]) and tumor size (HR by unit increase 1.08, 95%CI [1.01-1.15]) did so for OS. No association was found between DFS or OS and age, gender, race, region, baseline performance status, quantitative MAGE-A3 expression, chemotherapy administration or type of chemotherapy, smoking status or type of LN sampling (minimal/systematic). Among patients with SCC, univariate analysis identified increased number of chemotherapy cycles and operative technique (pneumectomy) as associated with improved DFS (p<0.05). Only operative technique remained in the multivariate model. When including N-category (p<0.10 in univariate analysis) in the multivariate model, N-category and number of chemotherapy cycles were also selected. Lower N-category and smaller tumor size were significantly associated with improved OS, in univariate and multivariate analyses. Among patients with non-SCC, univariate analysis identified younger age, being female, lower N-category and earlier disease stage with improved DFS, and lower N-category, earlier disease stage and region (East Asia) with improved OS. N-category and gender, and N-category and region remained significant in the multivariate analysis for DFS and OS, respectively.
Conclusion:
This is the first prognostic factor analysis in resected NSCLC performed on data from a large, prospective randomized study. It highlighted that in terms of DFS, SCC patients have a better prognosis than non-SCC patients. N-category plays a major role in determining prognosis. Operative technique (pneumectomy), number of chemotherapy cycles (SCC) and gender (non-SCC) are also associated with outcome. Variables predictive for OS are N-category and tumor size (all) and region (non-SCC). These results confirm retrospective studies done within the context of TNM classification, but add that histopathology subtype is a strong determinant for DFS in resected NSCLC.
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P1.01 - Poster Session/ Treatment of Advanced Diseases – NSCLC (ID 206)
- Event: WCLC 2015
- Type: Poster
- Track: Treatment of Advanced Diseases - NSCLC
- Presentations: 2
- Moderators:
- Coordinates: 9/07/2015, 09:30 - 17:00, Exhibit Hall (Hall B+C)
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P1.01-075 - Phase III, Randomized, Double-Blind Trial of Bavituximab Plus Docetaxel in Previously Treated Stage IIIb/IV Non-Squamous NSCLC (SUNRISE) (ID 1581)
09:30 - 09:30 | Author(s): K. Park
- Abstract
Background:
Exposed phosphatidylserine (PS) in the tumor microenvironment is highly immunosuppressive. PS binding to PS receptors on myeloid derived suppressor cells (MDSC) and M2 macrophages leads to production of anti-inflammatory cytokines such as TGF-β and IL-10. Bavituximab, a first-in-class PS-targeting monoclonal antibody, counters these effects, resulting in production of pro-inflammatory cytokines such as TNF-α and IL-12, maturation of dendritic cells and induction of tumor specific cytotoxic T lymphocyte (CTL) immunity. Docetaxel has also been shown to suppress MDSCs while increasing tumor antigens and T-cell mediated cytotoxicity, thereby enhancing bavituximab’s immunomodulatory effects. In a prior double-blind Phase II trial in 2nd line non-squamous non-small cell lung cancer, bavituximab 3 mg/kg plus docetaxel was well-tolerated and demonstrated 60% improvement (11.7 vs 7.3 month) in median overall survival (OS) compared to control.
Methods:
SUNRISE is a Phase III, double-blind trial where patients with previously treated Stage IIIb/IV non-squamous, non-small cell lung cancer are randomized in a 1:1 ratio to receive up to six 21-day cycles of docetaxel in combination with either weekly 3 mg/kg bavituximab or placebo, followed by maintenance with weekly bavituximab or placebo until progression or toxicity. Patients will be stratified by region (North America, Europe, or Rest of World), disease stage (IIIb or IV), and previous maintenance/targeted therapy (yes or no). This trial was initiated in December 2013 and accrual of 582 patients across 160+ sites in 14 countries is planned over 24 months. The primary endpoint is OS and two interim analyses are planned. Secondary endpoints include progression-free survival (PFS), overall response rate (ORR) and safety. Radiographic tumor response is centrally assessed every two cycles during combination therapy and every nine weeks during maintenance. Exploratory analysis will include the assessment of changes in circulating immune cells and cytokines to better understand the immunotherapeutic mechanism.
Results:
Trial in progress
Conclusion:
Trial in progress
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P1.01-076 - TIGER-1: A Phase 2/3 Study of First Line Rociletinib or Erlotinib in EGFR-Mutant NSCLC (ID 944)
09:30 - 09:30 | Author(s): K. Park
- Abstract
Background:
Activating EGFR mutations including the L858R mutation and exon 19 deletions (del19) are key drivers of non-small cell lung cancer (NSCLC) in 10%–15% of patients of European and 30%–35% of Asian descent.[1] Acquired resistance to first-generation EGFR tyrosine kinase inhibitors (TKIs) such as erlotinib can be driven by additional EGFR mutations, with exon 20 T790M accounting for 50%–60% of cases.[2] Rociletinib (CO-1686) was designed to inhibit T790M as well as L858R and del19 while sparing wild-type EGFR and has demonstrated response rates up to 67% in patients with T790M mutations who had progressed on first or later line EGFR inhibitor therapy. Rociletinib continues to be well tolerated by patients in ongoing studies.[3] Given that T790M mutated subclones commonly emerge during treatment with existing EGFR inhibitors, early targeting of T790M along with initial activating mutations is a rational approach to delay progression.
Methods:
TIGER-1 (NCT02186301) is a randomized, open label study of rociletinib vs erlotinib in patients with mutant EGFR NSCLC. Patients with histologically or cytologically confirmed metastatic or unresectable locally advanced treatment-naive NSCLC (no prior therapy in the metastatic setting and no CNS disease), with documentation of ≥1 activating EGFR mutation (excluding exon 20 insertions) and biopsy within 60 days will be enrolled in this 2-part study. All patients will be randomized 1:1 to rociletinib (500 mg twice daily) or erlotinib (150 mg once daily) and treated until death, qualifying adverse events or disease progression. Patients will be stratified by sensitizing EGFR mutation (T790M, del19, L858R, or other) and territory (Asian vs non-Asian geography). The same patient eligibility criteria will be used for the Phase 2 and Phase 3 portions of TIGER-1. The phase 2 portion is currently enrolling and will transition to the Phase 3 portion upon enrollment of the 201[st] patient. The maturing Phase 2 dataset will contribute to decision-making rules for the Phase 3 interim analyses. The Phase 3 portion will incorporate larger cohorts; the final sample sizes will be determined by interim analyses where the chances of success will be estimated at pre-planned enrollment milestones. The primary endpoint is PFS; secondary efficacy endpoints include objective response rate, duration of response, disease control rate and overall survival. Safety will be assessed via standard adverse event reporting. PFS and OS will be summarized with Kaplan-Meier plots. The stratified log-rank and hazard ratio will compare PFS distributions for rociletinib- vs erlotinib-treated patients. Enrollment is ongoing. 1. Herbst R et al. N Engl J Med. 2008 2. Yu H et al. Clin Cancer Res. 2013 3. Sequist LV J Clin Oncol. 2014
Results:
Not applicable
Conclusion:
Not applicable
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P1.08 - Poster Session/ Thymoma, Mesothelioma and Other Thoracic Malignancies (ID 224)
- Event: WCLC 2015
- Type: Poster
- Track: Thymoma, Mesothelioma and Other Thoracic Malignancies
- Presentations: 1
- Moderators:
- Coordinates: 9/07/2015, 09:30 - 17:00, Exhibit Hall (Hall B+C)
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P1.08-037 - PD-L1 Expression in Surgically Resected Thymic Epithelial Tumor (ID 1488)
09:30 - 09:30 | Author(s): K. Park
- Abstract
Background:
Blockade of the immune checkpoint programmed death receptor ligand-1 (PD-L1)/PD-1 pathway has recently shown clinical activity across many tumor types. PD-L1 protein expression by immunohistochemistry (IHC) is emerging as a predictive biomarker of response to these therapies. Hence, we studied PD-L1 expression in a thymic epithelial tumor (TET).
Methods:
Of the patients who previously underwent resection of TET at Samsung Medical Center between January 2000 and January 2013, 220 patients who had available tissue block for immunohistochemistry were included. Formalin-fixed paraffin embedded tumor samples were stained with murine monoclonal antibody (clone h5H1) to human PD-L1. PD-L1 staining was classified based on intensity and moderate or strong intensity in 5% or more of tumor tissues was considered as positive PD-L1 expression.
Results:
The median age was 52 years (range, 18-81), and 57.7% of patients were male. WHO histologic type was mostly B2 (N=96, 43.6%), followed by C (N=48, 21.8%), B3 (N=47, 21.4%) and neuroendocrine tumor (N=17, 7.7%). R0 resection was possible in 193 patients (87.7%). Positive PD-L1 expression was observed in 83 samples (37.7%). PD-L1 expression and histologic type was significantly correlated, with high PD-L1 expression in histologic type B2/B3/C (7.1% vs. 42.4% in type A/AB/neuroendocrine tumor vs. type B2/B3/C; P<0.001). PD-L1 expression did not affect overall survival both in univariate and multivariate survival analysis.
Conclusion:
In TET, PD-L1 expression was positive in 37.7% and it was more frequently observed in aggressive histology (B2/B3/C). PD-1/PD-L1 targeting agents could be a promising therapy for TET.
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P2.01 - Poster Session/ Treatment of Advanced Diseases – NSCLC (ID 207)
- Event: WCLC 2015
- Type: Poster
- Track: Treatment of Advanced Diseases - NSCLC
- Presentations: 2
- Moderators:
- Coordinates: 9/08/2015, 09:30 - 17:00, Exhibit Hall (Hall B+C)
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P2.01-094 - Phase II Trial of Tepotinib/Gefitinib vs Cisplatin/Pemetrexed in T790M-/c-Met+ NSCLC (ID 2105)
09:30 - 09:30 | Author(s): K. Park
- Abstract
Background:
The recommended phase II dose of the highly selective c-Met inhibitor tepotinib (MSC2156119J) for use in combination with gefitinib was confirmed as 500 mg/day in the phase Ib part of the current trial, in which patients with gefitinib-resistant locally advanced/metastatic c-Met-positive NSCLC were treated with tepotinib plus gefitinib. This trial demonstrated that the combination regimen is well tolerated and has evidence of antitumor activity that may be associated with c-Met-positive tumor status. These observations suggest that c-Met inhibition may have a role in EGFR tyrosine kinase inhibitor-resistant NSCLC and that a phase II trial is warranted.
Methods:
The design of the phase II part of a phase Ib/II trial (NCT01982955) is described. Asian adults with histologically or cytologically confirmed, gefitinib-resistant locally advanced/metastatic NSCLC other than predominantly squamous histology and ECOG PS 0/1 are eligible. Patients must have tumors with documented activating mutations of EGFR. Tumor tissue obtained between documentation of acquired resistance to gefitinib and enrollment must be available. Tumors must be confirmed as being c-Met positive (2+/3+ c-Met protein overexpression by immunohistochemistry using CONFIRM anti-total c-MET [SP44] rabbit MAb [Ventana] or c-Met gene amplification on IQ FISH [Dako] [c-Met:CEP7 ratio ≥2 or <2.0 with >15 c-Met signals/cell in >10% of cells or clusters in >10% of tumor cell nuclei]). EGFR mutation status will be assessed centrally using the therascreen[®] EGFR RGQ PCR Kit (QIAGEN). Patients will be enrolled into different parts of the trial based on tumor T790M status. Patients with c-Met-positive, T790M-negative NSCLC (n=136) will be randomized to tepotinib 500 mg/day p.o. + gefitinib 250 mg/day q3w or cisplatin 75 mg/m[2] + pemetrexed 500 mg/m[2] q3w for up to 6 cycles. Patients with c-Met-positive, T790M-positive NSCLC (n=15) will be treated with tepotinib 500 mg/day p.o. + gefitinib 250 mg/day q3w. The primary objective is to determine whether progression-free survival (PFS) in patients treated with second-line tepotinib combined with gefitinib is superior to that of pemetrexed + cisplatin in patients with c-Met-positive, T790M-negative advanced NSCLC and acquired resistance to first-line gefitinib. The two T790M subgroups will be analyzed separately. An interim analysis of the randomized part of the study is planned when 50% of PFS events have occurred in both arms. Secondary objectives are to evaluate: the safety and tolerability tepotinib combined with gefitinib; the efficacy of tepotinib combined with gefitinib; the antitumor activity of tepotinib combined with gefitinib in patients with c-Met-positive, T790M-positive tumors; and patient-reported outcomes.
Results:
not applicable
Conclusion:
This randomized phase II trial will provide the first evidence regarding whether tepotinib has a role in the treatment of Asian patients with gefitinib-resistant, c-Met-positive, T790M-negative NSCLC.
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P2.01-100 - Phase Ib Trial of Afatinib and BI 836845 in Advanced Non-Small Cell Lung Cancer (NSCLC) (ID 1767)
09:30 - 09:30 | Author(s): K. Park
- Abstract
Background:
Patients harboring epidermal growth factor receptor (EGFR)-mutated NSCLC treated with EGFR tyrosine kinase inhibitors (TKIs) invariably develop acquired resistance (AR). The mechanisms of AR are unknown in 30–40% of patients. In pre-clinical studies, insulin-like growth factor (IGF) signaling has been implicated in AR to EGFR TKIs in the absence of other known mechanisms including T790M mutation. It is hypothesized that an EGFR TKI combined with an IGF inhibitor can overcome this resistance. BI 836845 is a fully human, affinity-optimized, IGF ligand-neutralizing antibody. BI 836845 binds to IGF-1 and IGF-2 and neutralizes growth-promoting signaling. Preliminary results from two Phase I studies have shown a tolerable safety profile. This trial was designed to evaluate the safety and anti-tumor activity of BI 836845 combined with afatinib in patients with EGFR-mutated NSCLC progressing following prior treatment with reversible or irreversible EGFR TKIs.
Methods:
This is an open-label, dose-escalation trial in Korea, Taiwan and Singapore (NCT02191891; Study 1280.16) consisting of a dose confirmation part (Part A) followed by an expansion part (Part B). Eligible patients are aged ≥18 years with advanced and/or metastatic NSCLC progressing during continuous treatment with single-agent EGFR TKI ≤30 days immediately prior to study treatment, with documented presence of an activating EGFR mutation and lacking an EGFR T790M mutation (confirmed by central testing in Part B). Patients with prior afatinib treatment at a dose below the assigned dose level (Part A only) or <30 mg/day (Parts A and B), or disease progression on an insufficient dose of EGFR TKI immediately prior to study in the investigator’s opinion, or >2 (Part A) or >1 (Part B) prior EGFR TKI treatment regimens for relapsed or metastatic NSCLC are excluded. Part A follows a 3+3 design to determine the MTD and/or recommended Phase 2 dose (RP2D) of BI 836845 combined with afatinib (starting dose: BI 836845 1000 mg/week intravenous infusion over 60 minutes plus oral afatinib 30 mg/day administered in 4-week courses). Patients receive continuous treatment until disease progression, intolerable adverse events (AEs), consent withdrawal or non-compliance with the study protocol. Patients are entered sequentially into escalating/de-escalating dose tiers to determine the MTD based on the occurrence of dose-limiting toxicities (DLTs) during Course 1 (3–6 patients per cohort); 6 additional patients will be enrolled in an extension cohort at the R2PD. Part B consists of two separate expansion cohorts of patients previously treated with irreversible EGFR TKIs (e.g. afatinib, dacomitinib; Cohort 1) and those previously treated with reversible EGFR TKIs (gefitinib or erlotinib; Cohort 2). In each cohort, 18 patients will be treated with the RP2D determined in Part A. Primary endpoints are the MTD and DLTs during Course 1 (Part A) and the objective response assessed using Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 (Part B). Secondary endpoints include disease control, time to objective response, duration of objective response, and pharmacokinetic parameters. AEs are evaluated according to Common Terminology Criteria for AEs (CTCAE) v4.03. All analyses will be descriptive and exploratory.
Results:
Not applicable.
Conclusion:
Not applicable.
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P2.04 - Poster Session/ Biology, Pathology, and Molecular Testing (ID 234)
- Event: WCLC 2015
- Type: Poster
- Track: Biology, Pathology, and Molecular Testing
- Presentations: 1
- Moderators:
- Coordinates: 9/08/2015, 09:30 - 17:00, Exhibit Hall (Hall B+C)
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P2.04-004 - The BIM Deletion Polymorphism in Patients with EGFR-Mutant Non-Small Cell Lung Cancer Treated with EGFR Tyrosine Kinase Inhibitors (ID 1126)
09:30 - 09:30 | Author(s): K. Park
- Abstract
Background:
A germline BIM deletion polymorphism has been proposed to predict poor treatment response to certain kinase inhibitors. The purpose of this study was to explore whether the BIM deletion polymorphism predicts treatment efficacy of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) in Korean patients with EGFR-mutant NSCLC.
Methods:
Peripheral blood samples from a total of 205 patients with EGFR-mutant NSCLC who were treated with EGFR TKIs between July 2008 and April 2013 were included. The incidence of BIM deletions in these samples was detected by polymerase chain reaction. We compared the clinical outcomes in patients with and without the polymorphism after treatment with EGFR TKIs (gefitinib or erlotinib).
Results:
The BIM deletion polymorphism was present in 15.6% (32/205) of patients. One patient was homozygous for the deletion, and the remaining 31 had heterozygous deletions. The majority of patients were < 65 years old (74%), female (68%), never smokers (76%), and had stage IV NSCLC (67%). There were no associations between the BIM deletion polymorphism and clinicopathological features including gender, age, smoking status, histology, stage, and number of metastasis sites. Patients with and without the BIM deletion polymorphism had similar ORRs (91% vs. 84%, P = 0.585). Progression-free survival (PFS) and overall survival (OS) did not differ significantly between patients with and without the BIM deletion polymorphism (median PFS 12 vs. 11 months, P = 0.160; median OS 31 vs. 30 months, P = 0.452). Multivariate analysis identified significantly predictive markers for clinical outcomes of EGFR TKIs including ECOG PS 0-1, adenocarcinoma histology, recurrent disease, and EGFR mutation type. The results were validated in an independent cohort of 69 NSCLC patients.
Conclusion:
It remains to be determined whether the BIM deletion polymorphism provides intrinsic resistance or decreased sensitivity to EGFR TKIs in EGFR-mutant NSCLC patients.
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P3.01 - Poster Session/ Treatment of Advanced Diseases – NSCLC (ID 208)
- Event: WCLC 2015
- Type: Poster
- Track: Treatment of Advanced Diseases - NSCLC
- Presentations: 4
- Moderators:
- Coordinates: 9/09/2015, 09:30 - 17:00, Exhibit Hall (Hall B+C)
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P3.01-011 - Antitumor Activity of Tepotinib plus Gefitinib in Asian Patients with Met+ EGFRm+ NSCLC (ID 763)
09:30 - 09:30 | Author(s): K. Park
- Abstract
Background:
c-Met abnormalities are key in resistance to EGFR TKIs in EGFRm+ NSCLC patients (pts). The highly selective c-Met inhibitor tepotinib (MSC2156119J) had promising activity in a phase I trial in pts with advanced solid tumors. We report phase Ib data from a trial evaluating tepotinib + gefitinib in pts with Met+ NSCLC (NCT01982955).
Methods:
Asian adults with locally advanced/metastatic NSCLC, Met+ status (2+/3+ c-Met protein overexpression by immunohistochemistry using CONFIRM anti-total c-MET [SP44] rabbit MAb [Ventana] or c-Met gene amplification on IQ FISH [Dako] [c-Met:CEP7 ratio ≥2 or <2.0 with >15 c-Met signals/cell in >10% of cells or clusters in >10% of tumor cell nuclei]) and ECOG PS 0/1 were eligible. EGFR mutation status was assessed using the therascreen[®] EGFR RGQ PCR Kit (QIAGEN). A 3+3 design was used for the phase Ib part; planned recruitment was 15-18 pts, who received tepotinib 300 or 500 mg p.o. + gefitinib 250 mg/d q3w. Primary objective: determine the RP2D of tepotinib for use in combination; secondary objectives: pharmacokinetics, safety, antitumor activity.
Results:
14 pts have been enrolled (median age 65 years; male 43%; ECOG PS 0/1 2/12; median prior therapy regimens including an EGFR TKI 3.5). 3 pts received tepotinib 300 mg + gefitinib and 11 tepotinib 500 mg + gefitinib. No DLTs were observed; 4 pts had grade 3/4 treatment-related adverse events (amylase increase [n=3], lipase increase [2], decreased neutrophil count [1]). Best overall response by c-Met status (cut-off Jan 20, 2015) for the 12 evaluable pts is shown in the table. EGFR mutation status for these 12 pts was T790M and L858R mutation (n=2), L858R mutation alone (4), exon 19 deletion (4), no mutation detected using the therascreen[®] kit (2).Best overall response (n) n=12 Partial response Stable disease Progression IHC 2+ 0 5 2 3+ 4 0 1 FISH c-Met:CEP7 ratio >2 1 0 0 ≥5 copies in >50% of cells 3 1 1 Negative 0 3 2 Not valid 0 1 0
Conclusion:
The RP2D of tepotinib in combination with gefitinib has been confirmed as 500 mg/d in pts with advanced NSCLC. The data show evidence of antitumor activity and that response may be associated with c-Met status. The phase II trial will randomize ≈136 pts with T790M-/c-Met+ tumors who have failed first-line gefitinib to tepotinib 500 mg/d + gefitinib or cisplatin/pemetrexed.
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P3.01-016 - Does Sequence of Cranial Radiotherapy Matter in EGFR Mutant Non-Small Cell Lung Cancer Patients with Brain Metastasis? (ID 2260)
09:30 - 09:30 | Author(s): K. Park
- Abstract
Background:
The incidence of brain metastasis in EGFR mutant advanced non-small cell lung cancer (NSCLC) is higher than EGFR wild type at the time of diagnosis. Although cranial radiotherapy is considered standard treatment for brain metastasis, EGFR tyrosine kinase inhibitors (TKIs) alone have shown promising activity with up to 80% of response in EGFR mutant NSCLC patients with brain metastasis. However, the role of sequential cranial radiotherapy in EGFR mutant NSCLC treated with EGFR TKIs remains to be determined.
Methods:
Advanced NSCLC patients harboring EGFR mutation (exon 19 deletion or L858R) with brain metastasis who were treated with EGFR TKIs were retrospectively reviewed. To investigate the role of cranial radiotherapy, we analyzed the clinical outcomes between patients treated with EGFR TKIs alone and those treated with cranial radiotherapy (WBRT or SRS) followed by EGFR TKIs (combination therapy). The primary end point was overall survival (OS) and secondary end points included intracranial and extracranial progression free survival (PFS).
Results:
A total of 573 patients who identified EGFR mutation and received EGFR TKIs treatment for NSCLC with brain metastasis from Jan 2007 to Dec 2013 at Samsung Medical Center were enrolled for analysis. Of all 573 patients, 121 patients had brain metastasis in initial work up. There were 38 males and 83 female, a median age was 59.5 years (range 30 – 80). All 121 patients were received gefitinib (n=103) or erlotinib (n=18) as EGFR TKI treatment for 1[st] line chemotherapy. 74 patients were treated with combination therapy (34 patients were taken SRS, 28 patients WBRT, 12 patients both), and 47 patients were treated with EGFR TKI alone. In combination therapy group, 32 patients had brain metastasis related symptoms.The median OS was 38.7 months [95% Confidence Interval 35.0 to 42.5] in combination therapy group and 28.6 months [95% CI 24.3 to 32.8] in EGFR TKI alone group (p=0.295). There were no significant differences in intracrainal PFS (18.6 vs 19.7 months, p=0.343) and extracranial PFS (15.7 vs 15.3 months, p=0.574) between two groups.
Conclusion:
In this retrospective analysis, the combination therapy with cranial radiotherapy followed EGFR TKI did not improve OS and intracranial PFS compared with EGFR TKI alone therapy in EGFR mutant NSCLC patients with brain metastases. Further prospective studies are needed to refine the role of sequential cranial radiotherapy in EGFR mutant NSCLC treated with EGFR TKIs.
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P3.01-072 - Final Efficacy and Safety Results of ECOG Performance Status (PS) Subgroup Analyses From the SQUIRE Phase III Study (ID 1660)
09:30 - 09:30 | Author(s): K. Park
- Abstract
Background:
As previously reported, the SQUIRE study demonstrated that the addition of necitumumab (N) to gemcitabine-cisplatin (GC) chemotherapy significantly improved survival in patients with stage IV squamous NSCLC. Overall survival (OS), progression-free survival (PFS), and safety results are presented for Eastern Cooperative Oncology Group (ECOG) PS 0–1/2 subgroups.
Methods:
Patients with stage IV squamous NSCLC were randomized 1:1 to N (800 mg iv, days 1 and 8) plus GC (G=1250 mg/m² iv, days 1 and 8; C=75 mg/m² iv, day 1) or GC alone every 21 days for up to six cycles in this multicenter, open-label study. N+GC patients without progression continued on N alone until progressive disease or intolerable toxicity. The study was powered for OS and PFS (previously reported). Preplanned subgroup analyses were performed for ECOG PS 0–1 and 2.
Results:
Subgroups PS 0–1/2 (n=996 [91%]/n=96 [9%]) were well balanced regarding baseline characteristics (males, 83% vs 86%; median age, 62 vs 65 yrs; smoking/ex-light smoker/nonsmoker, 91/4/5% vs 89/6/5%). GC median relative dose intensity was similar between PS 0–1/2 subgroups; N (overall) was higher for the PS 0–1 than for PS 2 subgroup (94.8% and 90.0%). Post-study therapy use was generally higher in the PS 0–1 than in the PS 2 subgroup, but was balanced between both arms. The OS hazard ratio (HR) for N+GC vs. GC was 0.85 (95% CI: 0.74, 0.98; p=0.026) for PS 0–1 and 0.78 (95% CI: 0.51, 1.21; p=0.275) for PS 2. The PFS HR (N+GC vs. GC) was 0.86 (95% CI: 0.75, 0.99; p=0.035) for PS 0–1 and 0.79 (95% CI: 0.50, 1.24; p=0.292) for PS 2. Select Grade ≥3 treatment-emergent adverse events (TEAEs) are shown in the table. The percentage of patients with adverse events leading to discontinuation of any study drug was lower in the PS 0–1 subgroup (N+GC=30%; GC=23%) than the PS 2 subgroup (N+GC=42%; GC=41%). The percentage of patients hospitalized was higher in the PS 0–1 subgroup (N+GC=43%; GC=34%) than the PS2 subgroup (N+GC=25%; GC=30%). Table. Select TEAEs
[*][Adverse events of possible relevance to treatment, according to either composite categories or preferred terms (febrile neutropenia only)]Grade ≥3 Event* PS 0-1 N+GC (%) N=490 PS 0-1 GC (%) N=495 PS 2 N+GC (%) N=48 PS 2 GC (%) N=46 Neutropenia 25.5 28.1 12.5 21.7 Febrile neutropenia 0.6 1.4 2.1 0 Anemia 11.2 10.3 4.2 17.4 Thrombocytopenia 10.4 10.5 8.3 13.0 Fatigue 7.1 7.1 8.3 6.5 Hypomagnesemia 9.8 1.0 4.2 2.2 Rash 7.8 0.4 0 0 Arterial thromboembolic events 3.7 1.8 6.3 4.3 Venous thromboembolic events 5.5 2.6 0 2.2
Conclusion:
OS and PFS treatment results for N+GC were consistent and considered favorable across subgroups including ECOG PS 2 patients. Administration of N+GC was well tolerated in PS 2 patients, with no evidence of an increased safety risk in this subgroup.
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P3.01-078 - Avelumab (MSB0010718C), an Anti-PD-L1 Antibody, Evaluated in a Phase III Trial versus Docetaxel in Patients with Relapsing NSCLC (ID 1588)
09:30 - 09:30 | Author(s): K. Park
- Abstract
Background:
The programmed death-1 receptor (PD-1) and its ligand (PD-L1) are key therapeutic targets in the reactivation of the immune response against multiple cancers. Avelumab* (MSB0010718C) is a fully human anti-PD-L1 IgG1 antibody currently being investigated in clinical trials. The phase III study (NCT02395172) is an open-label, multicenter trial of avelumab compared with docetaxel in patients with non-small-cell lung cancer (NSCLC) that has progressed after treatment with a platinum-containing doublet.
Methods:
The primary objective of this head-to-head phase III study is to demonstrate superiority defined by overall survival (OS) of avelumab versus docetaxel in patients with locally advanced unresectable, metastatic, or recurrent NSCLC whose tumors express PD-L1 and whose disease has progressed following treatment with a platinum-containing doublet. Approximately 650 eligible patients (ECOG performance status 0-1 at trial entry, tumor archival material or fresh biopsy suitable for PD-L1 expression assessment, histologically confirmed NSCLC, and known-negative ALK mutation status, among other inclusion and exclusion criteria), including 522 patients with PD-L1—positive tumors, will be randomized 1:1 to receive either avelumab at a dose of 10 mg/kg as a 1h intravenous (IV) infusion Q2W or docetaxel at a starting dose of 75 mg/m2 (per label) by IV infusion Q3W. Patients will be stratified according to PD-L1 status. NSCLC histology and EGFR mutation status will be used to define 3 stratified levels for randomization: squamous cell, non-squamous cell/EGFR wildtype, and non-squamous cell/EGFR-activating mutations. Treatment will continue until disease progression, unacceptable toxicity, or any criterion for withdrawal occurs. Responses will be evaluated according to RECIST 1.1 and adjudicated by a blinded independent review committee. In addition to the primary endpoint of OS, secondary endpoints include progression-free survival, best overall response, quality of life assessments, and safety profile. Exploratory endpoints include duration of response, tumor shrinkage in target lesions per timepoint, immunogenicity, PK profile, and evaluation of molecular, cellular, and soluble markers in peripheral blood or tumor tissue that may be relevant to the mechanism of action of, or response/resistance to, avelumab. Safety profiling of trial drugs includes incidence of adverse events (AEs), serious AEs, and other assessments according to NCI-CTCAE v4.03. Patients receiving avelumab who have achieved a complete response (CR) will be treated for a minimum of 6 months and a maximum of 12 months after confirmation. In the case of relapse following a CR, treatment with avelumab may be re-initiated once at the discretion of the investigator and in the absence of treatment-related toxicity. For patients whose disease progresses with avelumab, treatment may continue past the initial determination of disease progression per RECIST 1.1 if the patient’s performance status has remained stable, other criteria are fulfilled, and the investigator’s opinion supports a possible benefit of continued treatment with avelumab. Patients treated with docetaxel may not crossover to the avelumab arm as long as the primary endpoint has not been met in the planned interim or final analyses. Enrollment in this trial began in April 2015. *Proposed INN.
Results:
not applicable
Conclusion:
not applicable
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P3.03 - Poster Session/ Treatment of Locoregional Disease – NSCLC (ID 214)
- Event: WCLC 2015
- Type: Poster
- Track: Treatment of Locoregional Disease – NSCLC
- Presentations: 1
- Moderators:
- Coordinates: 9/09/2015, 09:30 - 17:00, Exhibit Hall (Hall B+C)
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P3.03-001 - Comparison of Adjuvant Therapy Modes Following Resection in Lung Cancer Patients with Clinically (-) but Pathologically (+) N2 Disease (ID 1298)
09:30 - 09:30 | Author(s): K. Park
- Abstract
Background:
Mediastinal nodal staging is very important before recommending surgical resection in newly diagnosed non-small cell lung cancer patients. Following curative resection for having apparently clinically uninvolved mediastinal node (cN0-1), some proportion of patients, however, turns out to have pathologically involved mediastinal node (pN2). There have been controversies on optimal adjuvant therapy during past 2 decades in this clinical setting. Systemic chemotherapy, either followed by or concurrent with radiation therapy, has remained most important modality. This study is to evaluate clinical outcomes following similar, but different, 3 adjuvant therapy modalities, in all of which included systemic chemotherapy, at authors’ institute.
Methods:
Between 2006 and 2012, authors identified 240 cN0-1/pN2 patients who received adjuvant systemic chemotherapy following curative resection: chemotherapy alone in 85 patients (Group A); chemotherapy concurrent with thoracic radiation therapy (CCRT) in 68 (Group B); and CCRT followed by consolidation chemotherapy in 87 (Group C), respectively. Chemotherapy dose intensity was lower in CCRT setting than in upfront or consolidation chemotherapy settings, while thoracic radiation therapy dose schedule was the same (50 Gy/25 fractions). Clinical outcomes of loco-regional control (LRC), distant-metastasis free survival (DMFS) and overall survival (OS) were compared among Groups.
Results:
Median follow-up duration was 30 (5~93) months. Median age of all patients was 60 years and 149 patients (62.1%) were male. Majority of patients (224 patients, 93.3%) underwent lobectomy, while 16 (6.7%) did pneumonectomy. Adenocarcinoma was most common in 165 patients (68.8%) followed by squamous cell carcinoma in 53 (22.1%), and others in 22 (9.2%). There was no difference among Groups with respects to pretreatment and treatment characteristics except median age (Group A was older: 63 years vs. 58 years vs. 58 years, p=0.022). LRC, DMFS and OS rates at 5 years in all patients were 75.1%, 38.0% and 76.2%, respectively. Though no significant difference in OS at 5 years among Groups (76.8% vs. 68.4% vs. 82.5%, p=0.096), LRC rate at 5 years was significantly improved by addition of thoracic radiation therapy (62.9% vs. 78.9% vs. 82.9%, p=0.011), while DMFS rate at 5 years was significantly improved by delivering full dose chemotherapy (40.6% vs. 19.4% vs. 28.6%, p=0.018).
Conclusion:
Although in retrospective nature having potential selection bias, current observations support that maximal benefit could be achieved by thoracic radiation therapy concurrent with chemotherapy and consolidation full dose chemotherapy with respects to LRC and DMFS. Further prospective clinical trial would be desired.
