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M. Villalona
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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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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MINI30.01 - 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
- 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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MINI 35 - Biology (ID 161)
- Event: WCLC 2015
- Type: Mini Oral
- Track: Biology, Pathology, and Molecular Testing
- Presentations: 1
- Moderators:T.A. Boyle, M.G. Kris
- Coordinates: 9/09/2015, 18:30 - 20:00, Mile High Ballroom 2c-3c
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MINI35.01 - Genetic Alterations in the Fanconi Anemia Pathway in Lung Cancers (ID 2325)
18:30 - 18:35 | Author(s): M. Villalona
- Abstract
- Presentation
Background:
The FA pathway contains 17 complementation groups, referred to as FA subtypes A, B, C, D1/BRCA2, D2, E, F, G, I, J, L, M, N, O, P, Q and S. Cells with FA deficiency are hypersensitive to DNA damaging agents such as cisplatin and mitomycin C (MMC). Disruptions of the FA pathway may involve epigenetic silencing of the FA-core complex, mutations or deletion of one or several FA genes. Recently we developed a FA triple-staining immunofluorescence (FATSI) method to detect FANCD2 foci formation using formalin fixed paraffin embedded (FFPE) tumor samples. We screened 139 non-small cell lung cancer (NSCL) FFPE tumors for FANCD2 foci formation by FATSI analysis. Based on the FATSI analysis, 104 of 139 tumor samples were evaluable (lack of Ki67 was defined as non-evaluable samples) for FANCD2 foci status. Among 104 evaluable tumors, 23 (22%) were FANCD2 foci negative. However, further investigation and confirmation of the genetic and epigenetic alterations involved in the FANCD2 foci defective tumors is critical for supporting application of this selection process to justify subsequent clinical treatment strategies for cancer patients.
Methods:
The aim of the study is to investigate the genetic alterations in the FANCD2 foci defective lung tumors and matching non-tumors. The FANCD2 foci defective tumors were identified with the FATSI method. DNA samples isolated from frozen tumor and matching non-tumor tissues were analyzed with whole exome sequencing. All 17 genes involved in the FA pathway were analyzed.
Results:
To investigate the gene involved in disrupting the FA pathway in patient tumors, we applied exome sequencing to 18-paired DNA samples (15 paired foci-negative non-small cell lung tumor and non-tumor frozen tissues, and 3 paired foci-positive non-small cell lung tumor and non-tumor frozen tissues). Among the 15 foci negative tumors, 7 tumors contain 9 somatic mutations including FANCA, FANCC, FANCD2, FANCM, FANCM, FANCP/ SLX4 and FANCS/BRCA1. There was no mutation detected among the three foci positive tumors. Loss of heterozygosity (LOH) events were detected in nine tumors, including one foci positive and eight foci negative tumors. The LOHs occurred in FANCA, FANCD1, FANCD2, FANCM, FANCI, FANCP/SLX4, FANCQ/ERCC4. LOHs on FANCA gene were found in three tumors and LOHs on FANCD2 gene were detected in four tumors including one foci positive tumor.
Conclusion:
Based on our preliminary study, 7 of the 15 FANCD2 foci negative lung tumors contained somatic mutation and 8 of the 15 foci negative tumors contained LOHs in the FA genes. A higher frequency of somatic mutation (2 of 7 tumors) and LOHs (3 of 9 tumors) was detected in FANCA gene. In addition, 4 of 9 tumors contained LOHs on FANCD2 indicating the importance of this gene in maintaining FA foci formation. However, we are uncertain if these alterations are functional. Given that FA pathway disruptions may also involve epigenetic silencing of the FA-core complex, plus its collaboration with other proteins, it is necessary to investigate the genetic alteration in the FA associated proteins and promoter methylation status of these genes.
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