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Shun Lu
Moderator of
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MA 02 - Emerging Targets (ID 656)
- Event: WCLC 2017
- Type: Mini Oral
- Track: Clinical Design, Statistics and Clinical Trials
- Presentations: 12
- Moderators:Ravi Salgia, Shun Lu
- Coordinates: 10/16/2017, 11:00 - 12:30, Room 511 + 512
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MA 02.01 - Evidence of Clinical Activity of Sitravatinib in Combination with Nivolumab in NSCLC Patients Progressing on Prior Checkpoint Inhibitors (ID 9720)
11:00 - 11:05 | Presenting Author(s): Ticiana A. Leal | Author(s): T. Campbell, A. Mapes, K. Schneider, M.J. Staab, K. Velastegui, J.G. Christensen, I. Chen, A. Traynor
- Abstract
- Presentation
Background:
Combination therapy with agents that target the molecular and cellular mechanisms of resistance to checkpoint inhibitor therapy (CIT) is a rational approach to restoring or improving the efficacy of CIT in patients with immunotherapy resistant NSCLC. Sitravatinib is a spectrum-selective TKI which targets TAM receptors (Axl, MER), split family receptors (VEGFR2 and KIT), and MET. Inhibition of these target classes by sitravatinib may enhance anti-tumor activity through targeted depletion of immunosuppressive Type 2 tumor associated macrophages, regulatory T cells and myeloid-derived suppressor cells (MDSCs) and increasing antigen presentation capacity of dendritic cells in the tumor microenvironment (TME) thereby enhancing anti-tumor T effector and NK cell responses. Given these pleiotropic immune activating effects, the combination of sitravatinib with nivolumab is a rational approach to restoring or enhancing the clinical activity of CIT in patients with immunotherapy resistant NSCLC.
Method:
MRTX-500 is a Phase 2 Study of sitravatinib in combination with nivolumab in non-squamous NSCLC patients who have experienced progression of disease on or after treatment with CIT. The primary objective is to assess the clinical activity of the combination using ORR by RECIST 1.1. Enrollment into the Phase 2 treatment arm is stratified by prior outcome of CIT (e.g., clinical benefit versus progression of disease in ≤12 weeks). The investigational agent sitravatinib is administered orally in continuous regimen; nivolumab is administered intravenously, 240 mg every 2 weeks. The sample sizes for the treatment arms are based on two-stage Simon Optimal Design.
Result:
The recommended phase 2 dose of the combination is 120 mg of sitravatinib orally, once daily with nivolumab given at a flat dose of 240 mg IV Q 2 weeks. As of June 20, 2017, the study has enrolled 11 patients and 6/11 patients have had at least one on-study tumor assessment. Two patients out of 6 have achieved PR by RECIST. The first patient is a 72 yo female with pan-wild type metastatic NSCLC with history of treated brain metastases with multiple prior therapies who previously received pembrolizumab (stable disease for 14 months) and obtained confirmed PR at first disease evaluation. The second patient is a 71 yo female with pan-wild type metastatic NSCLC with multiple prior therapies who previously received nivolumab (progressive disease as best overall response) but who obtained unconfirmed PR at first disease evaluation. Treatment has been associated with manageable side effects to date.
Conclusion:
This study is ongoing and actively accruing patients.
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MA 02.02 - Phase 2 Study of Pembrolizumab Plus CC-486 vs Pembrolizumab Plus Placebo in Previously Treated Patients with Advanced NSCLC (ID 8581)
11:05 - 11:10 | Presenting Author(s): Luis Paz-Ares | Author(s): B.P. Levy, Giuseppe Giaccone, Benjamin Besse, Enriqueta Felip, Marina Chiara Garassino, M. Domine, Pilar Garrido, B. Piperdi, S. Ponce Aix, R. Slepetis, X. Wu, A. Fandi
- Abstract
- Presentation
Background:
Studies have demonstrated that epigenetic modifiers, such as azacitidine, may sensitize tumor cells to treatment with checkpoint inhibitors, such as pembrolizumab (pembro). Efficacy and safety results from a phase 2, randomized, double-blind study of pembro in combination with CC-486, an oral formulation of azacitidine, vs pembro+placebo (PBO) for 2L treatment of advanced NSCLC are reported.
Method:
Patients aged ≥ 18 years with stage IIIB/IV NSCLC with only 1 prior platinum-based chemotherapy were randomized 1:1 (stratified by histology) to pembro 200 mg day 1 plus either CC-486 300 mg or placebo days 1-14 of a 21-day cycle. Primary endpoint was PFS. Key secondary endpoints included OS, ORR and safety.
Result:
51 and 49 patients were randomized to the pembro+CC-486 and pembro+PBO arms. Baseline characteristics were generally balanced between treatment groups. Efficacy results are shown in Table 1. Median duration of treatment for pembro+CC-486 vs pembro+PBO was 14 vs 24 weeks, and median number of cycles was 5 vs 7. The most common grade 3/4 TEAEs associated with pembro+CC-486 were nausea (14%), vomiting (12%), asthenia (10%), and diarrhea (8%), vs diarrhea (6%), asthenia (6%) and pneumonia (6%) with pembro+PBO. Patients treated with pembro+CC-486 vs pembro+PBO experienced a higher rate of pembro dose interruptions (29% vs 16%) and discontinuations (20% vs 10%), and a higher rate of CC-486 or PBO dose interruptions (61% vs 24%) and discontinuations (33% vs 12%). Gastrointestinal events, asthenia/fatigue, and elevated transaminase levels were the most common TEAEs leading to discontinuations.
Conclusion:
The addition of CC-486 to pembro did not improve the primary endpoint of PFS compared with pembro+PBO. PD-L1 expression did not appear to be predictive of CC-486 treatment efficacy. The increase in TEAEs in the combination arm, particularly gastrointestinal (nausea and vomiting), which are known to be associated with CC-486, may have influenced treatment exposure.Efficacy Endpoints Pembro + CC-486 n = 51 Pembro + PBO n = 49 Overall PFS, median, months 3.1 4.0 ORR, n (%) 10 (19.6) 7 (14.3) By PD-L1 Level at Baseline n = 45 n = 44 PFS, median, months ≥ 50% ≥ 1%-49% 0% 5.5 1.6 3.6 8.0 1.4 3.9 ORR, % ≥ 50% ≥ 1%-49% 0% 37.5 20.0 18.5 37.5 0.0 7.1
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MA 02.03 - Selective Histone Deacetylase Inhibitor ACY-241 Plus Nivolumab for Refractory Advanced NSCLC: Results From a Phase 1b Study (ID 8189)
11:10 - 11:15 | Presenting Author(s): Mark Awad | Author(s): Y. Le Bruchec, R. Markelewicz, P. Chen, A. Fandi, A. Spira
- Abstract
- Presentation
Background:
ACY-241, an oral inhibitor of histone deacetylase 6, has demonstrated activity in preclinical NSCLC models in combination with immunotherapy. The objectives of this study are to evaluate safety, dose-limiting toxicities (DLTs), the maximum-tolerated dose (MTD), and preliminary antitumor activity of ACY-241 in combination with the immune checkpoint inhibitor nivolumab.
Method:
In the 3+3 dose-escalation design, previously treated patients with advanced NSCLC and ECOG PS of 0 or 1 will receive ACY-241 on days 1 to 28 of each 28-day cycle at 3 dose levels (180, 360, and 480 mg) in combination with nivolumab 240 mg on day 15 of cycle 1 and days 1 and 15 of each subsequent cycle. Antitumor activity will be assessed per RECIST v1.1 and immune-related response criteria (irRC).
Result:
As of 16 June 2017, 13 patients have been treated in the 3 dose-escalation cohorts. All patients had received first-line treatment with platinum-based chemotherapy. The median age of all patients was 66 years, 62% were male, 54% had an ECOG PS of 0, 54% had stage IV disease, and 85% had adenocarcinoma (15% had squamous histology). No DLTs were observed in the 180- or 360-mg ACY-241 cohorts. The 480-mg cohort is currently under investigation. The most common all-grade adverse events (AEs) in all cohorts were cough (15%), arthralgia (15%), and fatigue (15%, including grade 3 in 1 patient). One patient experienced a grade 3 cerebrovascular accident related to a brain metastasis but unrelated to study drug. No immune-related AEs have been observed. Six patients were evaluable for response: 2 experienced objective responses (1 complete and 1 partial); 2 patients had stable disease; 2 patients had disease progression. Two patients were not evaluable for efficacy, and 5 patients have not yet undergone a response assessment.
Conclusion:
No DLTs have been observed with ACY-241 at 180 or 360 mg. Preliminary antitumor activity has been observed with the combination treatment. Updated pharmacokinetic data will be presented at the meeting. NCT02635061
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MA 02.04 - Discussant - MA 02.01, MA 02.02, MA 02.03 (ID 10779)
11:15 - 11:30 | Presenting Author(s): Grace K Dy
- Abstract
- Presentation
Abstract not provided
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MA 02.05 - Nivolumab in Advanced Non-Squamous NSCLC Patients with KRAS Mutations: Results from the Italian Expanded Access Program (EAP) (ID 9608)
11:30 - 11:35 | Presenting Author(s): Domenico Galetta | Author(s): A. Ardizzoni, P. Bidoli, R. Chiari, L. Bonomi, D. Turci, L. Landi, L. Toschi, M. De Tursi, G. Francini, M. Giordano, O. Alabiso, A. De Censi, L. Livi, A. Berruti, M. Minelli, E. Ricevuto, A. Illiano, G. Puppo, A. Delmonte
- Abstract
- Presentation
Background:
Nivolumab significantly improved overall survival (OS) versus docetaxel in patients (pts) with previously treated non-squamous non small cell lung cancer (non-Sq-NSCLC) in the Checkmate 057 study. In a pre-specified subgroup analysis of this trial, this advantage was confirmed also in patients (pts) with KRAS-mutation (KRAS+). However, since the number of KRAS+ pts enrolled in the trial was too small to draw definitive conclusions, the Italian nivolumab expanded access program (EAP) for non-Sq-NSCLC might represent an important source of information about this subpopulation. Here we report the results of the use of nivolumab in pts with KRAS mutation treated in the Italian EAP.
Method:
Nivolumab was provided upon physicians’ request for pts aged ≥18 years who had relapsed after a minimum of one prior systemic treatment for stage IIIB/stage IV non-Sq-NSCLC. Nivolumab 3 mg/kg was administered intravenously every 2 weeks for <24 months. Pts included in the analysis received ≥1 dose of nivolumab and were monitored for adverse events (AEs) using Common Terminology Criteria for Adverse Events.
Result:
Overall, 1588 pts with advanced non-Sq-NSCLC, enrolled in 168 sites, received at least one dose of nivolumab in the Italian EAP. Among 532 pts evaluated for KRAS mutation, 206 (39%) resulted positive. In this subgroup of pts, the best overall response rate (BORR) was 20%, including 2 pts with complete response and 39 pts with partial response. The median OS was 10.7 months (8.6-12.8), with a median follow-up of 7.7 months (0.1-21.2) and a median number of 8 doses (1-45). These results were in line with those ones showed in the overall population (18% BORR and 11 months median OS, respectively). Overall, among pts with KRAS mutation, 166 discontinued treatment for any reason, with only 14 (8%) pts who discontinued treatment due to adverse events, in line with what observed in the general population and in previous studies.
Conclusion:
To date, no direct targeted therapy is available for pts with KRAS mutation. This analysis seems to confirm, in a real word setting and in a larger number of pts, the results obtained with nivolumab in KRAS-positive pts in CheckMate 057, thus representing a potentially effective therapeutic option for this subpopulation.
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MA 02.06 - BRAF Mutant NSCLC: Correlation with PD-L1 Expression,TMB, MSI and Response to ICPi and Anti-BRAF Therapy (ID 10473)
11:35 - 11:40 | Presenting Author(s): Elizabeth Dudnik | Author(s): Nir Peled, M. Wollner, Amir Onn, A. Agbareya, H. Nechushtan, T. Kuznetsov, L.C. Roisman, A. Belilovski Rozenblum, Smadar Geva, A. Zer, Jair Bar
- Abstract
- Presentation
Background:
The efficacy of immune check-point inhibitors (ICPi) in BRAF mutant non-small cell lung cancer (NSCLC) is largely unknown. The correlation with different parameters predicting efficacy of ICPi (e.g., PD-L1 expression, tumor mutational burden (TMB) and microsatellite instability status (MSI) in these tumors needs further evaluation.
Method:
A retrospective analysis of 30 patients with BRAF mutant advanced NSCLC treated between Aug 2013 and May 2017 was performed. The patients were divided into 2 groups: BRAF V600 E (Group A, N=16), non-V600E BRAF (Group B, N=14). PD-L1 was assessed by immunohistochemistry using 22C3 Dako antibody clone on Dako or Ventana's platform in 16 patients. TMB and MSI were assessed in 9 and 11 patients, respectively. Median progression-free survival (mPFS) with ICPi and targeted agents as well as median overall survival (mOS) were assessed in each group by Kaplan-Meier method.
Result:
Baseline characteristics of the cohort: median age 66y (range 39-98); males 53%; current/past smokers/never smokers/NA 13%/44%/40%/3%; adenocarcinoma/other histology 80%/20%; ECOG PS 0/1/2/3/4/NA 27%/33%/10%/13%/0%/17%. The distribution of TMB, PD-L1 expression and MSI status between the 2 groups is presented in Table 1. Ten patients received ICPi (nivolumab-8, pembrolizumab-2), and thirteen patients received anti-BRAF therapy (dabrafenib+trametinib-6, dabrafenib-4, vemurafenib-3). mOS and mPFS with ICPi and anti-BRAF therapy are summarized in Table 1. Four patients with BRAF V600 E PD-L1 ≥ 50% tumors were included in the series; one patients responded to dabrafenib+trametinib combination (response ongoing, 7.1months+); in two patients ICPi were initiated, response assessment pending. One patient with a non-V600E BRAF mutant NSCLC responded to dabrafenib for 6.7 months.Figure 1
Conclusion:
BRAF mutant NSCLC tumors are associated with high level of PD-L1 expression, low/intermediate TMB and MSI stable status. ICPi may induce prolonged responses both in BRAF V600E and non-V600E BRAF mutant NSCLC. Some non-V600E BRAF mutant NSCLC may benefit from anti-BRAF targeted therapy.
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MA 02.07 - A Phase II Study of Pembrolizumab in EGFR Mutant, PD-L1+, Tyrosine Kinase Inhibitor (TKI) Naïve Patients with Advanced NSCLC (ID 9525)
11:40 - 11:45 | Presenting Author(s): Aaron Lisberg | Author(s): J. Hunt, N. Reese, T. Wang, P. Coluzzi, M. Spiegel, K. Bornazyan, J. Carroll, J. Madrigal, B. Ledezma, M. Mendenhall, J.L. Bui, H. Lu, A. Cummings, Z. Noor, Jonathan W. Goldman, Edward Brian Garon
- Abstract
- Presentation
Background:
Pembrolizumab, a humanized monoclonal antibody that inhibits the interaction between programmed cell death 1 (PD-1) and programmed death-ligand 1 (PD-L1) has demonstrated significant antitumor activity and produced durable responses in non-small cell lung cancer (NSCLC). However, data to date suggests that responses are less frequent in patients whose tumors harbor mutations in the epidermal growth factor receptor (EGFR) gene. Our single center experience with the KEYNOTE-001 trial suggested that EGFR mutation positive NSCLC patients with a history of prior tyrosine kinase inhibitor (TKI) therapy had worse clinical outcomes than those who were TKI naïve. However, that analysis was limited by small sample size. As a result of this observation, we are currently enrolling an open-label, phase II trial, of front-line pembrolizumab in EGFR mutation positive NSCLC patients that are PD-L1+.
Method:
This is an open-label, phase II trial of pembrolizumab in patients with EGFR mutation positive NSCLC whose tumors are PD-L1 positive [>1% tumor membranous staining by immunohistochemistry (IHC), 22C3 pharmDx test in a CLIA certified laboratory]. Patients receive pembrolizumab 200mg by IV infusion every three weeks and are evaluated every 9 weeks +/- 1 week with radiographic imaging to assess response to treatment for a maximum of 35 trial treatments of pembrolizumab. After progression on pembrolizumab, patients are followed for evaluation of EGFR TKI efficacy. The primary end point of the study is objective response rate (ORR) to pembrolizumab, per RECIST 1.1. Secondary endpoints include safety and efficacy [progression-free survival (PFS), overall survival (OS)] of front-line pembrolizumab in this population, as well as efficacy [PFS, OS, ORR] of subsequent EGFR TKI after progression on pembrolizumab. Correlative analyses include whole exome sequencing and IHC of patient specimens. To date, 8 out of the 25 planned patients have been enrolled.
Result:
Section not applicable
Conclusion:
Section not applicable
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MA 02.08 - Discussant - MA 02.05, MA 02.06, MA 02.07 (ID 10780)
11:45 - 12:00 | Presenting Author(s): Barbara Melosky
- Abstract
- Presentation
Abstract not provided
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MA 02.09 - A Ph I/II Study of BGB324, a Selective AXL Inhibitor as Monotherapy and in Combination with Erlotinib in Advanced NSCLC (ID 10388)
12:00 - 12:05 | Presenting Author(s): Don Lynn Gibbons | Author(s): L. Byers, David E Gerber, J. Peguero, D. Micklem, M. Yule, J. Lorens
- Abstract
- Presentation
Background:
BGB324 is an orally available selective inhibitor of the receptor tyrosine kinase AXL (Biochemical IC50 0.4nM). In animal models of NSCLC exposure, BGB324 restricts cellular plasticity and prevents the development of resistance to Epithelial Growth Factor Receptor (EGFR) inhibitors through mesenchymal transformation.
Method:
BGB324 was administered at an oral loading dose (600 mg) on days one and two followed by a daily maintenance dose (200 mg) to eight patients with previously treated NSCLC (EGFR mutant or wildtype). The tolerability of two different loading doses BGB324 (600 mg on days one and two or 400 mg on days one two and three) were then explored in combination with erlotinib at a dose of 150 mg daily in patients with EGFR mutated NSCLC.
Result:
Two of eight patients treated with BGB324 monotherapy achieved at least six months of stable disease. Both dose levels of BGB324 were tolerated in combination with erlotinib although most patients experienced a transient worsening in gastrointestinal toxicity during the loading dose prior to returning to baseline. A three day loading dose was preferred. Treatment with BGB324 was accompanied by increases in patient serum levels of soluble AXL receptorconsistent with receptor inhibition. One patient who previously experienced progression during treatment with another EGFR inhibitor remains on treatment with erlotinib plus BGB324 for more than eighteen months with a best response of stable disease. The most common treatment related adverse events were increased serum creatinine, diarrhea, nausea and dysguesia.
Conclusion:
Conclusion BGB324 can be safely administered to patients with advanced NSCLC for prolonged periods at doses that abrogate AXL signalling either as monotherapy or in combination with erlotinib. A proportion of patients achieve durable disease stabilisation following treatment with BGB324 alone further exploration of the efficacy of the combination is ongoing.
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MA 02.10 - Phase I Study of ABBV-399 (Telisotuzumab Vedotin) as Monotherapy and in Combination with Erlotinib in NSCLC (ID 9466)
12:05 - 12:10 | Presenting Author(s): Jonathan Wade Goldman | Author(s): E. Angevin, J. Strickler, D. Ross Camidge, R. Heist, D. Morgensztern, M. Barve, H. Yue, J. Beaulieu, M. Motwani, D. Afar, L. Naumovski, Karen Kelly
- Abstract
- Presentation
Background:
The c-Met receptor is overexpressed in ~50% of patients (pts) with non-small cell lung cancer (NSCLC). ABBV-399 is a first-in-class antibody-drug conjugate composed of ABT-700, an anti–c-Met antibody, conjugated to monomethyl auristatin E (a microtubule inhibitor). Preclinical data demonstrate that ABBV-399 can deliver a potent cytotoxin directly to c-Met+ tumor cells.
Method:
ABBV-399 was administered at doses ranging from 2.4 to 3.0 mg/kg (dose expansion and combination cohorts at 2.7 mg/kg) once every 21 days to 29 pts with advanced c-Met+ (immunohistochemistry [IHC] H-score ≥150) NSCLC both as monotherapy (ABBV-399/monotherapy; 16 pts) and in combination with oral erlotinib 150 mg daily (ABBV-399/ERL; 13 pts) (NCT02099058). c-Met expression was assessed by IHC utilizing the SP44 antibody (Ventana; Tucson, AZ, USA).
Result:
As of April 26, 2017, 16 pts with c-Met+ NSCLC received ≥1 dose of ABBV-399/monotherapy. Monotherapy treatment-related adverse events (TRAEs) occurring in ≥10% of pts (all dose levels and all grades) were fatigue (43.8%), nausea (37.5%), neuropathy (25.0%), vomiting (18.8%), anemia, constipation, and diarrhea (12.5% each). Three of 16 (19%) ABBV-399–treated c-Met+ NSCLC pts had a confirmed partial response (PR) with duration of response (DOR) 3.1, 4.8, and 11.1 months. At week 12, 9 of 16 pts (56.3%) had disease control. TRAEs in ABBV-399/ERL occurring in ≥10% of pts (all grades) were neuropathy (46.2%), nausea (23.1%), fatigue, acneiform rash, dry skin, and diarrhea (15.4% each). Four of 13 (31%) evaluable ABBV-399/ERL–treated c-Met+ pts had a PR (3 confirmed, 1 unconfirmed) with DOR 2.8, 5.3, 4.2+, and 9.1+ months. Three of the 4 pts with PR had EGFR-mutated tumor and recently progressed on TKI. At week 12, 10 of 13 pts (76.9%) had disease control. There were no treatment-related deaths as monotherapy or in combination with erlotinib. Responses were seen in both squamous and non-squamous histology.
Conclusion:
ABBV-399 is well tolerated at 2.7 mg/kg once every 21 days and has demonstrated antitumor activity in pts with c-Met+ NSCLC both as monotherapy and in combination with erlotinib. Early evidence suggests that ABBV-399 represents a novel treatment paradigm effective against multiple c-Met+ NSCLC molecular subtypes and histologies. Updated efficacy/safety data and c-Met IHC status will be presented. Safety and efficacy data from Q2week dosing of ABBV-399 will also be presented.
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MA 02.11 - A Phase I Trial of Erlotinib and Onalespib in EGFR-mutant NSCLC: Focus on EGFR Exon 20 Insertions (ID 9046)
12:10 - 12:15 | Presenting Author(s): Jonathan W Riess | Author(s): Karen L Reckamp, J. Longmate, Karen Kelly, David R. Gandara, Philip Christopher Mack, E. Newman, Primo Lara
- Abstract
- Presentation
Background:
Onalespib (AT13387) is a non-ansamycin small molecule that inhibits heat shock protein-90 (Hsp90). Hsp90 inhibitors (Hsp90i) preferentially degrade overexpressed and mutated oncoproteins including those that mediate resistance to EGFR-TKIs. Previous Hsp90i studies demonstrated activity in EGFR-mutant NSCLC including EGFR Exon 20 insertions (EGFRex20ins) - uncommon EGFR mutations typically refractory to 1[st] and 2[nd] generation EGFR-TKIs. A phase I study of onalespib plus erlotinib was conducted to determine the MTD, DLT, RP2D, pharmacokinetics (PK) and preliminary antitumor activity for a planned phase 2 trial in EGFR-mutant NSCLC including EGFRex20ins.
Method:
Using a 3 + 3, dose escalation design, onalespib was examined at 2 dose levels (DL) from 150 (DL0) to 120 (DL-1) mg/m[2] IV weekly (D1, D8, D15 on a q28 day cycle). Daily erlotinib was given at 150 mg at both DL. Key eligibility: NSCLC with EGFR activating mutation including EGFRex20ins, age ≥ 18, ECOG PS≤2, acceptable organ function, and ≥1 systemic therapy for advanced disease (platinum-based chemotherapy for EGFRex20ins and EGFR-TKI for other EGFR-mutations). Plasma for PK and ctDNA for next-generation sequencing of ~70 cancer related genes was collected at relevant timepoints.
Result:
9 pts have been treated on 2 DL (3 DL0, 6 DL-1). Pt characteristics: median age 65, M/F (2/7), ECOG PS 0-1 (4/5), EGFRex20ins (8), EGFR E19del (1). 7 pts completed ≥1 cycle. Two DLTs (grade (Gr) 3 maculopapular rash and Gr 3 hypophosphatemia) occurred in DL0. Common drug-related adverse events (AE) of any Gr were diarrhea (100%) and rash (44%), fatigue (55%), increased bilirubin (22%), nausea (44%) and vomiting (33%). Drug-related Gr 3 AEs were diarrhea (55%), maculopapular rash (11%) and hypophosphatemia (11%). At the planned 2-month evaluation, 5 pts had SD, 3 PD, and 1 had withdrawn for toxicity. Of the 5 pts continuing, 2 had SD and 1 PD at the 4-month evaluation. Kaplan-Meier estimate on therapy without progression at the second evaluation is 30% (95% CI: 10 to 87%).
Conclusion:
In patients with EGFR-mutant NSCLC, onalespib plus erlotinib is feasible, tolerable and demonstrates disease control in EGFRex20ins, thereby addressing a key unmet need in NSCLC. The RP2D is erlotinib 150 mg PO daily and onalespib 120 mg/m[2] weekly (D1, D8, D15 q28days). Diarrhea was the most common AE, and generally manageable with supportive care and dose reduction to DL-1. Updated results including PK as well as ctDNA for EGFR-mutation and relevant bypass tracts mediating EGFR-TKI resistance will be presented.
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MA 02.12 - Discussant - MA 02.09, MA 02.10, MA 02.11 (ID 10781)
12:15 - 12:30 | Presenting Author(s): Dean A Fennell
- Abstract
- Presentation
Abstract not provided
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Author of
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GR 03 - Treatment Options for Early Stage Lung Cancer Patients with Limited Pulmonary Reserve (ID 522)
- Event: WCLC 2017
- Type: Grand Rounds
- Track: Early Stage NSCLC
- Presentations: 1
- Moderators:Alexander Vincent Louie, I. Yoshino
- Coordinates: 10/18/2017, 11:00 - 12:30, F205 + F206 (Annex Hall)
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GR 03.05 - Any Roles of Systemic Therapy (Chemotherapy, Targeted Therapy, Immunotherapy) for Early Stage NSCLC with Limited Pulmonary Reserve? (ID 7638)
11:50 - 12:10 | Presenting Author(s): Shun Lu
- Abstract
- Presentation
Abstract:
The standard treatment of early stage non-small cell lung cancer (NSCLC) is lobectomy with systematic mediastinal lymph node evaluation. Unfortunately, up to 25% of patients with stage I NSCLC are not lobectomy candidates because of severe medical comorbidity including limited pulmonary reserve. During the past decade, stereotactic ablative radiotherapy (SABR) has resulted in local control in excess of 90% of tumours with medically inoperable and operable clinical stage I NSCLC. The local treatment including surgery and SABR is the stand of care for these patients . No definite evidence-based medicine data about the systemic therapy had been reported in this subgroup patients. A systemic therapy approach to the treatment of patients with medically inoperable, early stage NSCLC is not warranted. The management suggestions were unanimously agreed upon based on available literature. Systemic Therapy combined with local treatment could be a good option for these patients. 1. Chemotherapy+ local treatment: It seems that it is not recommended to add chemotherapy to local treatment for those medically inoperable, early stage NSCLC. It is reported that no evidence of an improvement in event-free survival was seen with the addition of weekly gemcitabine at this dose for patients with early stage NSCLC unfit for surgery, although the power of the study was low. 2. Targeted Therapy+ local treatment: No clear data about the targeted therapy for those medically inoperable, early stage NSCLC patients. For those driven gene positive patients, targeted therapy combined with local treatment seems to be a good choice. Some people worried about the combined therapy may increase the potential for pulmonary toxicity in patients with baseline pulmonary dysfunction, however, there is no cases of interstitial lung disease in early stage NSCLC as adjuvant therapy in 2017 ASCO (CTONG 1104). Further studies should be developed for these patients. 3. Immunotherapy + local treatment: The integration of radiation with immunotherapy is a conceptually promising strategy, as radiation has potent immune-modulatory effects and may contribute not only to local control but also augment systemic antitumor immune response. The advent of novel immunotherapy agents affords patients and clinicians therapeutic modalities to improve patient longevity and avenues to study innovative combinations of therapies. Preclinical data and case reports suggest the potential for robust clinical responses in metastatic NSCLC patients using this strategy, but prospective clinical trials evaluating the integration of radiation and immunotherapy are limited. The use of immunotherapy in non-metastatic settings is also intriguing but understudied. Summary: The assessment of treatment options for limited pulmonary reserve patients that requires uniform reporting of comorbidities and outcomes in clinical studies, which often is lacking. Systemic Therapy combined with local treatment could be a good option for these patients. Trials involving systemic therapy for patients with medically inoperable NSCLC should be developed.
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JCSE 01 - Joint IASLC/CSCO/CAALC Session: Immunotherapy for Management of Lung Cancer: Ongoing Research from East and West (ID 630)
- Event: WCLC 2017
- Type: Joint Session IASLC/CSCO/CAALC
- Track: Immunology and Immunotherapy
- Presentations: 2
- Moderators:C. Bai, Fred R. Hirsch, Tony SK Mok, Yi-Long Wu
- Coordinates: 10/15/2017, 07:30 - 11:30, F203 (Annex Hall)
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JCSE 01.12 - A Phase II Study of Fruquintinib in Combination with Gefitinib in Stage IIIb/IV NSCLC Patients Harboring EGFR Activating Mutations (ID 10907)
10:35 - 10:50 | Presenting Author(s): Shun Lu
- Abstract
- Presentation
Background:
Seveal studies have demonstrated targeting EGFR mutations and tumor angiogenesis simultaneously has synergistic effect in the 1[st] line setting in EGFR mutant NSCLC. However, in JO25567 trial, the ≥grade 3 hypertension incidence with combination therapy was much higher (60%) when compared to historic incidence of hypertension with bevacizumab (10-15%). Considering relatively shorter half-lives for small molecule tyrosine kinase inhibitors, it might be a better choice to combine EGFR TKI and VEGFR TKI when it comes to hypertension management. Fruquintinib is a potent and highly selective oral kinase inhibitor targeting VEGFR and it has demonstrated favorable benefit-to-risk profile in third line treatment in NSCLC patients.Thus it is important to assess safety, tolerability and efficacy of this new combination in the 1[st] line setting in EGFR mutant NSCLC patients. NCT02976116
Method:
This is a single arm, open-label, multi-center study. All patients will receive gefitinib continuously at 250 mg qd. Fruquintinib will be given at 4 mg as starting dose for 3 weeks followed by 1 week off in the first 4-week cycle. Fruquintinib dose can be escalated to 5 mg with the same 4-week cycle if no ≥grade 3 adverse event (AE) or ≥grades 2 liver dysfunction occurs in the first cycle. Treatment continues until disease progression, unacceptable toxicity, or patient withdrawal. The primary objective is to assess the safety and tolerability of this combination. Key eligibility criteria include: histologically or cytologically confirmed NSCLC, ECOG PS 0-1, no prior systematic treatment, no brain metastasis. Key exclusion criteria include: known T790M mutation and bleeding history within 1 month before enrollment.
Result:
As of Jun 20, 2017, 9 patients have been enrolled and received at least one dose of fruquintinib and gefitinib. Six patients had L858R mutations, and three patients had exon 19 deletions. All patients reported AEs, but only one patient (11.1%) had grade 3 proteinuria. No SAE was reported. The most common AEs were increased ALT (3 [33.3%] patients), increased AST (3 [33.3%] patients), increased TBIL (3 [33.3%] patients), proteinuria (3 [33.3%] patients) and rash (3 [33.3%] patients). Fruquintinib dose reduction occurred in 3 patients due to grade 3 proteinuria, grade 2 increased ALT and grade 2 hemoptysis, respectively.
Conclusion:
The study is ongoing. As of the cut-off date, no unexpected toxicities were identified. The combination of fruquintinib and gefitinib showed an expected and manageable preliminary safety profile. Additional patients and follow-up data are required to further confirm the full potential of this combination treatment.
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JCSE 01.24 - Detection of EGFR, ALK and Other Driver Oncogenes from Plasma cfDNA by Single Molecule Amplification and Re-sequencing Technology (cSMART) (ID 10920)
11:30 - 11:30 | Author(s): Shun Lu
- Abstract
Background:
All patients with advanced stage NSCLC should have their EGFR and ALK mutation status known prior to initiation of first line therapy. Multiple plasma-based technologies such as ARMS and ddPCR are available for rapid detection of EGFR mutation, while only the more laborious Next Generation Sequencing (NGS) may cover EGFR, ALK and other uncommon mutations in a single blood test. cSMART is a novel NGS-based technology with rapid turnaround time that can detect EGFR, ALK and KRAS mutations plus others less common lung cancer specific driver oncogenes (BRAF, ROS-1, HER-2, PIK3CA, RET, MET14skipping).
Method:
Objectives of this study is to investigate the clinical application of cSMART on patients with advanced NSCLC. In cSMART assay, each cfDNA single allelic molecule is uniquely barcoded and universally amplified to make duplications. The amplified products are circularized and re-amplified with target-specific back-to-back primers. These DNA are then ligated with sequencing adapters and pair-end sequenced (>40,000x) with illumine sequencers. The original cfDNA molecules are reconstituted by multi-step bioinformatics pipeline for censor and correction. The final products are quantified for calculation of allele frequencies
Result:
Out of the 1664 samples tested, total of 1469 were of advanced stage NSCLC. We detected EGFR mutations in 758 (51.6%), ALK translocation in 34 (2.3%) and KRAS mutation in 78 (5.8%) patients. Among the patients with activating EGFR mutations, 301(39.7%) have exon 19 deletion and 279 (36.8%) have exon 21 point-mutation. Total of 6 (0.8%) patients with EGFR mutation have concurrent presence of ALK translocation. Incidence and mean allele frequency of the less common target mutation is summarized in Table. Median sample turnaround time is 7 days.Incidence (%) Median Mutation Allele frequency (%) BRAF 29 (1.97%) 0.08% ROS1 2 (0.14%) 0.77% HER-2 19 (1.29%) 0.20% PIK3CA 70 (4.77%) 0.17% RET 14 (0.95%) 0.57% MET14skipping 63 (4.29%) 0.08%
Conclusion:
cSMART is a novel plasma cfDNA-based technology that can detect the actionable target oncogenes for patients with advanced NSCLC. This is a sensitive method with capacity of detecting the uncommon targets at relatively low allele frequency.
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MA 03 - Chemotherapy (ID 651)
- Event: WCLC 2017
- Type: Mini Oral
- Track: Advanced NSCLC
- Presentations: 1
- Moderators:Jin-Hyoung Kang, W. Su
- Coordinates: 10/16/2017, 11:00 - 12:30, Room 502
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MA 03.03 - Nedaplatin plus Docetaxel versus Cisplatin plus Docetaxel as First-Line Chemotherapy for Advanced Squamous Cell Carcinoma of the Lung (ID 8154)
11:10 - 11:15 | Presenting Author(s): Shun Lu
- Abstract
- Presentation
Background:
A previous phase III randomized trial improved overall survival of patients with advanced or relapsed squamous cell lung carcinoma, compared with cisplatin plus docetaxel. However, evaluation of nedaplatin plus docetaxel’s effect on progression free survival (PFS) and time to progression (TTP) was limited.
Method:
To compare the efficacy and safety of nedaplatin plus docetaxel and cisplatin plus docetaxel. In this randomized, open-label, multicenter trial, patients diagnosed with advanced or relapsed squamous cell carcinoma pathologically or cytologically were enrolled in China. All the patients have no previous oncology medication. Patients were randomly assigned (1:1) to 80 mg/m² nedaplatin and 75 mg/m² docetaxel intravenously, or 75 mg/m² cisplatin and 75 mg/m² docetaxel, every 3 weeks for four cycles. The primary end points was PFS. Secondary endpoints included TTP and best overall response. The efficacy endpoint were analyzed in the intention-to-treat set and in the per protocol set. （Clinical trial number: NCT02088515; Funding:Jiangsu Simcere Pharmaceutical Co., Ltd.）
Result:
From December 2013 to December 2015, 286 patients were randomly assigned. Two hundred and eighty patients were included in the modified intention-to-treat analysis (141 in the nedaplatin group and 139 in the cisplatin group). In the intention-to-treat analysis set, median PFS was 4.63 months (95% confidence interval (CI), 4.43-5.10) in the nedaplatin group and 4.23 months (95% CI, 3.37-4.53) in the cisplatin group. PFS did not differ significantly between two groups (log-rank test, p =0.056). In per protocol set, PFS was significantly longer in the nedaplatin group (median 4.63 months, 95% CI, 4.43-5.10) than in the cisplatin group (median 4.27 months, 95% CI, 3.37-4.53; hazard ratio 0.760, 95% CI 0.585-0.989; p=0.039, log-rank test). Best overall response and TTP were improved in nedaplatin group than in cisplatin group (p= 0.002, median 4.57(4.30-4.80) vs 3.67(3.13-4.43) p= 0.020, respectively) in the intention-to-treat analysis set. Grade III or IV adverse events was more frequent in the cisplatin group than in the nedaplatin group (46 of 141 patients in the nedaplatin group and 62 of 139 in the cisplatin group, p=0.039). Grade 3 or worse nausea (0 vs 7) and fatigue (1 vs 3) were more frequent in the cisplatin group than in the nedaplatin group.
Conclusion:
There was no significant difference of PFS between cisplatin group and nedaplatin group. However, more adverse events was observed in the cisplatin group than in the nedaplatin group. Nedaplatin plus docetaxel could be a new treatment option for advanced or relapsed squamous cell lung cancer.
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MA 07 - ALK, ROS and HER2 (ID 673)
- Event: WCLC 2017
- Type: Mini Oral
- Track: Advanced NSCLC
- Presentations: 1
- Moderators:Robert C. Doebele, J.C. Ho
- Coordinates: 10/17/2017, 15:45 - 17:30, Room 316
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MA 07.04 - Clinical Impact of Crizotinib on Brain Metastases in Patients with Advanced ROS1-Rearranged Non-Small Cell Lung Cancer (ID 9852)
16:00 - 16:05 | Presenting Author(s): Shun Lu
- Abstract
- Presentation
Background:
Brain metastases are common in patients with advanced non–small cell lung cancer (NSCLC). Approximately 1% of NSCLC patients have ROS1-rearranged, and these patients achieved prolonged survival when treated with crizotinib, which is approved for the treatment of ROS1-rearranged NSCLC. However, this efficacy might not translate to intracranial control of disease. Herein, we evaluated the clinical impact of crizotinib on brain metastases in patients with advanced ROS1-rearranged NSCLC.
Method:
Between April 2014 and October 2016, 53 ROS1-rearranged NSCLC patients treated with crizotinib were retrospectively evaluated for baseline characteristics, brain metastases status, progression patterns and the overall prognosis.
Result:
Of the 53 ROS1-rearranged NSCLC patients who received crizotinib as treatment, 13 (24.5%) patients had baseline brain metastases before crizotinib treatment. Among patients without baseline brain metastases who developed progressive disease after initiation of crizotinib (n=27), 22.2% were diagnosed with brain metastases. Among patients without baseline brain metastases, systemic progression-free survival (PFS) and overall survival (OS) after initiation of crizotinib was significantly longer than that of patients with brain metastases (median PFS: 20.4 months vs. 11.0 months, p = 0.003; median OS: not reached vs. 16.5 months, p = 0.027). There was no significant difference in systemic PFS and OS between patients developing brain metastases before and after crizotinib treatment (median PFS: 11.0 months vs. 6.4 months, p = 0.469; median OS: 16.5 months vs. not reached, p = 0.605). Among the patients with baseline brain metastases, 6 had received prior brain radiotherapy and 7 had received no prior radiotherapy. A total of 2 patients in the treated group had an event of brain metastases progression, as compared with 4 patients in the untreated group (33.3% vs 57.1%, p = 0.592). There was no significant difference in intracranial PFS in the previously brain treated patients versus the untreated patients before crizotinib treatment (median intracranial PFS: 12.5 months vs. 11.0 months, p = 0.790).
Conclusion:
Brain metastases status before crizotinib treatment was significantly associated with both PFS and OS in crizotinib-treated ROS1-rearranged NSCLC patients. Patients with brain metastases received prior radiotherapy have not prolonged survival compared with the patients treated with crizotinib alone.
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MA 08 - Supportive Care and Communication (ID 669)
- Event: WCLC 2017
- Type: Mini Oral
- Track: Nursing/Palliative Care/Ethics
- Presentations: 1
- Moderators:E. Esposito-Nguyen, John McPhelim
- Coordinates: 10/17/2017, 11:00 - 12:30, Room 511 + 512
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MA 08.02 - Efficacy of Single-Dose NEPA versus 3-Day Aprepitant Regimen for Prevention of CINV: A Phase 3 Lung Cancer Subset Analysis (ID 8460)
11:05 - 11:10 | Presenting Author(s): Shun Lu
- Abstract
- Presentation
Background:
Cisplatin, a systemic treatment component for many lung cancer types, is highly emetogenic (HEC). The guideline-recommended antiemetic combination for patients receiving HEC includes a NK~1~ receptor antagonist (NK~1~RA), a 5-HT~3~RA, and dexamethasone (DEX). NEPA is the first oral fixed combination of an NK~1~RA (netupitant) and a 5-HT~3~RA (palonosetron). The approval of oral NEPA was based on studies demonstrating superior prevention of chemotherapy-induced nausea and vomiting (CINV) over oral palonosetron; an intravenous formulation of NEPA is under FDA evaluation. A new Phase 3 study in Asia has reached its primary objective: a single day oral dose of NEPA is non-inferior to a 3-day regimen of aprepitant (APR) and granisetron (GRAN) [both combined with DEX] in preventing CINV in patients receiving cisplatin. This post-hoc analysis explores the efficacy of NEPA vs APR/GRAN within the lung cancer subset of that study.
Method:
Chemotherapy-naïve lung cancer patients in this double-blind, parallel group study received either a single oral dose of NEPA prior to cisplatin-based HEC or a 3-day regimen of APR/GRAN, both with oral DEX on days 1-4. Efficacy endpoints were complete response (CR: no emesis/no rescue medication), no emesis, and no significant nausea (<25 mm on 100 mm visual analog scale) during the acute (0-24h), delayed (25-120h) and overall (0-120h) phases post-chemotherapy. The risk difference for NEPA – APR/GRAN and associated 95% confidence intervals (CIs) were analyzed for each endpoint using the Cochran-Mantel-Haenszel test.
Result:
542 (65%) of the 828 patients had lung cancer. Mean age was 56.1; 73% males. Response rates were comparable for both arms during the acute phase, and favored NEPA in delayed phase (Table). Figure 1
Conclusion:
As a fixed oral combination of an NK~1~RA and 5HT~3~RA in a single capsule/cycle, NEPA offers a convenient and effective prophylactic antiemetic in lung cancer patients receiving cisplatin-based HEC regimens.
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P1.01 - Advanced NSCLC (ID 757)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: Advanced NSCLC
- Presentations: 2
- Moderators:
- Coordinates: 10/16/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)
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P1.01-032 - Detection of EGFR, ALK and Other Driver Oncogenes from Plasma cfDNA by Single Molecule Amplification and Re-sequencing Technology (cSMART) (ID 8603)
09:30 - 09:30 | Author(s): Shun Lu
- Abstract
Background:
All patients with advanced stage NSCLC should have their EGFR and ALK mutation status known prior to initiation of first line therapy. Multiple plasma-based technologies such as ARMS and ddPCR are available for rapid detection of EGFR mutation, while only the more laborious Next Generation Sequencing (NGS) may cover EGFR, ALK and other uncommon mutations in a single blood test. cSMART is a novel NGS-based technology with rapid turnaround time that can detect EGFR, ALK and KRAS mutations plus others less common lung cancer specific driver oncogenes (BRAF, ROS-1, HER-2, PIK3CA, RET, MET14skipping).
Method:
Objectives of this study is to investigate the clinical application of cSMART on patients with advanced NSCLC. In cSMART assay, each cfDNA single allelic molecule is uniquely barcoded and universally amplified to make duplications. The amplified products are circularized and re-amplified with target-specific back-to-back primers. These DNA are then ligated with sequencing adapters and pair-end sequenced (>40,000x) with illumine sequencers. The original cfDNA molecules are reconstituted by multi-step bioinformatics pipeline for censor and correction. The final products are quantified for calculation of allele frequencies
Result:
Out of the 1664 samples tested, total of 1469 were of advanced stage NSCLC. We detected EGFR mutations in 758 (51.6%), ALK translocation in 34 (2.3%) and KRAS mutation in 78 (5.8%) patients. Among the patients with activating EGFR mutations, 301(39.7%) have exon 19 deletion and 279 (36.8%) have exon 21 point-mutation. Total of 6 (0.8%) patients with EGFR mutation have concurrent presence of ALK translocation. Incidence and mean allele frequency of the less common target mutation is summarized in Table. Median sample turnaround time is 7 days.Incidence (%) Median Mutation Allele frequency (%) BRAF 29 (1.97%) 0.08% ROS1 2 (0.14%) 0.77% HER-2 19 (1.29%) 0.20% PIK3CA 70 (4.77%) 0.17% RET 14 (0.95%) 0.57% MET14skipping 63 (4.29%) 0.08%
Conclusion:
cSMART is a novel plasma cfDNA-based technology that can detect the actionable target oncogenes for patients with advanced NSCLC. This is a sensitive method with capacity of detecting the uncommon targets at relatively low allele frequency.
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P1.01-037 - Circulating Tumor DNA Clearance During Treatment Associates with Improved Progression-Free Survival (ID 9653)
09:30 - 09:30 | Presenting Author(s): Shun Lu
- Abstract
Background:
Therapeutic selection has been shown to lead to marked clonal evolution, thus revealing limitations in imaging scan as a monitoring method, which does not reflect biological processes at a molecular level. However, currently, response assessment of patients with non-small cell lung cancer (NSCLC) primarily relies on imaging scans, necessitating the development of methodologies for dynamic monitoring of treatment response. We evaluated ctDNA as a tumor clonal response biomarker.
Method:
We screened 831 advanced NSCLC patients with a mixture of prior treatment exposure by performing capture-based ultra-deep targeted sequencing on plasma samples using a panel consisting of 168 NSCLC-related genes. Eighty-six patients with driver mutations and a minimum of 2 evaluation points in addition to baseline were included for further analysis.
Result:
At baseline, 79.9% patients harbored at least one mutation from this panel; the remaining 20.1% had no mutation detected. Sixty-nine percent of patients (570/831) harbored driver mutation. Patients harboring 2 mutations or fewer at baseline had a median progression-free survival (PFS) of 7.4 months; in contrast, patients harboring more than 2 mutations had a median PFS of 3.8 months (P=6.6x10[-5 ]HR=0.34), suggesting a significant inverse correlation between number of mutations at baseline and PFS. Next, we evaluated the ability of ctDNA as a tumor clonal response biomarker in 86 patients with a minimum of 2 follow-ups. After a median follow-up of 314 days, 64 patients (74.4%) reached disease progression. During treatment, 46 patients, treated with either matched targeted therapy (MTT) or chemotherapy, had a minimum of one time of ctDNA clearance, occurring from 1.6 months to 7.5 months after the commencement of treatment, with a median PFS of 8.07 months, an overall response rate (ORR) of 41% and a disease control rate (DCR) of 93%. Median overall survival (OS) for this group has not reached. In contrast, 40 patients who had consistent detectable ctDNA throughout the course of treatment had a median PFS of 3.47months, a median OS of 425 days, an ORR of 20% and a DCR of 53%. Our data revealed that patients with a minimum of one time ctDNA clearance are associated with a better ORR (p=0.05), DCR (p=5.9x10[-5]), a longer PFS (p=5.4x10[-10 ]HR=0.21) and OS (p=2.3x10[-5 ]HR=0.21), regardless the type of treatment commenced and the time of evaluation.
Conclusion:
This real world study comprising a heterogeneous population reveals the predictive and prognostic value of ctDNA and warrants further investigations to explore its clearance as a surrogate endpoint of efficacy.
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P1.04 - Clinical Design, Statistics and Clinical Trials (ID 690)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: Clinical Design, Statistics and Clinical Trials
- Presentations: 1
- Moderators:
- Coordinates: 10/16/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)
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P1.04-010 - CheckMate 870: An Open-label Safety Study of Nivolumab in Previously Treated Patients With Non-Small Cell Lung Cancer in Asia (ID 8231)
09:30 - 09:30 | Presenting Author(s): Shun Lu
- Abstract
Background:
Programmed death-1 (PD-1) is an immune checkpoint receptor that attenuates T-cell activation by binding to its ligands, PD-L1 and PD-L2, which are expressed on tumor cells. Nivolumab, an anti–PD-1 antibody, showed durable antitumor activity and a favorable safety profile compared with docetaxel in previously treated patients with advanced non-small cell lung cancer (NSCLC) in 2 global phase 3 studies (CheckMate 017 and CheckMate 057). Data from these trials led to the approval of weight-based nivolumab 3 mg/kg administered as a 60-minute infusion every 2 weeks (Q2W) in previously treated patients with NSCLC. Data from exposure-response simulations indicated that flat-dose nivolumab 240 mg Q2W has comparable pharmacokinetic, safety, and efficacy profiles to the weight-based dose, and data from CheckMate 153 demonstrated that nivolumab 3 mg/kg can be safely infused over 30 minutes. CheckMate 078 is an ongoing phase 3 registrational trial evaluating second-line nivolumab 3 mg/kg as 60-minute infusions Q2W versus docetaxel in patients with advanced NSCLC in a predominantly Chinese population. CheckMate 078 excludes patients with hepatitis B virus (HBV) infection, which represent a clinically relevant subgroup of patients in Asia; approximately 15% of patients with lung cancer in China are seropositive for HBV surface antigens. CheckMate 870 is an open-label, single-arm phase 3b study evaluating the safety and tolerability of flat-dose nivolumab 240 mg infused over 30 minutes Q2W in Asian patients with advanced or metastatic NSCLC, with or without HBV infection.
Method:
Approximately 400 patients in Asia with advanced or metastatic NSCLC and disease progression during or after 1 prior systemic platinum-based therapy will be enrolled; those with EGFR mutations (maximum of 40 patients) or ALK translocations should have received 2 prior systemic treatments including a tyrosine kinase inhibitor and chemotherapy. Nivolumab will be administered 240 mg over 30 minutes Q2W until disease progression or unacceptable toxicity, for a maximum of 24 months. Nivolumab may be reinitiated for subsequent disease progression and administered for up to 1 additional year. The primary objective is to evaluate the safety and tolerability of nivolumab in non–HBV-infected patients with NSCLC. The secondary objective is to assess safety and tolerability in all patients and in HBV-infected patients. Exploratory objectives include efficacy, patient-reported outcomes, health care resource utilization and direct medical costs, biomarker characterization in all patients, and viral load change and HBV reactivation rate in HBV-infected patients.
Result:
Section not applicable
Conclusion:
Section not applicable
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P3.01 - Advanced NSCLC (ID 621)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: Advanced NSCLC
- Presentations: 5
- Moderators:
- Coordinates: 10/18/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)
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P3.01-026 - Analysis of Long-Term Response to First-Line Afatinib in the LUX-Lung 3, 6 and 7 Trials in Advanced EGFRm+ NSCLC (ID 9051)
09:30 - 09:30 | Author(s): Shun Lu
- Abstract
Background:
In patients with advanced EGFR mutation-positive (EGFRm+) NSCLC, first-line afatinib significantly improved PFS and objective response rate (ORR) versus platinum-doublet chemotherapy in the phase III LUX-Lung (LL) 3 and LL6 studies, and PFS, time-to-treatment failure (TTF) and ORR versus gefitinib in the phase IIb LL7 study. Here, we present post-hoc analyses of efficacy, safety and patient-reported outcomes (PROs) in afatinib long-term responders (LTRs) in LL3/6/7.
Method:
Treatment-naïve patients with stage IIIb/IV EGFRm+ NSCLC who were randomized to 40mg/day afatinib in LL3/6/7 and remained on treatment for ≥3 years were defined as LTRs. In these patients, we assessed efficacy and safety outcomes, as well as PROs measured using the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life (QoL) Questionnaire and the EQ-5D™ health status self-assessment questionnaire; these included scores on the EORTC Global Health [GH]/QoL scale (0–100), EORTC Performance Functioning scale (PF; 0–100), EQ Visual Analogue Scale (VAS; 0–100) and EQ-5D UK utility scale (EQ UK utility; 0–1).
Result:
In LL3/6/7, there were 24/229 (10%)/ 23/239 (10%)/ 19/160 (12%) afatinib-treated LTRs; 6/9/14 remained on treatment at time of analysis. Baseline characteristics were similar to the overall study populations, except for the proportion of women (LL3/6 only [LTRs versus overall]: 92/78% vs 64/64%) and Del19+ patients (LL3/6/7: 63–79% vs 49–58%). In LL3/6/7, 4–11% of LTRs had brain metastases at enrolment. Median (range) duration of treatment in LL3/6/7 LTRs was 50 (41–73)/56 (37–68)/42 (37–50) months. Due to few deaths, median OS could not be estimated. Median follow-up for OS in LL3/6/7 was 64.6/57.0/42.1 months. ORR among LTRs in LL3/6/7 was 70.8% (complete response: 4.2%; n=1)/78.3% (13.0%; n=3)/89.5% (5.3%; n=1). The frequency of afatinib dose reductions due to treatment-related AEs, and the frequency/duration of subsequent treatments were similar to the overall LL3/6/7 populations. In afatinib-treated LTRs in LL3/6/7, PROs appeared stable between ~Week 24 to ~Week 160, with slight improvements after ~3 years afatinib treatment versus scores at the start of treatment.
Conclusion:
In LL3/6/7, 10%–12% of afatinib-treated patients were LTRs. Afatinib was well tolerated among these patients. Long-term treatment was independent of tolerability-guided dose adjustment or presence of brain metastases at time of enrolment, and had no detrimental impact on subsequent treatment. In afatinib-treated LTRs, PROs were not negatively affected by long-term treatment, and were slightly improved after ~3 years of treatment versus scores at treatment initiation.
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P3.01-043 - Impact of ErbB Mutations on Clinical Outcomes in Afatinib- or Erlotinib-Treated Patients with SCC of the Lung (ID 9457)
09:30 - 09:30 | Author(s): Shun Lu
- Abstract
Background:
In LUX-Lung 8 (LL8), second-line afatinib (an irreversible ErbB family blocker) significantly improved OS (median 7.9 versus 6.8 months; HR [95% CI]: 0.81 [0.69‒0.95]; p=0.0077), and PFS (2.6 versus 1.9 months; 0.81 [0.69‒0.96]; p=0.0103) versus erlotinib in lung SCC (N=795). Comprehensive genetic analysis in LL8 patients assessed whether afatinib efficacy varied according to genetic aberrations in cancer-related genes, including ErbB family mutations.
Method:
Tumor genetic analysis (TGA) was performed using Foundation Medicine FoundationOne™ next-generation sequencing (NGS). The cohort was enriched for patients with PFS >2 months, reflecting a range of responsiveness to EGFR-TKIs. EGFR expression was assessed by immunohistochemistry (IHC) in a largely separate cohort. Cox regression analysis correlated PFS/OS with genetic mutations (individual/grouped) and EGFR expression.
Result:
Of 440 patients selected for TGA (PFS >2 months: n=320; ≤2 months: n=120), samples from 245 were eligible (afatinib: n=132; erlotinib: n=113). In the selected TGA population, PFS/OS outcomes were improved in the afatinib versus erlotinib arm. Baseline characteristics were similar in TGA and IHC cohorts and LL8 overall. In the TGA subset, 53 patients (21.6%) had ≥1 ErbB family mutation (EGFR: 6.5%; HER2: 4.9%; HER3: 6.1%; HER4: 5.7%). Beyond the benefit seen for afatinib in the overall population, in afatinib-treated patients, PFS/OS were longer when ErbB mutations were present (PFS: 4.9 versus 3.0 months; OS: 10.6 versus 8.1 months). Conversely, survival outcomes in erlotinib-treated patients were similar with/without ErbB mutations. Presence of HER2 mutations predicted favorable PFS/OS with afatinib versus erlotinib. The Table shows outcomes in patients with/without ErbB family mutations, and by EGFR expression levels (afatinib: n=157; erlotinib: n=188).
Conclusion:
These data are provocative and suggest that NGS may enable identification of lung SCC patients who would derive additional clinical benefit from afatinib. Differential outcomes with respect to ErbB mutations for afatinib and erlotinib are hypothesized to reflect afatinib’s broader mechanism of action.Subgroup n Afatinib vs erlotinib PFS OS HR (95% CI) p~interaction~ HR (95% CI) p~interaction~ ErbB mutation-positive ErbB mutation-negative 53 192 0.56 (0.29–1.08) 0.70 (0.50–0.97) 0.718 0.62 (0.35‒1.12) 0.76 (0.56‒1.03) 0.683 EGFR mutation-positive EGFR mutation-negative 16 229 0.64 (0.17–2.44) 0.67 (0.50–0.91) 0.981 1.01 (0.32–3.16) 0.72 (0.54–0.95) 0.529 HER2 mutation-positive HER2 mutation-negative 12 233 0.06 (0.01–0.59) 0.72 (0.54–0.97) 0.006 0.06 (0.01–0.57) 0.76 (0.58–1.00) 0.004 HER3 mutation-positive HER3 mutation-negative 15 230 0.52 (0.16–1.72) 0.69 (0.51–0.94) 0.692 0.84 (0.27–2.59) 0.73 (0.56–0.97) 0.998 HER4 mutation-positive HER4 mutation-negative 14 231 0.21 (0.02–1.94) 0.67 (0.50–0.91) 0.909 0.22 (0.05–1.04) 0.75 (0.56–0.99) 0.272 EGFR IHC positive EGFR IHC negative 292 53 0.74 (0.56–0.97) 0.76 (0.41–1.40) 0.985 0.82 (0.63–1.06) 0.75 (0.41–1.40) 0.882 EGFR amplification present EGFR amplification absent 17 228 0.72 (0.18–2.90) 0.68 (0.50–0.92) 0.994 0.50 (0.15–1.65) 0.76 (0.58–1.00) 0.413 HER2 amplification present HER2 amplification absent 9 236 0.94 (0.20–4.38) 0.68 (0.50–0.91) 0.861 1.10 (0.27–4.48) 0.72 (0.54–0.94) 0.388
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P3.01-052 - The Prevalence and Genotype Distribution of Dual in Cis EGFR Mutations in Chinese Advanced Non-Small Cell Lung Cancer Patients (ID 9721)
09:30 - 09:30 | Author(s): Shun Lu
- Abstract
Background:
The prevalence of EGFR mutation has been well elucidated in different ethnicities. Recently, increasing attention has been given to dual EGFR mutations. However, less attention has been invested in dual in cis EGFR mutations. Until now, none of retrospective or prospective research has focused on dual in cis EGFR mutations except case reports.
Method:
In this real world study, we performed capture-based ultra-deep targeted sequencing on circulating tumor DNA to identify and investigate the prevalence and genotype distribution of dual in cis EGFR mutations in 3,000 Chinese advanced NSCLC patients. This cohort consisted of both treatment-naïve and previously treated patients. Ten milliliter of peripheral blood was collected from every patient and a minimum of 50ng of ctDNA was needed for library construction. The panel covered critical exons and introns of 168 genes (160kb of human genomic regions).
Result:
1,266 patients harbored EGFR mutant in this cohort; among them, 501 patients harbored 19 deletions, 489 harbored L858R, and the remaining harbored other EGFR mutations. We identified 1.5% patients (19/1,266) harboring dual in cis EGFR mutations. Among them 37% (7/19）carried two rare EGFR mutations and the remaining 63% (12/19) carried EGFR L858R in combination with a rare mutation. No patient carried EGFR 19 del in combination with other rare mutations was identified in this cohort, suggesting EGFR 19del is a stronger oncogenic driver than EGFR L858R (p=0.000197, Fisher’s exact test). For patients carried two rare mutations, both mutations were either located on exon 18 or exon 21. The allelic fractions (AF) of both mutations were similar. The AF of either EGFR mutations was the maximum AF in all patients, demonstrating the clones harboring EGFR mutations were major clones. Interestingly, 1 patient carried additional KRAS mutation and 2 patients had EGFR amplification.
Conclusion:
In cis dual EGFR mutation was rare (1.5%) in EGFR mutant Chinese advanced NSCLC patients. EGFR L858R was significantly more likely to couple with a rare in cis dual mutation than 19 del. EGFR 19del might be a stronger oncogenic driver than EGFR L858R.
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P3.01-070 - A Phase II Study of Fruquintinib in Combination with Gefitinib in Stage IIIb/IV NSCLC Patients Harboring EGFR Activating Mutations (ID 8365)
09:30 - 09:30 | Presenting Author(s): Shun Lu
- Abstract
Background:
Seveal studies have demonstrated targeting EGFR mutations and tumor angiogenesis simultaneously has synergistic effect in the 1[st] line setting in EGFR mutant NSCLC. However, in JO25567 trial, the ≥grade 3 hypertension incidence with combination therapy was much higher (60%) when compared to historic incidence of hypertension with bevacizumab (10-15%). Considering relatively shorter half-lives for small molecule tyrosine kinase inhibitors, it might be a better choice to combine EGFR TKI and VEGFR TKI when it comes to hypertension management. Fruquintinib is a potent and highly selective oral kinase inhibitor targeting VEGFR and it has demonstrated favorable benefit-to-risk profile in third line treatment in NSCLC patients.Thus it is important to assess safety, tolerability and efficacy of this new combination in the 1[st] line setting in EGFR mutant NSCLC patients. NCT02976116
Method:
This is a single arm, open-label, multi-center study. All patients will receive gefitinib continuously at 250 mg qd. Fruquintinib will be given at 4 mg as starting dose for 3 weeks followed by 1 week off in the first 4-week cycle. Fruquintinib dose can be escalated to 5 mg with the same 4-week cycle if no ≥grade 3 adverse event (AE) or ≥grades 2 liver dysfunction occurs in the first cycle. Treatment continues until disease progression, unacceptable toxicity, or patient withdrawal. The primary objective is to assess the safety and tolerability of this combination. Key eligibility criteria include: histologically or cytologically confirmed NSCLC, ECOG PS 0-1, no prior systematic treatment, no brain metastasis. Key exclusion criteria include: known T790M mutation and bleeding history within 1 month before enrollment.
Result:
As of Jun 20, 2017, 9 patients have been enrolled and received at least one dose of fruquintinib and gefitinib. Six patients had L858R mutations, and three patients had exon 19 deletions. All patients reported AEs, but only one patient (11.1%) had grade 3 proteinuria. No SAE was reported. The most common AEs were increased ALT (3 [33.3%] patients), increased AST (3 [33.3%] patients), increased TBIL (3 [33.3%] patients), proteinuria (3 [33.3%] patients) and rash (3 [33.3%] patients). Fruquintinib dose reduction occurred in 3 patients due to grade 3 proteinuria, grade 2 increased ALT and grade 2 hemoptysis, respectively.
Conclusion:
The study is ongoing. As of the cut-off date, no unexpected toxicities were identified. The combination of fruquintinib and gefitinib showed an expected and manageable preliminary safety profile. Additional patients and follow-up data are required to further confirm the full potential of this combination treatment.
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P3.01-075 - Afatinib Dose Adjustment: Effect on Safety, Efficacy and Patient-Reported Outcomes in the LUX-Lung 3/6 Trials in EGFRm+ NSCLC (ID 9365)
09:30 - 09:30 | Author(s): Shun Lu
- Abstract
Background:
Afatinib 40mg/day is approved globally for first-line treatment of EGFR mutation-positive (EGFRm+) NSCLC. Afatinib is available in several tablet strengths (20/30/40/50mg), and tolerability-guided dose adjustment schemes are well established. Here, we evaluate the impact of afatinib dose reduction on safety (AEs), pharmacokinetics, PFS and patient-reported outcomes (PROs) in the Phase III LUX-Lung (LL) 3 and 6 trials.
Method:
Treatment-naïve patients with stage IIIB/IV EGFRm+ NSCLC in LL3/6 received either 40mg/day afatinib or chemotherapy. In case of any treatment-related grade ≥3 AEs or selected prolonged grade 2 AEs, afatinib dose was reduced by 10mg decrements (minimum dose 20mg/day). In this post-hoc analysis of all afatinib-treated patients in LL3/6 (n=229/n=239), we compared incidence and severity of common AEs before and after dose reduction, afatinib plasma concentrations in patients who reduced to 30mg versus those remaining on 40mg, and PFS in patients with/without dose reductions in the first 6 months of treatment. PROs were measured using the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire and the EQ-5D™ health status self-assessment questionnaire, and pooled data from both trials were assessed before/after dose reduction; these included scores on the EORTC Global Health/Quality of Life scale (GH/QoL; 0–100), EORTC Performance Functioning scale (PF; 0–100), EQ Visual Analogue Scale (VAS; 0–100) and EQ-5D UK utility scale (EQ UK utility; 0–1).
Result:
Dose reductions occurred in 122/229 (53.3%) patients in LL3 and 67/239 (28.0%) in LL6; >80% of dose reductions occurred in the first 6 months of treatment. Dose reductions decreased the incidence of treatment-related AEs (grade ≥3 AEs before/after dose reduction: LL3, 73%/20%; LL6, 81%/12%), and were more likely among patients who had higher afatinib plasma concentrations prior to subsequent dose reduction (Day 22). On Day 43, geometric mean afatinib plasma concentrations were comparable between patients who had dose reduced (n=59; 23.3ng/mL) and patients who remained on 40mg (n=284; 22.8ng/mL). Median PFS was comparable between patients with or without dose reductions in the first 6 months (LL3: 11.3 versus 11.0 months; HR [95% CI] 1.25 [0.91–1.72]; p=0.175; LL6: 12.3 versus 11.0 months; 1.00 [0.69–1.46]; p=0.982). There were no clinically meaningful changes in PROs following afatinib dose reduction: GH (40/30mg: 59.1/66.9; n=136); PF (79.4/83.0; n=136); EQ VAS (70.1/75.1; n=135); EQ UK utility (0.70/0.78; n=135).
Conclusion:
Tolerability-guided dose adjustments effectively reduced afatinib-related AEs without negatively affecting therapeutic efficacy and PROs.
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P3.02 - Biology/Pathology (ID 620)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: Biology/Pathology
- Presentations: 1
- Moderators:
- Coordinates: 10/18/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)
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P3.02-014a - Diagnostic Value of FR<sup>+</sup>-CTCs Detected by LT-PCR for Lung Cancer in SPN and Tumor Invasiveness in Adenocarcinoma (T≪3cm) (ID 8805)
09:30 - 09:30 | Author(s): Shun Lu
- Abstract
Background:
To investigate the diagnostic value of folate receptor (FR)-positive circulating tumor cells (CTCs) detected by ligand-targeted polymerase chain reaction (LT-PCR) in distinguishing lung cancer from lung benign diseases in patients with solitary pulmonary nodules (SPN), and to identify the tumor invasiveness in lung adenocarcinomas of 3cm or smaller.
Method:
We enriched FR[+]-CTCs by immunomagnetic depletion of leukocytes and labeling with a conjugate of a tumor specific ligand folic acid and a synthesized oligonucleotide. The bounded conjugates were then analyzed by quantitative PCR (qPCR). Blood samples were collected from 319 lung cancer patients (257 adenocarcinoma patients), 120 benign patients. Including 257 lung adenocarcinoma patients, 41 were adnocarcinoma in situ (AIS), 53 were microinvasive adnocarcinoma (MIA), and 163 were invasive adnocarcinoma (INV). The clinicopathological characteristics were analyzed from medical records.
Result:
Patients were randomly assigned to a training set and a validation set. FR[+]-CTC levels of patients with lung cancer were significantly higher than patients with benign lung diseases (p=0.000). With a threshold of 8.74 CTC units, FR[+]-CTC showed a markedly sensitivity (training set, 72.05%; validation set, 74.36%) and specificity (training set, 80.9%; validation set 77.42%) in the diagnosis of lung cancer. When compared with established clinical biomarkers including carcinoembryonic antigen (CEA), cytokeratin 19 fragment (CYFRA21-1), CA-125, squamous cell related antigen (SCC), and neuron-specific enolase (NSE), FR[+]-CTC showed the highest area under the receiver operative characteristic curve (training set, 0.754; validation set 0.765). With a threshold of 9.051 CTC units, FR[+]-CTC showed a comparable sensitivity (training set, 77.50%; validation set, 79.07%) and specificity (training set, 61.24%; validation set 60%) to CEA and CA-125 in distinguishing the AIS from INV. Notably, the combination of FR[+]-CTC with established clinical biomarkers including CEA, CYFRA21-1, CA-125, SCC and NSE could significantly improve the diagnostic efficiency.
Conclusion:
LT-PCR based FR[+]-CTC detection platform is reliable to be used as a biomarker for the diagnosis of lung cancer in patients with SPN, moreover, the FR[+]-CTC level might be a promising biomarker to identify the tumor invasiveness in lung adenocarcinomas of 3cm or smaller.
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P3.04 - Clinical Design, Statistics and Clinical Trials (ID 720)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: Clinical Design, Statistics and Clinical Trials
- Presentations: 1
- Moderators:
- Coordinates: 10/18/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)
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P3.04-005 - PD-L1 and Other Immuno-Markers Influenced by Osimertinib Treatment in Advanced Non-Small Cell Lung Cancer Patients (ATHENE Study) (ID 9749)
09:30 - 09:30 | Presenting Author(s): Shun Lu
- Abstract
Background:
This study will investigate whether PD-L1 and other immuno-markers will be influenced by osimertinib treatment in advanced EGFR T790M positive advanced NSCLC patients，who have progressed on an EGFR-TKI.
Method:
This study is an ASTRIS companion study. Major eligibility criteria include locally advanced (stage IIIB) or metastatic (stage IV) EGFR sensitive mutation NSCLC, not amenable to curative surgery or radiotherapy, with confirmation of the presence of the T790M mutation, prior therapy with an EGFR-TKI, PS 0-2, and the patients are willing to provide tumor specimens before osimertinib treatment and at the time of disease progression. The FFPE tissue samples will be collected at the time of baseline and disease progression. PD-L1 and CD8+ T cell will be detected by IHC (Ventana SP263). Immune-related gene will be detected by ThermoFisher Oncomine[TM] Immune Response Panel (398genes). The plasma samples will be collected at the time of baseline and disease progression, and tumor mutational burden will be detected by QIAGEN Mix-561-Match Panel (561 genes). A sample size of 62 will provide a power of 80% to detect the change at an alpha level of 0.05 based on Wilcoxon rank sum test. Assuming re-biopsy will be obtained from 40% patients at disease progression, the total number of patients will be 155. Estimated date of first subject enrollment will be before March 2017, and last subject last visit will be at June 2018. (NCT03029858)
Result:
The clinical trial is open for enrollment.
Conclusion:
The study points are not reached now.
