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J. Von Pawel
Moderator of
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MA16 - Novel Strategies in Targeted Therapy (ID 407)
- Event: WCLC 2016
- Type: Mini Oral Session
- Track: Chemotherapy/Targeted Therapy/Immunotherapy
- Presentations: 12
- Moderators:G. Purkalne, J. Von Pawel
- Coordinates: 12/07/2016, 14:20 - 15:50, Strauss 2
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MA16.01 - Targeted Gene Therapy for Tobacco Carcinogen-Induced Lung Cancer (ID 3968)
14:20 - 14:26 | Author(s): N. Gankhuyag, C. Cho
- Abstract
- Presentation
Background:
Rab25, a member of Rab family of small GTPases, is associated with progression of various types of human cancer including lung cancer that is the leading cause of cancer-associated deaths around the globe.
Methods:
Figure 1In this study, we report the gene therapeutic effect of short hairpin Rab25 (shRab25) on 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK)-induced lung tumorgenesis in female A/J mice. Initially, Mice (six-week-old) were injected with single dose of NNK (2 mg/0.1 ml saline/mouse) by intraperitoneal injection to induce the tumor. 8 weeks later, shRab25 was delivered with GPT-SPE (glycerol propoxylate triacrylate (GPT) and spermine) complex into tobacco-induced lung cancer models through a nose-only inhalation system twice a week for 2 month.
Results:
Figure 1Remarkably, aerosol-delivered shRab25 significantly decreased the expression level of Rab25 and other prominent apoptosis related proteins in female A/J mice. The apoptosis in these mice were determined by detecting the expression level of Bcl-2, PCNA, Bax and further confirmed by TUNEL assay.
Conclusion:
Our results strongly confirm the tumorigenic role of Rab25 in tobacco carcinogen induced-lung cancer and hence demonstrate aerosol delivery of shRab25 as a therapeutic target for lung cancer treatment.
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MA16.02 - Mutational Landscape of TKI Naïve and Resistant EGFR Mutant Lung Adenocarcinomas (ID 5777)
15:44 - 15:50 | Author(s): K. Hastings, J. Choi, A. Wurtz, Z. Walther, G. Cai, I. Oliva, Z. Zhao, S. Gaffney, A. Iamarino, S. Zhao, M. Bi, S.B. Goldberg, A. Chiang, Z. Liu, J. Townsend, J. Schlessinger, R. Lifton, R. Herbst, S.N. Gettinger, K. Politi
- Abstract
- Presentation
Background:
The identification and development of tyrosine kinase inhibitors (TKIs) targeting the epidermal growth factor receptor (EGFR) have revolutionized and greatly improved the treatment of EGFR-mutant non-small cell lung cancer (NSCLC). Unfortunately, acquired resistance (AR) to these agents remains a major clinical problem hindering durable responses. Although significant work has been done to identify particular mechanisms of acquired resistance, little is known regarding the global mutational landscape of EGFR mutant tumors before therapy or at the manifestation of acquired resistance.
Methods:
Using specimens obtained in the IRB approved, Yale Lung Rebiopsy program, we completed whole exome sequencing of 15 EGFR mutant tumors with paired tissue obtained pre-treatment and at the time of AR to EGFR TKIs. An additional 5 unpaired AR samples were also analyzed. The mutational burden and copy number profile of the specimens were studied.
Results:
We found that the mutational burden of pre-treatment EGFR mutant tumors varies widely between tumors. TKI treatment, however, does not significantly alter the overall or non-synonymous mutation load at AR. Interestingly, EGFR[L858R]tumors had a significantly higher mutation burden at acquired resistance to EGFR TKIs than EGFR[Δ19] tumors. The higher mutation burden in EGFR[L858R] tumors compared to those harboring EGFR[Δ19 ]mutations was further confirmed through analysis of TCGA data. Recurrently altered genes shared in the pre- and AR specimens include TP53, EGFR and AKT1. Alterations in EGFR (T790M), MYCBP2, WHSC1L1, AXL, MET, HGF, MYC and NTRK1 were found at exclusively at AR.
Conclusion:
Collectively, these data provide valuable insight into the mutational landscape of EGFR mutant NSCLCs as they evolve on TKIs and identify potential resistance candidate genes for further investigation.
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MA16.03 - Global RET Registry (GLORY): Activity of RET-Directed Targeted Therapies in RET-Rearranged Lung Cancers (ID 4325)
14:26 - 14:32 | Author(s): O. Gautschi, J. Milia-Baron, T. Filleron, J. Wolf, D.P. Carbone, D. Owen, D..R. Camidge, V. Narayanan, R.C. Doebele, B. Besse, J. Remon, P. Jänne, M.M. Awad, N. Peled, C. Byoung, D. Karp, M. Van Den Heuvel, H. Wakelee, J.W. Neal, T. Mok, J.C. Yang, S. Ou, G. Pall, P. Froesch, G. Zalcman, D.R. Gandara, J.W. Riess, V. Velcheti, K. Zeidler, J. Diebold, M. Früh, S. Michels, I. Monnet, S. Popat, R. Rosell, N. Karachaliou, S.I. Rothschild, J. Shih, A. Warth, T. Muley, F. Cabillic, J. Mazieres, A. Drilon
- Abstract
- Presentation
Background:
GLORY is a global registry of patients with RET-rearranged non-small cell lung cancer (NSCLC). In order to complement ongoing prospective studies, the registry’s goal is to provide data on the efficacy of RET-directed targeted therapies administered outside the context of a clinical trial. We previously reported results from our first interim analysis (Gautschi, ASCO 2016). Following additional accrual into the registry, updated results are presented here, with a focus on an expanded efficacy analysis of various RET inhibitors.
Methods:
A global, multicenter network of thoracic oncologists identified patients with pathologically-confirmed NSCLC harboring a RET rearrangement. Molecular profiling was performed locally via RT-PCR, FISH, or next-generation sequencing. Anonymized data including clinical, pathologic, and molecular features were collected centrally and analyzed by an independent statistician. Response to RET tyrosine kinase inhibition (TKI) administered off-protocol was determined by RECIST1.1 (data cutoff date: April 15, 2016). In the subgroup of patients who received RET TKI therapy, the objectives were to determine overall response rate (ORR, primary objective), progression-free survival (PFS), and overall survival (OS).
Results:
165 patients with RET-rearranged NSCLC from 29 centers in Europe, Asia, and the USA were accrued. The median age was 61 years (range 28-89 years). The majority of patients were female (52%), never smokers (63%), with lung adenocarcinomas (98%) and advanced disease (91%). The most frequent metastasic sites were lymph nodes (82%), bone (51%) and lung (32%). KIF5B-RET was the most commonly identified fusion (70%). 53 patients received at least one RET-TKI outside of a clinical protocol, including cabozantinib (21), vandetanib (11), sunitinib (10), sorafenib (2), alectinib (2), lenvatinib (2), nintedanib (2), ponatinib (2) and regorafenib (1). In patients who were evaluable for response (n=50), the ORR was 37% for cabozantinib, 18% for vandetanib, and 22% for sunitinib. Median PFS was 3.6, 2.9, and 2.2 months and median OS was 4.9, 10.2, and 6.8 months for cabozantinib, vandetanib, and sunitinib, respectively. Responses were also observed with nintedanib and lenvatinib. Among patients who received more than one TKI (n=10), 3 partial responses were achieved after prior treatment with a different TKI.
Conclusion:
RET inhibitors are active in individual patients with RET-rearranged NSCLC, however, novel therapeutic approaches are warranted with the hope of improving current clinical outcomes. GLORY remains the largest dataset of patients with RET-rearranged NSCLC, and continues to accrue patients.
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MA16.04 - Discussant for MA16.01, MA16.02, MA16.03 (ID 7102)
14:32 - 14:44 | Author(s): M. Ahn
- Abstract
- Presentation
Abstract not provided
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- Abstract
- Presentation
Background:
EGFR tyrosine kinase (TKI) showed better progression free survival (PFS) in EGFR-mutant non-small cell lung cancer (NSCLC), but the overall survival (OS) benefit were not clear so far. Treatment sequence may contribute to OS, but there are little data so far. We aimed to analyze the impact of treatment sequence of EGFR TKI and chemotherapy on outcomes in EGFR-mutant NSCLC.
Methods:
Among NSCLC patients who had EGFR exon 18–21 mutation test results between 2009 and 2014 at Seoul St. Mary’s Hospital, 114 patients who had recurrent or metastatic disease, EGFR mutation positive excluding T790M mutation, and received both EGFR tyrosine kinase inhibitor (TKI) and chemotherapy as the 1[st] or 2[nd] line of treatment were included. Patients were categorized into two groups according to the treatment sequence: 1[st] line EGFR TKI followed by chemotherapy (group A), 1[st] line chemotherapy followed by EGFR TKI (group B). The median follow-up duration was 64.6 (15.8–202.8) months.
Results:
Among total 114 patients, 69 patients received EGFR TKI first and then chemotherapy (group A), and the remaining 45 patients received vice versa (group B). Group A was younger (P = 0.029) and less frequently received platinum-doublet agents than Group B (P <0.001). Performance status and EGFR mutation status were not different. Overall response or disease control rate were significantly better for EGFR TKI comparing to chemotherapy regardless of treatment sequence. However, PFS on both treatment were longer in group B (P = 0.008), especially for patients with exon 19 deletion (P = 0.002). On multivariate analyses, performance status (P = 0.006 for PFS, P <0.001 for OS) and treatment sequence [hazard ratio (HR) = 0.027, P = 0.027 for PFS; HR = 0.64, P = 0.065 for OS] were related to prognosis.
Conclusion:
For exon 19 deletion subtype of EGFR-mutant NSCLC patients, the sequence of cytotoxic chemotherapy followed by EGFR TKI showed better PFS comparing with the reverse sequence, EGFR TKI followed by cytotoxic chemotherapy . We will present the data from larger cohorts the WCLC meeting.
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- Abstract
- Presentation
Background:
AC0010 was designed specifically to inhibit EGFR active mutations and the T790M acquired resistant mutation. The purpose of the study is to determine the safety, antitumor activity and recommended phase II dose of AC0010 in T790M-postitive NSCLC patients after the first generation EGFR TKIs treatment.
Methods:
This is a dose escalation and expansion phase I/II study. Oral AC0010 was administered on a 28-day cycle with the starting dose at 50 mg BID. In any given dose cohort, if 1 out of 3 patients was evaluated as PR at the first cycle, and no DLT determined, up to 20 patients will be enrolled. Plasma samples were collected to evaluate pharmacokinetics of AC0010. T790M in biopsy samples was detected by a central laboratory. NCT02330367.
Results:
As of 10 Jul 2016, 136 patients have been treated across 7 cohorts (50, 100, 150, 200, 250, 300, and 350 mg BID). At the 30 Jun 2016 cutoff, 124 pts were evaluable. MTD has not been reached. The most common adverse events (AE) regardless of study drug relationship were diarrhea (38%), rash (26%) and ALT/AST elevation. Most AEs were grade 1 and 2. The most common Grade 3/4 drug-related AE was diarrhea (2%) rash (2%) and ALT/AST elevation (4%, 2%). All patients with AEs of the grade 3/4 were recovered after either stopped the treatment or reduced the dose. As of the cutoff date, there is no Grade 2,3 hyperglycemia, and grade 3 QTc prolongation. RECIST responses were observed at all dose levels except 50 mg BID. Amongst 124 evaluable patients in all cohorts, ORR (including unconfirmed responses) and disease control rate (DCR) was 44% and 85% respectively. In the dose cohorts between 150 mg BID and 300 mg BID (n=95 pts), the ORR and DCR were 51% and 89%. PK shows rapid absorption with a T~max~ of 2-4h and a median T1/2 of 8 h. At 300 mg BID, total 32 patients were treated and ORR and DCR are 53% and 90% respectively. Based on the efficacy, safety and PK results, the 300 mg BID was selected as RP2D. The phase II, AEGIS-1 study has started.The Phase II result will be presented.
Conclusion:
AC0010 shows a safe profile and antitumor activity against T790M mt NSCLC. Phase II, AEGIS-1 study is ongoing to evaluate therapeutic outcomes as a second line treatment for T790M positive NSCLC patients. Clinical trial information: NCT02330367
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MA16.07 - Drug Repurposing to Overcome De Novo Resistance of Non-Traditional EGFR Mutations (ID 6203)
14:56 - 15:02 | Author(s): J.P. Robichaux, Z. Tan, M. Nilsson, S. Zhang, K. Wong, J. Heymach
- Abstract
- Presentation
Background:
Approximately 10% of EGFR mutant NSCLCs have an in-frame insertion in exon 20 of EGFR resulting in innate resistance to 1[st] generation TKIs. The reported response rate of patients with EGFR exon 20 insertions to gefitinib and erlotinib is 5% with a median progression free survival of 1.5 months. It has been shown that exon 20 insertions stabilize the active conformation of EGFR and increase affinity to ATP over TKIs. We hypothesize that exon 20 insertions induce conformational changes to the drug binding pocket resulting in EGFR TKI resistance which can be overcome by covalently binding TKIs.
Methods:
Ba/F3 cells expressing 7 different clinically observed EGFR exon 20 insertion mutations spanning the helix (residues 763-766) and loop (residues 767-773) regions were generated and screened against 1[st], 2[nd], and 3[rd] generation EGFR inhibitors including erlotinib, gefitinib, afatinib, dacomitinib, neratinib, poziotinib, ibrutinib rocilentinib, EGF816, and osimertinib. Computational modeling was conducted to analyze the conformational changes and drug binding affinity.
Results:
In Ba/F3 cells with EGFR exon 20 insertions, most 1[st] and 3[rd] generation TKIs failed to inhibit growth of EGFR exon 20 insertions after residue 767 with IC~50 ~values above 100nM. However, poziotinib significantly inhibited cell growth of all EGFR exon 20 insertions tested across the helix and loop regions with an average IC~50~ value of 2.9nM, as compared to osimertinib and rocilentinib (IC~50~ values =103nM and 850nM, respectively). Further characterization using three-dimensional modeling revealed that exon 20 insertions induce conformational changes which cause a decreased affinity for 1[st] generation TKIs and steric hindrance of C797 reducing the ability of 3[rd] generation TKIs to covalently bind. A significant shift of the c-helix and p-loop result in a sterically hindered binding pocket. Therefore, the smaller, more flexible 1,2-dichloro-3-fluorobenzene terminal group of poziotinib can overcome the structural changes induced by the exon 20 insertions, whereas the ridged 1-methylindole terminal group of osimertinib cannot.
Conclusion:
EGFR exon 20 insertions induce a shift of the p-loop and c-helix resulting in steric hindrance of the binding pocket thereby preventing binding of 1[st] generation and 3[rd] generation EGFR inhibitors including rocilentinib and osimertinib. A smaller, more flexible inhibitor such as poziotinib can overcome the steric hindrance of the drug binding pocket. Currently, in vivo studies of the EGFR D770insNPG GEMM, and EGFR H773insNPH PDX model with poziotinib are underway, and a clinical trial testing poziotinib in EGFR exon 20 mutant NSCLC patients will begin enrollment this year.
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MA16.08 - Discussant for MA16.05, MA16.06, MA16.07 (ID 7051)
15:02 - 15:14 | Author(s): T. Reungwetwattana
- Abstract
- Presentation
Abstract not provided
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MA16.09 - Antitumor Activity and Safety of Crizotinib in Patients with MET Exon 14-Altered Advanced Non-Small Cell Lung Cancer (ID 5162)
15:14 - 15:20 | Author(s): A. Drilon, S. Ou, J.W. Clark, D..R. Camidge, M.A. Socinski, J. Weiss, B. Solomon, G.J. Riely, R. Heist, G.I. Shapiro, S.C. Wang, M. Winter, K. Monti, K.D. Wilner, P.K. Paik
- Abstract
- Presentation
Background:
MET alterations leading to exon 14 skipping occur in ~4% of non-squamous non‑small cell lung cancer (NSCLCs) and 20–30% of sarcomatoid lung carcinomas, resulting in MET activation and sensitivity to MET inhibitors in vitro.[1–4] Crizotinib, initially developed as a MET inhibitor, is currently approved for the treatment of ALK-rearranged and ROS1-rearranged advanced NSCLC. We present crizotinib antitumor activity and safety data in patients (pts) with MET exon 14-altered advanced NSCLC.
Methods:
Advanced NSCLC pts positive for MET exon 14-alteration status determined locally by molecular profiling were enrolled into an expansion cohort of the ongoing phase I PROFILE 1001 study (NCT00585195) and received crizotinib at a starting dose of 250 mg BID. Objective responses were assessed using RECIST v1.0.
Results:
As of the data cut-off of Feb 01, 2016, 21 pts with MET exon 14-altered NSCLC received crizotinib treatment (18 response-evaluable, 3 not yet evaluable). Median age was 68 y (range: 53−87). Tumor histology was: 76% adenocarcinoma, 14% sarcomatoid adenocarcinoma, 5% adenosquamous carcinoma, and 5% squamous cell carcinoma. Sixty-two percent (62%) of pts were former-smokers, 38% never-smokers, and there were no current smokers. Duration of treatment ranged from 0.2 to 12.2 mo, with 76% of pts (16/21) still ongoing. Five pts discontinued treatment (1 due to AE, 3 due to clinical or disease progression, and 1 preferred alternative treatment formulation). PRs were observed in 8 pts, for an objective response rate of 44% (95% CI: 22–69); 9 pts had stable disease. Median time to response was 7.8 weeks (range: 7.0–16.3), which was the approximate time of the scheduled first on treatment tumor scans for patients. Median progression-free survival could not be calculated. The most common (≥25%) treatment-related AEs (TRAEs) were edema (43%) diarrhea (33%), nausea (33%), vision disorder (33%), and vomiting (29%). Most TRAEs were grade 1/2 in severity and consistent with the known safety profile of crizotinib. Four grade 3 TRAEs (edema, bradycardia, anemia, and weight increased) and no grade 4 or 5 TRAEs were reported. Enrollment of pts with MET exon 14-altered NSCLC continues, and updated data will be available at the time of presentation.
Conclusion:
Crizotinib has clinically meaningful antitumor activity in pts with MET exon 14-altered advanced NSCLC. The drug has a tolerable AE profile, consistent with that previously reported for pts with ALK-rearranged or ROS1-rearranged advanced NSCLC. Further study of crizotinib in this pt population is warranted.
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MA16.10 - Lung-MAP (S1400) Lung Master Protocol: Accrual and Genomic Screening Updates (ID 3995)
15:20 - 15:26 | Author(s): V. Papadimitrakopoulou, M. Redman, D.R. Gandara, F.R. Hirsch, P. Mack, H. Borghaei, C. Langer, J. Wade, M. Edelman, K. Albain, P. Lara, C. Aggarwal, M.A. Socinski, S.N. Gettinger, L. Bazhenova, S. Malik, V. Miller, S. McDonough, E.V. Sigal, K. Kelly, R. Herbst
- Abstract
- Presentation
Background:
Lung-MAP (S1400), is a master protocol that incorporates genomic testing of tumors through a next generation sequencing (NGS) platform (Foundation Medicine) and biomarker-driven (matched) therapies for patients with squamous cell lung cancer (SCCA) after progression on first-line chemotherapy.
Methods:
The Lung-MAP trial, activated June 16, 2014, includes 3 matched- and 1 non-match study. Matched studies include: S1400B evaluating taselisib, a PI3K inhibitor, S1400C evaluating palbociclib, a CDK 4/6 inhibitor and, S1400D evaluating AZD4547, an FGFR inhibitor. The non-match study S1400I tests nivolumab + ipilimumab vs. nivolumab. Two studies have closed: S1400E evaluating rilotumumab an HGF monoclonal antibody + erlotinib closed 11/26/2014 and S1400A evaluating MEDI4736 in non-match pts, closed 12/18/2015.
Results:
From June 16, 2014 to June 15, 2016, 812 pts were screened and 292 pts registered to a study: 116 to S1400A, 27 to S1400B, 53 to S1400C, 32 to S1400D, 9 to S1400E and 55 to S1400I. Demographics: Screening was successful for 705 (87%) of screened eligible pts. Median age 67 (range 35-92); male 68%; ECOG PS 0-1 88%, PS 2 10%; Caucasian 85%, Black 9%, other 5%; never/former/current smokers 4%/58%/36%. Table 1 displays biomarker prevalence; 39% of pts matched; 33.9%, 4.8%, and 0.3% with 1, 2, and all 3 biomarkers, respectively. Tumor mutation burden (TMB) was available for 636 (90.4%) of eligible pts. The distribution of TMB is: 126 (19.8%) low (≤5 mutations Mb), 415 (65.1%) intermediate (6-19 mutations/Mb), and 96 (15.1%) high (≥20 mutations/Mb). The median TMB was 10.1.
Conclusion:
Genomic screening is feasible as part of this master protocol designed to expedite drug registration, confirm anticipated prevalence of targeted alterations in SCCA and reveal intermediate or high TMB in most (80.2%) pts. Treatment results are not yet available as patients continue to accrue. Clinical trial information: NCT02154490Total FGFR CDK PIK3CA FGFR (15.9%) 12.9% 2.4% 0.6% CDK (18.8%) 14.6% 1.8% PIK3CA (8.8%) 6.4% Biomarker prevalence and overlap.
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MA16.11 - CNS Response to Osimertinib in Patients with T790M-Positive Advanced NSCLC: Pooled Data from Two Phase II Trials (ID 4920)
15:26 - 15:32 | Author(s): G. Goss, C. Tsai, F. Shepherd, M. Ahn, L. Bazhenova, L. Crinò, F. De Marinis, E. Felip, A. Morabito, R. Hodge, M. Cantarini, T. Mitsudomi, P. Jänne, J.C. Yang
- Abstract
- Presentation
Background:
Brain metastases develop in 25–40% of patients with NSCLC. Osimertinib is an oral, potent, irreversible EGFR-TKI, selective for both sensitising (EGFRm) and T790M resistance mutations. Preclinical and early clinical evidence support central nervous system (CNS) penetration and activity of osimertinib. Two Phase II studies (AURA extension [NCT01802632] and AURA2 [NCT02094261]) evaluating the efficacy and safety of osimertinib are ongoing. We present a pre planned subgroup analysis assessing pooled CNS response from these two studies; data cut-off (DCO) was 1 November 2015. An earlier pooled analysis from these two studies (1 May 2015 DCO) showed the objective response rate (ORR) in patients with CNS metastases was consistent with ORR in the overall patient population.
Methods:
Patients with advanced NSCLC who progressed following prior EGFR-TKI therapy with centrally-confirmed T790M positive status (cobas® EGFR Mutation Test) received osimertinib 80 mg once daily (n=411). Patients with stable, asymptomatic CNS metastases were eligible for enrolment. CNS efficacy was assessed in an evaluable for CNS response analysis set, which included patients with at least one measurable CNS lesion on baseline brain scan (RECIST v1.1) by blinded independent central neuroradiology review (BICR). Effect of prior radiotherapy on CNS response was assessed.
Results:
As of 1 November 2015, 50/192 patients with baseline brain scans had at least one measurable CNS lesion identified by BICR. Baseline demographics were broadly consistent with the overall patient population. Confirmed CNS ORR was 54% (27/50; 95% CI: 39%, 68%), with 12% complete CNS response (6/50 patients). The median CNS duration of response (22% maturity) was not reached (95% CI: not calculable [NC], NC). The estimated percentage of patients remaining in response at 9 months was 75% (95% CI: 53, 88). CNS disease control rate (DCR) was 92% (46/50; 95% CI: 81%, 98%). Median time to first response was 5.7 weeks (range: 5.6–6.6). Median best percentage change from baseline in CNS target lesion size was 53% (range: -100% – +80%). Median follow up for CNS progression-free survival (PFS) was 11 months; the median CNS PFS was not reached (95% CI: 7, NC). At 12 months, 56% (95% CI: 40%, 70%) of patients were estimated to remain on study, alive and CNS progression-free. CNS response was observed regardless of prior radiotherapy to the brain.
Conclusion:
Osimertinib demonstrates durable efficacy in patients with T790M NSCLC and measurable CNS metastases, with a CNS response rate of 54% and a DCR of 92%.
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MA16.12 - Discussant for MA16.09, MA16.10, MA16.11 (ID 6945)
15:32 - 15:44 | Author(s): E.S. Santos
- Abstract
- Presentation
Abstract not provided
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Author of
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P3.02b - Poster Session with Presenters Present (ID 494)
- Event: WCLC 2016
- Type: Poster Presenters Present
- Track: Advanced NSCLC
- Presentations: 1
- Moderators:
- Coordinates: 12/07/2016, 14:30 - 15:45, Hall B (Poster Area)
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P3.02b-045 - Patritumab plus Erlotinib in EGFR Wild-Type Advanced Non–Small Cell Lung Cancer (NSCLC): Part a Results of HER3-Lung Study (ID 5473)
14:30 - 14:30 | Author(s): J. Von Pawel
- Abstract
Background:
Patritumab is a fully human monoclonal antibody that inhibits human epidermal growth factor receptor 3. In a subgroup analysis of the phase 2 HERALD study, addition of patritumab to erlotinib increased progression-free survival (PFS) in advanced NSCLC patients with high tumor expression of heregulin mRNA (HRG-High); a similar safety profile was seen with patritumab+erlotinib versus erlotinib. This 2-part, phase 3 study (HER3-Lung) investigated erlotinib±patritumab in advanced, EGFR wild-type NSCLC patients previously treated with a platinum doublet. The primary objective of Part A was to confirm PFS improvement in HRG-High subjects.
Methods:
HER3-Lung was a 2-part, randomized, placebo-controlled, double-blind study. Subjects aged ≥20 years with known HRG expression, advanced NSCLC previously treated with 1–2 systemic therapies including a platinum doublet, and EGFR wild-type (if adenocarcinoma histology) were eligible. Subjects were stratified by HRG expression, histology subtype (adenocarcinoma, squamous-cell carcinoma/NOS), ECOG performance status (0–1), and best response to most recent therapy (CR/PR/SD, PD). Within each stratum, subjects were randomized 1:1 to erlotinib+patritumab or erlotinib+placebo.
Results:
One-hundred forty-five subjects were randomized, and 125 had discontinued study treatment prior to the data cutoff date. Most common reason for discontinuation was progressive disease (n=70). In the erlotinib+patritumab and erlotinib+placebo arms, respectively, treatment-emergent adverse events (TEAEs) grade ≥3 were reported in 40.5% and 46.5% and any grade serious TEAEs in 35.1% and 36.6% of subjects. Most common TEAEs (by subject) in the erlotinib+patritumab and erlotinib+placebo arms, respectively, were diarrhea (51.4%, 31%) and rash (37.8%, 36.6%). Patritumab did not increase erlotinib efficacy in the intent-to-treat group or HRG subgroups (Table). The study was stopped at the end of Part A because efficacy criteria to proceed into Part B were not reached.
Conclusion:
HER-3Lung did not confirm patritumab efficacy in the HRG-High subgroup. Safety of patritumab in combination with erlotinib was acceptable.Figure 1
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PL04a - Plenary Session: Immune Checkpoint Inhibitors in Advanced NSCLC (ID 430)
- Event: WCLC 2016
- Type: Plenary
- Track: Chemotherapy/Targeted Therapy/Immunotherapy
- Presentations: 1
- Moderators:J. Soria, C. Zhou
- Coordinates: 12/07/2016, 08:45 - 09:40, Hall D (Plenary Hall)
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PL04a.02 - OAK, a Randomized Ph III Study of Atezolizumab vs Docetaxel in Patients with Advanced NSCLC: Results from Subgroup Analyses (Abstract under Embargo until December 7, 7:00 CET) (ID 5822)
08:55 - 09:05 | Author(s): J. Von Pawel
- Abstract
- Presentation
Background:
Atezolizumab inhibits PD-L1 binding to its receptors PD-1 and B7.1, thereby restoring tumor-specific T-cell immunity. Primary analysis of the Phase III OAK study in previously-treated NSCLC revealed superior survival for atezolizumab vs docetaxel in the ITT population (mOS, 13.8 vs 9.6 months; HR, 0.73) and in patients expressing ≥1% PD-L1 on TC or IC (TC1/2/3 or IC1/2/3; mOS, 15.7 vs 10.3; HR, 0.74). Here we present further subgroup analyses.
Methods:
OAK evaluated atezolizumab vs docetaxel in an unselected NSCLC population who had failed prior platinum-containing chemotherapy. Patients were stratified by PD-L1 expression, prior chemotherapy regimens and histology, and randomized 1:1 to atezolizumab (1200 mg) or docetaxel (75 mg/m[2]) IV q3w. PD-L1 expression by IHC and mRNA was centrally evaluated by VENTANA SP142 IHC assay and Fluidigm, respectively. Data cutoff, July 7, 2016.
Results:
For the first 850 of 1225 randomized patients (primary study population), OS was improved with atezolizumab vs docetaxel regardless of histology and this benefit was observed across PD-L1 subgroups within each histology (Table). PD-L1 gene expression showed a similar association with OS as PD-L1 IHC. In nonsquamous patients ORR was 14.4% vs 15.2%; in squamous patients ORR was 11.6% vs 8.2% (atezolizumab vs docetaxel). OS benefit vs docetaxel was seen across subgroups including patients with treated baseline brain metastases (n=85; mOS 20.1 vs 11.9 mo; HR 0.54, 95% CI 0.63-0.89) and never smokers (n=156; mOS 16.3 vs 12.6 mo, HR 0.71, 95% CI 0.47-1.08). Further secondary endpoints and exploratory biomarker analyses for these subgroups and by age and EGFR/KRAS status will be presented.
Conclusion:
OAK demonstrated clinically relevant improvements with atezolizumab in the ITT population, including in both histology subgroups regardless of PD-L1 expression (measured by IHC or tumor gene expression), and among other subgroups including never smokers and in patients with baseline brain metastases.OS Atezolizumab Docetaxel HR[a]95% CI n Median, mo n Median, mo Nonsquamous TC3 or IC3 49 22.5 47 8.7 0.35(0.21-0.61) TC2/3 or IC2/3 89 18.7 99 11.3 0.61(0.42-0.88) TC1/2/3 or IC1/2/3 171 17.6 162 11.3 0.72(0.55-0.95) TC0 and IC0 140 14.0 150 11.2 0.75(0.57-1.00) All 313 15.6 315 11.2 0.73(0.60-0.89) Squamous TC3 or IC3 23 17.5 18 11.6 0.57(0.27-1.20) TC2/3 or IC2/3 40 10.4 37 9.7 0.76(0.45-1.29) TC1/2/3 or IC1/2/3 70 9.9 60 8.7 0.71(0.48-1.06) TC0 and IC0 40 7.6 49 7.1 0.82(0.51-1.32) All 112 8.9 110 7.7 0.73(0.54-0.98) [a]Unstratified HRs. TC=tumor cell, IC=tumor-infiltrating immune cell
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