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Matthew G. Krebs
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MA11 - Expanding Targetable Genetic Alterations in NSCLC (ID 251)
- Event: WCLC 2020
- Type: Mini Oral
- Track: Targeted Therapy - Clinically Focused
- Presentations: 1
- Moderators:
- Coordinates: 1/31/2021, 14:15 - 15:15, Scientific Program Auditorium
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MA11.07 - Phase 1/2 TRIDENT-1 Study of Repotrectinib in Patients with ROS1+ or NTRK+ Advanced Solid Tumors (ID 3255)
14:15 - 15:15 | Author(s): Matthew G. Krebs
- Abstract
Introduction
Repotrectinib is a next-generation ROS1/TRK TKI with >90-fold greater potency than crizotinib and entrectinib against ROS1 and >100-fold greater potency than larotrectinib against TRK in engineered Ba/F3 cell proliferation assays. In the Phase 1 portion of TRIDENT-1 study, repotrectinib demonstrated encouraging overall clinical activity in patients (pts) with ROS1 fusion+ NSCLC and TRK fusion+ solid tumors, especially in those pts with ROS1+ NSCLC who are TKI naive.
Methods
In Phase 1 portion of the study, the Recommended Phase 2 Dose (RP2D) for repotrectinib was determined to be 160 mg QD for 14 days followed by 160 mg BID if tolerated. Currently, this global trial (Clinical trial information: NCT03093116) is actively enrolling pts whose cancers harbor a ROS1 or NTRK1/2/3 fusion in six phase 2 expansion cohorts (see table). The primary endpoint for the Phase 2 portion is confirmed overall response rate (cORR) by Blinded Independent Central Review (BICR) using RECIST v1.1. An early interim analysis on 39 pts enrolled in Phase 2 was conducted using investigator assessment.
Results
Phase 1: Utilizing a 22 July 2019 data cutoff, cORR was 91% by BICR in 11 ROS1 TKI-naïve pts with 5 responses ongoing. The median duration of response (DOR) for the 10 confirmed responders was 23.1 months (95% CI: 5.6–not reached [NR]) and median progression-free survival (PFS) was 24.6 months (95% CI: 7.2 – NR). As of 6 April 2020, with an additional 8.5 months of follow-up, 4 of the 5 previously responding TKI-naïve pts remained in a partial response (PR) per physician assessment data and 7 TKI-naïve pts remained on treatment, range (17.3+ - 34.2+ months).
Phase 2: The early Phase 2 TRIDENT-1 dataset utilizing a July 10, 2020 data cutoff includes the first 39 treated pts across six cohorts who have had at least one post-baseline scan. Data are summarized in table below:
TRIDENT-1 Study of Repotrectinib
(Phase 2 Cohorts)
ORR
95% CI
ROS1+ TKI-Naïve, up to 1 line of chemotherapy or immunotherapy
(EXP-1)
86%*
(6/7)
(42-100)
ROS1+ TKI-Pretreated, 1 prior TKI, with prior platinum-based chemotherapy
(EXP-2)
40%
(2/5)
(5-85)
ROS1+ TKI-Pretreated, 1 prior TKI, without prior platinum-based chemotherapy
(EXP-4)
67%
(4/6)
(22-96)
ROS1+ TKI-Pretreated 2-prior TKIs, without prior platinum-based chemotherapy
(EXP-Other)
40%
(2/5)
(5-85)
NTRK TKI-Pretreated
(EXP-6)
50%
(3/6)
(12-88)
* Since the data cutoff the 7th ROS1 TKI-naïve patient achieved an unconfirmed PR.
Repotrectenib was well tolerated, with predominantly grades 1/2 adverse events. TEAEs in > 25 % of pts were dizziness (62%), fatigue (39%), constipation (33%), dysgeusia (33%), and dyspnea (28%). 90% of 39 treated pts in Phase 2 escalated to 160 mg twice daily (BID) after 14 days per the study defined dose titration approach. There were no Grade 4 or Grade 5 TRAEs.
Conclusion
Repotrectinib was well tolerated and continues to demonstrate encouraging overall clinical activity in pts with ROS1 fusion-positive NSCLC and TRK fusion-positive solid tumors.
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OA01 - Established Drugs in Special Populations and New Drugs in Established Populations (ID 226)
- Event: WCLC 2020
- Type: Oral
- Track: Immunotherapy (Phase II/III Trials)
- Presentations: 1
- Moderators:
- Coordinates: 1/29/2021, 09:15 - 10:15, Scientific Program Auditorium
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OA01.07 - A Phase II Study of the Oral Selective AXL Inhibitor Bemcentinib with Pembrolizumab in Patients with Advanced NSCLC (ID 3647)
09:15 - 10:15 | Presenting Author(s): Matthew G. Krebs
- Abstract
- Presentation
Introduction
AXL is a mediator of resistance to immunotherapy and a negative prognostic factor for NSCLC. Bemcentinib (BGB324), a first-in-class, oral, selective and potent AXL kinase inhibitor, enhances checkpoint inhibitor (CPI) efficacy in pre-clinical models through tumor-immune mechanisms. Increasingly, the combination of doublet chemotherapy with checkpoint inhibitors (Chemo-CPI) is a commonly used option for advanced NSCLC, and recurrence following such first line therapy represents an area of great unmet need. BGBC008 addresses the unmet need for NSCLC patients who fail 1L SOC.
Methods
BGBC008 is a PhII single-arm, 2-stage study with bemcentinib (200mg/d) and pembrolizumab (200 mg/q3wk) for previously-treated Stage IV lung adenocarcinoma comprising 3 cohorts: chemotherapy-failed IO-naïve patients (post-Chemo), patients progressing on prior CPI therapy (post-CPI monotherapy) and platinum-doublet chemotherapy in combination with pembrolizumab (post-Chemo-CPI). Primary endpoint was ORR according to RECIST1.1 with pre-defined criteria to proceed from the first to second stage in each cohort. Secondary endpoints included DCR, PFS, OS and safety. Exploratory endpoints include biomarker analysis and correlation with clinical endpoints, including composite (tumor and immune cell) cAXL score, PD-L1 TPS, and genome-wide mutational and transcriptome analyses.
Results
As of August 2020, enrollment in the post-Chemo cohort and stage 1 of the post-CPI monotherapy cohort is completed. Results of the post-Chemo cohort (n=50) and post-CPI monotherapy stage 1 cohort (n=16) were previously presented. Stage 2 of the post-CPI monotherapy cohort and stage 1 of the post-Chemo-CPI cohort are currently recruiting into the study.
In patients treated to date, common TEAEs (>25% of patients) for NSCLC patients receiving the bemcentinib + pembrolizumab combination were: increased ALT (29%; 10% G3+), AST (29%; 5% G3+), and diarrhoea (29%; 1% G3+). All cases of treatment-related transaminase increase were reversible and managed with concomitant administration of steroids and treatment interruption.
Having previously demonstrated a very high clinical benefit rate in post-Chemo and post-CPI monotherapy (stage 1) in cAXL-positive patients (73% and 85%, respectively), and low probability of clinical benefit in cAXL-negative patients (40% and 0%, respectively) further focus on the predictive value of cAXL in second line patients following either CPI monotherapy or Chemo-CPI relapse will be reported, together with transcriptional analysis to identify gene based predictive signatures.
Conclusion
Overall, bemcentinib in combination with pembrolizumab was well-tolerated and shows promising clinical activity in relapsed lung cancer. The key unmet need population of second line patients refractory to CPI monotherapy or Chemo-CPI will be presented together with translational data. Clinical Trial Registration: NCT03184571
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P90 - Targeted Therapy - Clinically Focused - Misc. Topics (ID 267)
- Event: WCLC 2020
- Type: Posters
- Track: Targeted Therapy - Clinically Focused
- Presentations: 1
- Moderators:
- Coordinates: 1/28/2021, 00:00 - 00:00, ePoster Hall
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P90.04 - RAS Precision Medicine Trans-Atlantic Partnership: Multi-Centre Pooled Analysis of RAS Pathway Mutations in Advanced NSCLC (ID 3663)
00:00 - 00:00 | Author(s): Matthew G. Krebs
- Abstract
Introduction
The most common histological subtype of non-small cell lung cancer (NSCLC) is adenocarcinoma (50-55% of patients), of which the most common oncogenic driver is KRAS mutation (~30% internationally). Genetic data has altered the taxonomy of NSCLC over the past 10 years, highlighting subgroups such as EGFR mutation, which have improved prognosis and are susceptible to targeted therapies. Despite its frequency, targeting RAS has historically been limited by pre-clinical and clinical failures. Emerging preclinical/clinical data suggests there is value looking beyond RAS mutation, analysing subtypes- represented by a limited number of variations in its mutational isoforms, codons and alleles. Through international collaboration our partnership aims to extend existing knowledge of RAS precision medicine in NSCLC, evaluating biological, clinical and treatment effects at subtype level.
Methods
For this analysis, the first 309/384 patients with stage IIIb/IV RAS- and/or NF1-mutant NSCLC were identified from the Christie NHS Foundation Trust and the Gustave Roussy Cancer Centre between August 2008 and July 2020. DNA was extracted from archival FFPE samples, plasma or both to identify mutations using targeted next generation sequencing. Molecular, clinical, pathological and outcome data were collected on all patients and Kaplan-Meier survival analysis was performed to test for survival differences between subtypes based on treatment arms. For clinical characteristics, Mann-Whitney and Fisher’s exact tests were used for statistical comparisons in continuous and dichotomous datasets, respectively.
Results
Of 309 patients analysed, 151 patients were from the Christie NHS Foundation Trust and 158 patients from the Gustave Roussy Cancer Centre. Mean age was 63, range 19-92. 30 patients (10%) had stage IIIb disease with the remainder stage IV, 292 patients (94.5%) demonstrated non-squamous histology vs. 16 (5%) squamous vs 1 (0.5%) adenosquamous. Median PD-L1 status across the cohort was 20%. 209 patients (68%) had a mutation identified by tissue analysis, 38 patients (12%) by plasma and 62 (20%) by both. The most common RAS mutation identified was KRAS in 259 patients (84%), followed by NRAS in 13 patients (4%) and HRAS in 7 patients (2%). Amongst the KRAS mutant population, 111 pts (43%) harboured a mutation in G12C, followed by 52 (20%) G12D and 41 (16%) G12V. Codon 61 was most commonly mutated within this subgroup 16/259 (6%). 40 patients (13%) were identified as carrying a mutation in NF1; 35 non-squamous histology, 4 squamous and 1 adenosquamous. Progression free survival following first line chemotherapy plus immunotherapy or immunotherapy alone was variable across KRAS-, NRAS- and NF1-mutant subgroups (8.3 vs. 14.9 vs. 10.2 months; p=0.86). Median PD-L1 status was found to be 63% vs. 100% vs. 79% respectively. Analysis of RAS codon and allelic subgroups, including their therapeutic vulnerabilities beyond immunotherapy, will be presented following further analysis.
Conclusion
The RAS precision medicine Trans-Atlantic partnership is designed to evaluate prognostic/predictive value of RAS and NF1 mutations in advanced NSCLC, focusing specifically on signal seeking for therapeutic vulnerabilities in mutant RAS isoforms, codons, and allelic subtypes. Ongoing analysis is planned to expand the dataset and inform the optimal sequence of therapy for subtypes of RAS- and NF1-mutant patients.
