Jänne, Pasi A.

9008 Background: Amivantamab, a fully human bispecific antibody targeting epidermal growth factor receptor (EGFR) and MET, is approved for the treatment of non-small cell lung cancer (NSCLC) with EGFR exon 20 insertion after prior platinum-based chemotherapy. Given its bispecific nature, amivantamab is being explored in patients (pts) with primary MET exon 14 skipping mutation (METex14) in the MET-2 cohort of the CHRYSALIS study. Methods: CHRYSALIS (NCT02609776) is an ongoing phase 1 dose escalation/dose expansion study of amivantamab in pts with advanced NSCLC. Pts with primary METex14 whose disease progressed on or who declined current standard of care therapy were treated with amivantamab 1050 mg (pts <80 kg) or 1400 mg (pts ≥80 kg) weekly in cycle 1 and biweekly thereafter. Response was assessed by investigators using RECIST v1.1. Results: As of 2 Dec 2021, 43 pts with METex14 had received amivantamab. Median age was 70 y (range, 43-88), 58% were women, median prior lines of therapy was 2 (range, 0-10) [eg, crizotinib (n=13), capmatinib (n=11), tepotinib (n=5), anti-MET antibody (n=1)], and 23% had history of brain metastases at baseline. In 36 pts with ≥1 postbaseline disease assessment, median duration of follow-up was 5.8 months (range, 0.3-15.8); 6 pts had no prior treatment, 11 had no prior MET inhibitor, and 19 had a prior MET inhibitor. Overall response rate was 33% (50% [3/6] in treatment-naïve pts, 46% [5/11] in pts with no prior MET inhibitor, and 21% [4/19] in pts with prior MET inhibitor therapy). Clinical benefit rate was >54% regardless of prior treatment (Table). Median duration of response (DOR) was not reached (range, 2.1-12.2 months); 67% (8/13) had DOR ≥6 months. Ten of the 12 responders remain on treatment (6.0-14.4 months) with ongoing responses; 2 discontinued after 2 and 12 months, respectively. Safety profile was consistent with previously reported experience of amivantamab (Sabari 2021 JTO 16(3):S108-109). Treatment-related adverse events leading to dose reduction or discontinuation occurred in 3 pts, each. Conclusions: Amivantamab demonstrates anti-tumor activity in primary METex14 NSCLC including after prior MET inhibitor treatment. Enrollment is ongoing and updated data will be shown. Clinical trial information: NCT02609776. [Table: see text]

9002 Background: KRAS is a key mediator of the RAS/MAPK signaling cascade that promotes cellular growth and proliferation. KRASG12C mutation occurs in ̃14% of NSCLC. Adagrasib, an investigational agent, is a KRASG12C inhibitor that irreversibly and selectively binds KRASG12C, locking it in its inactive state. Adagrasib is optimized for favorable pharmacokinetic (PK) properties, including long half-life (̃24 h), dose-dependent PK, and central nervous system penetration; it has demonstrated objective response and favorable tolerability in the Phase 1/1b setting. Methods: KRYSTAL-1 (NCT03785249) is a multicohort Phase 1/2 study evaluating adagrasib as monotherapy or in combination regimens in patients with advanced solid tumors harboring a KRASG12C mutation. Here we report the first disclosure from all patients enrolled in Cohort A, a Phase 2 cohort with registrational intent, evaluating adagrasib given 600 mg orally BID in patients with NSCLC previously treated with platinum-based chemotherapy and anti-PD-1/L1 therapy. Study objectives include evaluating efficacy (objective response rate [ORR], duration of response [DOR], progression-free survival [PFS], overall survival [OS]), safety, PK, and exploratory correlative analyses. Objective tumor response was assessed per RECIST v1.1 by blinded independent central review (BICR). Results: As of the 15 October 2021 data cutoff, 116 patients with NSCLC harboring a KRASG12C mutation were enrolled and treated, with a median follow-up of 12.5 months. Baseline characteristics include median age 64 years, 65% female, and 15.5%/83.6% with ECOG PS 0/1; 98.3% of patients received adagrasib following prior treatment with immunotherapy and chemotherapy, with a median of 2 prior systemic therapies. The ORR (by BICR) was 42.9% (48/112) and the disease control rate was 79.5% (89/112); 31 patients remain on treatment. Median DOR was 8.5 months (95% CI 6.2–13.8), median PFS was 6.5 months (95% CI 4.7–8.4), median OS was 12.6 months (95% CI 9.2–NE). Treatment-related AEs (TRAEs) of any grade occurred in 97.4% of patients, grade ≥3 TRAEs in 45.7%, 2 grade 5 TRAEs, and 8 (6.9%) TRAEs led to discontinuation. The most commonly reported (≥25%) TRAEs (any grade) were diarrhea (62.9%), nausea (62.1%), vomiting (47.4%), fatigue (40.5%), ALT/AST increased (27.6%/25%), blood creatinine increased (25.9%); the most commonly reported (≥5%) TRAEs (grade 3/4) were lipase increased (6%) and anemia (5.2%). Additional subgroup analyses will be presented, including selected demographics, molecular markers and sites of metastases. Conclusions: Adagrasib is well tolerated and demonstrates promising efficacy in pretreated patients with NSCLC harboring a KRASG12C mutation. A Phase 3 trial evaluating adagrasib monotherapy versus docetaxel in previously treated patients with KRASG12C-mutant NSCLC is ongoing (NCT04685135). Clinical trial information: NCT03785249.

TPS9147 Background: KRAS is mutated (mt) in 25% of NSCLC adenocarcinoma, with KRAS G12V and G12C mt occurring in ̃7% and ̃13% of patients (pts), respectively. Whereas G12C inhibitors have demonstrated promising activity in pts with KRAS G12C NSCLC, KRAS G12V NSCLC remains an unmet need. BRAF mt occurs in ̃4% of NSCLC with roughly equal split between BRAF V600E and non-V600E. VS-6766 is a small molecule RAF/MEK clamp that inhibits BRAF, CRAF and MEK, enabling VS-6766 to block MEK signaling without compensatory activation of MEK observed with MEK-only inhibitors. VS-6766 potently inhibits proliferation of KRAS and BRAF mt cell lines. Focal adhesion kinase (FAK) activation is a putative resistance mechanism to RAF and MEK inhibition, and defactinib, a small molecule FAKi, has shown synergistic anti-tumor activity with VS-6766 in KRAS mt NSCLC models. In a KRAS G12V mt NSCLC mouse model, which was shown to be especially dependent on CRAF, VS-6766 induced strong tumor regressions both as monotherapy and in combination with FAKi (Coma AACR 2021). Clinically, VS-6766 monotherapy has shown responses in KRAS mt NSCLC including pts with KRAS G12V and in pts with BRAF V600E solid tumors (Guo 2020; Martinez-Garcia 2012). The combination of VS-6766 + defactinib is currently being evaluated in the Investigator Sponsored FRAME study. In an updated analysis of response in 20 pts with KRAS mt NSCLC, there were 2 confirmed PRs, 1 unconfirmed PR and 10 SDs (ORR = 15%; DCR = 65%) with 7/20 pts remaining on treatment for ≥24 weeks. The 2 pts with KRAS G12V NSCLC both had confirmed PRs (ORR = 100%). This combination regimen exhibited a manageable safety profile with no NSCLC pts discontinuing for adverse events (Krebs AACR 2021). Methods: This is an international phase 2, adaptive, multicenter, randomized, open label study designed to evaluate the efficacy and safety of VS-6766 vs. VS-6766 + defactinib in pts with recurrent KRAS or BRAF mt NSCLC (NCT04620330). Part A will determine the optimal regimen, either VS-6766 monotherapy or VS-6766 + defactinib based on pts with KRAS G12V. Part A will consist of 5 NSCLC arms: Arm 1 VS-6766 monotherapy in KRAS G12V, Arm 2 VS-6766 + defactinib in KRAS G12V, Arm 3 the combination in KRAS non-G12V, Arm 4 the combination in BRAF V600E and Arm 5 the combination in BRAF non-V600E. Part B will determine the efficacy of the optimal regimen identified in Part A. Pts must have histologic or cytologic evidence of NSCLC, measurable disease according to RECIST V1.1, known KRAS or BRAF mt and at least 1 prior systemic therapy (appropriate therapy for activating mutation and/or platinum-based therapy). Part A will enroll 102 pts Arms 1 and 2 (KRAS G12V), and Arms 4 and 5 (BRAF V600E and non-V600E) are currently open. Arm 3 (KRAS non-G12V) enrollment is completed. The total number of pts in Part B will be determined by results from Part A. Clinical trial information: NCT04620330.

e18634 Background: Informed patients have better health outcomes. In a study of 1,057 patient encounters with 3,552 clinical decisions, only 9% resulted in informed medical decisions.The complexity of treatments and patients' limitations in health literacy (especially common in underserved communities) make it difficult for patients to engage in SDM. In 2017, A Breath of Hope Lung Foundation introduced An Animated Patient’s Guide to Lung Cancer (APG), an online resource aimed at improving patient knowledge. Methods: APG consists of animations, expert FAQ videos, slide shows, infographics, patient-experience videos, knowledge-assessment tools, and learner feedback. Video views, duration of use, and learner responses to multiple-choice questions on the APG website were collected for 33 months – through August 2020. Total APG views, most frequently viewed animations and expert videos were monitored on the website and on YouTube, to measure learner responses to outcome-based questions, and learner intent-to-implement changes. Results: 212,336 total views: 142,998 unique visitors: 59% from U.S. and 41% from 50 other countries. Unique U.S. visitors: 43,872 patients, 16,030 caregivers, and 7,593 health providers. 94% reported they will ‘use new information to better self-manage their lung cancer’ (n = 277); 98% ‘will discuss information learned with their doctor’ (n = 455), and 93% ‘plan to discuss treatment options with their doctor’ (n = 272). Conclusions: Multimedia ‘animated’ formats of learning tailored to the needs and learning styles of lung cancer patients provides effective learning, informed patients, increased management skills, and improved engagement in shared decision making.

TPS9077 Background: ALCHEMIST (Adjuvant Lung Cancer Enrichment Marker Identification and Sequencing Trial) is a clinical trial platform of the National Cancer Institute that offers biomarker analysis for high-risk resected non-small cell lung cancer (NSCLC) to support randomized trials of novel adjuvant therapies within the National Clinical Trials Network (NCTN). EA5142, a trial of adjuvant nivolumab for patients (pts) without EGFR / ALK alterations, has completed enrollment. Given the survival benefit seen with 1st-line chemo-immunotherapy (chemo-IO) for advanced NSCLC without EGFR / ALK alterations, there was compelling rationale for the launch of a trial offering concurrent immunotherapy with adjuvant chemo. Here we report updated enrollment to ALCHEMIST as of Jan 14, 2020. Methods: ALCHEMIST includes a screening trial (A151216, 5362 registered) that enrolls pts with completely resected clinical stage IB (≥4 cm)–IIIA (per AJCC 7) NSCLC. Tissue and blood are collected, biomarker testing includes EGFR sequencing, ALK FISH and PD-L1 IHC. 733 active sites are enrolling across the NCTN. Pts with EGFR mutations may enroll to adjuvant erlotinib vs observation (A081105, 352 randomized); those with ALK fusions may enroll to adjuvant crizotinib vs observation (E4512, 99 randomized). A trial offering adjuvant nivolumab vs observation regardless of PD-L1 status (EA5142, 935 randomized) recently completed enrollment. To support ongoing investigation of adjuvant immunotherapy, ALCHEMIST is adding A081801 (opens spring 2020). Pts will be randomized to one of 3 arms: chemo-IO with pembrolizumab during and after chemo vs sequential chemo followed by pembrolizumab vs chemo alone. Pts with pathological N2 nodes are eligible and can undergo postoperative radiotherapy after completing chemo. Pts are eligible if enrolled to A151216, negative for EGFR and ALK alterations, and with PD-L1 testing completed (required for stratification). Local testing for EGFR, ALK and PD-L1 will be accepted for enrollment; central testing will not delay randomization. Pts may not have received any therapy except surgery for the lung cancer and must be age >18, Eastern Cooperative Oncology Group performance status 0-1, have no active autoimmune disease requiring systemic treatment within 2 years, must not be pregnant or nursing, have no active second malignancy within 3 years and meet standard organ function values. By building off the ongoing ALCHEMIST platform, we hope to facilitate rapid enrollment to A081801 across participating NCTN sites. Clinical trial information: NCT02194738.

Abstract The treatment of patients with metastatic non–small cell lung cancer (NSCLC) is slowly evolving from empirical cytotoxic chemotherapy to personalized treatment based on specific molecular alterations. Despite this 10-year evolution, targeted therapies have not been studied adequately in patients with resected NSCLC who have clearly defined actionable mutations. The advent of next-generation sequencing has now made it possible to characterize genomic alterations in unprecedented detail. The efforts begun by The Cancer Genome Atlas project to understand the complexities of the genomic landscape of lung cancer will be supplemented further by studying a large number of tumor specimens. The Adjuvant Lung Cancer Enrichment Marker Identification and Sequencing Trial (ALCHEMIST) is an NCI-sponsored national clinical trials network (NCTN) initiative to address the needs to refine therapy for early-stage NSCLC. This program will screen several thousand patients with operable lung adenocarcinoma to determine whether their tumors contain specific molecular alterations [epidermal growth factor receptor mutation (EGFR) and anaplastic lymphoma kinase rearrangement (ALK)], making them eligible for treatment trials that target these alterations. Patients with EGFR mutation or ALK gene rearrangement in their tumor will be randomized to placebo versus erlotinib or crizotinib, respectively, after completion of their standard adjuvant therapy. ALCHEMIST will also contain a large discovery component that will provide an opportunity to incorporate genomic studies to fully understand the clonal architecture, clonal evolution, and mechanisms of resistance to therapy. In this review, we describe the concept, rationale, and outline of ALCHEMIST and the plan for genomic studies in patients with lung adenocarcinoma. Clin Cancer Res; 21(24); 5439–44. ©2015 AACR.