Garon, Edward B.

TPS2676 Background: Solid tumors comprise > 90% of cancers. Metastatic colorectal cancer, non-small cell lung cancer, and pancreatic cancer are among the leading causes of cancer-related mortality (5-year overall survival: 14%, 6%, and 3%, respectively) (ACS. 2021). Chimeric antigen receptor (CAR) T-cell therapy has demonstrated clinical efficacy in hematologic malignancies (Neelapu S. et al. N Engl J Med. 2017). Translating engineered T-cell therapies to solid tumors has proven to be challenging due to a lack of tumor-specific targets that can discriminate cancer cells from normal cells. Previous studies using carcinoembryonic antigen (CEA) T-cell receptors and mesothelin (MSLN) CARs resulted in dose-limiting on-target, off-tumor toxicities (Parkhurst M, et al. Mol Ther. 2011; Tanyi J. Cellicon Valley '21). To create a therapeutic safety window, Tmod CAR T-cell therapy utilizes dual-signaling receptors to create a robust NOT logic gate capable of killing tumor cells, while leaving healthy cells intact (Hamburger A, et al. Mol Immunol. 2020). The 2 receptors in Tmod CAR T-cell therapy comprise an activator that recognizes an antigen on the surface of tumor cells that may also be present on normal cells, such as CEA and MSLN, and a blocker that recognizes a second surface antigen from an allele lost only in tumor cells. The frequency of HLA LOH among advanced GI solid tumor cancers in the Tempus real-world dataset is 16.3% with a range of 15.6%-20.8% between colorectal, pancreatic, and gastroesophageal tumors (Hecht R. et al. ASCO-GI 2022. Abstract #190). As such, HLA LOH offers a definitive tumor versus normal discriminator target for CAR T-cell therapy. Different activator/blocker combinations can be engineered with the Tmod platform technology and may be applied to T cells and natural killer cells in autologous and allogeneic settings. BASECAMP-1 is a currently enrolling observational study with key objectives of 1) To identify patients with somatic HLA LOH eligible for Tmod CAR T-cell therapy, and 2) To obtain leukapheresis and feasibility for the future EVEREST Tmod CAR T-cell trial. Methods: BASECAMP-1 (NCT04981119) patient eligibility has 2 parts: 1) Patients will be initially screened to identify germline HLA-A*02 heterozygosity by central NGS. If HLA-A*02 heterozygosity is confirmed, primary archival tumor tissue will be analyzed for somatic mutations by xT-Onco NGS testing. 2) If the tumor demonstrates HLA-A*02 LOH and the patient is eligible after screening, the patient will undergo leukapheresis. Banked T cells will be available for the autologous EVEREST Tmod CAR T-cell therapy interventional study to reduce waiting time at relapse. Clinical trial information: NCT04981119.

9520 Background: Capmatinib (INC280) has shown promising efficacy in patients (pts) with MET exon 14 ( METex14)–mutated NSCLC who were pretreated (cohort 4) or treatment (tx)-naïve (cohort 5b) in the ongoing, multicohort, phase 2 GEOMETRY mono-1 study. We report the results for pts enrolled in the expansion cohort 6 with either high-level MET amplification (gene copy number [GCN] ≥10) or METex14 mutation (any MET GCN) whose disease progressed on 1 prior line of systemic therapy. Methods: Adult pts (≥18 years), ECOG PS 0–1 who had ALK and EGFR wt, stage IIIB/IV NSCLC (any histology) received capmatinib tablets 400 mg twice daily (with or without food). Key efficacy endpoints were overall response rate (ORR) and duration of response (DOR) by blinded independent review committee (BIRC) per RECIST v1.1. Other secondary endpoints included investigator-assessed ORR, DOR, disease control rate (DCR), progression-free survival (PFS; BIRC and investigator assessment) and safety. Results: As of Jan 6, 2020, 34 NSCLC pts with METex14 mutation (n = 31) or high-level MET amplification (n = 3) were included in this analysis. Tx was ongoing for 38.2% of pts. In METex14-mutated NSCLC pts, per BIRC assessment: ORR was 48.4%, median DOR was 6.93 months (mo, not yet mature, 95% CI: 4.17–NE) and median PFS was 8.11 mo (not yet mature, 95% CI: 4.17–9.86). Investigator-assessed responses were similar to BIRC assessment (Table). Only 3 pts with high-level MET amplification were included in this cohort due to challenges in enrollment. All 3 pts had stable disease per BIRC assessment and were on treatment for 48, 85 and 97 days. Most common AEs (≥25%, all grades, N = 34) were peripheral edema (64.7%), nausea (35.3%), fatigue (29.4%), back pain (26.5%) and vomiting (26.5%). Data for pts with brain metastasis will be presented at the ASCO 2020 meeting. Conclusions: Capmatinib was confirmed to be efficacious in 2nd line, METex14-mutated NSCLC pts. This is the first cohort where capmatinib has been administered without fasting restriction and data confirm the favorable safety profile. Clinical trial information: NCT02414139 . [Table: see text]