Heist, Rebecca S.

8618 Background: Telisotuzumab vedotin (Teliso-V) is a c-Met–directed antibody-drug conjugate comprising the mAb telisotuzumab and the microtubule polymerization inhibitor monomethyl auristatin E. In the phase 2 LUMINOSITY trial (NCT03539536), Teliso-V monotherapy 1.9 mg/kg showed durable responses and a generally manageable safety profile in patients (pts) with c-Met protein–overexpressing (OE) non-squamous (NSQ) EGFR -wildtype (WT) non-small cell lung cancer (NSCLC). Herein we present an analysis of efficacy outcomes according to prior platinum or prior platinum and immune checkpoint inhibitor (ICI)-based therapies. Methods: Pts (≥18 years) with locally advanced/metastatic c-Met protein–OE NSQ EGFR -WT NSCLC who had ≤2 prior lines of therapy, including ≤1 line of chemotherapy, were treated with 1.9 mg/kg Teliso-V Q2W. c-Met protein overexpression (by immunohistochemistry clinical trial assay for MET [SP44] [Roche]) was defined as ≥25% tumor cells with 3+ staining intensity (high: ≥50% 3+; intermediate [int]: 25 to <50% 3+). The primary endpoint was overall response rate (ORR) by independent central review per RECIST v1.1. Results: As of 21 Feb 2024, 172 pts received ≥1 dose of Teliso-V and 168 pts were included in efficacy analyses (c-Met high, n=84; c-Met int, n=84). In the c-Met OE total population, 97.6% of pts received prior platinum and 78.6% received prior platinum + ICI. Efficacy data for pts with prior platinum and platinum + ICI therapies are shown in the Table. Among the 172 dosed pts, the most common any-grade treatment-related adverse events (TRAEs) were peripheral sensory neuropathy (31%), peripheral edema (16%), and fatigue (14%). The most common grade ≥3 TRAE was peripheral sensory neuropathy (7%). Conclusions: This analysis demonstrated that Teliso-V elicited durable responses in pts with c-Met protein–OE NSQ EGFR -WT NSCLC regardless of whether they had received prior platinum or platinum + ICI therapies; the efficacy outcomes in these subgroups were consistent with those in the overall pt population. Clinical trial information: NCT03539536 . Platinum Platinum + ICI Overall ORR, a n/N (%) [95% CI] c-Met OE total c-Met high c-Met int 48/164 (29.3) [22.4, 36.9]28/81 (34.6) [24.3, 46.0]20/83 (24.1) [15.4, 34.7] 38/132 (28.8) [21.2, 37.3]22/67 (32.8) [21.8, 45.4]16/65 (24.6) [14.8, 36.9] 49/168 (29.2) [22.4, 36.7]29/84 (34.5) [24.5, 45.7]20/84 (23.8) [15.2, 34.3] Median DOR, a mo [95% CI] c-Met OE total c-Met high c-Met int 7.2 [5.5, 11.3]9.0 [3.8, 12.0]7.2 [4.7, 11.5] 7.2 [5.5, 11.0]9.0 [3.8, 11.3]7.2 [5.3, 11.5] 7.2 [5.5, 11.0]7.2 [4.2, 12.0]7.2 [4.7, 11.5] a Per independent central review. DOR, duration of response.

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.

8106 Background: Bcl-2 family proteins are expressed in SCLC and are associated with chemotherapy resistance. AT-101 is an oral, pan Bcl-2 family protein inhibitor (Bcl-2, Bcl-XL, Mcl-1, and Bcl-w) and potent inducer of proapoptotic proteins. AT-101 has demonstrated activity in SCLC models, including those that express Mcl-1 and are resistant to other Bcl-2 inhibitors. The P1 portion of the study was previously reported. Methods: Pts ≥18 years of age, PS 0–1, with relapsed or refractory SCLC after first line chemotherapy with measurable disease per RECIST were eligible. Pts were stratified into 2 cohorts; cohort A ≥ 60 days and cohort B < 60 days relapse from prior chemotherapy and treated with T 1.25 mg/m2 daily and AT-101 40 mgs daily on days 1–5, q21 along with the use of myeloid growth factors. Adverse Events (AEs) were graded by the NCI CTCAE v. 3.0. Efficacy assessments (RECIST) were performed every 6-weeks. A 2-stage design was used with power/alpha of 80%/0.05 to detect a RR of > 25% and > 5%, in cohort A and B respectively. Results: 36 pts enrolled: ages 41–76; cohort A/B 23/13. The PR/SD/PD/NE rates were 17%/70%/9%/4% and 8%/54%/23%/15%, in cohorts A/B respectively. The median times to progression (TTP) were 18 and 13 weeks, respectively. The most common (>20 %) AEs (all grades): anemia (64%); neutropenia (53%); nausea (47%); fatigue (44%); thrombocytopenia (42%); dyspnoea (25%); and vomiting (22%). Most common Grade 3/4 related events (>5%): neutropenia (31%); thrombocytopenia (25%); anemia (14%); and asthenia (6%). No ileus was reported. Conclusions: AT-101 can be safely combined with T. The observed toxicities were consistent with the known rates of G4 cytopenias of T alone. The response rates observed did not meet the criteria for additional enrolment; however, many patients had a best response of SD and the median TTP in both cohorts was favorable compared to historical controls. Additional trials of AT-101 in SCLC are ongoing. [Table: see text]

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]

TPS2573 Background: Brain metastases, most commonly derived from melanoma, lung and breast cancers, are the most common brain tumor, with approximately 200,000 cases diagnosed annually in the United States. Median survival is on the order of months. For patients with clinically symptomatic brain metastases, approximately half succumb due to intracranial progression. In preclinical work, we demonstrated that brain metastases and primary tumors are often genetically distinct with frequent alterations in the CDK and PI3K pathway (Brastianos, Carter et al. Cancer Discovery 2015). Methods: We are currently accruing to a prospective multi-arm phase II study of CDK, PI3K/mTOR, and NTRK/ROS1 inhibitors in patients with brain metastases harboring alterations associated with sensitivity to these inhibitors (abemaciclib, paxalisib and entrectinib), respectively. Patients with new, recurrent or progressive brain metastases are eligible for this trial. Previously obtained tissue from brain metastases and extracranial sites (primary or extracranial metastases) are screened for the presence of these alterations, and if present in both tumor sites, patients will receive the appropriate corresponding targeted treatment. Screening is carried out with the SNaPshot NGS assay, which is a fully validated clinical test designed and developed at the MGH Center for Integrated Diagnostics. The primary endpoint of response rate (RR) in the central nervous system as per RANO criteria will be evaluated separately for each inhibitor, stratified by histology within each arm. There will be 21 evaluable patients assigned to each of the CDK and PI3K inhibitor and tumor type cohorts (breast, lung and other) and 10 patients assigned to the NTRK/ROS1 inhibitor cohort (lung) for a total of 136 evaluable patients. Although current systemic therapy for brain metastases is often ineffective, we hypothesize that targeted therapies will demonstrate efficacy in patients harboring the appropriate mutations. This study represents a novel individualized therapeutic approach in brain metastases, a disease with a critical need for effective therapy. Support: U10CA180821, U10CA180882, https://acknowledgments.alliancefound.org ; Genentech, Kazia Therapeutics Limited, Eli Lilly; Clinical trial information: NCT03994796 .