MA06.04 KRYSTAL-1: Two-Year Follow-Up of Adagrasib (MRTX849) Monotherapy in Patients with Advanced/Metastatic KRASG12C-Mutated NSCLC

Document Type

Conference Proceeding

Publication Date

11-1-2023

Publication Title

J Thorac Oncol

Abstract

Introduction: KRASG12C mutations occur in approximately 14% of patients with NSCLC. Adagrasib, an oral, selective KRASG12C inhibitor, was selected for favorable properties, including long half-life (23 hours), dose-dependent pharmacokinetics, and CNS penetration. Recently, based on data from KRYSTAL-1 (NCT03785249), a multicohort Phase 1/2 study evaluating adagrasib as monotherapy or in combination for patients with KRASG12C-mutated solid tumors, the FDA granted accelerated approval of adagrasib for patients with previously treated KRASG12C-mutated advanced/metastatic NSCLC. Adagrasib is also under review by the EMA and MHRA. Herein, we present data from a two-year follow-up pooled analysis of the Phase 1/1b Cohort and Phase 2 Cohort A of KRYSTAL-1. Methods: In the Phase 1/1b and Phase 2 Cohorts, patients with KRASG12C-mutated advanced/metastatic NSCLC were treated with adagrasib 600 mg orally BID. Study endpoints for both Cohorts included safety and efficacy (ORR, DOR, PFS, and OS). Objective tumor response was assessed per RECIST v1.1 by blinded independent central review (BICR), as were ORR, DOR, and PFS. Results: As of January 1, 2023, 132 patients with KRASG12C-mutated NSCLC had received adagrasib (Phase 1/1b: 16 patients; Phase 2: 116 patients; median follow-up: 26.9 months [95% CI 25.9-29.7]). Overall, the median age of patients was 64 years (range: 25-89), 56.8% were female, and 19.7% had CNS metastases at baseline; patients had received a median of 2 prior therapies, with 97.0% of patients receiving both platinum-based and checkpoint inhibitor therapies. ORR was 43.0% (55/128 evaluable patients); median DOR was 12.4 months (95% CI 7.0-15.1). Median PFS was 6.9 months (95% CI 5.4-8.7), with a 1-year PFS rate of 35.0% (95% CI 25.9-44.2). Median OS was 14.1 months (95% CI 9.2-18.7); 1-year and 2-year OS rates were 52.8% and 31.3%, respectively. Patients with common co-mutations, including KEAP1 (n=25), STK11 (n=44), or TP53 (n=42), had a median OS of 5.7 months (95% CI 3.6-9.2), 9.2 months (95% CI 5.0-12.7), and 18.7 months (95% CI 11.3-27.0), respectively. Patients with CNS metastases at baseline had a median OS of 14.7 months (95% CI 7.5-19.3). Treatment-related adverse events (TRAEs) of grade ≥3 occurred in 61 patients (40.9% grade 3, 3.0% grade 4, and 2.3% grade 5 [pneumonitis, cardiac failure, and pulmonary hemorrhage, 1 patient each]). TRAEs led to dose reduction in 68 patients (51.5%) and treatment discontinuation in 12 patients (9.1%). Overall, 32.6% of patients (43/132) had received adagrasib for >1 year. Additional safety data for patients on adagrasib >1 year and exploratory analyses will also be presented. Conclusions: In this pooled analysis with longer follow-up, adagrasib demonstrated durable clinical activity, with a median OS of 14.1 months and approximately one in three patients alive at two years. Exploratory analyses suggested heterogeneity of clinical benefit based on the presence of co-mutations, which should be further evaluated. The reported safety profile was manageable and consistent with previous reports. A Phase 3 trial evaluating adagrasib monotherapy compared with docetaxel in patients with previously treated advanced KRASG12C-mutated NSCLC is ongoing (NCT04685135). Keywords: KRAS, NSCLC, adagrasib

Medical Subject Headings

Hematology

PubMed ID

Not assigned.

Volume

18

Issue

11

First Page

S118

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