KRYSTAL-12: A randomized phase 3 study of adagrasib (MRTX849) versus docetaxel in patients (pts) with previously treated non-small-cell lung cancer (NSCLC) with KRAS^G12C mutation.

Abstract

TPS9129 Background: Despite significant advances in chemotherapy and immunotherapy for advanced NSCLC, the majority of pts ultimately develop progressive disease associated with poor outcomes. KRAS is a key mediator of the RAS/MAPK signaling cascade that promotes cell growth and proliferation. KRASG12C mutations occur in 14% of NSCLC (adenocarcinoma), and mutations in KRAS are associated with a poor prognosis. Although KRAS has historically been undruggable, recent research into the development of agents that specifically bind mutant KRAS has led to the development of direct inhibitors of KRASG12C. Adagrasib, an investigational agent, is a potent, covalent inhibitor of KRASG12C that irreversibly and selectively binds to and locks KRASG12C in its inactive state. Adagrasib was optimized for favorable pharmacokinetic (PK) properties, including oral bioavailability, long half-life (̃24 h), and extensive tissue distribution. Initial results have demonstrated encouraging antitumor activity and tolerability of adagrasib monotherapy in pts with NSCLC harboring a KRASG12C mutation. Methods: KRYSTAL-12 is a multicenter, randomized Phase 3 study evaluating the efficacy of adagrasib (600 mg BID) vs docetaxel in pts with advanced NSCLC harboring a KRASG12C mutation who have progressed during or after treatment with a platinum-based regimen and an immune checkpoint inhibitor. The study is designed to demonstrate improvement in the dual primary endpoints of progression-free survival (PFS) and overall survival (OS). Secondary endpoints include safety, objective response rate (ORR) per RECIST 1.1, duration of response (DOR), plasma PK parameters of adagrasib, and patient-reported outcomes (PROs). The study will also explore correlations between gene alterations (at baseline and upon development of treatment resistance) and efficacy. Approximately 450 patients will be randomized in a 2:1 ratio to receive adagrasib or docetaxel and will be stratified by region (United States/Canada vs other countries) and sequential vs concurrent administration of prior platinum-based chemotherapy and anti–PD-1/PD-L1 antibody. The planned sample size is sufficiently powered for the hypothesized treatment effect of the endpoints. Pts will receive study treatment until disease progression, unacceptable adverse events, investigator decision to terminate treatment, or patient withdrawal. This study is currently enrolling and will be open at sites in the United States, Europe, and Asia. Clinical trial information: NCT04685135.

Combined KRASG12Cand SOS1 inhibition enhances and extends the anti-tumor response in KRASG12C-driven cancers by addressing intrinsic and acquired resistance

“…Pharmacodynamic markers of the RAS-MAPK pathway and changes in cellular phenotype after 6 and 24 hours of treatment were evaluated following single-agent or combination treatment with adagrasib, BI-3406, and/or TNO155/SHP099. Study concentrations were matched to clinically relevant plasma exposures that were determined through clinical data [9][10][11]30 , or through preclinical and investigational new drug studies that leveraged several cancer models. After 6 hours of treatment, adagrasib plus BI-3406 or TNO155/SHP099 induced stronger inhibitory effects on MAPK and PI3K signaling, as evidenced by reductions in pERK and p-S6, compared to those induced by adagrasib, TNO155, or BI-3406 alone in both cell lines (Fig 3b, c).…”

“…Alterations in the KRAS gene are commonly found across all human cancers [1][2][3] , with the G12C mutant being one of the predominant KRAS variants occurring in non-small cell lung cancer (NSCLC; 13%) and colorectal cancer (CRC; 3%) 4,5 . Recent drug-discovery efforts 6,7 have led to the clinical testing of multiple KRAS G12C -specific inhibitors (KRAS G12C i) 5,8 , with sotorasib (AMG 510) 9 and adagrasib (MRTX849) 10 demonstrating significant benefit in KRAS G12C -mutated NSCLC and CRC patients and both receiving approval for patients with KRAS G12C -mutated NSCLC 11,12 . While the success of these trials is impressive, disease progression occurs in the majority of cancer patients treated with KRAS G12C -inhibitors 9,11 .…”

Targeting KRAS Mutant in Non-Small Cell Lung Cancer: Novel Insights Into Therapeutic Strategies

“…Overall, these studies evidence promising pre-clinical rationales to revert or delay the emergence of acquired resistance to sotorasib and adagrasib ( Figure 3 ). Several clinical trials are currently ongoing to evaluate the efficacy of KRAS G12C inhibitors in combination with chemotherapy ( 133 , 134 ) or with targeted therapies including cetuximab, afatinib, pembrolizumab and SHP2, mTOR, CDK4/6 inhibitors ( 91 , 135 , 136 ). These results would be of interest to evaluate whether combined treatments increased response rate to KRAS G12C inhibitors, thereby contributing to prevent or delay acquired resistance.…”

KRAS-Mutant Non-Small-Cell Lung Cancer: From Past Efforts to Future Challenges

“…Subsequent clinical trials are currently investigating adagrasib as monotherapy or in association with other compounds in patients with advanced or metastatic solid tumors. The phase III KRYSTAL-12 study is recruiting pre-treated patients with NSCLC to MRTX 849 versus docetaxel [ 79 ]. In the KRYSTAL-1 trial, a subgroup analysis was performed with the aim of exploring co-mutations in STK11 , KEAP1 , P53 and CDKN2A .…”