Adagrasib Induces 68% ORR in Subset of Patients With KRAS G12C–Mutated NSCLC

Pasi A. Jänne, MD, PhD

Adagrasib (Krazati) induced high overall response rates (ORR) in patients with KRAS G12C–mutated non–small cell lung cancer (NSCLC) who achieved at least 90% mutation allele frequency clearance (MAFC), according to findings from an exploratory analysis of KRAS G12C–mutant circulating tumor DNA (ctDNA) from the registrational phase 2 KRYSTAL-1 trial (NCT03785249).¹

Eighty-nine percent of patients (n = 31/35) had at least 90% MAFC, and the ORR was 68% among those patients. The ORR was 0% among the 11% of patients with MAFC below 90% (n = 4/35).

“This exploratory analysis of ctDNA MAFC suggests that objective response and progression-free survival [PFS] are increased in those associated with a greater than 90% clearance,” said Pasi A. Jänne, MD, PhD. He added that PFS was longer in patients with radiographic response. “All responses corresponded to MAFC greater than 90%.”

Jänne, director of the Lowe Center for Thoracic Oncology, the Belfer Center for Applied Cancer Science, and the Chen-Huang Center for EGFR Mutant Cancers at Dana-Farber Cancer Institute, presented the data during the 2023 European Lung Cancer Conference (ELCC).

In cohort A of KRYSTAL-1, 116 patients received twice-daily 600 mg adagrasib. Eligible patients had unresectable or metastatic disease and received prior treatment with a PD-1/PD-L1 inhibitor in combination or in sequence with chemotherapy. Patients with treated, stable central nervous system metastases were allowed.

The data reported at ELCC included 35 patients selected according to levels of KRAS G12C in those with detectable ctDNA at baseline and on day 1 of cycle 2 and cycle 4 who were evaluable for MAFC. The primary end point was ORR assessed by blinded independent central review per RECIST v1.1 criteria. Secondary end points included duration of response (DOR), PFS, overall survival (OS), and safety.

The median age for the full cohort (N = 116) was 64 years (range, 25-89). Fifty-six percent of patients were women and 84% were White. Eighty-four percent had an ECOG performance status of 1; 16% had a score of 0. Four percent of patients were never smokers, 10% were current smokers, and 86% were former smokers.

Fifty-seven percent received 2 or more previous lines of therapy. Forty-three percent received 1 previous line. The ORR among the overall population was 43%, and the median PFS was 6.5 months.

Among 39 patients analyzed for plasma response, the median age was 63 years (range, 25-84). Fifty-six percent of patients were women and 82% were White. Seventy-seven percent had an ECOG performance status of 1, and 23% had a score of 0. Three percent of patients were never smokers, 3% were current smokers, and 95% were former smokers.

Fifty-nine percent received 2 or more previous lines of therapy; 41% received 1 previous line. The ORR was 56% and the median PFS was 6.9 months.

Investigators in this analysis observed complete clearance of the KRAS G12C–mutant allele in 77% of patients at both day 1 of cycle 2 and cycle 4. Sixty-seven percent of those patients had a radiographic response.

Investigators found that mutation allele frequency (MAF) at baseline did not appear to correlate with response. The median MAF at baseline was 3.8 in non-responders vs 4.2 in responders.

“Not all patients with greater than 90% clearance demonstrated clinical benefit,” Jänne said. “So, it is sort of necessary, but not sufficient, for [clinical benefit].”

He added that investigators have initiated the confirmatory phase 3 KRYSTAL-12 trial (NCT04685135) assessing adagrasib monotherapy vs docetaxel in patients with previously treated advanced/metastatic KRAS G12C–mutant NSCLC.

The FDA granted accelerated approval to adagrasib for previously treated patients with KRAS G12C–mutant locally advanced or metastatic NSCLC, as well as the companion diagnostics QIAGEN therascreen KRAS RGQ PCR kit for tissue and the Agilent Resolution ctDx FIRST Assay for plasma in December 2022.² In data from KRYSTAL-1, adagrasib induced an ORR of 43% (95% CI, 34%-53%) with a median DOR of 8.5 months (95% CI, 6.2-13.8) in patients with locally advanced or metastatic KRAS G12C–mutant NSCLC.

Also in December 2022, Jänne presented findings from the KRYSTAL-1 phase 1b and the KRYSTAL-7 (NCT04613596) phase 2 cohorts evaluating adagrasib plus pembrolizumab (Keytruda) at the 2022 ESMO Immuno-Oncology Annual Congress. The ORR was 49% (95% CI, 35%-63%) among clinically evaluable patients in KRYSTAL-7 who received at least 1 on-study scan (n = 53). Among evaluable patients in the KRYSTAL-1 group (n = 7), the ORR was 57%.³

Disclosures: Dr Jänne reported owning stocks/shares in Gatekeeper Pharmaceuticals; study sponsorship: AstraZeneca, Boehringer Ingelheim, Eli Lilly, Revolution Medicines, Takeda Oncology, and Daiichi Sankyo; and payment for consulting from Advisory role: AstraZeneca, Boehringer Ingelheim, Pfizer, Roche/Genentech, Eli Lilly, SFJ Pharmaceuticals, Voronoi, Daiichi Sankyo, Novartis, Biocartis , Takeda Oncology, Transcenta , Silicon Therapeutics, Syndax , Nuvalent , Allorion Therapeutics, Accutar Biotech, AbbVie, Bayer, Eisai, Monte Rosa, Scorpion Therapeutics, Merus , Frontier Medicines, and Hongyun Biotechnology.

References

1. Jänne PA, Spira A, Riely GJ, et al. Adagrasib (MRTX849) in patients with advanced/metastatic krasg12c-mutated non-small cell lung cancer (NSCLC): preliminary analysis of mutation allele frequency. resented at: European Lung Cancer Congress 2023; March 29-April 1, 2023; Copenhagen, Denmark. Abstract 8MO.
2. FDA grants accelerated approval to adagrasib for KRAS G12C-mutated NSCLC. News release. FDA. December 12, 2022. Accessed April 4, 2023. https://www.fda.gov/drugs/
3. Jänne PA, Smit EF, de Marinis F, et al. Preliminary safety and efficacy of adagrasib with pembrolizumab in patients with advanced non-small cell lung cancer (NSCLC) harboring a KRASG12C mutation. Presented at: 2022 ESMO Immuno-Oncology Annual Meeting; December 7-9, 2022; Geneva, Switzerland. Presentation LBA4.