Adagrasib Elicits Deep and Durable Responses in Pretreated KRAS G12C–Mutant NSCLC

Alexander I. Spira, MD, PhD, FACP

Adagrasib led to early onset and deep responses translating to encouraging survival as a single agent in previously treated patients with KRAS G12C–mutated non–small cell lung cancer (NSCLC), according to results from cohort A of the phase 1/2 KRYSTAL-1 trial (NCT03785249) presented at the 2022 ASCO Annual Meeting.^1,2

At the meeting, Alexander I. Spira, MD, PhD, FACP, co-director of Virginia Cancer Specialists Research Institute, director of the Thoracic and Phase I Program, and clinical assistant professor at Johns Hopkins School of Medicine, presented data as of October 15, 2021, from the registrational phase 2 cohort A study, which was simultaneously published in the New England Journal of Medicine.

After a median follow-up of 12.9 months, the objective response rate (ORR) was 43% (95% CI, 33.5%-52.6%) among the 112 patients with measurable disease at baseline, which included 1 complete response (CR; 1%) and 47 partial responses (PRs; 42%). There were 41 patients with stable disease (SD; 37%) and 6 with progressive disease (5%) for a DCR of 80% (n = 89; 95% CI, 70.8%-86.5%). There were no differences in ORR by subgroup in exploratory analyses.

“Responses appear to be deep, with 75% of responders having a greater than 50% tumor reduction,” Spira said.

Moreover, the median time to response with the KRASG12C inhibitor was 1.4 months (range, 0.9-7.2) and median duration of response was 8.5 months (95% CI, 6.2-13.8).

Spira noted that as of the data cut-off, treatment is ongoing in half of patients who experienced a response (n = 24) and 33% (n = 16) have maintained their response.

Lastly, the median progression-free survival (PFS) was 6.5 months (95% CI, 4.7 to 8.4), with 6- and 12-month PFS rates of 52% and 29%, respectively. Similarly, the median OS was 12.6 months (95% CI, 9.2-19.2), with 6- and 12-month OS rates of 71% (95% CI, 61.1-78.3) and 51% (95% CI, 40.9-60.0), respectively.

The investigators further evaluated efficacy among 33 patients with treated, stable central nervous system (CNS) metastases. The intracranial ORR was 33% (n = 11; 95% CI, 18%-52%), which included 5 CRs (15%) and 6 PRs (18%). There were 17 patients with SD (52%) for a DCR of 85% (n = 28; 95% CI, 68%-95%). The median intracranial PFS was 5.4 months (95% CI, 3.3-11.6).

Treatment-related adverse events (TRAEs) of any grade occurred in 113 patients (97%), of which 50 (43%) were grade 3/4 in severity. The most frequent any-grade TRAEs were diarrhea (63%), nausea (62%), vomiting (47%), fatigue (41%), ALT increase (28%), blood creatinine increase (26%), AST increase (25%), and decreased appetite (24%). Two grade 5 events occurred: cardiac failure and pulmonary hemorrhage.

TRAEs led to dose reductions in 60 patients (52%), interruptions in 71 (61%), and discontinuation in 8 (7%).

Commenting on the presentation, Sukhmani Kaur Padda, MD, of the Samuel Oschin Cancer Center at Cedars-Sinai Medical Center, noted: “I am curious about a lower optimal starting dose. We talk about this all the time as it relates to targeted therapy… Co-mutations may help further delineate sequencing of therapeutics in KRAS–mutated non–small cell lung cancer.”

Adagrasib, formerly MRTX849, is a covalent inhibitor that irreversibly and selectively binds KRAS G12C. “We know that KRAS G12C mutations act as oncogenic drivers and occur in about 14% of patients with non–small cell lung cancer, predominantly adenocarcinoma,” Spira explained. “About 27% to 42% of these patients will have CNS metastases at diagnosis. Adagrasib…was optimized for desired properties of a KRAS G12C inhibitor, including a long half-life, about 23 hours, dose-dependent pharmacokinetics, and CNS penetration.”

In the first-in-human trial of the agent, 15 patients with KRAS G12C–mutated NSCLC demonstrated an ORR of 53.3%, a median DOR of 16.4 months, and a median PFS of 11.1 months. “As previously reported, clinical activity with adagrasib has been shown in various KRAS G12C–mutated solid tumors, including of course non–small cell lung, colorectal, pancreatic, ovarian, endometrial, and other GI cancers,” Spira said.

Therefore, in the multicohort KRYSTAL-1 trial, investigators are assessing adagrasib as monotherapy or in combination with other therapies in patients with advanced solid tumors harboring a KRAS G12C mutation.

In the registrational phase 2 cohort A study, 116 patients with NSCLC previously treated with platinum-based chemotherapy and anti–PD-1/L1 therapy received 600 mg oral adagrasib twice daily. Investigators aimed to evaluate ORR, DCR, PFS, OS, and safety.

Key eligibility criteria included patients with NSCLC who harbored a KRAS G12C mutation, unresectable or metastatic disease, and prior treatment with a PD-1/L1 inhibitor in combination or in sequence with chemotherapy. Those with treated, stable CNS metastases were allowed on the trial.

Median age was 64 years (range, 15-89). Most patients were women (56%), White (84%), had an ECOG status of 1 (84%), were former smokers (86%), and had received prior platinum-based therapy and checkpoint inhibitor therapy (98%).

“Based on these data, the [new drug application] for adagrasib has been accepted and is under review for accelerated approval in the US, and the [marketing authorization applications] has been recently submitted to the European Medicines Agency,” Spira said, adding that the phase 3 KRYSTAL-12 trial (NCT04685135), designed to evaluate adagrasib monotherapy versus docetaxel in previously treated patients with KRAS G12C–mutant NSCLC, is ongoing.

References

1. Spira AI, Riely GJ, Gadgeel SM, et al. KRYSTAL-1: activity and safety of adagrasib (MRTX849) in patients with advanced/metastatic non-small cell lung cancer (NSCLC) harboring a KRAS G12C mutation. J Clin Oncol. 2022;40(suppl 16):9002 doi:10.1200/JCO.2022.40.16_suppl.9002
2. Jänne PA, Riely G, Gadgee SM, et al. Adagrasib in non–small-cell lung cancer harboring a KRASG12C mutation. N Engl J Med. 2022;386:22. doi:10.1056/NEJMoa2204619