Adagrasib Shows Promise in Difficult-to-Treat Lung Cancer Subset

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Adagrasib demonstrated an 80% disease control rate among patients with previously treated KRAS G12C–mutated non–small cell lung cancer.

When given as a single-agent (not with any other drugs), adagrasib led to promising outcomes for patients with KRAS G12C-mutated non-small cell lung cancer (NSCLC), according to results from part of the phase 1/2 KRYSTAL-1 clinical trial that were presented at the 2022 American Society of Clinical Oncology Annual Meeting.

At the meeting, Dr. Alexander I. Spira, 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 Oct. 15, 2021, from the 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 (percentage of patients whose disease shrunk as a result of treatment) was 43% among the 112 patients with measurable disease at baseline, which included one complete response (no detectable disease) and 47 partial responses. There were 41 patients with stable disease and six with progressive disease (5%) for a disease control rate of 80%. There were no differences in overall response rate 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 adagrasib, a KRASG12C inhibitor, was 1.4 months and median duration of response was 8.5 months.

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

Lastly, the median progression-free survival (time from treatment until disease worsens) was 6.5 months with six- and 12-month progression-free survival rates of 52% and 29%, respectively.

Similarly, average overall survival was 12.6 months, with six- and 12-month overall survival rates of 71% and 51%, respectively.

The investigators further evaluated efficacy among 33 patients with treated, stable central nervous system (CNS) metastases. The intracranial overall response rate was 33% (11 patients), which included five complete responses (15%) and six partial responses (18%). There were 17 patients with stable disease (52%) for a disease control rate of 85% (28 patients). The median intracranial progression-free survival was 5.4 months.

Side effect of any grade occurred in 113 patients (97%), of which 50 (43%) were severe (grade 3 or grade 4). The most frequent any-grade side effects were diarrhea (63%), nausea (62%), vomiting (47%), fatigue (41%), alanine transaminase increase, which can indicate liver issues (28%), blood creatinine increase (26%), aspartate aminotransferase increase, which can also indicate liver issues (25%) and decreased appetite (24%). Two deaths occurred: cardiac failure and pulmonary hemorrhage.

Side effects led to dose reductions in 60 patients (52%), interruptions in 71 (61%) and discontinuation in eight (7%).

Commenting on the presentation, Dr. Sukhmani Kaur Padda, 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, works by irreversibly and selectively binds KRAS G12C, which can play a role in cancer proliferation.

“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 (central nervous system) 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 (central nervous system) penetration.”

In the first-in-human trial of the agent, 15 patients with KRAS G12C–mutated NSCLC demonstrated an overall response rate of 53.3%, a median duration of response of 16.4 months and a median progression-free survival 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 (gastrointestinal) 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 overall response rate, disease control rate, progression-free survival, overall survival 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 central nervous system metastases were allowed on the trial.

“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, designed to evaluate adagrasib monotherapy versus docetaxel in previously treated patients with KRAS G12C–mutant NSCLC, is ongoing.

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