Adagrasib Response Remains Strong in NSCLC

In the phase II KRYSTAL-1 trial, the KRAS^G12C inhibitor adagrasib (MRTX849; Mirati Therapeutics) continued to demonstrate solid efficacy in patients with non–small cell lung cancer (NSCLC), boasting an objective response rate (ORR) of 43%, on par with the 45% ORR reported in 2020 (N Engl J Med 2022 Jun 3 [Epub ahead of print]). The new data, published and simultaneously reported at the 2022 American Society of Clinical Oncology Annual Meeting in Chicago, IL, on June 3, have been submitted to regulators in the United States and Europe to support the drug's application for marketing approval.

Researchers enrolled 116 patients with KRAS^G12C-mutant inoperable or metastatic NSCLC, all of whom had previously received platinum-based chemotherapy and a PD-1 or PD-L1 inhibitor, and tracked them for a median of 12.9 months. For the 112 patients with measurable disease at baseline, “adagrasib demonstrated promising clinical activity,” said Alexander Spira, MD, PhD, of Virginia Cancer Specialists and NEXT Oncology Virginia, both in Fairfax, who presented the findings.

Spira reported that one patient (1%) experienced a complete response, 47 (42%) achieved a partial response, and 41 (37%) had stable disease, for a disease control rate of 80%. Further, median progression-free survival (PFS) was 6.5 months and overall survival (OS) was 11.7 months; however, after an extended median follow-up of 15.6 months, median OS increased to 12.6 months. Half of the 48 responding patients continue to receive treatment.

In addition, adagrasib, which can penetrate the blood–brain barrier, proved beneficial to most of the 33 patients in the trial with central nervous system metastases, Spira noted. These metastases completely disappeared in five patients (15%), partially regressed in six more (18%), and remained stable in 17 (52%).

After researchers discovered that one of the trial's first patients had a dramatic response to the drug despite a co-occurring STK11 mutation, which was thought to make tumors immunologically cold, the study team assessed responses in participants with both a KRAS^G12C mutation and either a STK11, TP53, CDKN2A, or KEAP1 mutation. ORRs in those cases, Spira said, were nearly as high or higher than that of the overall study cohort, with one exception: Patients with KRAS^G12C and KEAP1 mutations fared worse, with an ORR of 28.6%.

“How will we take into account [these] comutations?” wondered invited discussant Sukhmani Padda, MD, of the Samuel Oschin Cancer Center at Cedars-Sinai Medical Center in Los Angeles, CA. The S1900E substudy of the Lung-MAP trial “may provide some clarity,” she suggested, because it is assessing how patients with these co-occurring alterations respond after receiving the competing KRAS^G12C inhibitor sotorasib (Lumakras; Amgen).

Heading off questions about which KRAS^G12C inhibitor—adagrasib or sotorasib—might have an edge, Padda noted that both drugs had virtually identical rates of disease control, time to response, and median PFS and OS.

However, toxicity could be the differentiating factor. Diarrhea, nausea, vomiting, fatigue, changes in liver enzymes, and numerous other treatment-related adverse events affected 97% of the patients who took adagrasib compared with 70% who took sotorasib. The severity of the adverse events was also greater with adagrasib—43% versus 21%, respectively—as were the number of dose reductions and interruptions. Yet, “both drugs have treatment-related adverse events that lead to discontinuation in the minority of patients—just 7%,” Padda remarked.

To determine whether taking a smaller amount of adagrasib—in lieu of the trial's prescribed 600 mg twice-daily regimen—might mitigate toxicity without a significant drop in efficacy, the researchers are testing 400 mg twice a day, Spira said.

“I am curious about a lower optimal starting dose,” Padda remarked.

A confirmatory phase III trial, KRYSTAL-12, comparing adagrasib with docetaxel in already treated patients is currently underway, Spira said. –Suzanne Rose