乌鸦传媒

NEW ORLEANS -- Sotorasib (Lumakras) continued to show efficacy in patients with KRAS G12C-mutated non-small cell lung cancer (NSCLC) in the longest follow-up of any KRAS G12C inhibitor, according to trial investigators.

Among 174 patients included in this updated analysis, the objective response rate (ORR) was 40.7%, with a median duration of response of 12.3 months, reported Grace Dy, MD, of Roswell Park Comprehensive Cancer Center in Buffalo, New York.

Prolonged tumor response was observed regardless of tumor mutation burden, PD-L1 expression, or STK11 co-mutation status, Dy noted during the plenary session at the American Association for Cancer Research meeting.

Of the key secondary endpoints, median overall survival (OS) was 12.5 months, with 1- and 2-year OS rates of 50.8% and 32.5%, respectively. The disease control rate was 83.7%, and median progression-free survival (PFS) was 6.3 months.

"This is certainly highly encouraging and sets the benchmark for expectations for the upcoming readout of the confirmatory phase III trial," said Dy, who noted that the 2-year OS rate compared favorably to what has been seen with docetaxel.

The reported ORR and PFS represent "significant headway for this molecularly defined subgroup of lung cancer, but not quite the response rate that we are used to seeing with some of our other classes [of drugs] and not quite the duration of PFS that we are used to seeing with EGFR and ALK [inhibitors]," said discussant Mark Awad, MD, PhD, of Dana-Farber Cancer Institute in Boston.

He pointed out that adagrasib has demonstrated a comparable response rate to sotorasib in KRAS G12C-mutated NSCLC, which raises a question: "Are we hitting a therapeutic ceiling with KRAS G12C inhibitor monotherapy?"

He suggested that the therapeutic efficacy of these inhibitors is limited by patient factors, intrinsic biology, and the emergence of complex resistance mechanisms, and that new approaches are needed to delay and overcome drug resistance.

Awad also wondered how the current standard of care for KRAS G12C-mutated NSCLC can be advanced. "Are there ways we can start thinking about incorporating this earlier on in the first-line setting?" he asked. "Can we incorporate this in the unresectable stage III population? Or in the resectable stage II to III lung cancer population?"

The FDA granted accelerated approval to sotorasib last spring as a second-line agent for NSCLC harboring KRAS G12C mutations, based on data from the phase II component of the CodeBreaK 100 study.

CodeBreaK 100 was a global study that was conducted in 52 centers across 10 countries in four continents. Of the 174 included patients, mean age was 64.1 years, 52.3% were women, and over 90% were current or former smokers.

The median number of prior lines of therapy was two; 90.2% received prior PD-1/L1 inhibitors, and 82.8% received both prior platinum-based chemotherapy and PD-1/L1 inhibitors.

Patients who progressed on prior therapy received sotorasib 960 mg once daily. Median time to response was 6 weeks.

As for safety, most treatment-related adverse events (TRAEs) were grade 1 or 2 in severity, and mostly gastrointestinal in nature. Grade 3 or 4 TRAEs occurred in 21% of patients, and 22% required treatment interruption or dose modification, and 6% discontinued treatment.

Among patients who remained on treatment for more than a year, "there were surprises in terms of late toxicity," Dy noted.

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