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KRAS Inhibitor Tops Docetaxel for Previously Treated NSCLC

— "New second-line standard" in KRAS G12C-mutant disease, says study investigator

MedpageToday

PARIS -- Targeted therapy in previously treated non-small cell lung cancer (NSCLC) patients harboring KRAS G12C mutations reduced the risk of disease progression or death by 34% compared with standard second-line chemotherapy, a phase III trial showed.

In this group of patients with locally advanced unresectable or metastatic disease, median progression-free survival (PFS) was a superior 5.6 months with the KRAS inhibitor sotorasib (Lumakras) versus 4.5 months with docetaxel (HR 0.66, 95% CI 0.51-0.86, P=0.002), reported Melissa Johnson, MD, of the Sarah Cannon Research Institute at Tennessee Oncology in Nashville.

This benefit was consistent across subgroups, she said here at the European Society for Medical Oncology (ESMO) annual congress. At 12 months, PFS rates were 24.8% with sotorasib compared with 10.1% with docetaxel.

Response rates were also significantly higher with sotorasib (28% vs 13%, P<0.001), and more patients experienced disease control with the targeted drug (83% vs 60%).

"Sotorasib is well tolerated, with clinically meaningful patient-reported outcomes that were superior with sotorasib versus docetaxel," said Johnson. "These findings support sotorasib as a new second-line standard in the treatment of patients with non-small cell lung cancer harboring KRAS G12C mutations."

With a median follow-up of nearly 18 months, overall survival was no different between the sotorasib and chemotherapy arms (10.6 vs 11.3 months, respectively; HR 1.01, 95% CI 0.77-1.33). About a third of patients in the docetaxel arm crossed over to sotorasib or received another KRAS inhibitor after disease progression.

"The magnitude of benefit is of concern. It's not what we'd hoped for," said ESMO-invited discussant Natasha Leighl, MD, of the Princess Margaret Cancer Centre in Toronto. "And does the 34% crossover really account for the lack of survival benefit?"

But she noted the "clear differences" in quality of life between the two treatment arms. "Although quality of life wasn't improved on sotorasib, patients did not deteriorate, whereas -- as you know -- they very quickly deteriorated with docetaxel."

CodeBreaK 200 randomized 345 NSCLC patients with a KRAS G12C mutation to either oral sotorasib (960 mg daily) or IV docetaxel (75 mg/m2 every 3 weeks). Over 70% were recruited from Europe and 12% from North America. PFS in the intent-to-treat population was the primary endpoint.

A majority of patients were women, the median age was 64 years, and all had received at least one prior line of therapy, including platinum-based chemotherapy and a checkpoint inhibitor. One-third of patients had a history of central nervous system involvement, which was a stratification factor, and roughly two-thirds had PD-L1 expression levels of 1% or greater. In terms of past treatments, 45% of patients had one previous line, 38-40% had two prior lines of therapy, and the rest had two or more.

Common treatment-related adverse events (TRAEs) with sotorasib included diarrhea (33.7%), nausea (14.2%), decreased appetite (10.7%), and transaminase elevations (10.1%). Grade ≥3 TRAEs occurred in 33.1% of patients on sotorasib (transaminase elevation and diarrhea most commonly) and 40.4% of those on docetaxel. Serious TRAEs occurred in 10.7% and 22.5%, respectively.

"We will need to be very proactive in the clinic in terms of managing diarrhea, and also monitoring and managing transaminitis," said Leighl.

The cost of sotorasib, which was approved by the FDA last year, could be a potential grade 3/4 financial toxicity, Leighl said, but "hopefully this will make it through the ranks and somewhere be considered cost-effective."

TRAEs leading to dose interruptions were higher with sotorasib (35.5% vs 15.2%), while TRAEs leading to dose reductions (15.4% vs 26.5%) and discontinuation (9.5% vs 11.3%) were less frequent with the targeted drug.

While the trial was limited to patients with an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, Leighl said the findings would likely be applicable to treating patients with a performance status of 2 or even 3.

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    Ian Ingram is Managing Editor at ľֱ and helps cover oncology for the site.

Disclosures

The study was funded by Amgen.

Johnson disclosed relationships with Amgen, and various other industry entities.

Leighl disclosed institutional, honoraria, or consulting relationships with Amgen, Array, AstraZeneca, Bayer, Bristol Myers Squibb, Eli Lilly, EMD Serono, Guardant Health, GSK, Inivata, Janssen, Merck Sharp & Dohme, Novartis, Pfizer, Puma, Roche, Sanofi, and Takeda.

Primary Source

European Society for Medical Oncology

Johnson ML "Sotorasib versus docetaxel for previously treated non-small cell lung cancer with KRAS G12C mutation: CodeBreaK 200 phase III study" ESMO 2022; Abstract LBA10.