Lung cancer

Sotorasib shows incremental benefit in KRAS-mutated NSCLC

The small molecule sotorasib improves progression-free survival (PFS) but not overall survival (OS) in patients with previously treated advanced KRASG12C-mutant NSCLC.

Results from CodeBreaK 200, an international phase 3 RCT, show a 34% decrease in the relative risk of disease progression or death with sotorasib.

The study, published in The Lancet [link here] and coauthored by Professor Ben Solomon from the Peter MacCallum Cancer Centre in Melbourne, randomised 345 patients to either oral sotorasib (960 mg daily) or standard-of-care IV docetaxel (75 mg/m² every 3 weeks).

After a median follow-up of 17·7 months, the study met its primary endpoint of a statistically significant improvement in median PFS with sotorasib versus docetaxel (5·6 v 4·5 months; HR 0·66 [95% CI 0·51–0·86]; p=0·0017).

As well, the benefit appeared to be durable with PFS rates at 12 months of 24·8% with sotorasib and 10·1% with docetaxel.

There was also a higher overall response rate with sotorasib (28.1% v 13.2%), higher disease-control rate (82.5% v 60.3%) and, in those patients with a response, a faster time to response (1.4 v 2.8 months) and longer duration of response (8.6 v 6.8 months).

“Sotorasib showed a consistent benefit in the overall response rate, compared with docetaxel, in all prespecified subgroups across demographics, ECOG performance status, previous lines of therapy, PD-L1 expression levels, and history of CNS involvement,” the study said.

Sotorasib also delayed CNS recurrence in a subgroup of patients with previous CNS disease (15.8 v 10.5 months; HR 0.52).

However the study found no significant difference in overall survival between the treatment groups (10.6 v 11.3 months; HR 1·01).

The study found sotorasib had a better toxicity profile – fewer grade 3 or worse (33% V 40%) and serious treatment-related adverse events (11% V 23%) – and was associated with better quality of life in patient-reported outcomes than docetaxel.

“Overall, these findings indicate that sotorasib represented a new treatment option in this patient population with poor prognosis and a high unmet need,” the study authors said.

“Upfront next-generation sequencing testing will allow for the identification of these patients at diagnosis but carrying through this knowledge is crucial to ensure that patients are appropriately treated in subsequent treatment lines.”

An accompanying Comment in the journal [link here] said the ability to target KRAS was one of the most significant breakthroughs in oncology in recent years.

It said the PFS data in the CodeBreaK 200 trial was encouraging although the lack of OS benefit was disappointing.

“The lack of survival benefit probably reflects the heterogeneity in outcomes in patients with KRASG12C-mutated NSCLC, with many patients not deriving benefit and others responding to treatment but quickly acquiring resistance.”

It said the high crossover rate from docetaxel treatment to sotorasib (34%) might also dilute any survival benefit.

The article said ASCO has previously proposed 4 months as a clinically meaningful PFS improvement in NSCLC [link here].

“In the era of targeted therapies in lung cancer when we have come to expect response rates well above 60%, median progression-free survival measured in years rather than months, and median overall survival approaching 5 years in some cases, sotorasib does appear to be inferior,” the US authors of the Comment said.

“However, as a second-line therapy with a better toxicity profile than that of docetaxel and the potential for durable benefit, KRASG12C inhibitors including sotorasib are very likely to remain the preferred agents to use in the clinic after progression on first-line chemotherapy and immune checkpoint inhibitors despite the small difference in median progression-free survival and lack of a demonstrated benefit in overall survival.”

CodeBreaK 200 was funded by Amgen.

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