Sotorasib continues to impress at 2 years in KRAS G12C–mutant NSCLC

Long-term findings from the pooled phase I/II CodeBreak 100 trial support the efficacy of sotorasib in certain patients with KRAS ^G12C–mutant non–small cell lung cancer (NSCLC).

At the 2-year time point, the overall survival (OS) rate was 32.5 percent in patients treated with sotorasib 960 mg daily (the US FDA-approved dose). The overall response rate (ORR) was 40.7 percent, and the disease control rate (DCR) was 83.7 percent. [AACR 2022, abstract CT008]

“Our findings provide a rationale for the inclusion of sotorasib earlier in the treatment course of patients with NSCLC and KRAS ^G12C oncogenic driver who are less likely to benefit from immunotherapy,” said study investigator Dr Grace Dy, chief of thoracic oncology and professor of oncology at Roswell Park Comprehensive Cancer Center in Buffalo, New York, US.

As for the median duration of response (DOR),  12.3 months was achieved with sotorasib. Over 50 percent of responders were in response for 1 year.

Patients lived a median of 6.3 months without their cancer getting worse while the median OS was 12.5 months. At 1-year, the OS rate was 50.8 percent with sotorasib.

Meaningful results, longest follow-up

“Sotorasib demonstrated a meaningful and durable efficacy in this longest follow-up of patients on a KRAS ^G12C inhibitor,” said Dy. “The safety profile was consistent with what had been reported previously.”

Sotorasib is FDA-approved for locally advanced or metastatic KRAS ^G12C–mutant NSCLC in patients who have not received prior therapy, based on earlier findings from the CodeBreaK 100 trial.

“In the phase I cohort(n=48), sotorasib was well tolerated and showed a confirmed response rate of 32.2 percent, a median DOR of 10.9 months, and a median progression-free survival (PFS) of 6.3 months,” said Dy.

In the phase II cohort (n=126), sotorasib therapy led to a durable clinical benefit without new safety signals in patients with previously-treated KRAS ^G12C–mutated NSCLC. [N Engl J Med 2021;384:2371-2381]

In the updated analysis of the pooled phase I/II cohorts (n=174),  the clinical activity of sotorasib was observed regardless of PD-L1 expression. Moreover, prolonged clinical benefit was observed regardless of tumour mutation burden, PD-L1 expression, and STK11 co-mutation status.

No new safety concerns were observed with 2-year treatment with sotorasib. Grade 3/4 treatment-related adverse effects (TRAEs) occurred in 21 percent of patients. One had a new-onset grade 3 TRAE of haemolytic anaemia after 1 year. No TRAE-related deaths occurred, nor did any TRAEs lead to discontinuation after 1 year of treatment.

“Most toxicities were grade 1/2 in severity. Major AEs were mainly gastrointestinal, specifically nausea, diarrhoea, and liver function abnormalities. Twenty-two percent of patients required dose modifications or dose interruptions. Six percent required dose discontinuation,” Dy said. “Still, approximately one-quarter of patients remain on treatment after 1 year.”

As sotorasib is the first-in-class KRAS ^G12C inhibitor approved for this NSCLC subset, longer-term follow-up is warranted to better define its safety and efficacy in this setting, pointed out Dy. The phase III trial of sotorasib, CodeBreak 200 (with docetaxel as the comparator), is currently underway, and results are expected this year, she added.