Sotorasib demonstrates durable efficacy in KRASG12C-mutated NSCLC

The KRAS^G12C inhibitor sotorasib has demonstrated durable efficacy in patients with locally advanced or metastatic KRAS^G12C-mutated non-small-cell lung cancer (NSCLC), with 2-year overall survival (OS) reported in one-third of patients in the CodeBreaK 100 trial.

The updated analysis, presented at the American Association for Cancer Research (AACR) Annual Meeting 2022, included 174 patients enrolled in the phase I and II components of the trial (mean age, 64.1 years; female, 52.3 percent; former smoker, 81.6 percent; current smoker, 10.3 percent; median lines of prior therapy, 2; prior platinum-based chemotherapy, 92.5 percent; prior anti–PD-[L]1 therapy, 90.2 percent; prior platinum-based chemotherapy and anti–PD-[L]1 therapy, 82.8 percent). The patients received sotorasib 960 mg QD orally for disease that had progressed on prior therapies. [Dy GK, et al, AACR 2022, abstract CT008]
“After a median follow-up of 24.9 months, OS rate was 50.8 percent at 1 year and 32.5 percent at 2 years,” reported investigator Professor Grace Dy of Roswell Park Comprehensive Cancer Center, Buffalo, New York, US.
“The 2-year OS rate compares favourably with historical treatment in NSCLC,” she continued. [J Clin Oncol 2017;35:3924-3933] “This sets the bar for what we would expect with results of the confirmatory phase III CodeBreaK 200 trial.”
Consistent with previously reported results from the phase II component of CodeBreaK 100, median OS was 12.5 months in the updated analysis. [N Engl J Med 2021;384:2371-2381] Updated median progression-free survival (PFS) was 6.3 months.
Centrally confirmed objective response rate was 40.7 percent, with complete response and partial response observed in 2.9 percent and 37.8 percent of patients, respectively, while disease control rate was 83.7 percent.
“The median duration of response was 12.3 months. Median time to response was 6 weeks, with 70 percent of patients showing a response at the first scan,” Dy said. “About half [50.6 percent] of the responders remained in response for ≥12 months.”
“Long-term clinical benefit, defined as PFS of ≥12 months, was achieved in about a quarter of patients [n=40],” she highlighted.
Exploratory analysis showed similar baseline characteristics between patients with long-term clinical benefit and nonresponders with PFS ≤3 months (n=62), except for a lower rate of prior platinum-based chemotherapy and anti–PD-(L)1 therapy in the former subgroup of patients (70 percent vs 91.9 percent).
“Prolonged clinical benefit with sotorasib was observed across KRAS^G12C variant allele frequency and PD-L1 expression levels, including in tumours with low PD-L1 expression, and in patients with STK11 comutations who may derive less benefit from immunotherapy,” reported Dy. “In addition, lower baseline plasma circulating tumour DNA levels were observed in patients who had long-term benefit.”
The updated analysis also demonstrated long-term tolerability of sotorasib, with no new safety signals identified. Grade 3/4 treatment-related adverse events (TRAEs) were reported in 21 percent of patients.
“TRAEs led to treatment modification and discontinuation in 22 percent and only 6 percent of patients, respectively,” said Dy. “The most common TRAEs were diarrhoea [31 percent], nausea [16 percent], and liver enzyme abnormalities [8–18 percent].”
“About 25 percent of patients remained on treatment after 1 year. Among these patients, late-onset TRAEs were mild and manageable, and did not result in treatment discontinuation,” she noted. “Only one patient had new-onset grade 3 TRAE after 1 year [haemolytic anaemia]. No fatal TRAEs were reported.”
“This longest follow-up of patients treated with a KRAS^G12C inhibitor demonstrated meaningful and durable efficacy as well as a favourable safety profile of sotorasib,” she concluded.