A retrospective study published in JCO Precision Oncology identified factors associated with clinical response and toxicity in patients taking sotorasib for advanced KRASG12C-mutant non-small cell lung cancer (NSCLC), including KEAP1 co-mutation status and previous exposure to anti-PD-L1 therapies.
The FDA granted accelerated approval to sotorasib, a KRASG12C inhibitor, in 2021, on the strength of clinical trial data that showed improvements to progression-free survival (PFS) and overall survival (OS) in patients with KRAS-mutant NSCLC. Because KRAS mutations affect up to 40% of patients with lung cancer, targeted therapies are warranted, but scant real-world data exist on the utility of sotorasib in clinical practice.
Kathryn C. Arbour, MD, a thoracic oncologist at Memorial Sloan Kettering Cancer Center, and colleagues identified patients treated with sotorasib at three high-volume cancer centers in New York City to assess and determine markers of treatment response and resistance in the real-world setting. The study included data from 105 patients (median age, 70 years; range, 51-90; 59% women).
Median follow-up was 13.1 months. For the overall cohort, the researchers observed a median real-world PFS of 5.3 months (95% CI, 3.6-6.6) and OS of 12.6 months (95% CI, 8.3-not evaluable), with a median time on sotorasib of 7.2 months (95% CI, 4.6-10.4). The real-world response rate was 28% (95% CI, 20-37), and the disease control rate was 74% (95% CI, 64-81). Among 13 treatment-naive patients, the researchers observed a median real-world PFS of 11 months (95% CO, 7.3-not evaluable), with a median OS not reached (median follow-up, 14.1 months).
The presence of KEAP1 co-mutations was associated with significantly shorter median real-world PFS (median, 2 months; hazard ratio [HR] = 3.19; 95% CI, 1.46-6.95; P = .004) and OS (median 5.2 months; HR = 4.1; 95% CI, 1.64–10.3; P = .003). STK11 co-mutations were not associated with significant real-world PFS or OS differences, nor were TP53, STK11, or KEAP1 mutations.
The most common grade 3 treatment-emergent adverse events included increased alanine aminotransferase levels (9%), increased alkaline phosphatase (6%), and increased aspartate transferase levels (6%). The researchers noted that among 16 patients who developed grade 3 sotorasib-related adverse events, nearly all (n = 15) had previous exposure to anti-PD-L1 therapies. Conversely, among 19 patients who were naive to anti-PD-L1 therapies, only 1 patient developed a grade 3 sotorasib-related adverse event.
Fourteen patients discontinued sotorasib due to treatment-emergent adverse events, all of whom had previous exposure to anti-PD-L1 therapies. The researchers identified a potentially causal relationship between the risk for grade 3 or higher adverse events and the timing of previous anti-PD-L1 therapy. Patients who received anti-PD-L1 therapies within 12 weeks of initiating sotorasib were significantly more likely to develop these adverse events (P < .001) and to discontinue treatment (P = .014).
“Our study suggests that sotorasib is associated with modest single-agent activity in the real-world setting, and that assessment of KRAS co-mutation status and recent exposure to anti-PD-L1 therapy are important considerations before sotorasib administration in the clinic,” Arbour and colleagues concluded. “Further exploration of best strategies to mitigate toxicity is crucial to optimize targeted therapies for patients with advanced NSCLC harboring KRASG12C mutations.”
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Disclosures: Arbour declared financial ties to drugmakers. See full study for details.
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