Low-dose Sotorasib 'turn-in' strategy holds promise in NSCLC subgroup

VIENNA — Sotorasib (Lumakras) is feasible as a “lead-in” therapy as first-line therapy in advanced KRAS patients prior to combining sotorasib (Lumakras) with immunotherapy G12C non-small cell lung cancer (NSCLC), according to the study presented here.

Patients treated with low-dose sotorasib versus lead-in regimens of either pembrolizumab (Keytruda) or atezolizumab (Tecentriq) showed “durable clinical activity and deep responses,” New York Bob T. Li, MD, MPH, MPH of Memorial Sloan Kettering Cancer Center reported at the World Congress on Lung Cancer (WCLC).

“KRAS G12C is a druggable target and complex resistance mechanisms can be addressed by rational combinations,” concludes study discussant Helena Linardou Medicine, Metropolitan Hospital, Athens, Greece PhD.

The study by Li and colleagues provides preliminary evidence that G12C inhibitors “may be compatible with immunotherapy is used in combination,” she added. , Li said.

His group’s CodeBreaK 100/101 Phase 1b dose-finding study was designed to evaluate the safety and efficacy of sotorasib versus anti-PD-1/PD-L1 immunotherapy. An obvious concern, however, was the higher rate of grade 3 or 4 treatment-related adverse events (TRAEs) with these combinations compared with sotorasib monotherapy.

“But we did see how we could mitigate this,” Lee noted.

Specifically, Li and colleagues were able to reduce the incidence of hepatotoxicity — which accounts for the majority of grade 3 or 4 TRAEs — by reducing sotora patients were treated with either a dose of zebracil or by an introduction regimen in which they were given sotoracide monotherapy prior to the first dose of immunotherapy.

“The incidence of bidirectional hepatotoxicity tends to decrease,” Li said. ) was 29% in the entire cohort of 58 patients (evenly split between lead-in regimen treatment and concurrent regimen treatment). The disease control rate was 83%, with responses lasting more than 10 months observed in 5 patients and 8 sustained responders. The median duration of response was 17.9 months.

In addition, durable clinical activity and depth of response were observed in the introduction of sotorasib versus pembrolizumab, Li said. Therefore, “low-dose sotorasib at 240 mg is currently being explored as a lead-in agent in combination with pembrolizumab as a potential first-line strategy,” Li said.

Patients in this study received various doses of sotorasib (120-960 mg twice daily) in combination with IV atezolizumab or pembrolizumab in 12 dose-finding cohorts , administered concurrently every 3 weeks until intolerance or disease progression.

Half of the patients in the introduction cohort in which patients received sotorasib monotherapy for 21 or 42 days prior to the first immunotherapy and then received atezolizumab or atezolizumab while continuing sotorasib pembrolizumab.

The median age of patients in this analysis was 66 years, and 67% of patients had prior anti-PD-1 or PD-L1 therapy, with a median of One treatment (ranging from none to seven).

Li and colleagues found that 15 of the 19 patients receiving concomitant sotorasib y TRAE with pembrolizumab were grade 3 or 4. For the highest doses of sotorasib (720 mg and 960 mg), those grade 3 or 4 TRAEs were mainly hepatotoxicity and liver enzyme elevations. As the dose of sotorasib was reduced to 120 mg or 360 mg, there was “a trend toward lower incidence of hepatotoxicity,” Li reported.

Comparing lead-in to investigators found that whether they were evaluating the pembrolizumab or atezolizumab cohorts, “the risk of either grade 3 or 4 adverse events was numerically lower with the lead-in regimen, “Li said. )

Grade 3 or 4 TRAE rates were 30% with sotorasib/atezolizumab lead-in and 53% with sotorasib/pembrolizumab lead-in, respectively, 60% and 79% with concurrent comparisons. The incidence of discontinuation due to grade 3 or 4 TRAEs was also lower in the lead-in group.

Most high-grade hepatotoxic events occurred outside the 21-day dose-limiting toxicity window, resolved in 97% of patients with corticosteroids, treatment modification, treatment discontinuation, or a combination thereof .

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  Mike Bassett is a staff writer specializing in oncology and hematology. He lives in Massachusetts.