Low-Dose Sotorasib 'Lead-in' Strategy Promising in NSCLC Subset

VIENNA -- Using sotorasib (Lumakras) as "lead-in" therapy prior to combining it with immunotherapy was feasible as first-line therapy for patients with advanced KRAS G12C non-small cell lung cancer (NSCLC), according to research presented here.

Patients treated with lead-in regimens of lower doses of sotorasib with either pembrolizumab (Keytruda) or atezolizumab (Tecentriq) demonstrated "durable clinical activity and deep responses," reported Bob T. Li, MD, PhD, MPH, of Memorial Sloan Kettering Cancer Center in New York, at the World Conference on Lung Cancer (WCLC).

"KRAS G12C is a druggable target and complex resistant mechanisms can be addressed by rational combinations," concluded the session's designated study discussant, Helena Linardou, MD, PhD, of Metropolitan Hospital in Athens, Greece.

The study by Li and his colleagues provides preliminary evidence that KRAS G12C inhibitors "can be combined with immunotherapy as long as we can be cautious, and address specific toxicities," she added.

The lead-in combination appeared to have mitigated higher grade toxicities seen with combinations administered concurrently, Li said.

His group's CodeBreaK 100/101 phase 1b dose exploration study was designed to assess the safety and efficacy of sotorasib with anti-PD-1/PD-L1 immunotherapy. However, an issue that became apparent was the higher incidence of grade 3 or 4 treatment-related adverse events (TRAEs) seen with these combinations compared with sotorasib monotherapy.

"But we did see ways we could mitigate this," Li noted.

Specifically, Li and his colleagues were able to lower the incidence of hepatotoxicity – which accounted for most of the grade 3 or 4 TRAEs -- either by lowering the dose of sotorasib or by treating patients with a lead-in regimen in which they were given sotorasib monotherapy prior to their first dose of immunotherapy.

"Both ways trended towards a lower incidence of hepatotoxicity," Li said.

As for efficacy, at a median follow-up of 12.8 months, sotorasib combined with immunotherapy achieved an objective response rate (ORR) of 29% for the entire cohort of 58 patients (split evenly between treatment with the lead-in regimen versus a concurrent regimen). The disease control rate was 83%, with five patients having an observed duration of response greater than 10 months and eight ongoing responders. The median duration of response was 17.9 months.

Furthermore, durable clinical activity and depth of response was observed with sotorasib lead-in with pembrolizumab, Li said. Thus, "a lower-dose of sotorasib as lead-in at 240 mg is currently being explored in combination with pembrolizumab as a potential first-line strategy," Li said.

Patients in this study were treated in 12 dose exploration cohorts at different doses of sotorasib (120-960 mg twice daily) in combination with either IV atezolizumab or pembrolizumab, administered concurrently every 3 weeks until intolerability or disease progression.

Half of the patients were in the lead-in cohorts, in which patients received sotorasib monotherapy for either 21 or 42 days prior to their first dose of immunotherapy, and then received either atezolizumab or pembrolizumab while continuing with sotorasib.

Patients in this analysis had a median age of 66 years, with 67% having previous anti-PD-1 or PD-L1 therapy, with a median of one prior line of therapy (range none to seven).

Li and colleagues found that 15 of 19 patients treated with sotorasib concurrently with pembrolizumab had TRAEs of grade 3 or 4. For the highest doses of sotorasib (720 mg and 960 mg), those grade 3 or 4 TRAEs were primarily hepatotoxicity with elevations of liver enzymes. With de-escalation of doses of sotorasib to 120 mg or 360 mg, there was "a trend toward a lower incidence of hepatotoxicity," Li reported.

When comparing lead-in versus concurrent regimens, the researchers found that, regardless of whether they were assessing the pembrolizumab or atezolizumab cohorts, "the lead-in regimens had a numerically lower risk of grade 3 or 4 adverse events," Li said.

Grade 3 or 4 TRAE rates were 30% with sotorasib/atezolizumab lead-in and 53% with sotorasib/pembrolizumab lead-in versus 60% and 79% with their concurrent comparators, respectively. The lead-in groups had a lower incidence of grade 3 or 4 TRAEs leading to discontinuation as well.

Most high-grade liver toxicity events emerged outside of the 21-day dose-limiting toxicity window, and 97% were resolved with corticosteroids, treatment modification, treatment discontinuation, or a combination thereof.

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