Lead-in therapy in patients with advanced KRASG12C-positive non-small cell lung cancer (NSCLC) with the small molecule sotorasib that specifically and irreversibly inhibits KRASG12C, followed by immunotherapy with pembrolizumab or atezolizumab, demonstrated durable clinical activity with lower rates of grade 3-4 treatment-related adverse events compared with patients who received both therapies at the same time. These data were presented by Dr Bob Li, medical oncologist and specialist in thoracic oncology at the Memorial Sloan Kettering Cancer Center, NY, at the International Association for the Study of Lung Cancer World Conference on Lung Cancer (WCLC 2022) held in Vienna Austria, August 6 – 9, 2022 . Medicom contacted Dr Li about the implications of his results.
Sotorasib monotherapy has demonstrated a durable objective response rate of 41%, and 33% two-year overall survival in advanced pre-treated KRASG12C-mutated NSCLC. In preclinical studies, sotorasib combined with anti-PD-1 therapy increased CD8+ T-cell infiltration and enhanced anti-tumour efficacy.
Dr Li and colleagues have been running the phase 1b dose exploration study called CodeBreak 100/101 (NCT03600883), with the primary endpoint to provide the first assessment of safety and efficacy of sotorasib with either pembrolizumab or atezolizumab anti-PD-1/PD-L1 immunotherapy, as well as finding the recommended phase 2 dose.
The researchers enrolled KRASG12C-mutated NSCLC patients who had never been exposed to a KRASG12C-inhibitor (n=58). A total of 12 dose exploration cohorts were established at varying doses of sotorasib (120-960 mg per day) in combination with either intravenous atezolizumab at 1200mg or pembrolizumab at 200mg, administered every 3 weeks until intolerability or disease progression. Half of the cohorts received lead-in sotorasib monotherapy for either 21 or 42 days prior to their first dose of immunotherapy, followed by atezolizumab or pembrolizumab in combination with with sotorasib. Key secondary efficacy objectives included objective response rate and disease control rate. The dose limiting toxicity window was 21 days following initiation of combination treatment.
Dr Li reported the data with a median follow-up of 12.8 months (range 1.6 – 29.9 months). At baseline, the median prior lines of therapy was 1 (range 0-7), of which 67% patients had been previously exposed to an immunotherapy agent. The median doses of sotorasib administered were 83 (range 22-791), whereas the median rounds of immunotherapy administered were 3 (range 1-26).
With regard to safety, no fatal adverse events occurred. The most common grade 3-4 treatment-related adverse events were increased liver enzymes aspartate transaminase and alanine transaminase. Among the patients with grade 3-4 adverse events, 88% patients occurred outside the dose limiting window, most were managed with corticosteroids, and 97% of events resolved. Across all 12 cohorts, serious adverse events and adverse events leading to treatment discontinuation were less frequent in the cohorts which had the sotorasib lead-in regiment, as opposed to cohorts receiving both sotorasib and immunotherapy at the same time. Although numbers are low, atezolizumab appeared somewhat more tolerable than pembrolizumab, with more median number of treatment doses (2.5 versus 1.0, respectively) and fewer patients discontinuing in the lead-in cohorts (10% versus 32% respectively). Objective response was observed in 17 of the evaluated 58 patients (29%), in whom the median duration of response was 17.9 months. Median overall survival was 15.7 months (95% CI 9.8-17.8).
Dr. Li answered Medicom by email: “Combining sotorasib with pembrolizumab or atezolizumab in advanced KRASG12C NSCLC led to a higher incidence of grade 3-4 treatment-related adverse events than previously observed with monotherapy, primarily liver enzyme elevations. However, these effects can be mitigated by dose reduction and lead-in administration of sotorasib. Dose expansion is ongoing in treatment-naïve patients using sotorasib lead-in followed by combination with immunotherapy as a potential first-line treatment.”
Li BT, Falchook GS, Durm GA, et al. CodeBreaK 100/101: first report of safety/efficacy of sotorasib in combination with pembrolizumab or atezolizumab in advanced KRAS p.G12C NSCLC. Presented at: 2022 World Conference on Lung Cancer; August 6-9, 2022; Vienna, Austria. Abstract OA03.06.
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