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Sotorasib, Pembrolizumab Combination Merits Further Investigation In KRAS-Mutated NSCLC

Lead-in sotorasib monotherapy followed by the addition of pembrolizumab has shown early promise for the treatment of advanced KRAS G12C-mutated NSCLC
08 Aug 2022
Cytotoxic Therapy;  Clinical Research;  Immunotherapy;  Targeted Therapy
Non-Small Cell Lung Cancer

Author: By Shreeya Nanda, Senior medwireNews Reporter

medwireNews: A combined regimen of sotorasib and pembrolizumab, where the KRAS G12C inhibitor is initiated as lead-in, has demonstrated manageable toxicity and promising efficacy in patients with advanced non-small-cell lung cancer (NSCLC) harbouring KRAS G12C mutations. 

The findings from the phase Ib CodeBreaK 100 and 101 trials were presented at the IASLC World Conference on Lung Cancer 2022 in Vienna, Austria, by Bob Li, from Memorial Sloan Kettering Cancer Center in New York, USA. 

Preclinical studies have shown that sotorasib synergises with PD-1 inhibitors to inhibit tumour growth in mice, and also increases CD8+ T-cell infiltration, explained the presenter. 

The researchers therefore investigated the safety and efficacy of sotorasib at doses ranging from 120–960 mg/day in combination with pembrolizumab 200 mg or atezolizumab 1200 mg given every 3 weeks in people with advanced KRAS G12C-mutated NSCLC. In the lead-in cohorts, sotorasib was initially given as monotherapy for 21 or 42 days before immunotherapy was started, while in the concurrent cohorts, the agents were given together from the beginning. 

Participants were aged a median of 66 years and the majority (79%) had received prior systemic treatment (median lines of therapy 1, range 0–7). In all, 67% had previously received anti-PD-1 or anti-PD-L1 therapy. 

Bob Li reported that regardless of the immunotherapeutic agent used, toxicity was worse with concurrent rather than lead-in sotorasib. For instance, treatment-related adverse events of grade 3 occurred in 74% of the 19 patients in the concurrent sotorasib–pembrolizumab cohort and in 53% of the 19 in the lead-in sotorasib–pembrolizumab cohort. The corresponding rates for the atezolizumab cohorts, each of which had 10 patients, were 50% and 30%. 

Looking at the safety profile by sotorasib dose, Bob Li highlighted that “there was a trend towards less liver enzyme elevations” with lower doses. For example, in the concurrent sotorasib–pembrolizumab cohort, the rates of grade 3 or worse hepatotoxicity were 40% with the 120 mg dose of sotorasib and 25% with the 360 mg dose versus 100% and 75% with the 720 and 960 mg doses, respectively. 

He noted that the sample sizes for these dose subgroups “were limited”, but summarised that “overall safety data from the lead-in and concurrent cohorts support lower-dose sotorasib as well as lead-in administration for better tolerability.” 

With regard to efficacy, 17 of the total 58 participants had a complete or partial response lasting a median of 17.9 months, giving an objective response rate of 29%. Another 31 had stable disease, and therefore the disease control rate was 83%. 

The median overall survival for the full study population was 15.7 months. 

Focussing just on the patients who received low-dose lead-in sotorasib plus pembrolizumab, the investigator noted that responses were “durable and deep.” He reported that six patients continued to derive clinical benefit at the time of data analysis, with four remaining on combination therapy and two continuing sotorasib monotherapy. 

Based on these results “we will be exploring sotorasib as lead-in therapy in combination with pembrolizumab as first-line therapy for patients with advanced KRAS G12C NSCLC to further assess the benefit–risk ratio”, concluded Bob Li. 

Discussant Helena Linardou, from Metropolitan Hospital in Athens, Greece, said that “this study is giving us preliminary evidence that indeed KRAS inhibitors can be combined with immunotherapy as long as we can be cautious and address specific toxicities”. 

She added that more data are awaited, such as the efficacy in the atezolizumab cohorts as well as by PD-L1 expression status, but Helena Linardou expects to see further clinical development of the KRAS inhibitor–immunotherapy combination. 



OA03.06: Li BT, Falchook G, 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. IASLC World Conference on Lung Cancer 2022; Vienna, Austria: 6–9 August. 

medwireNews is an independent medical news service provided by Springer Healthcare Ltd. © 2022 Springer Healthcare Ltd, part of the Springer Nature Group

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