Study on the therapeutic efficacy and safety of adagrasib (Krazati) combined with pembrolizumab

Adagrasiib combined with pembrolizumab is used in the first-line treatment ofKRAS G12C mutated advanced non-small cell lung cancer. Multiple studies in recent years have given positive signals. KRYSTAL-7The KRYSTAL-7 study, as a key Phase II/Phase III project, has shown a higher response rate and longer-lasting disease control in people who have not had systemic treatment in the past. In the latest conference and journal abstract updates, the combination regimen achieved an objective response rate of close to 50% to 60% in the intention-to-treat population, and a disease control rate of more than 80%; among which PD-L1 expressed higher levels (≥50%) patients benefit particularly prominently, with reports showing that the median progression-free survival can reach approximately 27.7 months, suggesting that the biological synergy between immunity and KRAS inhibition is more significant within specific subgroups. The above data echoes the early KRYSTAL-1 cohort and provides a basis for the first-line implementation of the combination strategy.

From the perspective of survival endpoints, combination therapy has a more stable improvement in progression-free survival, while the follow-up of overall survival is still being extended. Multiple conference reports and press releases pointed out that the updated data of KRYSTAL-7 shows that the combination regimen maintains considerable depth and duration of remission in the overall population. Some patients can achieve sustained remission and survival for more than two years, especially among those with high PD-L1 expression. It should be noted that there is currently no direct head-to-head randomized controlled evidence with final results comparing standard first-line immunotherapy single agents, and the ongoing randomized phase will provide a clearer answer as to whether the combination is significantly better than pembrolizumab alone. Overall, the existing evidence has suggested that the combination strategy is expected to become one of the important first-line options for KRAS G12C mutated NSCLC, but it still needs to wait for the phase III confirmatory endpoints to mature.

In terms of safety, a core concern when combining KRAS inhibitors with PD-1 inhibitors is hepatotoxicity and immune-related adverse reactions. The risk of significant transaminase elevation has been observed when combined with similar drugs, but in KRYSTAL-7, the incidence of treatment-related liver events with adagrasib plus pembrolizumab was generally low. Although transaminase elevations are common, most of them can be managed through dose interruption or reduction. The rate of permanent discontinuation of both drugs due to liver toxicity is extremely low. The incidence of treatment-related adverse events of any grade was high, but they were mainly manageable gastrointestinal events, fatigue and abnormal laboratory indicators. Serious immune-related adverse events were basically consistent with the previous safety spectrum of pembrolizumab. Overall tolerability was considered manageable, with dose interruptions and short-term discontinuations common, but most patients were able to resume treatment after management.

In terms of clinical application, the combination regimen is currently mainly in the stage of clinical research and guideline discussion, and is yet to be determined by phase III randomized controlled studies and further review by regulatory agencies whether it will become the standard first-line treatment. Actual decision-making should take into account factors such as KRAS G12C mutation status, PD-L1 expression level, comorbidities, and baseline liver function. If the patient has high PD-L1 levels and is in good general condition, priority can be given to entering clinical trials to obtain combination treatment opportunities; if there is active liver disease or a history of immune-related hepatitis, more caution should be exercised and monitoring of transaminase, bilirubin, and coagulation function should be strengthened. For those who experience ≥ grade 3 aminotransferase elevation or persistent symptomatic immune-related adverse events, it is key to ensure efficacy and safety by following the established algorithm to promptly discontinue the drug, add glucocorticoids, and gradually reduce the dose before challenging. As the results of KRYSTAL-7 and subsequent studies mature, adagrasib combined with pembrolizumab is expected to bring longer-lasting disease control and survival benefits in a precisely stratified population.

Reference materials:https://www.drugs.com/