The KRYSTAL-7 study

The KRYSTAL-7 study, presented at the ESMO Congress 2023, holds substantial promise for advancing the treatment of advanced NSCLC. This phase 2 trial focused on assessing a combination treatment involving adagrasib, a KRAS inhibitor, and pembrolizumab, an anti-PD1 agent. Notably, the trial’s objective was to evaluate this combination as a first-line treatment for patients with advanced NSCLC, specifically those with a high PD-L1 expression.

One of the primary concerns surrounding the utilisation of KRAS inhibitors in combination with immunotherapy has been the potential for liver toxicity. As such, the KRYSTAL-7 study generated significant interest in the oncology community as it sought to address this issue.

One of the most striking outcomes was the high response rate observed in PD-L1 high patients, which soared to approximately 60%. This response rate significantly surpassed the response rate achieved with pembrolizumab monotherapy, traditionally around 45%. The difference in response rates demonstrated the potential benefits of combining a KRAS inhibitor with immunotherapy, as it seemed to boost the overall response.

A noteworthy aspect of these findings was the manageable nature of the liver toxicity observed. While concerns were raised, as expected due to previous experiences with liver toxicity in similar combination therapies, the data revealed that the liver toxicity associated with the adagrasib-pembrolizumab combination was mostly low-grade. Furthermore, with prolonged treatment, these liver toxicity issues tended to diminish. The vital takeaway from these observations was that liver toxicity did not result in the need for treatment interruption, which is a positive development for patient care.

A key point of consideration that emerged from the discussion revolved around the categorisation of liver toxicity. While the assessment primarily relied on ALT and AST elevation, it was recognised that oncologists may need to improve the classification of liver toxicity. In-depth assessments involving measures such as bilirubin levels, MRI imaging, and liver biopsies could provide a more comprehensive understanding of the liver-related issues associated with this combination therapy.

As the results of the KRYSTAL-7 study reflect a significant advancement in the field of NSCLC treatment, the researchers believe that more extensive phase three trials are warranted. These trials should aim to gather additional data on various aspects, including co-mutations, toxicity profiles, and, most importantly, overall survival. This extended research is critical to gaining a comprehensive view of the combination therapy’s efficacy and its potential to transform the management of advanced NSCLC.

Marina C. Garassino – KRYSTAL-7: Efficacy and safety of adagrasib with pembrolizumab in patients with treatment-naïve, advanced non-small cell lung cancer (NSCLC) harboring a KRASG12C mutation – ESMO 2023? # LBA65