EMA recommends refusal of conditional marketing approval for Krazati (adagrasib), read our thoughts

Last week we heard the disappointing news that the European Medicines Agency recommended the refusal of the conditional marketing authorisation for Krazati (adagrasib), a medicine intended for treating advanced non-small cell lung cancer (NSCLC) with KRAS G12C mutation [1]. The Marketing Application was based on a single arm study (KRYSTAL-1) showing an objective response rate of 43%, a median duration of response of 8.5m and a well-tolerated safety profile in NSCLC patients with the KRAS G12C mutation who had progressed after at least one line of systemic therapy.

This is a poor decision for patients with advanced NSCLC who might benefit from access to this new medicine. Technically, the “window” for conditional approval is threatened based on the earlier conditional approval of another new medicine, Lumykras (sotorasib), which also targets the KRAS G12C mutation [2], and also the recent delivery of randomised clinical data (Lumykras versus docetaxel), which showed a small (1.1m) improvement in progression-free survival (PFS) [3-4]. However, EMA approval of Lumykras does not mean that all NSCLC patients with the KRAS G12C mutation have access to this important new treatment for a variety of reasons, including pricing, reimbursement, negotiations between the marketing authorisation holder and local health systems, drug supply and availability of testing for the KRAS G12C mutation.

Competition in any market is healthy because the ultimate customers – in this case the needy patients – are more likely to be able to access a medicine that might benefit them. Clearly, more clinical data are needed on Krazati in the future to show the full extent of clinical efficacy and safety. These data will better inform both clinician and patient in selecting the treatment most appropriate for the patient. However, the response rate and safety data delivered in the single arm study with Krazati are not dissimilar to those delivered earlier by Lumykras as the basis for its conditional approval. So why deny Krazati conditional approval based on a similar data set?

KRAS was long viewed as an undruggable but important target to combat the devastating disease that is advanced NSCLC [5-7]. With the persistent efforts of many researchers over the years, we now have some important new medicines emerging. Let’s not overly restrict access to these medicines, but show we understand the broader picture and do what is best for cancer patients.

References

1. https://www.ema.europa.eu/en/documents/smop-initial/questions-answers-refusal-marketing-authorisation-krazati-adagrasib_en.pdf
2. https://www.ema.europa.eu/en/medicines/human/EPAR/lumykras
3. Johnson ML, de Langen AJ, Waterhouse DM, et al. LBA10 – Sotorasib versus docetaxel for previously treated non-small cell lung cancer with KRAS G12C mutation: CodeBreaK 200 phase III study. Annals of Oncology (2022) 33 (suppl_7): S808-S869. 10.1016/annonc/annonc1089
4. de Langen AJ, Johnson ML, Mazieres J, Dingemans AC, Mountzios G, Pless M, et al. Sotorasib versus docetaxel for previously treated non-small-cell lung cancer with KRAS(G12C) mutation: a randomised, open-label, phase 3 trial. Lancet. 2023;401(10378):733-46.
5. Hofmann MH, Gerlach D, Misale S, Petronczki M, Kraut N. Expanding the Reach of Precision Oncology by Drugging All KRAS Mutants. Cancer Discov. 2022;12(4):924-37.
6. Parikh K, Banna G, Liu SV, Friedlaender A, Desai A, Subbiah V, et al. Drugging KRAS: current perspectives and state-of-art review. J Hematol Oncol. 2022;15(1):152.
7. Huang L, Guo Z, Wang F, Fu L. KRAS mutation: from undruggable to druggable in cancer. Signal Transduct Target Ther. 2021;6(1):386.