Key messages
- Sotorasib shows antitumor activity in patients with pancreatic cancer KRAS p.G12C mutated already undergoing other treatments.
- The security profile appears acceptable.
Pancreatic cancer remains one of the most lethal. In recent times, research efforts are focusing, rather than on the identification of new chemotherapy regimens to be used in all patients indiscriminately, on the identification of therapies indicated for groups of patients with specific mutations.The latest molecularly targeted drug to appear on the scene is sotorasib. The phase 1 and 2 data just published in the New England Journal of Medicine are encouraging.
Sotorasib is an irreversible inhibitor of a mutated form of the KRAS protein, specifically KRAS G12C. About 90% of pancreatic ductal adenomas have mutations in KRAS, and 1-2% of patients have glycine replaced with cysteine at position 12. The Food and Drug Administration has already approved sotorasib for non-small cell lung cancer KRAS p.G12C mutated, as a second-line treatment. The CodeBreaK 100 trial, sponsored by Amgen, explored its activity and safety in pancreatic cancer.
The open-label study enrolled 38 adult patients with mutated KRAS p.G12C pancreatic cancer. Both patients with locally advanced and metastatic disease were eligible, but in fact all participants had metastases upon enrollment.Patients had to have already received at least one systemic therapy. Phase 1 explored the safety of the drug and allowed to identify the dosage (960 mg/day) to be used in phase 2 that was used to assess the objective response (confirmed by a centralized review).
Most study participants had already received 2 lines of treatment (range 1-8). A total of 8 patients (21%) achieved an objective response. Median progression-free survival time was 4.0 months (95% CI 2.8-5.6) and overall survival time 6.9 months (95% CI 5.0-9.1). The median time to response to treatment was 1.5 months. 42% of patients reported treatment-related adverse events; In 16% of patients, these events were grade 3. The most common adverse events were diarrhoea and fatigue. In no case did treatment-related adverse events cause the patient to die or lead to discontinuation of treatment.
«The clinical activity shown by sotorasib in this trial documents the fact that targeting KRAS is a viable strategy for the treatment of advanced pancreatic cancer,» the study authors said.The clinical activity of sotorasib against the mutation KRAS p.G12C should also reinvigorate efforts to design and develop inhibitors specific to the most common KRAS mutations in pancreatic ductal adenocarcinomas.» The evaluation of the efficacy and safety of sotorasib will therefore be carried out in larger studies, and trials (e.g. CodeBreakK 101) have already been launched to test the efficacy of sotorasib in combination with other therapies.
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Source — https://www.univadis.it/viewarticle/una-nuova-terapia-target-il-tumore-del-pancreas-2023a10000gb