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Triplet Regimen Induces Clinical Benefit at 24-Month Follow-Up in BRAF-Mutant Melanoma

Danielle Ternyila
Published Online:8:52 PM, Mon January 20, 2020
Pier Francesco Ferrucci, MD
Pier Francesco Ferrucci, MD
An updated analysis of the KEYNOTE 022 after 24 months of follow-up, demonstrated a statistically significant improvement in progression-free survival (PFS) with the triplet combination of dabrafenib (Tafinlar), trametinib (Mekinist), and pembrolizumab (Keytruda) in patients with BRAF-mutated advanced melanoma, according to Pier Francesco Ferrucci, MD, from the European Institute of Oncology in Milan, Italy.

Prior data indicated that the combination of dabrafenib plus trametinib alone is safe and efficacious in this patient population, representing the current standard of care. The addition of pembrolizumab was thought, and indeed it does, to increase the efficacy of the regimen in patients with BRAF-mutated disease allowing for a durable anti-tumor effect on the tumor cells. The triplet combination was then compared to the doublet dabrafenib plus trametinib in the randomized phase II KEYNOTE 022 clinical trial.

Initial results after 9-month follow-up were negative, although there was a clear improvement in PFS and overall survival (OS). The improvements, however, were not statistically significant as per the very stringent study design. At the 24-month follow-up, the data did reach significance, demonstrating the triplet’s potential as a treatment option for patients with BRAF-mutant advanced melanoma.

In an interview with Targeted Oncology, Ferrucci discussed the findings from the updated analysis, which he shared in a presentation at the 16th International Congress of the Society for Melanoma Research, highlightening the important takeaways from this follow-up analysis.

TARGETED ONCOLOGY: What was the rationale for investigating this new combination in BRAF-mutant melanoma?

FerrucciThe rationale is very strong because treating patients with dabrafenib and trametinib would allow to liberate antigens from the tumor cells, which could be more easily recognized by the immune system. The efficacy can also be enhanced by adding pembrolizumab with the aim of maintaining response over time. Moreover, preclinical data showed that targeted therapy itself have an impact on the immune system, possibly enhancing the activity of pembrolizumab.
The opportunity to administer 3 drugs together, would allow to induce tumor death and develop an immune response with a synergistic effect.

TARGETED ONCOLOGY: What were the methods of design?

FerrucciThis was the part 3, randomized phase II of the KEYNOTE 022 trial, comparing the combination of targeted therapy and immunotherapy to targeted therapy alone. The study enrolled BRAF-mutated patients with advanced metastatic melanoma. They were randomized, 60 patients per arm, to receive, in the experimental arm, a combination of dabrafenib, trametinib and pembrolizumab versus dabrafenib and trametinib alone in the comparator arm. Primary end point was PFS, secondary end points were OS, duration of response (DOR) and safety.

TARGETED ONCOLOGY: What were the findings?

FerrucciResults  were presented as a follow-up of a previous evaluation, which was published in Nature Medicine a few months ago. Previous analysis was based on a cutoff date performed in February 2018, which had just 9 months of follow-up. It was a very early evaluation, but patients receiving the triplet still performed better, showing a better PFS, even though, statistically, it did not reach significance per study design. At that point, the study was considered a negative study, since it missed the primary end-point. After 24 months of follow-up, data matured, and PFS reached a hazard ratio of 0.53 favoring the triplet in comparison with the doublet combination. Results showed also a higher DOR and a better OS for patients receiving the triplet.

TARGETED ONCOLOGY: What data are particularly important to highlight from this updated analysis?

FerrucciResults are very interesting because, at 24 months, we have a PFS of 41% in the triplet arm versus 16% in the doublet arm. Another important result is the DOR, which is much longer in the triplet arm with 55% of patients versus 16% that maintained benefit overtime. Finally, the third point I would like to underline is OS: after 24 months of follow-up, 63% of patients in the triplet arm versus 52% in the doublet arm are still alive, and most of them did not need to receive further treatments.

TARGETED ONCOLOGY: Would you like to highlight any takeaways from these data?

FerrucciThe triplet combination is causing much more toxicity, so this could be a limit for the use of this kind of combination on all patients, especially those with a bad performance status. On the other hand, disease control is evident and most of the patients were able to receive the 3 drugs together at least to the point of obtaining a clinical benefit. In fact, there was a high range of patients who were obliged to interrupt the treatment, especially in the triplet arm, but even more discontinued the treatment due to progressive disease in the standard arm. 
We showed a huge difference between the 2 treatments, which is becoming much more evident as time passes by, and this is mainly evident in favor of patients who have bad prognostic factors, like M1c disease and elevated LDH. There is an unmet need which this triplet combination could cover.

TARGETED ONCOLOGY: Do you have any concerns with using this triplet regimen in regard to the toxicity profile? 

FerrucciThere could be some concerns, but we have been to administer this kind of combination also in patients over the age of 65 years old, and the complications are quite similar to younger patients, where results are even better. We have new drugs, we have new combinations: we need to learn how to manage toxicities in order to take advantage of the positive returns of this effective armamentarium on disease control.

TARGETED ONCOLOGY: What do you hope oncologists take away from all of this?

FerrucciWe finally have a lot of new drugs that we can use in treating metastatic melanoma, and we are trying to find the best schedules for using these drugs. For example, we are trying to understand if combination therapy could be better than sequencing or if intermitted schedules could be less toxic than continuous ones. In any case, this is the first randomized trial that compares a triplet combination with immunotherapy and targeted therapy, showing the possibility to enhance the target of our hopes. There are 2 other randomized phase III trials comparing this kind of triplet combination to doublets which would clarify the real role of this options in a much wider population of patients.

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