Caroline Robert, MD, PhD, head of the Dermatology Unit at the Institut Gustave-Roussey, co-director of the Melanoma Research Unit at INSERM 981 Paris-Sud University, explains why patients with melanoma and brain metastases were excluded from a trial evaluating the efficacy of dabrafenib (Tafinlar) plus trametinib (Mekinist).

Patients with brain metastases generally have a poor prognosis, says Robert. Prognosis is dependent upon the number of metastases and where they are located in the brain. A patient can have just 1 small lesion in a bad location and as such, will have a bad prognosis, she explains.

The combination of dabrafenib and trametinib showed positive results in patients with 

 V600-mutated, unresectable and metastatic melanoma in a trial presented at the 2019 ASCO Annual Meeting. Although patients with brain metastases were excluded from the trial, trials exploring whether these patients could benefit from this treatment are underway. While early data show some efficacy with this combination in these patients, response rates were lower and less durable.

Going forward, Robert hopes to explore radiosurgery as well as focal radiotherapy with the addition of a targeted agent in patients with brain metastases.

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Caroline Robert, MD, PhD, head of the Dermatology Unit at the Institut Gustave-Roussey, co-director of the Melanoma Research Unit at INSERM 981 Paris-Sud University, explains why patients with melanoma and brain metastases were excluded from a trial evaluating the efficacy of dabrafenib plus trametinib.

Dr. Robert on Potential of Dabrafenib/Trametinib in Melanoma Brain Metastases

Caroline Robert, MD, PhD, head of the Dermatology Unit in Gustave Roussy Cancer Center, Villejuif-Paris, France, discusses results of a 5-year analysis evaluating the long-term effects of dabrafenib (Tafinlar) and trametinib (Mekinist) in patients with 

 V600—mutant unresectable or metastatic melanoma.

Long-term follow-up of these data show that 20% of patients who were treated with the BRAF/MEK inhibitor combination did not experience disease progression, and approximately one-third of patients were alive. However, more work needs to be done on these patient characteristics. Thus far, it has been identified that patients who do well on this therapy have low tumor burden and low lactate dehydrogenase levels.

Next steps involve best combining the targeted regimens with immunotherapy, or whether they should be administered sequentially, Robert says. Researchers are also aiming to find ways to increase the number of complete responders to the combination regimen, she concludes. 

Caroline Robert, MD, PhD, head of the Dermatology Unit in Gustave Roussy Cancer Center, Villejuif-Paris, France, discusses results of a 5-year analysis evaluating the long-term effects of dabrafenib (Tafinlar) and trametinib (Mekinist) in patients with BRAF V600–mutant unresectable or metastatic melanoma.

Dr. Robert on 5-Year Analysis of Dabrafenib/Trametinib in BRAF V600-Mutant Melanoma

Caroline Robert, MD, PhD, Head of Dermatology, Institute Gustave-Roussy, discusses the next steps following the results of the phase III COMBI-v study in 

The study evaluated the efficacy of the combination of dabrafenib (Tafinlar) plus trametinib (Mekinist) compared with vemurafenib (Zelboraf) monotherapy in patients with 

Next steps should focus on developing a better understanding of which subgroups of patients are responding best, and for the longest durations, says Robert. She also recommends a focus on more biomarker research, as well as an examination of potential combinations with immunotherapy that do not add too much toxicity.

Caroline Robert, MD, PhD, Head of Dermatology, Institute Gustave-Roussy, discusses the next steps following the results of the phase III COMBI-v study in BRAF-mutant melanoma.

Dr. Robert on Next Steps Following the Phase III COMBI-v Study in Melanoma

Caroline Robert, MD, PhD, Head of Dermatology, Institute Gustave-Roussy, discusses the results of the phase III COMBI-v study in BRAF-mutant melanoma during an interview at the ESMO 2016 Congress.

The study evaluated the efficacy of the combination of dabrafenib (Tafinlar) plus trametinib (Mekinist) compared with vemurafenib (Zelboraf) monotherapy in patients with BRAF V600 mutation-positive advanced melanoma.

Results of this study showed a 3-year survival rate of 45% for patients who received dabrafenib plus trametinib. Robert highlights the importance of these findings, given that before the era of targeted agents and immunotherapy, survival was quite dismal for the majority of patients. Future studies in this space will continue to examine the efficacy of combination therapies.

Dr. Robert on the Phase III COMBI-v Study in BRAF-Mutant Melanoma

Caroline Robert, MD, PhD, Head of Dermatology at the Institute Gustave Roussy in Paris, France, discusses results from the METRIC trial, which examined the oral targeted therapy trametinib, a first-in-class MEK inhibitor for patients with advanced melanoma.

The METRIC trial enrolled patients with advanced 

-mutated melanoma who had received up to one prior chemotherapy regimen. These patients were selected because MEK, which trametinib inhibits, is downstream from BRAF in the MAP kinase pathway.

In the trial, patients were randomized 2:1 to receive either trametinib or the standard chemotherapy for metastatic melanoma (dacarbazine or paclitaxel). The progression-free survival (PFS) for those taking trametinib was 4.8 months compared to 1.5 months for those receiving chemotherapy, which represented a 55% reduction in the risk of progression. Additionally, the response rate to trametinib was 22% compared to only 8% for those receiving chemotherapy.

Robert notes that the METRIC trial was design to allow crossover from the trametinib arm to the chemotherapy arm, following progression. This generally confounds the collection of an overall survival benefit; however, at the six-month interim analysis 81% of patients on the trametinib group were still alive, compared to 67% for those receiving chemotherapy.

Overall, the METRIC trial shows that inhibiting the MEK protein, using trametinib, resulted in a significant increase in PFS, higher response rates, and an increase in overall survival, when compared to chemotherapy alone.

Dr. Caroline Robert, from the Institute Gustave Roussy in Paris, France, Discusses the MEK Inhibitor, Trametinib, METRIC Trial Results.


Caroline Robert, MD, PhD

Articles

Dr. Robert on Potential of Dabrafenib/Trametinib in Melanoma Brain Metastases

Dr. Robert on 5-Year Analysis of Dabrafenib/Trametinib in BRAF V600-Mutant Melanoma

Dr. Robert on Next Steps Following the Phase III COMBI-v Study in Melanoma

Dr. Robert on the Phase III COMBI-v Study in BRAF-Mutant Melanoma

Dr. Robert on the Trametinib METRIC Trial Results