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New evidence supports combination therapy for metastatic melanoma


Evidence-based data about molecular features is evolving to support the use of combination therapy as an option for treating metastatic melanoma.

Clinicians cannot yet make a fully-informed decision to choose monotherapy or combination therapy to treat melanoma in the metastatic setting when it comes to immune therapies, but the data are sound to support combination therapy when using targeted therapies in metastatic disease, according to a Professor of Medicine at Harvard Medical School/Massachusetts General Hospital Cancer Center and Director, Termeer Center and Clinical Research in Boston, Mass.

It is uncertain if combination therapy involving targeted therapies is beneficial in the adjuvant setting, and targeted therapies are not yet on the menu in the adjuvant setting, according to Keith Flaherty, M.D.

Speaking at the 10th annual Canadian melanoma conference, Dr. Flaherty points out that there are two major classes of therapies that have made a major impact on advanced melanoma: molecular targeted therapies and immune therapies.

"We offer patients immune therapies broadly, independent of additional molecular features," says Dr. Flaherty. "When it comes to molecular therapies, we consider patients as candidates if they have the underlying relevant genetic features."

Not all melanomas are expected to respond equally to treatment, notes Dr. Flaherty. "The immune therapies, such as nivolumab [an anti PD-1 antibody] or pembrolizumab [a PD-1 inhibitor], are highly impactful, but there are a significant proportion of patients who are refractory right away," says Dr. Flaherty.

"Increasingly,” he says, “We are trying to develop the evidence base for the molecular features and diagnostic features that we would use to assign patients to that type of therapy [immune therapy]. We have really compelling data that suggest what the molecular features might be. We have more work to do to develop real-world tests that could be used in clinical practice to assign patients to immune therapy."
More information, better choices

Having information about molecular features, and not just clinical features, would better inform the choice of combination or monotherapy in terms of immune therapy, says Dr. Flaherty.

Amongst targeted therapies, the "overwhelming evidence" suggests that efficacy is enhanced with combination therapy compared to BRAF inhibitor monotherapy, he points out. "We have three randomized, Phase III trials, all indicating almost identical results," says Dr. Flaherty. "They improve response rate, progression-free survival, and overall survival across the board. That was with two different combinations of BRAF and MEK inhibitors."

In a clinical trial that compared BRAF inhibitor monotherapy with vemurafenib to combination therapy with the BRAF inhibitor dabrafenib plus the MEK inhibitor trametinib, the combination therapy demonstrated superiority in overall survival and progression-free survival.1

 A meta-analysis of phase II and III trials with BRAF and BRAF/MEK inhibition demonstrated the greatest improvements in overall survival are with the combination of kinase inhibitors rather than use of a single kinase inhibitor.2

"Of course, we always balance the improvements with toxicity concerns," says Dr. Flaherty. "It turns out combination therapy toxicity is not significantly different [from monotherapy toxicity], when considering the BRAF/MEK combination regimens. With toxicity not being significantly worse, we generally say that we choose combination therapy for these patients [with metastatic disease]."

The degree of impact that molecular targeted therapies offer, either as monotherapy or combination therapy, in the adjuvant setting is less clear than in the metastatic setting, notes Dr. Flaherty. That data should be available in the next one to two years, when clinical trials are completed.

Risk factors for melanoma and genetic testing

Next: The adjuvant landscape

The adjuvant landscape

It is critical for dermatologists to have a knowledge of what therapies are emerging in the adjuvant treatment arena for melanoma, according to Dr. Flaherty.

"When a drug comes onto the adjuvant therapy landscape, it is of high significance for oncology, but particularly for practitioners who manage patients in an earlier diagnosis setting," says Dr. Flaherty, such as patients diagnosed with stage IIc or stage III.

One of the concerns expressed with the use of immune therapies such as ipilimumab has been the development of auto-immune toxicity, which can be life-threatening, says Dr. Flaherty. "That is an important caveat with that therapy," he says.

Combination therapy of immune therapies is more of a relevant question in the metastatic setting than adjuvant setting because the PD1 inhibitors are "not on the menu" in the adjuvant setting, says Dr. Flaherty.

While two immune therapies together, such as nivolumab and ipilimumab, have controlled disease and induced remission in metastatic disease in the short term to a greater extent than PD-1 or CTLA-4 antibody monotherapy, the effect comes with significant toxicity, says Dr. Flaherty.

"We do not have enough granular or long-term data to say we can produce better long-term survival rates with combination therapy," he says.

In young patients in excellent health outside of having metastatic melanoma and who are highly motivated to pursue potentially superior efficacy with less concern for toxicity, there is likely a stronger case for using the combination approach, according to Dr. Flaherty.

Disclosures: Dr. Flaherty is a consultant for Novartis, GSK, Roche, and Merck.


Grob JJ, Amonkar MM, Karaszewska B, et al. Comparison of dabrafenib and trametinib combination therapy with vemurafenib monotherapy on health-related quality of life in patients with unresectable or metastatic cutaneous BRAF Val600-mutation-positive melanoma (COMBI-v): results of a phase 3, open-label, randomised trial. Lancet Oncol. 2015;16(13):1389-98.

Ugurel S, Röhmel J, Ascierto PA, et al. Survival of patients with advanced metastatic melanoma: The impact of novel therapies. Eur J Cancer. 2016;53:125-34.    


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