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NCCN 2016

NCCN Melanoma Guideline Update: It's About Immunotherapy and Targeted Therapy

Surabhi Dangi-Garimella, PhD
At the National Comprehensive Cancer Network 21st Annual Conference, John A. Thompson, MD, presented an update on where the field of melanoma treatment stands today.
Predictive Biomarkers

Not everyone responds to these checkpoint inhibitors, and there could be multiple reasons for this, said Thompson. “With respect to immunostaining for biomarkers, there are a wide variety of methods being used and there still is a lack of convergence on percentage of staining for positivity.”
Thompson then showed data from the CA209-067 study that compared nivolumab alone, ipilimumab alone, and the combination of nivolumab and ipilimumab in treatment-naïve individuals diagnosed with unresectable or metastatic melanoma. The trial found that patients in the combination arm had a much better progression-free survival and higher overall response rate (ORR) than those treated with nivolumab alone. “However, importantly, grade 3/4 toxicities were also higher with the combination in half the patients in that treatment arm,” Thompson said. “So we need to be mindful of that.” The trial concluded that the combination works better in this patient population, especially among individuals who express less than 5% PD-L1 protein.
Clinical studies have also evaluated ipilimumab as adjuvant therapy in resected high-risk stage 3 melanoma, an example being the EORTC 18071/CA184-029 study. Thompson showed trial results that found significantly improved recurrence-free survival in patients treated with ipilimumab, which resulted in the drug being approved for patients in this category as adjuvant therapy.
However, treatment-related deaths were observed in 1.1% of patients, he said, including colitis, myocarditis, and neurological symptoms.
The Talimogene Laherparepvec (T-VEC) oncolytic virus has been found to improve durable response rates in patients with advanced melanoma. “The attenuated virus does not kill healthy tissue and causes tumor cells to secrete GM-CSF, followed by cell lysis,” said Thompson. He shared data from a trial comparing T-VEC vs GM-CSF in patients with advanced melanoma found T-VEC resulted in a durable response in 16% of patients, as against 2.1% in the GM-CSF arm. Further, CR was 10.8% vs less than 1%, PR was 15.6% vs 5%, and ORR was 26.4% vs 5.7%, respectively in the T-VEC and GM-CSF arms, the study found.
The last part of Thompson’s talk focused on combination regimens of BRaf-MEK inhibitors being used in first line therapy, especially in patients in whom a rapid antitumor response is necessary. The Combi-d study, he showed, evaluated BRaf (dabrafenib) and MEK inhibitors (trametinib) as first line in patients with BRAF V600E/K metastatic melanoma. Longer term follow-up showed a significant difference in the tail of the survival curve between dabrafenib alone and in combination with trametinib, and the response seems to plateau out at 34 months into treatment.
“Immunotherapies as well as targeted therapies are offering better outcomes,” said Thompson. “I believe we need to assess the patient and their ability to bear toxicity, as well as their ease of access to a clinic. This should decide the intensity of their therapeutic intervention.”
Thompson summarized the NCCN recommendations as follows:

For BRaf-mutated melanoma:

1. Preferred therapy for an early response is:
a. BRaf/Mek inhibitor combination
b. BRaf inhibitor monotherapy
2. For all other cases:
a. Anti–PD-1 monotherapy
b. Ipilimumab/nivolumab combination
c. Clinical trial
For BRaf wild type melanoma:
1. Anti–PD-1 monotherapy
2. Ipilimumab/nivolumab combination
3. Clinical trial
Thompson concluded with a series of questions that currently elude the field. “What should be the duration of therapy? Do we have predictive biomarkers? Should combination therapy or sequential therapy be administered?” Studies are ongoing to answer these unknowns. 

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