With single-agent PD-1/PD-L1 therapy, melanoma patients are achieving outcomes once thought impossible for the disease, with some responses lasting more than a decade. Nevertheless, this pillar of cancer therapy is still in its infancy. Oncologists are exploring combination approaches that involve multiple checkpoint inhibitors, vaccines, and/or targeted agents as well as chemotherapy and radiation.
At the 2017 ASCO-SITC Clinical Immuno-Oncology Symposium, Omid Hamid, MD, provided an overview of combination therapies that have succeeded in phase 1 and 2 studies with greater than 50% response rates and are currently accruing in phase 3 trials for melanoma.
“Oncologists are just beginning to unleash immunotherapy’s full potential,” said Dr Hamid, Chief of Translational Research and Immuno-Oncology at The Angeles Clinic and Research Institute in Los Angeles, CA. “Multiple combinations exist to increase response, and response rates of greater than 50% have been seen, but we’re not yet sure what that means for overall survival. We need better biomarkers to predict response, and we need to take all of these combinations to overcome primary resistance and second-line therapies.”
As Dr Hamid reported, combination therapy with ipilimumab plus nivolumab is the “granddaddy of them all.” Having started in melanoma, the ipilimumab plus nivolumab combination has moved forward in multiple solid tumors, including lung and bladder cancer. Regardless of PD-L1 expression, he explained, response rates are higher with the combination, but there is a trade-off of increased toxicity.
“In tumors with high PD-L1 expression, response rates can go from 57% to 72%, and with low expression, patients can still get a benefit and higher complete response,” said Dr Hamid. “However, with this combination, 50% of patients experience grade 3 or 4 toxicity, and about a third of patients discontinue therapy due to toxicity.”
T-VEC plus Checkpoint Inhibitors
Talimogene laherparepvec (T-VEC) is an oncolytic viral therapy (a modified herpesvirus) injected directly into melanoma lesions. When combined with anti–PD-1 or anti–CTLA-4 agents, the therapy has led to response rates exceeding 50% in phase 1 and 2 studies.
“We can see greater progression-free survival and a hint toward possible overall survival benefit with rapid, deep, and durable responses,” said Dr Hamid, who noted that even after just T-VEC monotherapy, increases in CD8+ T cells from baseline were observed, especially in patients with disease control.
“This increase in activated CD8+ T-cell count may be a way to understand which patients will respond and which won’t,” he explained.
T-VEC is currently being studied in combination with pembrolizumab or ipilimumab in separate, randomized phase 3 studies.
MAP Kinase Signaling Pathways
As Dr Hamid reported, researchers are also studying the effect of blocking MAP kinase (MAPK) signaling pathways in cancer. The BRAF mutation, which is important in melanoma, exists in colorectal cancer, lung cancer, and about 8% of all solid tumors as well. According to Dr Hamid, MAPK inhibitors have been shown to induce the following changes: increased melanoma antigen expression, decreased immunosuppressive cytokine production, and increased CD8+ T-cell infiltration.
“Given these changes, it absolutely makes sense to combine MAPK inhibition with PD-L1 inhibition,” he said.
In BRAF V600–mutant metastatic melanoma, for example, the triplet combination of atezolizumab plus cobimetinib plus vemurafenib yielded an 83% response rate along with “significant and durable” responses. The trial is moving into phase 3, where the triplet combination will be compared with BRAF and MEK inhibitors alone.
However, this therapy is not just for BRAF-mutant patients. Atezolizumab is also being studied in combination with a MEK inhibitor in patients with metastatic melanoma who do not have the mutation.
“MEK inhibition, via direct effects on T cells and the tumor microenvironment, may help to unlock the full antitumor potential of PD-L1 inhibition,” Dr Hamid observed.
In BRAF-mutant and wild-type tumors, for example, a response rate above 40% and a clinical benefit of 75% has been demonstrated.
“While this is interesting in melanoma,” he added, “a similar trial was presented in colorectal cancer in patients who were microsatellite instability high, KRAS mutant, and who had historically poor response to immunotherapy. In that trial, there was a 20% response rate and a 40% clinical benefit. Clearly, there’s the ability to move forward in this area.”
Better Biomarkers Needed
Finally, clinicians are looking at combination therapies such as ipilimumab plus nivolumab in patients for whom initial PD-1/PD-L1 inhibition failed. Better biomarkers in the future will help protect patients from unnecessary toxicity, risk, or cost of combination, said Dr Hamid.
“Patients with high CTLA-4 and high PD-1 staining responded to single-agent PD-1 therapy at an 81% clip. Those with low staining, on the other hand, did not respond, which would be an indicator,” he concluded. “This is where we need to go.”