PHILADELPHIA-The treatment of unresectable or metastatic melanoma has come a long way in a short time. Only a few years ago, treatments were limited and, at best, only modestly effective. Since then, as Lynn Schuchter, MD, Professor of Hematology-Oncology and leader of the melanoma program at the University of Pennsylvania Abramson Cancer Center, has said, the landscape was "a desert" but is now a garden blooming with a good handful of new treatments that are approved or in development. Already, marketed drugs and candidate compounds target several pathways: the immune "checkpoints" CTLA-4 (cytotoxic T lymphocyte-associated antigen 4) and PD-1/PD-L1, the kinase products of mutated BRAF genes, and the intracellular cascade set off by kinases at the cell surface.
Ipilimumab was the first medicine to demonstrate overall survival for patients with metastatic melanoma, with some patients in trials and an expanded access program still alive 10 years later. The BRAF inhibitors vemurafenib and dabrafenib, which inhibit the protein kinase products of mutated BRAF genes, have also extended survival.
"However, we also know that the number of patients who derived long-term benefit from those medicines still is not as high as we want it to be," Jedd D. Wolchok, MD, PhD, Director of Immunotherapy Clinical Trials and an attending physician on the Melanoma-Sarcoma Service at Memorial Sloan-Kettering Cancer Center, said in an interview here at the 10th International Meeting of the Society for Melanoma Research.
The number of patients responding to ipilimumab is only about 20 to 25 percent, and the responses to BRAF inhibitors are relatively transient, with a median time to relapse of about seven months. At the meeting, Wolchok described his group's results combining ipilimumab and nivolumab either concurrently or sequentially in a total of 86 patients.
The concurrent cohorts (53 patients) received ipilimumab once every three weeks for four doses and nivolumab every three weeks for eight doses. The drugs were continued once every 12 weeks for up to eight doses.
The sequenced cohorts (33 patients) received nivolumab every two weeks for a maximum of up to 48 doses after receiving ipilimumab.
"We have some encouraging results from a Phase I trial which show an overall response rate of 40 percent across all dose levels, and for the dose levels that were chosen to move forward to the Phase II and Phase III setting, that response rate is just over 50 percent, with all of those patients having a decrease in their baseline tumor burden of 80 percent or more by the time of the first imaging," he said.
As expected, there were toxicities, but none that were distinct from the adverse effects seen with each medicine by itself, and there were no drug-related deaths, he emphasized. Prospective Phase II and III trials are now under way to explore whether CTLA-4 and PD-1 blockade concurrently is better than either approach alone.
Most responding patients had tumor regression by 12 weeks, but some responses occurred later. The concurrent cohort had a one-year overall survival rate of 82 percent, with a survival plateau just over 70 percent starting at 15 months and continuing to 36 months for all dosage regimens in the concurrent cohorts, he reported.
Among the patients with tumor regression, some had had radiographic progression and others had stable disease with prior ipilimumab. All the patients whose disease progressed on nivolumab had also progressed on prior ipilimumab. More patients responded with concurrent dosing compared with the sequential protocol.
Biomarkers Complement Drugs
Biomarkers are another focus of research, he continued. PD-L1 expression on tumor cells has been an area of active investigation as a predictor of response to PD-1 or PD-L1 blockade, with tumors expressing PD-L1 indicating that patients have a better chance of response to blockade.
"But I think it's very important to keep in mind that even tumors that are scored negative for this biomarker can be recognized by the immune system, and even patients whose tumors are scored as PD-L1-negative may benefit from blocking this receptor-ligand interaction. This is not a binary biomarker," he said, as in the case of BRAF, where if a patient has that mutation, it is very likely that a BRAF inhibitor will work, and if there is no mutation, such an inhibitor will not work.
In contrast, the PD-L1 situation is a "much more dynamic system," in which PD-L1 expression can vary between tumors, within tumors, and can be induced during the course of treatment. Thus, more work is needed to understand how each patient's tumor PD-L1 expression should influence therapeutic choices.
Melanomas lacking PD-L1 have a low rate of response to nivolumab alone or sequenced after ipilimumab compared with PD-L1-positive tumors, he said. PD-L1-positive tumors respond well to nivolumab monotherapy, nivolumab after ipilimumab, or when they are given together. Much investigation is also proceeding on biomarkers to predict response to CTLA-4 blockade, he said.
Absolute Lymphocyte Count as Pharmacodynamic Rather than Predictive Biomarker
In addition, Wolchok and others have looked at changes in the absolute lymphocyte count (ALC) as a pharmacodynamic biomarker rather than a predictive one. Higher objective response rates are seen in association with higher ALCs during treatment. Similarly, pre-existing immune responses to representative tumor antigens indicate patients whose immune responses have already recognized the tumor and are therefore already primed.
Another area of inquiry is on a population of myeloid-derived suppressor cells, "which when present at a high frequency before treatment seems to identify a group of patients who are at lower likelihood of response, and this also points to this population of cells as one that needs attention as we begin to think about adding on to CTLA-4 blockade," Wolchok said. "That would be another very innovative treatment target."
Cancer/Testis Antigens
Finally, he discussed a family of antigens called cancer/testis antigens (CTAs), which are expressed on many cancer cells but are transcriptionally silenced on most adult normal tissues except on the testis. As such, the immune system is not tolerized to them and recognizes them on tumors. CTAs may best be seen at this point as surrogate markers for immunity to the tumor, Wolchok said, adding that current trials are also looking at them as therapeutic targets.
In summary, he said immune checkpoint blockade is an effective treatment for melanoma with durable results. But, combination therapy will be required for optimal effectiveness of immune therapy, and it may include immune modulators, vaccines, radiation, chemotherapy, and targeted and anti-angiogenic therapies.
Predictive and pharmacodynamic biomarkers-both of response and of toxicity-should better enable clinicians to match patients with treatments as well as point to novel targets for drug discovery.
iPad Extra!
In a video interview with Dan Keller on the iPad edition of this issue, Jedd Wolchok, MD, elaborates on his presentation at the meeting about the need for therapies for melanoma beyond current CTLA-4 blockade, findings on biomarkers for response, PD-L1 expression as a biomarker on tumor cells, and the potential for targeted combination treatments.
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