Every year, new cancer treatment insights are shared at the American Society of Clinical Oncology (ASCO) Annual Meeting. Here are some of the most notable recent developments in melanoma treatment, gleaned from researchers’ presentations at ASCO last month:
In recent years, more and more patients have been treated with targeted therapies, which are drugs ‘targeted’ to specific genetic mutations found in patients’ tumor cells. The U.S. Food and Drug Administration (FDA) has approved three targeted drugs for treating people with metastatic melanoma whose tumors have mutations in the BRAF gene: vemurafenib (Zelboraf) in 2011, dabrafenib (Tafinlar) in 2013, and trametinib (Mekinist) also in 2013.
Zelboraf, Tafinlar, and Mekinist all shrink tumors in most of the patients who take them, but most patients eventually develop resistance to the drugs and their tumors grow back. Oncologists are rushing to figure out how to thwart resistance to targeted therapies. One solution may be to combine multiple targeted drugs.
Indeed, earlier this year, the FDA granted accelerated approval to a new treatment that combines Tafinlar and Mekinist for advanced melanoma patients with BRAF-mutated tumors. This designation means that the FDA is willing to change its requirements for approval so that doctors across the U.S. can begin prescribing it to patients sooner.
At ASCO, researchers reported results from a large clinical trial testing the Tafinlar/Mekinist combination in volunteer patients. The trial, called COMBI-d, compared the new treatment to Tafinlar alone and confirmed that the combo treatment performs better: 93% of the patients who took Tafinlar/Mekinist were alive after 6 months, compared to 85% of the patients who took only Tafinlar.
Unlike for BRAF+ melanoma, no targeted drugs have been FDA-approved for treating melanoma with mutations in the NRAS gene, and so far there has not been much success with investigational (new) drugs. This is why a report on a promising combination treatment specifically for NRAS-mutant tumors was of high interest at ASCO this year.
The treatment combines a new drug called binimetinib (made by a company called Array BioPharma) with drug called LEE011 (made by Novartis). Binimetinib works by targeting a protein called MEK; LEE011 attacks cancer cells by inhibiting certain proteins called CDK4 and CDK6. Promising studies done in the lab and on animals raised hopes, and results of tests in volunteer patients were eagerly awaited. Now, as reported at ASCO, a phase Ib/II clinical trial testing the combination has shown promising antitumor activity in NRAS-mutant melanoma patients. Out of 21 patients in the trial, 7 experienced partial shrinkage of their tumors (33%) and 11 experienced no further growth of their tumors (52%). Several patients experienced early tumor shrinkage with major improvement in their symptoms.
Immunotherapy treatments boost a patient’s own immune system to fight cancer. There has been particular interest in immunotherapy drugs called ‘immune checkpoint inhibitors,’ which release brakes on immune system cells, freeing them to attack tumors. One immune checkpoint inhibitor called ipilimumab (aka Yervoy) has been FDA-approved for treating metastatic melanoma, but it is still being extensively tested in clinical trials, including for patients with stage III disease, and in combination with other drugs. Yervoy shrinks tumors in only a minority of treated patients, but its major advantage is that these responses are long-lasting.
At ASCO, researchers reported new results from a phase III clinical trial testing Yervoy in patients with stage III melanoma. They reported that patients who took Yervoy experienced a significantly longer period of time without signs of symptoms of their cancer than patients who took a ‘fake’ placebo drug (a median of 26 months vs 17 months, respectively).
Yervoy was also featured at ASCO in a poster presentation of a small trial that combined it with an investigational drug called INCB24360. INCB24360 works by attacking a protein called IDO1, releasing its hold on the immune system so that immune cells can fight cancer. In previous studies, treating patients with INCB24360 did not produce good clinical responses. But when it was combined with Yervoy, 42% of patients’ tumors shrank or disappeared, and additional 33% had stable disease (tumors neither grew nor shrank), which is a promising result.
This year, more results came in from studies of newer, investigational immune checkpoint inhibitors that made a splash at last year’s ASCO meeting. Two major contenders in this area are pembrolizumab (MK3475), made by Merck, and nivolumab, from Bristol Myers Squibb. The largest-ever phase I trial with pembrolizumab for patients with advanced melanoma boasted an overall response rate (ORR) of 34%, meaning that 34% of patients experienced tumor shrinkage that met a predefined goal for the study. After 1 year, 69% of the patients were still alive, with ongoing tumor shrinkage, testifying to the durability of the responses. The FDA has already granted a Breakthrough Therapy Designation to MK-3475, which signifies that the review and approval of the drug will be expedited, and the expected approval decision date is October 28. Even better, patients who were previously treated with Yervoy have also responded well to pembrolizumab, though at a lower rate than those who haven’t previously taken Yervoy.
The competing checkpoint inhibitor nivolumab showed similar activity to pembrolizumab in a clinical trial. The overall response rate to nivolumab was 32%, with 1-, 2- and 3-year survival rates of 63%, 48% and 41%, respectively. These results were reported as an update to a still ongoing study. All melanoma patients involved in this trial had no prior Yervoy exposure.
Promising preliminary results from a study combining nivolumab and ipilimumab were reported at ASCO last year, to everyone’s delight. This year, updates showed 1- and 2-year survival rates of 94% and 88%, respectively—fantastic rates for metastatic melanoma, a cancer that was considered to be fatal just a few years ago.
Immunotherapy reports went beyond the already-familiar checkpoint inhibitors. A company called Amgen revealed new data on its investigational cancer-killing virus, called talimogene laherparepvec, or T-VEC. In a small phase Ib trial that combined T-VEC with ipilimumab, tumors shrank or disappeared in 56% of patients with metastatic melanoma.
The drugs above are taken orally or intravenously, but researchers are also testing treatment strategies for cutaneous melanoma, whereby drugs are directly injected into tumors. One strategy, called ImmunoPulse, uses a procedure called electroporation to get DNA molecules directly into melanoma tumor cells. Once inside, the DNA provides instructions for the cells to make a molecule called IL-12, which activates the movement of destroyer cells into the tumors. So far, the treatment has caused tumor shrinkage in 9 of 22 patients who have tried it. In some of the patients, even tumors that were not directly treated have shrunk as well, indicating that IL-12 acts throughout the body.
Another promising injection treatment uses a dye with the exotic name Bengal Rose. In a clinical trial, it was injected directly into some or all of each patient’s melanoma tumors. Sixty-four percent of the injected tumors completely disappeared or shrank after one or more injections of the dye. Even more exciting, 39% of tumors that were not directly injected also shrank. Perhaps by next year’s ASCO meeting, we will see even more promising results.