Nick Mulcahy

June 02, 2014

The combination immunotherapy of ipilimumab (Yervoy, Bristol-Myers Squibb) and the investigational antibody nivolumab (Bristol-Myers Squibb) continues to rewrite the melanoma record book.

Concurrent use of the 2 immune-checkpoint blockade agents has produced the "unprecedented" overall survival rates for metastatic melanoma of 85% at 1 year and 79% at 2 years in a phase 1 study, said lead author Mario Sznol, MD, from the Yale University School of Medicine in New Haven, Connecticut.

Dr. Mario Sznol

He discussed the data during a press conference here at the 2014 Annual Meeting of the American Society of Clinical Oncology® (ASCO).

The median overall survival for the 53 patients treated in the study was 40 months — also unprecedented. "That's amazing," Dr. Sznol told Medscape Medical News.

The best median overall survival in a cohort of patients with metastatic melanoma, even those treated with new targeted therapies, had been about 24 months, he said.

That's amazing.

"The advance here is more than incremental," he emphasized. "This is why oncologists are so excited."

Combination therapy is the future of treatment for melanoma, said Ryan Sullivan, MD, from the Massachusetts General Hospital Cancer Center in Boston, who was not involved in the study.

"We are already using combinations for the BRAF-targeted treatment of metastatic disease," he told Medscape Medical News. The combination of the MEK inhibitor trametinib (Mekinist, GlaxoSmithKline) and the BRAF inhibitor dabrafenib (Tafinlar, GlaxoSmithKline) was approved by the US Food and Drug Administration for advanced melanoma earlier this year.

This new study demonstrates where we are going with immunotherapy.

"This new study demonstrates where we are going with immunotherapy," Dr. Sullivan noted.

However, the most effective immunotherapy combination (or combinations) remains to be seen, Dr. Sullivan said. Impressive efficacy data are emerging for other programmed death 1 (PD-1) agents, such as MK-3475 (Merck), and other experimental combination therapies are in early-phase trials.

Another expert was more cautious. "This is a small group of patients," said Patrick O'Day, MD, from the University of Southern California Keck School of Medicine in Los Angeles, who moderated the press conference.

Dr. O'Day pointed out that the overall response rate for the combination does not appear to be much different from the PD-1 single agents reported thus far. Furthermore, the combination had more toxicity than either ipilimumab or nivolumab used as single agents.

Complete Response Rates Likely Higher Than Reported

All 53 patients enrolled in the phase 1 study, which is ongoing, had inoperable stage III or IV (metastatic) melanoma and had received up to 3 previous therapies.

The group received nivolumab and ipilimumab every 3 weeks for 4 doses (12 weeks), followed by nivolumab every 3 weeks for 4 doses. Then, at week 24, concurrent combination treatment was administered every 3 months.

Last year at ASCO, Dr. Sznol reported that the concurrent ipilimumab and nivolumab combination yielded an objective response rate of 40%.

But the rate was 53% in the subset of 17 patients who received a combination that contained maximum doses — also a new high in the treatment of metastatic melanoma.

This year, Dr. Sznol was back with an update on response rates and survival. The 53 patients have about another year of follow-up.

The confirmed complete response rate is now 17% (9 of 53 patients), which is up from the 10% (5 of 52 patients) reported last year. Dr. Sznol said that the complete response rate is "probably higher," but was tamped down by CT scans that show tremendous amounts of detail.

To illustrate that partial responses are often very substantial, Dr. Sznol revealed that tumor reduction of at least 80% was observed in 22 of 53 patients (42%). "Many of those had near complete responses," he said.

There has been concern in the field that patients with BRAF genetic mutations, which are present in about half of all melanomas, might not respond as well to immunotherapy, Dr. Sznol explained.

But activity was similar in patients with mutant and wild-type BRAF disease. Likewise, activity was similar regardless of programmed death ligand 1 (PD-L1) status, which is an emerging biomarker in melanoma and other cancers.

Dr. Sznol also reported that, in another cohort of 41 patients being treated with a phase 2/3 dosing regimen, the overall response rate is 43%. Thus, the activity of the combination has been confirmed, he said.

The downside of combination immunotherapy is an increased rate of adverse events. But Dr. Sznol emphasized that they were "manageable and reversible in a vast majority of patients."

The 1 drug-related death in the trial involved colitis and multiorgan failure.

But overall, there are no new "safety signals" at this point, said Dr. Sznol, meaning that no new adverse events have emerged in these early-phase trial patients.

This study was funded by Bristol-Myers Squibb Company. Dr. Sznol reports financial relationships with Bristol-Myers Squibb, Amgen, Symphogen, Anaeropharma, MedImmune, Nektar, and Genentech. A number of study authors are employees and stockholders of Bristol-Myers Squibb. Dr. O'Day has been an investigator of ipilimumab. Dr. Sullivan has disclosed no relevant financial relationships.

2014 Annual Meeting of the American Society of Clinical Oncology (ASCO): Abstract LBA9003. Presented June 2, 2014.


Comments on Medscape are moderated and should be professional in tone and on topic. You must declare any conflicts of interest related to your comments and responses. Please see our Commenting Guide for further information. We reserve the right to remove posts at our sole discretion.