Nick Mulcahy

May 31, 2015

CHICAGO — Two cancer immunotherapies are significantly better than one in slowing the progression of advanced melanoma, new phase 3 study results indicate.

The results likely represent yet another sea change in the treatment of this disease because, to date, single-agent immunotherapy with ipilimumab (Yervoy, Bristol-Myers Squibb) has been the gold standard in the first-line treatment of non-BRAF-mutated disease.

This study shows that first-line nivolumab (Opdivo, Bristol-Myers Squibb), either in combination with ipilimumab or used alone, produced a longer progression-free survival than ipilimumab alone.

Patients were free of disease for twice as long with nivolumab alone as with ipilimumab alone, and nearly four times as long as with the combination.

But the two drugs together are much more toxic than either single agent, and the combination would be very expensive, cautioned study observers. Together, ipilumumab and nivolumab cost nearly $300,000.

Figuring out who is an optimal candidate for potent combination therapy is "the heart of the issue," said lead study author Jedd Wolchok, MD, PhD, from the Memorial Sloan Kettering Cancer Center in New York City, during a press briefing here at the American Society of Clinical Oncology 2015 Annual Meeting.

"We need to carefully define who will benefit from the combination and from nivolumab as a single agent because, as a society, we cannot afford to treat everyone with the combination," said Frances Collichio, MD, from the University of North Carolina in Chapel Hill, who was not involved with the study.

But these data are a good starting place, said Dr Collichio, who told Medscape Medical News that results are "thrilling."

"We now have a disease we can cure in the stage IV setting," she said.

We cannot afford to treat everyone with the combination.

The investigators of the CheckMate 067 trial randomized 945 patients with previously untreated stage III or IV melanoma with either no or mild symptoms to receive ipilimumab, nivolumab, or a combination of the two.

After a follow-up period of at least 9 months, median progression-free survival was 2.9 months for ipilimumab alone, 6.9 months for nivolumab alone, and 11.5 months for the combination.

Use of the combination resulted in a 58% reduced risk for progression or death compared with ipilimumab alone (hazard ratio [HR], 0.42; P < .001). Use of nivolumab alone reduced these risks by 43% compared with ipilimumab alone (HR, 0.57; P < .001).

Despite the fact the study was not designed to make the comparison, Dr Wolchok reported that the twosome reduced the risk for progression by 26% compared with nivolumab alone (HR, 0.74).

The combination also had superior rates of complete and partial responses in the study, which was simultaneously published online in the New England Journal of Medicine.

Overall survival data will be forthcoming, said Dr Wolchok.

History suggests that there will be a survival benefit, said Steven O'Day, MD, from the Los Angeles Skin Cancer Institute, who acted as expert commentator at the press briefing.

"What strikes us is this progression-free survival difference between [nivolumab] monotherapy and the combination of almost 5 months. Historically, that has correlated well with survival," said Dr O'Day.

The key data will be survival at 2 or 3 years, he said. "If [a survival benefit with the combination] holds up at a high plateau compared to monotherapy, then it will be obvious what we need to do," explained Dr O'Day, referring to combination therapy.

In the short term, the combination data are "incredibly encouraging," he added.

But does that mean all fit patients with advanced disease should undergo treatment with the combination of two checkpoint inhibitors?

A fledging biomarker suggests not.

In the study, patients who had higher levels (>5%) of the PD-1 ligand, which is a protein on immune cells, did no better, on average, with regard to disease progression when treated with combination therapy. That is, patients with PD-L1-positive tumors who were treated with either the combination or nivolumab alone had the same median progression-free survival of 14 months.

Notably, in patients with lower levels (<5%) of the PD-1 ligand, the median progression-free survival was longer with the combination than with nivolumab alone (11.2 vs 5.3 months).

In short, combination therapy was better at delaying disease progression, but the benefit occurred largely in the patients with PD-L1-negative tumors. Patients with PD-L1-positive tumors appear less likely to benefit from this combination immunotherapy, which is in contrast to results from other studies.

Using a biomarker, the PD-1 ligand, is an effort "to try to introduce a precision aspect to immunotherapy," said Dr Wolchok. And it might enable conversations with patients "about whether the combination is right for them."

But PDL-1 is a "weak biomarker" that has a high rate of false negatives and a host of problems in the pathology lab, said Michael Atkins, MD, PhD, from the Georgetown Lombardi Comprehensive Cancer Center in Washington, DC. He was not involved with the study and acted as discussant of the study at the meeting's plenary session.

The subset analysis in CheckMate 067 was not valid because the biomarker has too many shortcomings, he said.

Dr Atkins is not a fan of PD-L1, but he is high on combination therapy for advanced melanoma.

It is the treatment of choice in this setting, he said, unless toxicity is a "concern"; in that case, single-agent nivolumab is preferable.

In other words, ipilimumab is no longer the standard in the first-line treatment of advanced melanoma, he stated clearly.

The new trial is proof of this change, said Dr Atkins, as are the recent results from KEYNOTE-006, a head-to-head comparison that showed that pembrolizumab (Keytruda, Merck) significantly prolonged progression-free and overall survival and had less high-grade toxicity than ipilimumab in advanced melanoma.

He also opined that there is no "clear-cut difference" in efficacy between nivolumab and pembrolizumab. Both PD-1 immunotherapies are approved by the US Food and Drug Administration (FDA) for use in the treatment of advance melanomas.

Toxicity Highlight: No Deaths

Treatment-related adverse events were much more common in patients treated with the combination, Dr Wolchok reported.

Specifically, adverse events of grade 3/4 occurred in 55% of the combination group, compared with only 16% of the nivolumab group and 27.3% of the ipilimumab group.

"There is no signature adverse event with the combination," said Dr Wolchok.

However, 9.3% of the combination treatment group had grade 3/4 diarrhea, and 7.7% had similarly high-grade colitis. Both were among the most common serious adverse events with the combination treatment.

However, these and other serious adverse events can be "reversed relatively rapidly," said Dr O'Day, who has been an ipilimumab investigator.

In the combination group, 36% of patients discontinued treatment because of adverse events. Some will go on to derive treatment benefit nonetheless, said Dr Wolchok.

But Dr Collichio was not as breezy as Dr O'Day and Dr Wolchok in describing the impact of serious adverse events. Seeing a patient with a high-grade adverse events, including those of the GI tract, is "not easy to forget" because of the severity of illness, she said.

Nonetheless, Dr Collichio considers herself a booster of the checkpoint inhibitors and recently saw a melanoma survivor in her clinic who is now 10 years out from ipilimumab treatment. She recalled that the patient had brain, skin, and lung metastases before receiving immunotherapy.

On the bright side of the adverse-event data, there were no treatment-related deaths in the study, which had occurred in early-stage trials. The study was conducted at 137 centers worldwide, Dr Wolchok pointed out. "This treatment can be safely applied in a global setting," he declared.

Nivolumab and ipilimumab are monoclonal antibodies that block two different immune checkpoints — PD-1 and CTLA-4, respectively — that thwart immune response. Both agents release immune system's natural ability to combat cancer, and both are FDA-approved for use as single agents in the treatment of advance melanomas.

The study was funded by Bristol-Myers Squibb. Dr Wolchok and Dr O'Day have financial relationships with Bristol-Myers Squibb. Some of the study authors are company employees.

American Society of Clinical Oncology (ASCO) 2015 Annual Meeting: Abstract LBA1. Presented May 31, 2015.


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.