Nivolumab (Opdivo, Bristol-Myers Squibb) — alone or in combination with ipilimumab (Yervoy, Bristol-Myers Squibb) — improved overall survival (OS) in treatment-naive patients with advanced melanoma compared with ipilimumab alone, according to new findings.
The findings are notable, in part, because they are the first OS data from the first phase 3 trial with the combination of anti–programmed cell death-1 (PD-1) (nivolumab) and anti–cytotoxic T lymphocyte-associated protein 4 (ipilimumab) therapies, said James Larkin, PhD, from the Royal Marsden Hospital in London, the United Kingdom.
He spoke at a press conference here at the American Association for Cancer Research (AACR) 2017 Annual Meeting.
Dr Larkin reported that in the 945-patient, three-arm CheckMate 067 trial, the median OS had not yet been reached in the two nivolumab treatment groups and was 20 months for the ipilimumab-alone group.
Nivolumab in combination with ipilimumab and as a monotherapy reduced the relative risk for death of 45% (hazard ratio [HR], 0.55; P < .0001) and 37% (HR, 0.63; P < .0001), respectively, compared with ipilimumab alone.
There was a minimum follow-up of 28 months among the three treatment groups.
Earlier results from the trial, first presented at the American Society of Clinical Oncology 2015 Annual Meeting, showed that nivolumab alone or in combination resulted in superior progression-free survival than ipilimumab alone. The findings spurred the US Food and Drug Administration to grant accelerated approval for the use of the combination.
The new results fulfill the FDA requirement to further demonstrate improved OS, said Dr Larkin.
What the results do not show is whether the "nivo-ipi" combination is more effective than nivolumab alone.
"It is important to note that this study was not designed to compare between the nivolumab-containing arms," Dr Larkin told reporters at the beginning of his talk.
But 10 minutes later, he could not help himself when wrapping up: "In conclusion, first-line nivolumab plus ipilimumab may represent a means to improve outcomes vs nivolumab."
The question of superiority here is a pressing one clinically, as nivolumab plus ipilimumab is the only immunotherapy combination currently approved for advanced melanoma in the United States.
So how do clinicians and patients decide among nivolumab-based treatment options for the first-line treatment of advanced melanoma?
"There really isn’t any one thing that says we are going to go down this route or that route," said Dr Larkin.
There are a lot of different factors to consider, he said: general level of fitness, BRAF status (for BRAF-targeted therapy), and side effects (which are much higher with the combination).
Noticeably absent from his list were cost and affordability, perhaps reflecting his work in a country with universal coverage and a single, government-payer healthcare system. But he also later observed that the United Kingdom's National Institute for Health and Care Excellence judged the combination to be an acceptable value based on its efficacy.
In the United States, ipilimumab and nivolumab together cost around $300,000.
"Decisions about the optimal treatment choice should be made on an individual patient basis," continued Dr Larkin.
There is a trade-off between the "powerful antitumor effect" of the combination and toxicity, he suggested.
The rates of grade 3/4 treatment-related adverse events (AEs) were 58.5% for the combination arm, 27% for the ipilimumab-alone arm, and 20.8% for the nivolumab-alone arm.
The combination also resulted in many more discontinuations. The rates of discontinuation due to treatment-related AEs were 39.6% for the combination arm, 16.1% for the ipilimumab-alone arm, and 11.5% for the nivolumab-alone arm.
The investigators performed subgroup analyses to seek information about a biomarker that might help guide treatment. However, Dr Larkin cautioned that such subgroup analyses are not "robust" enough to actually provide definitive results.
Nevertheless, Suzanne Topalian, MD, a medical oncologist at the Kimmel Comprehensive Cancer Center at Johns Hopkins University in Baltimore, Maryland, who moderated the press conference, said the search for biomarkers to guide treatment decision-making yielded "intriguing results."
There seemed to be an OS advantage among patients with PD-ligand 1 (PD-L1)–"negative" expression (ie, <5% levels) treated with the combination, she observed.
But Dr Larkin said that PD-L1 is "not an ideal marker" in this setting and is not "binary" in the way that BRAF mutation status is for patients with melanoma, where its presence or absence means that a patient will or won't have a chance to respond to targeted therapies, such as vemurafenib and dabrafenib.
Dr Topalian also highlighted that patients who had a BRAF mutation appeared to do "a lot better" on the combination therapy than on nivolumab monotherapy. This was a reference to the 2-year OS rate of 71% in the former group and 62% in the latter. But, again, Dr Larkin was subdued in his response to her observation, saying that there did not appear to be any cutoff point by which clinicians could judge the level of BRAF-based responsiveness.
Dr Larkin presented an array of efficacy results from the new trial.
The 2-year OS rates were 64% for the nivolumab plus ipilimumab group, 59% for nivolumab alone, and 45% for ipilimumab alone.
Median duration of response had not been reached in the nivolumab plus ipilimumab group; these durations were 31.1 months and 18.2 months for the nivolumab-alone and ipilimumab-alone groups, respectively.
Notably, the complete response rates have improved with both nivolumab-containing regimens since the 2015 data were presented. The rates are now reported as 17.2% in the combination group and 14.9% in the nivolumab alone group.
The toxicity findings also yielded an interesting efficacy result. The objective response rate was 70.7% for the patients who discontinued the combination because of AEs, which was higher than the 58.9% rate in the full combination group. "Early discontinuation did not preclude benefit," said Dr Larkin.
There were four treatment-related deaths: two in the combination group and one each in the other two monotherapy groups.
Whatever immunotherapy choice that clinicians and patients currently make in advanced melanoma, the list of possibilities is likely to expand in the future.
But "there is a very competitive landscape for melanoma," said Laura Q.M. Chow, MD, from the University of Washington, Seattle, during another session at the AACR meeting, as reported by Medscape Medical News.
"There are more than 20 PD-1 agents in development, more than 140 melanoma combination trials with immune checkpoint inhibitors, more than 803 immune checkpoint inhibitor combination trials, and over 167,000 patients on immunotherapy trials," she said.
The study was funded by Bristol-Myers Squibb. Dr Larkin declares institutional research support from Bristol-Myers Squibb and other pharmaceuticals, as well as consultancy for Bristol-Myers Squibb and multiple other companies. Dr Topalian is an investigator of nivolumab and has financial ties with multiple other pharmaceutical companies.
American Association for Cancer Research (AACR) 2017 Annual Meeting. Abstract CT075. Presented April 3, 2017.
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Cite this: First Phase 3 OS Results With Melanoma ImmunoTx Combo - Medscape - Apr 07, 2017.