ASCO 2015: Opdivo melanoma phase III beats Yervoy in combo and alone

Source: BioWorld, May 2015

CHICAGO – Bristol-Myers Squibb Co.’s programmed cell death-1 inhibitor Opdivo (nivolumab), cleared by the FDA late last year for melanoma and in March for squamous non-small cell lung cancer (NSCLC), worked better than the firm’s other approved melanoma drug Yervoy (ipilimumab) in patients with previously untreated cases of the deadly skin cancer not only when the two drugs were given together but also when Opdivo was administered by itself.

Data from the first phase III trial, called Checkmate 067, to compare a combination of immune checkpoint inhibitors with single-agent Yervoy were unveiled at the American Society of Clinical Oncology (ASCO) meeting, where attendees heard that Opdivo by itself more than doubled the average time to disease progression compared to Yervoy (6.9 months vs. 2.9 months), and the benefit jumped to 11.5 months with the combo regimen.

Response rates proved higher with the duo (57.6 percent) and single-agent Opdivo (43.7 percent), too, compared to Yervoy by itself (19 percent). Yervoy, which blocks cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) to stimulate T cells, was approved in 2011. (See BioWorld Today, April 4. 2011.)

Sorting out which patients might want to elect Opdivo alone or use it with Yervoy is “really at the heart of the issue,” said lead study author Jedd Wolchok, chief of melanoma and immunotherapeutics at Memorial Sloan Kettering Cancer Center in New York. “We are talking about PDL-1 expression, which is not a binary discriminator of absolute benefit,” he said, noting that the experiment is “the first effort to try and introduce a precision aspect to immunotherapy.”

Earlier at ASCO, a 582-patient study with Opdivo was the first to show that a PD-1 inhibitor significantly improves overall survival (OS) vs. docetaxel in previously treated patients with non-squamous NSCLC. It also highlighted the role of PD-L1 expression in the disease, finding that patients with high levels (>/= 1 percent of tumor cells) turned up a doubling of median OS at 17 months to 19 months, compared with standard-of-care docetaxel, at eight to nine months.

The Opdivo-Yervoy results in melanoma offer “a way to initiate meaningful conversations between patients and clinicians about whether the combination is the right fit for them vs. nivolumab alone,” Wolchok said. “For example, if a patient comes in and they are frail or have multiple comorbidities and their tumor expresses more than 5 percent PDL-1, you can actually tell a patient they can be reassured that that their progression-free survival [PFS], as the most robust endpoint available now, will be the same, regardless of whether they receive the combination regimen with its increased toxicity compared to nivolumab alone.”

On the other hand,

“if a patient is more fit and focused on knowing all the data, they might be interested in receiving the combination, which has a higher response rate,” Wolchok said. “In the end, I think this is a very good opportunity to have these conversations, to talk about the value of risk and benefit with patients. Ultimately, what we’re going to need is the OS data; response rate and PFS are both surrogates for OS. Until we have that, we will continue to have these discussions with each patient to find out what therapy is optimal.”

Steven O’Day, director of the Los Angeles Skin Cancer Institute and director of clinical research at the Beverly Hills Cancer Institute in Beverly Hills, Calif., noted that

“response differences are relatively modest, but what strikes us is this PFS difference between monotherapy and the combination. Historically, that correlates well with survival.” Patients alive at two to three years with the combo will tell the full story, he said. “If it holds up at a high plateau, then it will be obvious what we need to do.” For now, he called the data “incredibly encouraging.” Though he acknowledged “toxicity has been a big issue,” educating physicians let the global trial proceed with no deaths due to drugs. Toxic effects “can be managed and reversed relatively rapidly,” he said.

The Yervoy approach represents “a very important target and drug in the field of melanoma,”

O’Day said. “It’s not going away.” The compound “tends to work to generate this army of T cells to go into battle,” he said, whereas “PD-1 is more about activating or resurrecting these tired T cells in the tumor micro-environment,” and the strategies are “potentially additive, synergistic approaches,” he said. “The question is what sequence or combination is the best.”

Investigator Wolchok, asked about other CTLA-4 therapies on the horizon, likened Yervoy to tremelimumab, which faltered in late-stage melanoma efforts while in the hands of New York-based Pfizer Inc. Medimmune LLC, of Gaithersburg, Md., a unit of Astrazeneca plc, in-licensed tremelimumab from Pfizer Inc. for undisclosed terms in 2011.

“There were differences in the trial design that led to the approval of Yervoy, but [tremelimumab] is an active drug,” he said.