Bristol-Myers Squibb Co. (BMS) pulled a coup in cancer therapeutics by garnering the first FDA approval of a regimen that combines two of its checkpoint inhibitors and launching the eagerly awaited coupling of cancer immunotherapies.

Opdivo (nivolumab) and Yervoy (ipilimumab) gained accelerated approval from the agency to treat BRAF V600 wild-type unresectable or metastatic melanoma. Yervoy – the first approved checkpoint inhibitor and the first drug to show an effect on the life expectancy of patients with late-stage melanoma – and Opdivo target the separate and complementary checkpoint pathways of CTLA-4 and PD-1, respectively. Yervoy blockade of CTLA-4 was shown in clinical trials to augment T-cell activation and proliferation, while Opdivo restored the active T-cell response directed at the tumor. (See BioWorld Today, March 28, 2011.)

Opdivo, initially approved in Japan before gaining the FDA's nod, also is approved by the FDA to treat metastatic squamous non-small-cell lung cancer with progression on or after platinum-based chemotherapy. (See BioWorld Today, July 9, 2014.)

BMS said accelerated approval of the combo treatment in metastatic melanoma was based on tumor response rate and durability of response, with continued approval contingent upon verification of clinical benefit in confirmatory trials.

According to the FDA, Opdivo was approved as a weight-based dose in the indication, in combination with Yervoy. The regimen consists of Opdivo 1 mg/kg, followed by Yervoy on the same day every three weeks for four doses, then Opdivo 3 mg/kg every two weeks.

But the price point for the combo treatment, which is already commercially available, is certain to test the budget boundaries of cancer therapeutics. Reuters reported that the cost of four combination doses is expected to be approximately $141,000, or $256,000 for patients remaining on the combination regimen for a full year. The price tag is especially noteworthy considering that the incidence of melanoma has been increasing for at least 30 years, with an estimated 73,870 cases expected to be diagnosed in the U.S. this year. And the disease is still deadly at its late stages, where average five-year and 10-year survival rates in the U.S. remain below 20 percent and 15 percent, respectively.


The potential benefits of the Opdivo/Yervoy combination in metastatic melanoma first wowed the crowd as an abstract presentation at the 2013 annual meeting of American Society of Clinical Oncology (ASCO) in Chicago, when data from a phase I study that included six arms of concurrent or sequenced cohorts suggested the combination regimen led to an objective response rate (ORR) of 53 percent in the largest group of patients on concurrent therapy. (See BioWorld Today, May 16, 2013.)

FDA approval was based on data from the pivotal Checkmate-069 study, which was the first to report outcomes of Opdivo/Yervoy in previously untreated patients with unresectable or metastatic melanoma. The double-blind, randomized phase II study enrolled 140 patients, including those with both BRAF wild-type and BRAF mutation-positive melanoma.

Results showed a statistically significant (p<0.001) increase in confirmed ORR in patients with BRAF wild-type melanoma (n=109) treated with the combination [60 percent (95 percent CI: 48-71; p<0.001)] compared to those treated with Yervoy monotherapy [11 percent (95 percent CI: 3-25)]. Complete responses were seen in 17 percent of patients, and partial responses were seen in 43 percent of the combination group compared to 11 percent of the Yervoy monotherapy group.

The combo regimen also demonstrated a 60 percent reduction in the risk of progression-free survival (PFS) compared to Yervoy alone (HR=0.40; 95 percent CI: 0.22-0.71; p<0.002). Median PFS was 8.9 months with the combo (95 percent CI: 7.0, NA) and 4.7 months with Yervoy alone (95 percent CI: 2.8-5.3).

In Checkmate-069, patients in the Opdivo/Yervoy arm were more likely than those who received Yervoy alone to have serious adverse reactions (62 percent vs. 39 percent, respectively), adverse reactions (AE) that led to permanent discontinuation (43 percent vs. 11 percent) or dose delays (47 percent vs. 22 percent), and Grade 3 or 4 AEs (69 percent vs. 43 percent). More than one-fourth (27 percent, or 25/94) of patients in the Opdivo/Yervoy arm did not complete all four cycles in the study.

The most common AEs associated with the combination, compared to Yervoy alone, included colitis, diarrhea, pyrexia and pneumonitis.

BMS said Checkpoint-069 provided the clinical rationale for targeting the immune system with two immuno-oncology agents in metastatic melanoma.

But in June, the New York-based pharma also reported that Opdivo worked better than Yervoy in patients with previously untreated melanoma not only when the drugs were combined but also as monotherapy. Those findings, reported at this year's ASCO annual meeting, came from the company's phase III Checkmate-067 trial, which found that Opdivo alone more than doubled the average time to disease progression compared to Yervoy (6.9 months vs. 2.9 months), with the benefit jumping to 11.5 months in the combo regimen. (See BioWorld Today, June 2, 2015.)

Several months earlier, at the annual meeting of the American Association for Cancer Research in Philadelphia, investigators reported that patients treated with the anti-PD-1 therapy Keytruda (pembrolizumab), developed by Merck & Co. Inc., of Kenilworth, N.J., had better outcomes than could be achieved with the respective standards of care in melanoma and lung cancer trials. In particular, full data from the Keynote-006 study, a head-to-head comparison of Keytruda and Yervoy in metastatic melanoma, showed that Keytruda was "superior on all counts" to Yervoy, study lead Antoni Ribas of the UCLA Jonsson Comprehensive Cancer Center said at the time. (See BioWorld Today, April 21, 2015.)

Jedd Wolchok, a medical oncologist and clinical investigator at Memorial Sloan Kettering Cancer Center, where he serves as chief of the melanoma and immunotherapeutics service, presented the phase I Opdivo/Yervoy combo data in 2013 and provided this year's Checkmate-067 update at ASCO. Although the combo was approved in a subset of patients who represented the immediate unmet medical need, with no other treatment options in terms of BRAF and MEK inhibitors, "we don't have any evidence that this treatment works any better or worse in patients whose tumors do or don't have a BRAF mutation," Wolchok told BioWorld Today.

Underscoring that point, BMS said last week that the FDA accepted for review its supplementation biologics license application for the Opdivo/Yervoy combo to treat patients with previously untreated advanced melanoma, based on data from Checkmate-067. The FDA also granted priority review for that application, setting a PDUFA date of Jan. 23, 2016.

A first approval in any therapeutic category is significant, Wolchok maintained, and the Opdivo/Yervoy checkpoint combo is no different. Investigators noticed as far back as the phase I that more than 50 percent of patients were showing response on the regimen.

"We were appropriately careful and cautious about the interpretation of those findings, since those were modest numbers of patients," until the data were validated in the phase II and larger phase III programs, he said. "This is really an impressive number of people who are having objective responses, and the duration of response is – as expected – long."

Although the combo regimen also heightened toxicity, investigators saw nothing unexpected in the safety profile and were well-prepared to manage them, Wolchok added.

As to the potential effectiveness of newer checkpoint agents as monotherapy compared to combos that include trailblazer Yervoy, "there's no question that PD-1 blockade is a more effective intervention by itself than CTLA-4 blockade," Wolchok acknowledged, but he cautioned against drawing additional conclusions, at least for now.

"Some people benefit from the CTLA-4 blockade even though they don't benefit from PD-1 blockade," he pointed out. "In addition, we have much longer follow-up from patients treated with ipilimumab than we do for any of the PD-1 agents. We really need to follow the patients treated with nivolumab or pembrolizumab monotherapy out for a longer period of time to see whether that very characteristic horizontal tail on the survival curve is reproduced. Certainly, with the two agents together, we would hope to take advantage of the strengths of each one."


James Allison, professor and chair in the department of immunology at the University of Texas MD Anderson Cancer Center, agreed that the beauty of combining Opdivo and Yervoy lies in the "very, very different mechanisms" of the checkpoints. Last month, Allison received the 2015 Lasker-DeBakey Clinical Medical Research Award for his discoveries involving checkpoint inhibition and his role in developing Yervoy. (See BioWorld Today, Sept. 9, 2015.)

Wednesday evening, Allison received the American Cancer Society's 2015 Medal of Honor for Basic Research.

"The record with Yervoy shows that about 22 percent of the patients treated are alive 10 years later," Allison told BioWorld Today. "Now, half of patients can respond to this combination immunotherapy. In comparison, five years ago, the median survival was 11 months."

Allison predicted that checkpoint combos, including the Opdivo/Yervoy regimen, will quickly, move into other indications, citing kidney, bladder and lung cancer as early opportunities.

"Right now, the dominant combination is going to be a CTLA-4 with PD-1, and we're going to see these from other companies, as well, given the number of PD-1 antibodies out there," he said. "But we need to move carefully and pay attention to the mechanisms to make sure the combinations don't cancel each other out."

With the first combo regimen now approved, Allison was less enthused about monotherapy – even using new agents – than about studying various pairings and starting to investigate triplets.

"What this requires right now is a lot of good, basic science to understand how they work," he said. "This is an example of what the future holds."

Thankfully, the pipeline of checkpoint inhibitors is rich and growing, with hundreds of assets in the category now tracked by Cortellis Competitive Intelligence. In addition to the potential benefit to patients – "that's what we're all here for," Wolchok said – a "very nice secondary effect" of recent success in the space is the additional investment into cancer therapeutics, both from an intellectual and financial perspective.

"We now see many different biotech and larger pharma companies developing quite rich pipelines of new agents and forming collaborations with academic investigators to explore correlative studies around the current trials," Wolchok said. "As we learn more about why some patients respond to these currently available medicines and others don't, we'll be able to inform the investigation of additional immunologic modulating drugs."

Allison went a step further in his prediction. "What we're learning is that the important thing isn't moving the median survival over," he said. "That's been the goal of cancer drugs for a long time. We see now, with Yervoy, that the tail of the survival curve flattens out – it's still a fraction – at 20 percent. If this combination flattens out at 50 percent, then we can start thinking about cures."

On Thursday, shares of BMS (NYSE:BMY) gained 83 cents to close at $60.03.