Merck, Roche and Bristol Myers nab 4 of 6 positive ODAC votes for ‘dangling’ accelerated approvals
What looked at the outset like a prime opportunity for the FDA to critique industry over failed confirmatory trials for lagging accelerated approvals ended up being mostly a triumph for the large biopharma companies.
The FDA’s Oncologic Drugs Advisory Committee voted in favor of keeping on the market four of the six “dangling” accelerated approvals presented to it over the last three days. Even despite the failed trials, companies and their physicians raised concerns about unmet treatment needs and the long duration of responses for the checkpoint inhibitors before each of the six votes.
The two ODAC votes that didn’t receive a majority of “yes” votes from the outside experts were Merck’s Keytruda (pembrolizumab) as a third-line treatment for stomach cancer and Bristol Myers Squibb’s Opdivo (nivolumab) as a second line treatment for liver cancer. In both cases, Richard Pazdur, director of the FDA’s Oncology Center of Excellence, raised concerns with the committee, while noting the unintended consequences of keeping Keytruda on the market and questioning BMS data (see more below).
Leerink senior research analyst Daina Graybosch said in an investor note on Friday, “We believe market impact from the two indications recommended for withdrawal are inconsequential, with a small and shrinking number of patients eligible” for Keytruda as a third-line treatment for gastric cancer (~1,000), and as there’s an opportunity for Bristol Myers to shift patients from Opdivo to the combination of Opdivo and Yervoy (ipilimumab), which also won accelerated approval last year as a second-line treatment in hepatocellular carcinoma (HCC).
Graybosch called the FDA “objective, but also forceful in a couple arguments with sponsors” during the three days, in line with recent observations from the agency. He also noted that Pazdur made a “powerful case for withdrawal in two cases, which seemed to sway the ODAC vote.”
Overall, however, the main takeaway from the last three days seemed to be that if you’re a biopharma company that has won an accelerated approval and your confirmatory trial has failed, it may be unwise to voluntarily withdraw that approval. Taking the decision to ODAC may end up with a thumbs up to remain on the market while future trials are being conducted.
Some outside oncologists raised serious concerns about maintaining the integrity of the accelerated approval pathway if companies and the FDA don’t get rid of certain drug indications that have failed in confirmatory trials.
“If the drugs remain on the market, the very nature of accelerated approval should fall into question,” Vinay Prasad, oncologist at UCSF, told Endpoints. “Perhaps we cannot realistically give conditional approval because no one will ever have the courage to pull the drugs.”
Keytruda in stomach cancer
On Thursday morning, ODAC voted 6-2 against keeping Keytruda as a third-line treatment for stomach cancer. Panelists voting no pointed to the changing treatment landscape as earlier this month another checkpoint inhibitor, Bristol Myers Squibb’s Opdivo (nivolumab), won full approval from the FDA and showed positive overall survival benefit as a first line treatment for stomach cancer.
The accelerated approval first came in September 2017, but the FDA noted in its presentation Thursday that two follow-up trials did not confirm the benefit that was initially seen.
Pooja Bhagia, VP of oncology research at Merck, countered that these two studies were evaluating Keytruda as first- and second-line treatments for stomach cancer. She also explained how four ongoing Phase 3 trials (three of which are either fully enrolled or greater than 90% enrolled) have the potential to confirm clinical benefit of Keytruda in stomach cancer before the end of 2024.
Peter Enzinger of the Dana Farber Cancer Institute and a paid consultant to Merck and other physicians raised concerns about the lack of treatment options in the third line, especially since Keytruda is the only immunotherapy available.
But Pazdur, FDA’s head of oncology, shifted the tone of the morning meeting and offered the agency’s perspective, stressing the unintended consequences of keeping Keytruda in this indication as physicians might see checkpoint inhibitors as options in the first or third line, even though positive overall survival results have only been seen in the first line with Opdivo.
And as more receive checkpoint inhibitors in the first line setting, fewer will receive it in the third line setting, Steven Lemery, acting director of FDA’s Division of Oncology 3, added. He also noted immune-related adverse events with Keytruda, how most patients do not benefit from Keytruda in this indication, and he questioned the relevance of the four proposed confirmatory trials for this third-line indication as they all are studying Keytruda in combo with chemo.
“Many of these potential confirmatory trials won’t be available for years. Would we grant this indication at this time? The definitive answer is no,” Pazdur said.
He also stressed that even if Keytruda is pulled for this indication, patients who might be caught in limbo between treatments may still be able to access Keytruda because the FDA can set up an expanded access protocol.
Keytruda in HCC
The situation turned against the FDA again in the afternoon, although the agency isn’t obliged to follow the advice of its advisory committees.
In the first session, ODAC voted unanimously, 8-0, to maintain Keytruda’s accelerated approval for patients with hepatocellular carcinoma (HCC), a common type of liver cancer, as a second line treatment.
Merck first won that accelerated approval in November 2018, and the company made the case for why Keytruda should remain on the market as, even with the new approval in the first line setting for the combination of atezolizumab and bevacizumab, and the two new second-line accelerated approvals in this indication, there’s a need for anti-PD-1 monotherapy in the second line setting.
The FDA argued that the treatment landscape changed after the atezolizumab-bevacizumab combo was approved in the first-line setting.
Richard Finn, a professor of medicine at UCLA and paid consultant for Merck, said there does not seem to be any benefit to pulling this accelerated approval for Keytruda while two other confirmatory results are expected soon. One of those results from a trial in Asia is expected to read out in June or July, and is in the same setting as the accelerated approval.
FDA’s Steve Lemery noted that if this larger study in Asia is negative, it’s unclear if another trial could be useful as a confirmatory study as there would then be two negative confirmatory trials against placebo. He also noted that while some patients did see long duration of response, most patients do not benefit from the treatment. And he raised questions, given the changing treatment landscape, if Keytruda would win accelerated approval in this second line setting today.
Opdivo in HCC
In the late afternoon session, ODAC voted 5 to 4 to not maintain Bristol Myers Squibb’s Opdivo’s (nivolumab) indication for the monotherapy use of nivolumab in patients previously treated with sorafenib pending the conduct or completion of additional trial(s).
Panelist Anthony Sung, assistant professor of medicine at Duke University School of Medicine, voted “no” and said he didn’t think the data was there on the whole. Susan Halabi, a professor of biostatistics at Duke, also voted no and said that although there’s an unmet need, she wasn’t convinced there was a clinical benefit.
Back in September 2017, Bristol Myers Squibb’s Opdivo (nivolumab) won accelerated approval as a second-line treatment for HCC. Two years later, a confirmatory study did not meet statistical significance in its primary endpoint of overall survival and other treatments for this indication made their way to the market.
As seen with Keytruda in the prior session, the altered treatment landscape was a question for Opdivo, partly because the drug also won another, separate accelerated approval in combination with Yervoy (ipilimumab) last March for the same setting — patients with HCC who have been previously treated with sorafenib.
Bristol Myers discussed the significant unmet need in the second line treatment space for HCC and some long response rates with Opdivo.
Anthony El-Khoueiry, associate professor of medicine at the University of Southern California, said Opdivo offers a more favorable benefit-risk profile than second-line anti-VEGF targeted options.
Lemery presented again for FDA, explaining the failed confirmatory trial and noting that the agency found the combo of Opdivo and Yervoy to be “highly relevant” given the considerably lower response rate for monotherapy.
But Thomas Abrams, an associated professor at Harvard Medical School and paid Merck consultant, said the combo treatment is really reserved for the fitter patients who failed a TKI (tyrosine kinase inhibitor) in the first line. For monotherapy with Opdivo, Abrams said the patients have more comorbidities, and “they really are two different patient populations.”
FDA’s Pazdur again weighed in, claiming that BMS is essentially trying to make the case for Opdivo as a monotherapy for those who cannot tolerate the Opdivo and Yervoy combination. But when Pazdur pressed BMS on data around the response rate for this population, BMS said it didn’t have the data.
“You’re advocating for a new indication, please provide the response rate – not anecdotal information,” Pazdur said.
Leerink’s Graybosch said ODAC’s vote to withdraw nivolumab from this indication “seemed somewhat unfair as ODAC voted unanimously earlier to keep accelerated approval for pembrolizumab in the same indication. Three differences, however, were that Merck did share ORR [overall response rate] data for pembrolizumab in patients who would be considered ineligible for bevacizumab, placed more emphasis on comparable efficacy in 2L to TKIs, and has an ongoing, randomized trial that could confirm monotherapy efficacy.”
Last two days
Thursday’s meeting followed three other votes on Tuesday and Wednesday to maintain Keytruda and Tecentriq accelerated approvals in other indications.
On Wednesday morning, ODAC voted 5-3 in favor of keeping Keytruda’s accelerated approval alive as a first line bladder cancer treatment for those who are cisplatin-ineligible and carboplatin-ineligible, even after a Merck confirmatory trial failed.
And on Wednesday afternoon, ODAC voted 10-1 in favor of keeping Genentech’s Tecentriq (atezolizumab) as a first-line treatment of cisplatin-ineligible patients with advanced/metastatic bladder cancer pending final overall survival results from a confirmatory trial, known as IMvigor130.
Committee members on Tuesday also voted 7-2 to maintain the accelerated approval for Tecentriq plus Abraxane (nab-paclitaxel) in metastatic triple negative breast cancer while additional confirmatory trials are ongoing.
These votes add to four other voluntary accelerated approval withdrawals for Opdivo and Keytruda as third-line treatments in small cell lung cancer, and Tecentriq and AstraZeneca’s Imfinzi (durvalumab) as second-line treatments for bladder cancer.
The FDA is not obligated to follow the advice of ODAC, but the agency will be faced with some difficult decisions, particularly on the precedent that might be set if some companies are allowed to conduct or wait for an additional confirmatory trial to read out before their accelerated approval indications are pulled or converted to a full approval.
Although none of the drugs will be pulled entirely from the market, meaning all can be used off-label for these indications no matter what happens, this three-day meeting may push the FDA, and possibly even Congress, to reassess the accelerated approval pathway overall and what should occur when a confirmatory trial fails.