As part of a U.S. FDA evaluation of confirmatory trials for anti-PD-1/PD-L1 antibodies, the agency’s Oncologic Drugs Advisory Committee (ODAC) is being asked this week to consider whether three blockbuster biologics should continue to be available for certain cancer indications for which they received accelerated approval.

At question is whether the data from the confirmatory trials for the Roche Group’s Tecentriq (atezolizumab), Merck & Co. Inc.’s Keytruda (pembrolizumab) and Bristol Myers Squibb Co.’s Opdivo (nivolumab) has proved sufficient benefit in particular indications and, if not, whether alternative or ongoing trials could do so.

In its briefing documents for the three-day meeting, which begins April 27, the FDA said it undertook the evaluation of the anti-PD-1/PD-L1 antibodies because of “the unprecedented level of drug development in this space in which there were many accelerated approvals.” As a result of the evaluation, the agency found a number of supplemental biologics license applications (sBLAs) that had received accelerated approval, but the clinical benefit wasn’t verified in subsequent confirmatory trials.

Since the FDA’s accelerated approval program began, only 6% of accelerated approvals for oncology indications have been withdrawn, the agency said. That’s including four withdrawn within the past few months – one each for Keytruda, Opdivo and Tecentriq, as well as an sBLA for Astrazeneca plc’s Imfinzi (durvalumab).

Added to the questions about clinical benefit for three of the indications to be discussed at the adcom – urothelial carcinoma, hepatocellular carcinoma, and metastatic gastric or gastroesophageal junction adenocarcinoma – is the change alternative checkpoint inhibitors have brought to the treatment landscape in the maintenance setting.

ODAC wasn’t consulted on the recent withdrawals of cancer indications, as the companies voluntarily complied with the FDA’s request to withdraw those sBLAs. But at this week’s meeting, the companies will make their case for why accelerated approval should continue for the indications in question. Keytruda has three indications on the line, Tecentriq has two and Opdivo has one.

Given the number of approvals the drugs have, a few withdrawn indications may not have much of a financial impact, especially if the landscape in a particular indication is shifting away from that particular biologic. For instance, even with three indications at stake – all of which have alternative checkpoint inhibitors – Keytruda likely will remain on track to dislodge Abbvie Inc.’s Humira (adalimumab) as the top-grossing drug in the world. Last year, Keytruda had global sales of $14.38 billion and, according to Cortellis, is expected to generate nearly $28 billion in sales in 2026. (In comparison, Humira, an immunotherapy drug, produced $19.83 billion in sales last year and is expected to peak at nearly $21 billion in 2022, the year before several adalimumab biosimilars hit the U.S. market.)

Regardless of any impact for the three biologics themselves, the optics of more withdrawals could add to congressional pricing pressures on the biopharma sector overall, and accelerated approvals specifically. Since biologics, including those with accelerated approval, are among the priciest drugs on the U.S. market, someone is sure to question why the U.S. is paying top dollar for drugs that have yet to be proven for certain indications. And the fact that companies often increase a drug’s price when a new indication is added to the label could lead to some lawmakers asking why the price isn’t lowered when an indication is withdrawn.



First up for the adcom is Tecentriq, used in combination with nab-paclitaxel, to treat metastatic triple-negative breast cancer (mTNBC). The March 2019 accelerated approval was based on progression-free survival (PFS) and made Tecentriq the first FDA-approved breast cancer regimen that includes immunotherapy. But the confirmatory trial failed to meet the primary PFS endpoint and demonstrated a “possible detriment” in overall survival (OS), according to the FDA.

Despite those results, Roche said Tecentriq “continues to fulfill an important unmet need for patients with mTNBC.” It will argue April 27 that the accelerated approval should be continued pending the submission and review of additional data to support conversion to full approval.

The following day, ODAC will review the data for Tecentriq’s use as first-line treatment for patients with locally advanced or metastatic urothelial carcinoma who aren’t eligible for cisplatin-containing chemotherapy. The drug received accelerated approval for the indication in April 2017 based on the early clinical benefit endpoint of durable response rate. But a large, randomized phase III confirmatory trial didn’t demonstrate a clinically meaningful improvement, even though it was statistically significant for PFS, the FDA said. Two interim analyses of OS haven’t passed the interim efficacy boundaries and the final OS analysis is pending.


Also on April 28, ODAC will consider Keytruda’s accelerated approval for the same indication. Granted a month after Tecentriq’s approval in urothelial carcinoma, Keytruda’s sBLA was based on a single-arm trial demonstrating a confirmed durable response rate (ORR). As with Tecentriq, a large, randomized phase III confirmatory trial failed to meet its primary endpoint. But given the unmet need, the FDA is asking ODAC to consider possible steps forward for Keytruda in the indication.

On the final day of the adcom, ODAC will discuss Keytruda’s accelerated approvals as treatment of hepatocellular carcinoma following sorafenib and as third-line treatment for certain patients with gastric cancer. The gastric cancer sBLA was granted accelerated approval in 2017 based on the durable response rate. Two later studies didn’t demonstrate statistically significant improvement in OS. Although ongoing studies are expected to help define the role of checkpoint inhibition in gastric cancer, the FDA said the role of monotherapy is less clear.

As for the hepatocellular carcinoma indication, Keytruda was granted accelerated approval as second-line treatment based on a modest response rate in a single-arm trial. A randomized, controlled trial didn’t confirm a clinical benefit, the FDA said, adding that more data would be necessary should the indication continue. The agency also noted that the approval of Tecentriq and Roche’s Avastin (bevacizumab) in the first-line setting has established a new standard of care in hepatocellular carcinoma.


ODAC also will weigh in April 29 on Opdivo’s sBLA as a single agent for the second-line treatment of hepatocellular carcinoma. Like Keytruda, Opdivo received accelerated approval based on a modest response rate in a single-arm trial that was not confirmed in a randomized, controlled trial. It also could be impacted by the new standard of care.