Next week, a panel of advisers to the Food and Drug Administration will convene to debate the merits of six recent cancer immunotherapy approvals handed out by the agency.
In each case, approval was granted on a conditional basis, backed by early data suggesting a treatment benefit that the drugs' makers were asked to confirm with follow-up studies. Now, several years later, those trials have come back with either inconclusive or negative data, resulting in unsupported accelerated approvals the FDA wants reviewed.
The three-day meeting, which starts April 27th, could lead the agency to request the withdrawal of some of those indications. Already, Merck & Co., Bristol Myers Squibb, Roche and AstraZeneca have each pulled their respective immunotherapies for use in certain types of lung and bladder cancers as part of an industry-wide evaluation by the FDA.
Any similar recommendation by the committee next week would be noteworthy — only 10 cancer drug indications approved on an accelerated basis have ever been subsequently withdrawn, including those recent four. But the meeting could be more broadly consequential, potentially fueling a larger debate about the balance between speeding drugs to market and confirming clinical benefit.
The question is particularly relevant for immunotherapy in cancer, development of which occurred faster than any other therapeutic area in the FDA's history. Yet the agency has argued withdrawals as a result of unconfirmed benefit do not necessarily undermine its approach to accelerated approval.
"The small percentage of drugs whose clinical benefit is ultimately not confirmed should be viewed not as a failure of accelerated approval but rather as an expected trade-off in expediting drug development that benefits patients with severe or life-threatening diseases," wrote Richard Pazdur, head of the FDA's Oncology Center of Excellence, and Julia Beaver, the center's chief of medical oncology, in a piece published by The New England Journal of Medicine Wednesday.
Here are the six approvals up for discussion at next week's meeting, grouped by cancer type:
In 2016, Roche won the first approval for its immunotherapy Tecentriq in urothelial cancer, which affects the lining of the bladder and other urinary tissue. AstraZeneca's Imfinzi and Merck's Keytruda quickly followed a year later.
But subsequent studies of all three drugs have been unable to confirm the promising signs that led to their speedy approvals. The trial results have called into question immunotherapy's role in treating the disease, which is one of the world's most common cancer types.
Doubts about Tecentriq were caused by the IMvigor 211 trial, which read out results just 11 months after the drug's approval. Unlike the Phase 2 test that supported the FDA's decision, IMvigor 211 pitted Roche's drug against chemotherapy and found no difference in survival or remission rates. Imfinzi, too, didn't help patients live longer in a confirmatory study.
Keytruda, as with the other two, was cleared for bladder cancer based on remission data from a mid-stage study. Similarly negative results followed. In a confirmatory trial, Keytruda plus chemotherapy didn't extend lives or keep patients' disease from progressing when compared to chemotherapy alone.
The FDA narrowed the label for Tecentriq and Keytruda after testing showed an increased risk of death in patients whose tumors don't express the protein PD-L1. The only immunotherapy to extend lives in Phase 3 testing in advanced bladder cancer, Bavencio, was tested as a “maintenance” therapy to keep tumors at bay after surgery. The FDA approved it in 2020.
Roche eventually withdrew one of two bladder cancer approvals for Tecentriq some four years after its initial clearance. AstraZeneca, too, pulled bladder cancer from Imfinzi's label. Keytruda's advanced bladder cancer approval — and a Tecentriq nod for patients who aren't eligible for chemotherapy — are two of the three that remain. Survival data has yet to be reported for the other approved immunotherapy in advanced disease, Bristol Myers' Opdivo.
Experts will scrutinize Merck's and Roche's approvals next week.
Hepatocellular carcinoma is the most common form of liver cancer and, by some counts, one of the fastest growing causes of cancer death in the U.S. Since 1980, the incidence of HCC, which is primarily caused by past infections with hepatitis B or C viruses, has more than tripled.
For more than a decade, doctors have prescribed a drug called Nexavar for treating HCC that's unremovable by surgery. Made by Bayer, Nexavar was cleared by the FDA in 2007 based on a study showing it extended patient survival for longer than placebo.
More recently, in 2017 and 2018, the FDA granted accelerated clearances to first Opdivo and then Keytruda for second-line use if Nexavar didn't stop patients' cancers from progressing. The approvals were based on early data showing a small minority of participants in single-arm studies responded to treatment with the immunotherapies. But almost no trial volunteers experienced remission following treatment and, in the case of each drug, about half of those treated in the studies had their disease progress within a year.
Follow-up studies from Merck and Bristol Myers weren't able to prove either drug extended survival versus, respectively, placebo or Nexavar in previously untreated HCC patients. Both approvals will be under review by the advisory panel next week.
In the case of Opdivo, however, only the drug's use as monotherapy is up for debate. The drug is also cleared for use together with Bristol Myers' Yervoy, for which the response data appear a bit better.
One factor that could influence the committee is the 2020 approval of Roche's Tecentriq, together with its other cancer drug Avastin for first-line HCC. Data supporting the OK showed treatment led to a 42% reduction in the risk of death versus Nexavar.
Roche made history when, in May 2019, Tecentriq became the first immunotherapy cleared for use in breast cancer. The approval was based on study results that showed the drug, when given alongside chemotherapy in patients with metastatic triple-negative breast cancer, helped keep tumors from spreading longer than chemotherapy alone.
The decision was a promising sign for immunotherapy's utility in triple-negative breast cancer, a particularly aggressive form of the disease that has mainly only been treatable with chemotherapy. A similar approval followed for Keytruda. Both drugmakers aim to bring immunotherapy into earlier disease settings, before or after surgery to remove a tumor.
Yet two years after Tecentriq's approval in triple-negative breast cancer, it's still unclear whether the drug actually helps patients. For one, the benefit underlying the FDA's decision was modest: Tecentriq and chemo held tumors in check for a median of 7.4 months versus 4.8 months for those on chemo alone. More importantly, the survival benefit Roche eventually revealed for the Tecentriq-chemo regimen — a median of 21 months versus 18.7 for chemo alone — wasn't statistically significant, according to results published in the journal The Lancet.
Another analysis suggested a greater benefit for patients whose tumors expressed PD-L1, a protein known to predict response to immunotherapy. But because the drug didn't extend lives for the full group of treated patients — one of the study's two main goals — that finding isn't considered statistically sound. What's more, the combination of Tecentriq and a similar type of chemotherapy also wasn't successful in a Phase 3 trial.
Experts will debate the merits of Roche's data next week, and their recommendations could have implications for Keytruda. Merck hasn't yet reported confirmatory results from the study that led to Keytruda's more recent approval in triple-negative breast cancer.
Gastric cancer is considered tough to treat because it's difficult to spot early. Often, a stomach tumor isn't found until it's already spread elsewhere. Up until recently, the only non-surgical treatments available were chemotherapy, radiation and, in some cases, targeted drugs. The disease has a five-year survival rate of 5%.
The dearth of good options factored into the FDA's decision in September 2017 to approve Keytruda as the first immunotherapy for gastric cancer as well as a rare type of esophageal tumor. The agency cleared Keytruda for patients who had progressed despite two treatments and whose tumors expressed PD-L1.
The decision was based on a small, single-arm Phase 2 study. Just 19 of the 143 patients who were PD-L1 positive responded to treatment. But 11 of those responses lasted at least six months and five continued for at least a year, suggestive of immunotherapy's potential, when it works, to have a lasting impact.
That approval was quickly called into question, however. Three months after Keytruda was cleared, a Phase 3 study showed it didn't help patients live longer when used as a second-line treatment. In 2019, the drug failed another study, this time in the frontline setting.
Merck still has other Keytruda trials ongoing in gastric cancer that could serve as confirmatory studies. But as of now, nearly four years after its initial approval, Keytruda's benefits remain unclear. Rival Opdivo, meanwhile, was just cleared for use after a study showed first-line treatment with it reduced the risk of death by a fifth.