Immunotherapy Withdrawals Put Spotlight on Accelerated Approval

The FDA's Accelerated Approval program is under scrutiny after four drug companies announced plans in recent months to withdraw indications for checkpoint inhibitors that, despite showing early promise, failed to demonstrate a survival benefit in confirmatory trials.

The agency's Oncologic Drugs Advisory Committee (ODAC) will meet in late April to discuss whether six more indications for some of these same immunotherapies should be nullified as well. The FDA needn't follow the advice of this committee, although it usually does so.

“This ODAC meeting is a good sign,” says Bishal Gyawali, MD, PhD, of Queen's University Cancer Research Institute in Kingston, Ontario, Canada. “This is what preserves the integrity of accelerated approval.”

Since its creation in 1992, the accelerated approval pathway has led to more than 250 drug authorizations, mostly in oncology, granted based on surrogate measures or intermediate trial endpoints. One assessment, conducted by FDA staff, found that the program—true to its mission—helped make cancer drugs available to patients 3.4 years earlier on average than if definitive proof of clinical benefit was required (JAMA Oncol 2018;4:849–56).

However, the regulatory mechanism is not without detractors. Gyawali and his colleagues found little correlation between overall survival (OS) and many surrogate endpoints used to underpin accelerated approvals in oncology (EClinicalMedicine 2020;21:100322). They also determined that only one fifth of cancer drug indications granted accelerated approval before 2017 had confirmatory trials indicative of OS benefit (JAMA Intern Med 2019;179:906-13). Specific to immune checkpoint inhibitors, other researchers have criticized what they see as the agency's rush to grant accelerated approvals when the reporting of clinically meaningful outcomes is imminent, and being slow to revoke approvals following negative confirmatory results (Nat Rev Clin Oncol 2019;16:656–8).

Acting FDA commissioner Janet Woodcock, MD, who headed the agency's Center for Drug Evaluation Research for 25 years, has defended the approval pathway, citing the need to balance access to effective therapies against the risk of ineffective agents reaching the marketplace temporarily.

Many others agree and argue that most criticisms directed at the accelerated approval pathway are misguided, outdated, or overblown. “This is a program that's working as intended,” says Dan Chen, MD, PhD, former head of cancer immunotherapy at Genentech and now chief medical officer of IGM Biosciences in Mountain View, CA.

That wasn't always so. For many years, “there were companies that were literally sitting on their hands and not even moving forward with doing phase IV confirmatory trials, which are required,” says Wyndham Wilson, MD, PhD, of the NCI's Center for Cancer Research, and a former ODAC chair.

Lately, though, regulators and drug makers have adopted a more collaborative and constructive approach, says Chen, who sees the recent voluntary withdrawals of four checkpoint inhibitor–related indications as a reflection of “a very real partnership.”

The withdrawals involved two PD-1 inhibitors, nivolumab (Opdivo; Bristol Myers Squibb) and pembrolizumab (Keytruda; Merck), both for patients with previously treated metastatic small cell lung cancer (SCLC); and two PD-L1 inhibitors, durvalumab (Imfinzi; AstraZeneca) and atezolizumab (Tecentriq; Genentech), to treat refractory urothelial carcinoma.

In each of those cases, confirmatory trials failed to demonstrate statistically significant OS benefits. Yet, even with those checkpoint inhibitors off the market, patients still have other immunotherapy options: atezolizumab is approved for treating SCLC, and pembrolizumab is approved for treating urothelial carcinomas refractory to platinum-containing chemotherapy.

That availability of in-class alternatives makes withdrawal decisions easier, notes Chen. A bigger challenge surrounds accelerated approvals when there are no other comparable agents with marketing authorization.

Such is the scenario for the six indications under discussion at the April ODAC meeting. These include prescribing atezolizumab for forms of breast and bladder cancer; nivolumab for refractory liver cancer; and pembrolizumab for cancers of the bladder, liver, and gastroesophageal tract. Phase III studies did not confirm clinical benefit—but they didn't demonstrate ineffectiveness either.

“I expect a reasonable but difficult discussion at this public forum,” Chen says. “This is going to be a real gut-check moment.”

Consider the use of pembrolizumab and atezolizumab among patients with urothelial carcinoma who cannot receive cisplatin-containing chemotherapy. The accelerated approvals were based on overall response rates and durations of response in single-arm studies involving cisplatin-ineligible patients. However, the confirmatory, randomized trials—for logistic and ethical reasons—did not involve the same study populations. Instead, they compared the checkpoint inhibitors with or without platinum-based chemotherapy in patients eligible for standard treatment.

What's more, those confirmatory trials were borderline positive. Both checkpoint inhibitors, when combined with chemotherapy, showed numerically longer median OS compared with chemotherapy alone. Yet, each trial, as of the last public data analysis, failed to cross the threshold of statistical significance, in part because multiple testing procedures were employed. Had the drug sponsors asked fewer questions of the data, it is possible that the benefits would have been statistically significant, notes William Slichenmyer, MD, of Alacrita Consulting in Waltham, MA.

So, should that count as a lack of confirmation? “It's a challenge about how strict we want to be with the statistical philosophy,” Slichenmyer says.

Regardless of what the FDA and its advisors decide, the fact that so many accelerated approvals for checkpoint inhibitors are up for discussion raises questions about whether the criteria for early market entry are set appropriately for these immunotherapies. The atypical response patterns for PD-1 pathway inhibitors can make it difficult to judge early indications of clinical activity via surrogate measures, experts acknowledge. But for the most part, they don't see a widespread problem in how the regulatory mechanism is applied to the drug class, especially because many accelerated approvals have been converted to regular approvals following confirmatory trials.

Recent events, they say, reflect just how many accelerated approvals the various checkpoint inhibitors have garnered in recent years—16 indications for pembrolizumab alone since 2013, plus many more for alternative dosing schedules—and the speed with which the companies have completed confirmatory trials.

Still, many see room for improvement. Last year, a working group convened by Friends of Cancer Research (FOCR) proposed more comprehensive risk–benefit assessments of the surrogate endpoints that underpin such approvals (see friendsofcancerresearch.org). Other recommendations from the group included increasing the use of real-world evidence to supplement confirmatory trial results; considering patient heterogeneity to potentially award accelerated approval to subpopulations of “excellent responders”; and expanding the use of synthetic control arms to support approvals when traditional control arms are not feasible.

Regulators are bound by law to focus on surrogate and intermediate clinical endpoints as the basis for approval—which “poses challenges,” acknowledged working group member Angelo de Claro, MD, of the FDA Oncology Center of Excellence. Speaking at the FOCR 2020 annual meeting, he said, “Reconsideration of the basis of accelerated approval could grant FDA more flexibility to have more therapies available for serious and life-threatening diseases.” –Elie Dolgin