Three more oncology indications given accelerated approval are being withdrawn from the U.S. market at the request of the FDA. Those mark just shy of 20 oncology indications and/or drugs that have been approved through that accelerated pathway and then subsequently retracted since 2020. While accelerated approval may be benefiting patients with nononcology indications, its track record for oncolytics is not quite as impressive, says one industry expert.
Most recently, Roche said on Nov. 29 that it was voluntarily withdrawing Tecentriq’s (atezolizumab) indication for the treatment of adults with locally advanced or metastatic urothelial carcinoma who are not eligible for cisplatin-containing chemotherapy and whose tumors express programmed death-ligand 1 or are not eligible for any platinum-containing chemotherapy regardless of PD-L1 status. The agency granted accelerated approval for that indication on April 17, 2017, to Roche’s Genentech USA, Inc. subsidiary.
The drug’s Phase III IMvigor 130 trial, which was required for conversion of accelerated approval to regular approval, did not meet the co-primary endpoint of overall survival (OS) for Tecentriq plus chemotherapy compared with chemotherapy alone, said the company. It also noted that the withdrawal would not impact other FDA-approved indications for the agent. The withdrawn bladder cancer indication is the last of the drug’s accelerated approvals that had not been confirmed.
Last year the company withdrew two other accelerated indications for the immunotherapy. On Aug. 27, Genentech said it would voluntarily withdraw the accelerated approval for Tecentriq in combination with chemotherapy (Abraxane, albumin-bound paclitaxel; nab-paclitaxel) for the treatment of adults with unresectable locally advanced or metastatic triple-negative breast cancer (TNBC) whose tumors express PD-L1, as determined by an FDA-approved test.
The move followed an April 27-28, 2021, meeting of the FDA Oncologic Drugs Advisory Committee (ODAC) that scrutinized six indications for a handful of checkpoint inhibitors that target PD-L1 and programmed death-1 (PD-1) and received accelerated approval to determine whether confirmatory trials verified the therapies’ clinical benefits. That Tecentriq TNBC indication was among those discussed, and committee members actually voted 7-2 to maintain that accelerated approval.
However, according to a company press release on the withdrawal, “Genentech made this decision following consultation with the FDA based on the agency’s assessment of the current [metastatic] TNBC treatment landscape and in accordance with the requirements of the accelerated approval program.” The release noted that the IMpassion131 postmarketing study did not meet the primary endpoint of progression-free survival for the first-line treatment of metastatic TNBC in people positive for PD-L1. The company said it had been working on an alternative postmarketing requirement, but “due to the recent changes in the treatment landscape, the FDA no longer considers it appropriate to maintain the accelerated approval.”
Prior to that, on March 8, 2021, the company said it was voluntarily withdrawing the U.S. indication for Tecentriq for the treatment of people with locally advanced or metastatic urothelial carcinoma that has progressed during or after platinum-based chemotherapy.
GSK Is Withdrawing Two Indications
More recently, GSK plc said it would pull back two oncology indications. On Nov. 11, the company revealed that it will limit the second-line maintenance indication for Zejula (niraparib) in patients with recurrent epithelial ovarian, fallopian tube or primary peritoneal cancer who are in a complete or partial response to platinum-based chemotherapy to those patients who have deleterious or suspected deleterious germline BRCA mutations. The drug launched after the FDA first approved it for use in the second-line setting on March 27, 2017.
The manufacturer says that the drug’s first-line indication for the maintenance treatment of adults with advanced epithelial ovarian, fallopian tube or primary peritoneal cancer who are in a complete or partial response to platinum-based chemotherapy remains unchanged. The move comes amid multiple withdrawals for poly (ADP-ribose) polymerase (PARP) inhibitor ovarian cancer late-line indications in 2022. It also occurred less than two weeks before a scheduled Nov. 22 ODAC meeting to discuss Zejula’s second-line use and whether it should remain on the drug’s label. ODAC canceled the meeting in late October.
Zejula’s most recent indication withdrawal follows GSK’s September notification of health care providers that it had voluntarily withdrawn the approval for the drug for the treatment of adults with advanced ovarian, fallopian tube or primary peritoneal cancer who have been treated with at least three chemotherapy regimens and whose cancer is associated with homologous recombination deficiency (HRD) positive status due to OS rates in the QUADRA study.
Then on Nov. 22, GSK said it would withdraw its U.S. marketing authorization for Blenrep (belantamab mafodotin-blmf). The FDA granted the B-cell maturation antigen (BCMA)-directed antibody and microtubule inhibitor conjugate accelerated approval on Aug. 5, 2020, for the treatment of adults with relapsed or refractory multiple myeloma who have received at least four therapies including an anti-CD38 monoclonal antibody, a proteasome inhibitor and an immunomodulatory agent.
The company said that the FDA requested the withdrawal based on the outcome of the Phase III DREAMM-3 confirmatory trial, which did not meet its primary endpoint of progression-free survival in a head-to-head study versus the combination of Bristol Myers Squibb’s Pomalyst (pomalidomide) plus dexamethasone (PomDex), the company revealed Nov. 7.
That indication was the only one for Blenrep. GSK said that patients enrolled in the Blenrep Risk Evaluation and Mitigation Strategy (REMS) program will have the option to enroll in a compassionate use program to continue undergoing treatment. The company will communicate enrollment logistics directly to REMS-enrolled prescribers. GSK will continue its DREAMM clinical trial program.
Studies Have Prompted Scrutiny of Pathway
Numerous studies over the past few years have brought increased scrutiny to the accelerated approval pathway and its use with cancer agents. A study published in August on JAMA Health Forum revealed that of the oncology indications given accelerated approval between Jan. 1, 2007, and Dec. 31, 2021, only 36% were rated as having high added therapeutic value compared with 53.3% for noncancer indications. A study published in JAMA Oncology in June 2018 found that of the 93 new accelerated approval hematology and oncology indications from Dec. 11, 1992, to May 31, 2017, only slightly more than half — 55% — had completed confirmatory trials in a median of 3.4 years after approval, while 40% had not completed those trials. And another study published in BMJ in September 2021 showed that even after a negative confirmatory trial, one-third of indications remained on a cancer drug’s label, and half had the second highest level of recommendation in National Comprehensive Cancer Network (NCCN) guidelines.
Various industry experts have called for a variety of overhauls to the pathway — and the FDA may have already begun following one of the suggestions. Richard Pazdur, M.D., director of the FDA’s Oncology Center of Excellence, has said he’d like to require manufacturers not only to communicate their confirmatory study plan early in the approval process but also to have these trials underway when they submit their applications for accelerated approval.
“Accelerated approval is aimed at the patients,” Pazdur said during the 2022 Friends of Cancer Research annual meeting. “It’s not an incentive program for the industry.”
At least one manufacturer has revealed that the agency seems to be taking this step. On Nov. 8, ADC Therapeutics SA revealed that it would not seek accelerated approval for its camidanlumab tesirine, or Cami, in Hodgkin lymphoma. In a September meeting with the FDA, the agency “provided strong guidance that, for it to consider an accelerated approval path, a randomized confirmatory Phase 3 study must be well underway and ideally fully enrolled at the time of any BLA [i.e., Biologics License Application] filing for Cami. As a result, the Company will not submit the BLA for Cami next year, as it is estimated that it would take at least two years to fully enroll a randomized confirmatory Phase 3 study,” said the company in a press release reporting third-quarter 2022 earnings. “The Company is engaged with the FDA in an ongoing and constructive dialogue regarding their guidance and the potential regulatory path forward.”
While drugs given accelerated approval for nononcology indications seem to be benefiting patients, many of the accelerated oncology indications are not showing progression-free survival, points out Jayne Hornung, chief clinical officer at MMIT. She suggests that perhaps the way the pathway is today is not the way it should be.
AIS Health is a division of MMIT.
She also points out that “the NCCN compendia recommendations are used to support Medicare coverage, meaning that Medicare will be required to reimburse use of these drugs. This has important financial consequences for patients — and the health care system overall.”
The FDA needs to take a stronger stance on these agents, she asserts, noting that many patients and providers look to the agency for assessments of drugs’ risk/benefit profiles, so there is the risk of patients being prescribed agents with no proven clinical benefit that have some toxicities.
According to an industry expert who declines to be identified, “what about the patients who got these drugs?”
At least one oncologist says he has found himself “struggling” to talk to patients about drugs with accelerated approval.
“Someone who’s not steeped in regulatory science really isn’t going to understand the nuances of accelerated approval and how, yes, it makes drugs available to people who have life-threatening conditions quickly, which is its purpose, which was its birth, but there’s a ‘but’ to it,” Mikkael A. Sekeres, M.D., told OBR Oncology. “There’s a second half to that where you’re waiting for another trial to really validate how safe and effective those drugs are.”
Sekeres was on the ODAC committee that voted to rescind Avastin’s (bevacizumab) accelerated approval in combination with chemotherapy for the treatment of HER2-negative breast cancer in 2010. Then-FDA Commissioner Margaret Hamburg, M.D., pulled the indication against manufacturer Genentech’s wishes, marking the only time the agency has even taken such a step. Sekeres recently wrote a book, Drugs and the FDA: Safety, Efficacy, and the Public’s Trust, on that process and how the FDA works.
“There were some drugs that were approved where I would offer them to patients and say, ‘It’s been approved under accelerated approval, but we really don’t have long-term outcome on clinically meaningful endpoints,’” he said. “And then there were some drugs that I didn’t offer to patients, and they would say, ‘Why not?’ I’d say, ‘Well, there’s this “but.” I’m really waiting for the confirmatory trial. I’m not sure I’m comfortable offering it based on the study of a hundred patients or 40 patients,’ or however many patients some drugs are getting approved on.”
Getting accelerated approval may be “a bad thing,” says the unidentified source. There can be “unintended consequences of getting out of the gate faster.”
This article was reprinted from AIS Health’s monthly publication Radar on Specialty Pharmacy.