Last year, US regulators granted drug approvals for about 40 oncology indications and completed withdrawals for seven indications.
Most of the approvals in 2022 involved expanding the indications for existing drugs, but about 11 novel drugs came onto the market as well.
Compared to previous years, the US Food and Drug Administration (FDA) granted fewer oncology drug approvals in 2022 — about 17 fewer than in 2021.
On the withdrawal front, the FDA tied its record from 2021 — completing withdrawals for seven accelerated approvals for oncology indications in each year. These account for nearly two thirds of the 22 total withdrawals for oncology accelerated approvals.
The approval and withdrawal trends in oncology may signal the growing challenges the FDA has encountered in balancing rapid therapeutic advances in cancer care with the need to evaluate the safety and efficacy of these drugs thoroughly.
On one hand, drugmakers have made great strides in drug development by focusing on immunotherapies that can unmask cells gone awry and can mobilize the immune system to target and destroy them. Some of the more notable 2022 approvals came from an emerging class of “off-the-shelf” T-cell targeting drugs, which included tebentafusp for uveal melanoma, mosunetuzumab for follicular lymphoma, and teclistamab for relapsed/refractory multiple myeloma.
On the other hand, the growing number of drugs receiving accelerated approvals has meant that for many of the agents that are on the market, there are no long-term data affirming their safety and effectiveness.
With accelerated approvals, the FDA, patients, and physicians are waiting to see whether a medicine can truly extend or improve lives, said Mikkael Sekeres, MD, of the University of Miami.
The uncertain benefit from drugs cleared by accelerated approval should be made clearer to patients and physicians, said Sekeres, who served as a member of the FDA’s Oncologic Drugs Advisory Committee — a time he recounts in his recent book.
“The FDA should have a big fat asterisk next to any drug that’s been approved under accelerated approval,” Sekeres told Medscape Medical News.
Still, Sekeres expressed enthusiasm about how increasing understanding of cancer’s ability to evade the immune system is paying off with novel drugs.
“It is an exciting time in cancer therapeutics,” he said. “We truly are seeing the fruits of 40 years of funding of basic science research.”
A Look at Novel Approvals
Among the 11 novel cancer drugs approved last year, five received accelerated approvals, and six received traditional approvals.
One of the more notable approvals in 2022 was for the chimeric antigen receptor (CAR) T-cell therapy ciltacabtagene autoleucel (Carvykti). Ciltacabtagene autoleucel, which received approval through the traditional pathway, is indicated for patients with refractory/relapsed multiple myeloma who have already received four or more lines of therapy. The CAR T-cell therapy is directed against B-cell maturation antigen, which represents a new target against multiple myeloma. It is the sixth unique agent in this drug category.
The FDA also approved several checkpoint inhibitors — opdualag, which combines the checkpoint inhibitors nivolumab and relatlimab, for unresectable or metastatic melanoma, and tremelimumab for hepatocellular carcinoma. These therapies, approved through the regular pathway, bring the total number of unique checkpoint inhibitors to nine, according to the American Cancer Society.
That growth is notable, considering that the FDA cleared the first CAR-T therapy in 2017 and the first checkpoint inhibitor in 2011. In fact, the checkpoint inhibitor class has become the “Wild West of drug development, featuring a stampede of commercial sponsors, clinical trials, and redundant development plans,” Richard Pazdur, MD, of the FDA, and oncologist Julia A. Beaver, MD, wrote last year in an article published in The New England Journal of Medicine.
Among the emerging class of “off-the-shelf” T-cell targeting drugs, tebentafusp (Kimmtrak, Immunocore) is the first bispecific T-cell engager to receive regulatory approval from the FDA to treat a solid tumor — metastatic uveal melanoma. The drug was designed so that one part makes the tumor cell visible to the immune system, while the other draws T cells to the tumor cell to kill it, Bahija Jallal, PhD, Immunocore’s chief executive officer, said last January at a healthcare conference.
The overall survival data that led to the drug’s approval challenged the notion that certain T-cell targeting drugs would work best in blood cancers.
Another big win on the novel drug front was for follicular lymphoma. In December, the FDA gave an accelerated approval to mosunetuzumab (Lunsumio, Genentech) for relapsed or refractory follicular lymphoma after two or more lines of systemic therapy.
“I saw first hand the impact follicular lymphoma has on patients, especially as it often relapses after initial treatment and becomes increasingly challenging to treat each time it returns,” said Ginna Laport, MD, who has treated patients with this relatively common form of lymphoma for almost 20 years.
Mosunetuzumab, a first-in-class bispecific antibody, now offers patients a chance to start treatment soon after diagnosis, she said.
“Other follicular lymphoma treatments, such as cell therapies, require the collection or genetic modification of cells and can take a month or longer to manufacture, leading to delays in treatment, and must be administered at an academic medical center,” said LaPort, vice president and global head of lymphoma/CLL development at Genentech. “Lunsumio offers patients a chemo-free option that can be given in an outpatient setting, allowing patients the flexibility of receiving treatment close to home even if they don’t live near an academic medical center.”
The following five novel drugs were approved in 2022:
adagrasib (Krazati, Mirati Therapeutics) for advanced or metastatic non–small cell lung cancer
mirvetuximab soravtansine (Elahere, ImmunoGen) for platinum-resistant epithelial ovarian, fallopian tube, or primary peritoneal cancer
futibatinib (Lytgobi, Taiho Oncology) for unresectable, locally advanced, or metastatic intrahepatic cholangiocarcinoma
olutasidenib (Rezlidhia, Forma Therapeutics) for relapsed or refractory acute myeloid leukemia
lutetium Lu 177 vipivotide tetraxetan (Pluvicto), a radioligand agent indicated for metastatic castration-resistant prostate cancer
Sometimes the FDA and drugmakers make the wrong bet on accelerated approvals and then have to withdraw an indication or discontinue a medicine. These outcomes are “absolutely predictable,” given the relatively small amount of evidence used in accelerated approvals, Sekeres said.
“Not all of those are going to be successes,” he said.
The growing number of withdrawals reflects efforts within the FDA’s cancer division to pressure companies to prove that drugs that have been approved through the accelerated pathway can deliver the benefits suggested in earlier trials — notably, extending survival or improving quality of life.
In November, for example, GSK announced that it had started the process of withdrawing an accelerated approval for the drug belantamab mafodotin-blmf (Blenrep). This was because of disappointing results from a large confirmatory trial in which the drug failed to meet the primary endpoint of improvement in progression-free survival.
This withdrawal, however, was not in the FDA’s tally of withdrawn oncology accelerated approvals for 2022 because there’s often a lag between the announcement of a company’s plan to withdraw a drug and the completion of the tasks the FDA needs to complete in order to make this official. These can include publishing a notice for the Federal Register and updating a drug label, an agency spokeswoman told Medscape Medical News.
Overall, last year, the FDA completed seven withdrawals that applied to six drugs.
For three of these drugs, the withdrawals led to the discontinuation of sales of these products, according to the FDA website. These were umbralisib (Ukoniq), which lost two accelerated approvals for different forms of lymphoma; the multiple myeloma drug panobinostat (Farydak); and the leukemia drug vincristine sulfate liposomal (Marqibo).
In the other three cases, the withdrawals completed last year were for additional uses of drugs that remain on the market. Genentech withdrew a bladder-cancer indication for atezolizumab (Tecentriq), Merck withdrew a gastric cancer indication for pembrolizumab (Keytruda), and Gilead Sciences Inc withdrew an indication for idelalisib (Zydelig) for certain patients with lymphoma.
In several of these withdrawals, studies intended to confirm benefits of drugs failed to do so. In other cases, newer treatment options evolved after these medicines received accelerated approvals, making it difficult to recruit patients for confirmatory trials.
The FDA and companies should seek to conclude confirmatory trials as quickly as possible so as to reduce the time in which people may take drugs that do not have the potential to help them, Sekeres said.
Although there’s often great enthusiasm about early results that suggest a benefit, such as tumor shrinkage, “that doesn’t in and of itself mean someone is living longer or living better,” Sekeres said. “At the end of the day, if we aren’t allowing patients to live longer or better, we are doing a disservice to them.”
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