FDA Advisory Committee Votes Against Poziotinib for NSCLC


Several concerns factored into the decision, including a low overall response rate and high rate of adverse events, a dose that was not optimized and a confirmatory trial that will not likely see results until 2026.

The FDA’s Oncologic Drugs Advisory Committee (ODAC) voted 9 to 4 on Sept. 22, 2022, against on whether the benefits of Spectrum Pharmaceuticals’ poziotinib outweigh its risks. The company was seeking accelerated approval of poziotinib for the treatment of patients with non-small cell lung cancer (NSCLC) with HER2 exon 20 insertion mutations. Poziotinib is a kinase inhibitor with a proposed dosage of 16 mg four time a day.

“We are disappointed by the outcome of the ODAC meeting, as patients with NSCLC HER2 exon 20 insertion mutations are in need of additional effective and safe therapies,” Tom Riga, president and chief executive officer of Spectrum Pharmaceuticals, said in a press release. “We plan to carefully evaluate our options for this program as we approach the November 24, 2022, PDUFA date. We would like to thank lung cancer patients and their families, as well as investigators and their staff, for their support.”

The committee members agreed there is an unmet need in this patient population, but many said after the vote that poziotinib doesn’t appear to provide meaningful benefit beyond existing therapies, echoing concerns brought by the regulatory agency.

In materials released ahead of the meeting, the FDA expressed concern about a low overall response rate (ORR) with minimal duration of response (DOR). In the ZENITH20 trial, there was a response rate of 28% with a median duration of response of 5.1 months among patients in Cohort 2.

The FDA expressed concerns about the toxicities associated with poziotinib, including high rates of treatment interruption and dose reduction, and very high rates of diarrhea, mucositis, and rash, as well as three fatal events of pneumonitis. In the ZENITH20 trial, poziotinib was poorly tolerated at the current proposed dosage (16 mg four times a day) with 57% of patients experiencing dose reductions and 85% of patients experiencing grade 3 to 4 adverse events.

A final concern of both regulators and the advisory committee was a dose that is not optimized. The dosage used in the ZENITH20 trial and the planned confirmatory trials are different. In ZENITH20, most patients started on 16 mg four times a day. Spectrum plans a randomized, open label confirmatory trial using poziotinib 8 mg twice day versus docetaxel 75 mg/m2 in about 268 patients with locally advanced or metastatic NSCLC. Confirmation of benefit will be delays because the confirmatory trial has not yet started enrolling patients, and results are not anticipated until at least 2026.

Scott A. Waldman, M.D., Ph.D.

Scott A. Waldman, M.D., Ph.D.

“The importance of the confirmatory trial is amplified by the FDA statement, that if this gets approved is going to be one of the most toxic as a PKI,” said Scott A. Waldman, M.D., Ph.D., chair, Department of Pharmacology, Physiology, & Cancer Biology at Thomas Jefferson University. “The confirmatory trial at least is going to be at least two years out and it’ll take two years to get to a first evaluation from the start of enrollment. That's a long time to put patients at risk.”

He also questioned whether poziotinib 16 mg four times a day was the right dose. “It's not clear what the right doses are,” Waldman said. “That's problematic. It communicates a lack of confidence in the dose was submitted for approval.”

One issue discussed was whether the confirmatory trial will be adequately enrolled because of the recent approval AstraZeneca/Daiichi Sankyo’s Enhertu (trastuzumab deruxtecan). The FDA issued an accelerated approval of Enhertu in August 2022 unresectable or metastatic non-small cell lung cancer whose tumors have HER2 mutations. In the DESTINY-Lung02 phase 2 trial, Enhertu demonstrated an objective response rate of 57.7%

Ashley Rosko, M.D.

Ashley Rosko, M.D.

One committee who did vote was Ashley Rosko, M.D., associate professor, Division of Hematology at The Ohio State University Comprehensive Cancer Center, who said she found the patients’ and their caregivers’ statements incredibly persuasive. “I believe the dosing schedule may not serve many of the patients, but it does serve a portion of the patient population,” she said after the vote. “I understand that there are dose reductions for many patients, but oncologists are familiar with the management of toxicities. I recognize that this patient population requires additional therapy and there’s much to be explored in this area.”

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