FDA lines up AdCom to review accelerated approvals for Keytruda, Opdivo, Tecentriq

The FDA on Thursday announced that it will hold an advisory committee (AdCom) meeting in April to review a number of indications for PD-(L)1 inhibitors that were granted under the agency's accelerated approval pathway with confirmatory trials that have not verified clinical benefit. The panel will look at certain indications for Bristol Myers Squibb's Opdivo (nivolumab), Merck & Co.'s Keytruda (pembrolizumab) and Roche's Tecentriq (atezolizumab).

According to the FDA, updates will be provided at the meeting on the status of confirmatory studies for the given indications, as well as any ongoing and planned trials. The regulator noted that the panel will discuss next steps for each product, including whether the indications should remain on the market.

Tecentriq up first…

The review gets under way on April 27, when the FDA will go over updates on use of Tecentriq in combination with Bristol Myers Squibb's Abraxane (nab-paclitaxel) for adults with unresectable, locally advanced or metastatic triple-negative breast cancer (TNBC) whose tumours express PD-L1. Accelerated approval in this indication was granted in 2019 based on progression-free survival (PFS) data from the Phase III IMpassion130 study. However last year, Roche announced that in the Phase III IMpassion131 trial, the combination of Tecentriq and paclitaxel failed to significantly improve PFS for the first-line treatment of patients with metastatic TNBC, in the PD-L1-positive population.

Tecentriq will also be discussed on April 28 regarding its use in patients with locally advanced or metastatic urothelial carcinoma who are not eligible for cisplatin-containing chemotherapy. The therapy gained accelerated approval in this indication in 2017 based on tumour response rate and duration of response data from the IMvigor210 study. The confirmatory IMvigor130 trial showed a significant reduction in the risk of disease worsening or death compared with chemotherapy alone, but failed to significantly improve overall survival (OS).

…followed by Keytruda…

The panel will look at updates on Keytruda for the same urothelial carcinoma indication on April 28 as well. The therapy gained accelerated approval in this indication in 2017 based on objective response rate (ORR) data from the Phase II KEYNOTE-052 trial, although the subsequent Phase III KEYNOTE-361 study failed on the dual primary endpoints of OS and PFS, compared with standard chemotherapy alone.

On April 29, the committee will also discuss Keytruda's use among patients with recurrent locally advanced or metastatic gastric or gastroesophageal junction adenocarcinoma whose tumours express PD-L1, with disease progression on or after two or more prior lines of therapy. Accelerated approval in this indication was secured in 2017 based on ORR findings from the KEYNOTE-059 trial, although later the same year, Merck said the Phase III KEYNOTE-061 study failed to meet its primary endpoint of OS, while results from the KEYNOTE-062 trial were inconclusive.

…and finally liver cancer

On the final day of the meeting, the committee will also hear updates on the use of both Keytruda and Opdivo in patients with hepatocellular carcinoma previously treated with Bayer's Nexavar (sorafenib). Opdivo gained accelerated clearance in this indication in 2017, while Keytruda was authorised in this setting the following year, based on tumour response rate and durability of response data from the CheckMate -040 and KEYNOTE-224 studies, respectively. However, Opdivo later failed to meet the primary OS endpoint in the Phase III CheckMate -459 study, as did Keytruda in the late-stage KEYNOTE-240 trial.

The AdCom meeting comes amid an industry-wide FDA evaluation of accelerated drug approvals that have not yet met their post-marketing requirements. Since December, the move by the regulator has led to withdrawn indications for Opdivo and Keytruda in small-cell lung cancer, Tecentriq in prior-platinum treated metastatic urothelial carcinoma and AstraZeneca's Imfinzi (durvalumab) in locally advanced or metastatic bladder cancer.

For related analysis, see ViewPoints: The FDA's accelerated approval purge – four down, more to come?

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