Roche joins the FDA accelerated approval revamp team, nixing a Tecentriq bladder cancer nod

tecentriq
Roche's Tecentriq, in withdrawing a bladder cancer indication, became the latest target in an FDA campaign reconsidering accelerated approvals contradicted by confirmatory trial failures. (Roche)

After similar moves by fellow immuno-oncology players Bristol Myers Squibb, AstraZeneca and Merck & Co., Roche has pulled a Tecentriq bladder cancer indication amid a long-overdue FDA campaign targeting accelerated approvals that have failed in confirmatory studies.

Roche is pulling Tecentriq’s approval in patients with metastatic urothelial carcinoma previously treated with chemotherapy, the company said Monday. Like the three other companies that withdrew PD-1/L1 indications recently, the Swiss drugmaker said it had made the decision as part of the FDA’s industrywide review of accelerated approvals.

Before it, AstraZeneca said it would remove the same second-line bladder cancer approval from Imfinzi’s U.S. label after the drug failed a confirmatory trial in previously untreated patients.

Second-line bladder cancer was actually Tecentriq’s entry ticket into the U.S. market, making the Roche drug the first in the PD-1/L1 class to reach this type of cancer. That original 2016 go-ahead was based on tumor shrinkage data from the phase 2 IMvigor210 study.

But data unveiled in 2017 from the phase 3 IMvigor211 trial showed Tecentriq wasn’t better than chemotherapy at extending the lives of previously chemo-treated patients who had at least 5% of PD-L1 expression in tumor-infiltrating immune cells.

RELATED: After Imfinzi's double flop, AstraZeneca walks away from FDA bladder cancer nod

That confirmatory trial failure threatened Tecentriq’s application in the indication. But the FDA allowed the drug to keep that nod—without converting it to a regular approval, though. Instead, the agency designated the phase 3 IMvigor130 study in previously untreated patients as the new confirmation study.

That trial produced top-line data in 2019, demonstrating the combination of Tecentriq and chemo reduced the risk of tumor progression or death by 18% over solo chemo, regardless of PD-L1 status. At that interim analysis, overall survival showed a trend for improvement with the combo, but it fell short of crossing the statistical significance bar.

While that study remains ongoing for final overall survival results, “the treatment landscape in prior-platinum (second-line) mUC has rapidly evolved with the emergence of new treatment options,” Roche’s Genentech said in a statement.

RELATED: FDA says Tecentriq won't lose its bladder cancer nod despite phase 3 failure, Roche reports

Merck’s Keytruda showed in Keynote-045 that it could pare down the risk of death by 30% over chemotherapy in previously treated bladder cancer, even though there was no significant improvement in stalling tumor progression. But that win came almost concurrently with Tecentriq’s second-line fail, so it can hardly count as a “new treatment option.”

Last year, Pfizer and Merck KGaA’s PD-L1 inhibitor Bavencio broke into the so-called first-line maintenance setting for bladder cancer patients who have responded to one round of chemo. That use is backed by phase 3 data showing the drug could slash the risk of death by 31% compared with best supportive care.

Outside the checkpoint inhibitor family, Seagen and Astellas’ antibody-drug conjugate Padcev recently showed it could reduce the risk of death by 30% over chemo in bladder cancer patients who had already failed on chemo and a PD-1/L1 inhibitor. Because most patients don’t respond to PD-1/L1 therapy post-chemo, doctors are already using Padcev in the second-line setting sans an FDA approval—and without payer pushback, SVB Leerink analyst Andrew Berens has noted. And Padcev has early tumor response data laying out its potential in cisplatin-ineligible patients treated upfront with a PD-1/L1 inhibitor.

Seagen and Astellas recently filed those data, seeking to convert Padcev’s third-line conditional nod into a full one and win approval in those patients first treated with immunotherapy.

RELATED: Pfizer, Merck KGaA's Bavencio breaks into new bladder cancer field with latest FDA nod

So far, four immunotherapy indications have landed on the chopping board in FDA’s reexamination of accelerated approvals. Besides Tecentriq and Imfinzi in second-line bladder cancer, Merck and Bristol Myers Squibb each removed their respective Keytruda and Opdivo indications in third-line small cell lung cancer.

These drugs all have other indications under question with confirmatory flops, but those failures haven’t triggered withdrawals. For example, Tecentriq’s use in tandem with Bristol’s chemotherapy Abraxane, or protein-bound paclitaxel, in PD-L1-positive triple-negative breast cancer (TNBC) was based on data showing the regimen could stave off cancer progression. But the confirmatory Impassion131 study recently delivered surprising data showing patients who got Tecentriq and the original paclitaxel formula didn’t live as long as those treated with chemo alone.

Noticing that difference, the FDA last year warned doctors not to substitute paclitaxel for Abraxane in TNBC. The agency raised the conditional approval status at the time, stressing that continued approval of the Tecentriq-Abraxane regimen may be contingent upon proven benefit in additional trials.