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

AstraZeneca has officially admitted that Imfinzi doesn’t deserve the FDA nod it won four years ago in previously treated bladder cancer—despite the fact that it was the PD-L1 inhibitor’s first entrée into the immuno-oncology market.

The reason? A twofold trial miss. After the med fell short in a confirmatory trial, AstraZeneca decided to voluntarily withdraw Imfinzi’s U.S. indication for previously treated locally advanced or metastatic bladder cancer, the company said Monday.

It’s not exactly an unbearable retreat for AZ; after all, the majority of Imfinzi’s revenue and growth is fueled by its non-small cell lung cancer indications, which Dave Fredrickson, AZ’s head of oncology business unit, labeled “an area of considerable focus” for the company in a Monday statement.

The FDA doled out Imfinzi's original accelerated go-ahead based on tumor shrinkage and response duration data from a phase 1/2 trial. AZ had hoped the phase 3 Danube trial in front-line metastatic bladder cancer would confirm the second-line use, but that was not to be.

Neither solo Imfinzi nor a combo of Imfinzi and investigational CTLA4 inhibitor tremelimumab managed to beat standard-of-care chemotherapy at extending the lives of newly diagnosed patients, the British pharma unveiled a year ago.

AZ did observe some trends in favor of the immuno-oncology combo, especially in patients bearing tumors with high PD-L1 expression levels. But after talking to the FDA, the company realized the therapy simply didn’t meet the marks required to keep the approval.

RELATED: ESMO: AstraZeneca, after Imfinzi's double miss, looks ahead to other bladder cancer tests

If it’s any consolation, bladder cancer appears to be a tough nut to crack for checkpoint inhibitors. Merck & Co.’s PD-1 king Keytruda, for instance, couldn’t contain the disease any better than chemo when used alone or in tandem with chemo. In the phase 3 Keynote-361 trial, neither of the two Keytruda regimens beat chemo at delaying tumor progression or extending the lives of newly diagnosed bladder cancer patients.

Keytruda currently bears a conditional FDA approval for first-line use in chemotherapy-ineligible patients whose tumors express PD-L1 at a combined positive score of at least 10, which was narrowed down from the original indication that didn’t limit that biomarker status.

Despite the Keynote-361 flop, SVB Leerink analyst Daina Graybosch, Ph.D., has predicted that Keytruda might be able to keep its front-line bladder cancer OK, pointing to the many confirmatory trial failures that didn’t lead to approval clawbacks.

RELATED: Merck's Keytruda flops bladder cancer trial, giving Roche's Tecentriq an open shot

Imfinzi’s second-line bladder cancer indication marks the second PD-1/L1 marketing withdrawal triggered by a confirmatory trial miss in just two months.

In late 2020, Bristol Myers Squibb ditched Opdivo’s third-line small cell lung cancer indication. Like Imfinzi, the Bristol PD-1 inhibitor failed both as a monotherapy and in combination with CTLA4 inhibitor Yervoy in phase 3 trials, despite showing early promise in a phase 1/2 study.

Meanwhile, AstraZeneca doesn’t plan to stop exploring Imfinzi in bladder cancer altogether.

A phase 3 trial dubbed Nile combines Imfinzi and chemotherapy with or without tremelimumab in front-line metastatic bladder cancer. The phase 3 Niagara trial is evaluating Imfinzi and chemo in muscle-invasive bladder cancer, with the combo used before surgery and solo Imfinzi afterward. Imfinzi’s also being paired with Merck’s standard-of-care BCG vaccine in non-muscle-invasive disease in the Potomac study.