AstraZeneca's Imfinzi records double bladder cancer failure, endangering first nod and dual-IO case

It’s one of those trials that bear some weight: It was meant to confirm a med’s first-ever approval, and industry watchers were looking for clues to assess the chance of future success. But in the case of AstraZeneca’s Imfinzi in bladder cancer, the immunotherapy has failed.

On Friday, AstraZeneca said Imfinzi, given alone and in combination with the company’s own experimental CTLA-4 inhibitor tremelimumab, failed to help newly diagnosed metastatic bladder cancer patients live longer when compared with standard-of-care chemotherapy.

That trial flop endangers Imfinzi’s accelerated FDA approval—the med’s first—in pre-treated bladder cancer. It also further weakens AZ’s argument around tremelimumab and the immuno-oncology pairing of its PD-L1 and CTLA-4 agents.

The flopped trial, called Danube, was meant to satisfy AZ's post-approval pledge to the FDA to confirm the conditional second-line nod it gave Imfinzi in 2017. In the study, Imfinzi monotherapy was tested in bladder cancer patients whose tumors express high levels of PD-L1, and Imfinzi-treme in all patients regardless of PD-L1 status.

Now, the company will need a new trial to prove Imfinzi deserves its place on the market. "We will engage with regulators to discuss our ongoing development program in bladder cancer to fulfill the confirmation of clinical benefit ... that formed the basis for the U.S. accelerated approval in this setting," AZ said in a statement.

Still, despite the outcome, AZ is hopeful that adding chemo to either Imfinzi or the dual-IO cocktail will make a difference, and it’s testing the idea in the phase 3 Nile trial, also in a first-line metastatic setting.

RELATED: AstraZeneca, on BMS' heels, scores lung cancer win with Imfinzi combos

As Wolfe Pharma analyst Tim Anderson expressed in a Monday note to clients, the Danube bladder cancer flop was somewhat expected, as the Imfinzi-treme duo has yet to yield any success. The combo most notably failed the Mystic study in all-important previously untreated non-small cell lung cancer (NSCLC), performing even worse than solo Imfinzi at paring down the risk of death. Then, second-line head and neck cancer also went down the drain, followed by the Neptune study in front-line NSCLC with high levels of investigational biomarker tumor mutational burden.

More could come. Himalaya, a phase 3 study testing the checkpoint duo in new liver cancer patients, is slated to read out in the second half of 2020. Even with an FDA orphan drug designation in that indication, “[i]t is difficult to be optimistic,” Anderson said.

But the combination of Imfinzi, treme and chemo could be a different story. The British drugmaker recently said the trio—as well as Imfinzi plus chemo—beat chemo alone at stalling cancer progression in previously untreated NSCLC. It followed a similar win by Bristol-Myers Squibb’s PD-1/CTLA-4/chemo regimen in the CheckMate-9LA trial.

RELATED: Roche's Tecentriq goes back to its roots with chemo combo win in bladder cancer

Nevertheless, how much tremelimumab contributed to that success is still unclear, which is important given that Merck & Co.’s market-leading Keytruda has a chemo combo approval. Though AZ said it plans to file for triplet approval based on the disease progression data, it's life-extension numbers that matter most.

Meanwhile, the Danube slip pushed Imfinzi further behind in its bladder cancer competition against Roche’s fellow PD-L1 inhibitor Tecentriq, which has shown promise in the front-line setting. Last year, the Swiss drugmaker showed a pairing of Tecentriq and chemo outperformed chemo at reducing the risk of cancer progression or death in new bladder cancer patients, putting it on track for an FDA nod.