AstraZeneca's lagging I-O drug tremelimumab finally pulls through with Imfinzi combo score in lung cancer

AstraZeneca
The combination of Imfinzi, tremelimumab and chemotherapy showed a statistically significant and clinically meaningful benefit in extending patients' lives versus chemotherapy alone, AstraZeneca said. (AstraZeneca)

As the second leg of AstraZeneca’s immuno-oncology plan, tremelimumab hasn’t exactly lived up to its expectations. After multiple flops that cast serious doubts over its worth, the CTLA4 inhibitor has finally helped Imfinzi chalk up an important win in non-small cell lung cancer.

Adding Imfinzi and tremelimumab to chemotherapy significantly prolonged the lives of patients newly diagnosed with stage IV, or metastatic, non-small cell lung cancer, AZ said Friday. The company said the improvement was clinically meaningful, but it didn’t provide detailed data.

Further, the survival benefit from the Imfinzi-chemo arm versus solo chemo didn’t meet statistical significance, meaning AZ’s med tremelimumab really pulled its weight in the triplet regimen.

AstraZeneca plans to present the detailed data at an upcoming medical meeting. Industry watchers have been eagerly waiting for the data to benchmark AZ’s position in the lucrative front-line NSCLC market, and things aren’t looking in AZ’s favor at the moment.

Currently, Merck & Co.’s pairing of Keytruda and chemotherapy has become the standard of care in first-line NSCLC. Bristol Myers Squibb’s PD-1/CTLA4 cocktail of Opdivo and Yervoy broke into the arena a year ago with an FDA nod for patients whose tumors express PD-L1.

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

In a statement Friday, Dave Fredrickson, AZ’s head of oncology business, flagged safety as a bright point for its triple combo.

“We were particularly pleased by the safety profile,” he said. “We’ve seen encouraging uptake of novel combinations in this setting and believe this new approach will add a further option for patients with high unmet medical need.” 

Lung cancer competition

AZ first disclosed that the Poseidon trial met one of its co-primary endpoints back in fall 2019. The company said both the pairing of Imfinzi plus chemo and the Imfinzi-treme-chemo triplet outdid solo chemo at preventing cancer from progressing. At that time Wolfe Pharma analyst Tim Anderson noted that Poseidon didn’t show a clear enough win at interim analysis.

By comparison, the landmark Keynote-189—in which the Keytruda-chemo combo cut the risk of death by half over chemo alone—hit both the disease progression and survival markers at interim analysis. And Bristol Myers’ Opdivo-Yervoy-chemo combo also crossed the statistical bar at the interim on both endpoints in its own first-line trial. 

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After those studies, Anderson said Merck had already become the clear market leader with a near-monopoly position in first-line NSCLC, so it would be commercially hard for Imfinzi-treme to compete.

Treme's track record

From there, treme’s track record didn’t exactly give industry watchers much confidence. Imfinzi monotherapy and the Imfinzi-treme combo failed to outperform chemotherapy in front-line metastatic bladder cancer in the phase 3 Danube trial, forcing AZ to withdraw a second-line nod from the U.S. market.

Then, the Caspian trial showed the addition of treme to Imfinzi and standard-of-care chemo didn’t offer any additional survival benefit for first-line patients with extensive-stage small-cell lung cancer. Imfinzi, either with or without treme, also recently failed in the first-line treatment of head and neck squamous cell carcinoma.

RELATED: ASCO: Has AstraZeneca finally found a place for long-plagued I-O candidate tremelimumab?

In NSCLC, the dual I-O regimen also came up short in the closely watched Mystic trial. It performed even worse than the failed solo Imfinzi arm in previously untreated disease. That flop precluded the large metastatic disease market for AZ for years.

Now, AZ will discuss next steps with regulators about the Poseidon data. Imfinzi is now mainly used in the curative-intent setting of stage III NSCLC after chemoradiation therapy. It’s also allowed for SCLC based on the Caspian trial.