In the increasingly crowded cancer immunotherapy field, AstraZeneca’s Imfinzi has mostly been used in stage III non-small cell lung cancer. But with the right combination strategy, the PD-L1 inhibitor has promise in other tumor types, AZ’s oncology R&D head said.
Imfinzi is “a core backbone component” of AZ’s overall strategy for oncology, Susan Galbraith, Ph.D., AZ’s executive vice president of oncology R&D, said during the Fierce JPM Week virtual conference. The drug just hit gold-standard life extension goals in two phase 3 trials when used alongside chemo in newly diagnosed biliary tract cancer and as part of a cocktail with AZ’s own CTLA4 inhibitor tremelimumab in first-line liver cancer.
Those trial wins fit AZ’s philosophy of developing treatments that can improve long-term survival and cure more patients by targeting earlier lines of treatment. But that ambition requires different components and mechanisms, such as the approach with Imfinzi and treme, Galbraith said.
In the first-line liver cancer trial dubbed Himalaya, the Imfinzi-treme pairing slashed the risk of death by 22% over Bayer’s aging standard-of-care Nexavar. That result marked a rare win for treme after multiple failures in non-small cell lung cancer (NSCLC), head and neck cancer and bladder cancer.
By incorporating lessons from previous trials, AZ's scientists homed in on a regimen called Stride, Galbraith said, which involves a single high dose of treme given in tandem with Imfinzi at the beginning of treatment, followed by Imfinzi alone.
That single punch of CTLA4 inhibition functions as priming the immune system. Previous research has found that with the proper priming, the body’s immune response against cancer can be very long-lasting, delivering a “durability effect with an improvement particularly in the tail of the survival curve,” Galbraith explained.
In the Himalaya trial, 40.5% of patients on the Stride regimen were still alive after two years, compared with 39.6% for the Imfinzi monotherapy group and 32.6% in the Nexavar arm. At three years, the survival rate stood at 30.7% for Stride, while Imfinzi monotherapy dropped faster to 24.7% and Nexavar to 20.2%.
“The dose and schedule refinement, particularly with the Stride regimen, really gives us some insight into how we can improve the therapeutic index,” Galbraith said.
Separately, by posting a 20% reduction in the risk of death previously untreated unresectable biliary tract cancer, Imfinzi’s chemo combo was the first immunotherapy regimen to improve survival in those patients.
Meanwhile, following its approach to target earlier lines of treatment with combos, AZ is running the phase 3 Emerald-1 trial to see whether adding Imfinzi—or Imfinzi and Roche’s VEGF inhibitor Avastin—on top of transarterial chemoembolization could help patients with locoregional liver cancer. That data could read out later this year. A separate Emerald-2 trial is examining Imfinzi alone or the Imfinzi-Avastin pairing as a post-surgery adjuvant therapy in early liver cancer patients at high risk of recurrence.
Roche won an FDA go-ahead in 2020 for its PD-L1 inhibitor Tecentriq alongside Avastin in newly diagnosed liver cancer. Given that success, Galbraith said she’s optimistic about the two Emerald trials.
Beyond treme, AZ recently turned in positive phase 2 results for Imfinzi’s combination with oleclumab, an anti-CD73 antibody, or monalizumab, an anti-NKG2A antibody, over solo Imfinzi in stage III non-small cell lung cancer. Now AZ is moving both new therapies into phase 3 testing.
AZ gained full rights to monalizumab from a collaboration with Innate Pharma originally signed in 2015. Last week, AZ paid Scorpion Therapeutics $75 million upfront to develop drugs against transcription factors, which have historically been hard to drug.
The British pharma is also known for two billion-dollar licensing deals with Daiichi Sankyo featuring antibody-drug conjugates Enhertu and datopotamab deruxtecan. BTK inhibitor Calquence also came to AZ while it was in late-stage development at Acerta Pharma.
While AZ has a productive internal R&D engine, the company doesn't have a monopoly on all innovation, Galbraith said. Moving forward, AZ is “very open to deals across the spectrum” of drug development stages for products that can deliver value, she said.