AstraZeneca’s Imfinzi regimen misses the mark in setback for ambitious lung cancer 2030 goal

One study in AstraZeneca’s elaborate R&D plan for lung cancer has reached a dead end.

Imfinzi, used concurrently with chemoradiotherapy, failed to beat chemoradiotherapy alone at delaying disease progression or death in unresectable, stage 3 non-small cell lung cancer, AZ said Tuesday.

The phase 3 PACIFIC-2 trial was part of AZ’s grand plan to be able to target more than half of lung cancer patients by 2030.

As a member of the crowded anti-PD-1/L1 club, Imfinzi has established a dominant role in stage 3, unresectable NSCLC when used following chemoradiotherapy. In patients who didn’t have disease progression after chemoradiation, Imfinzi cut the risk of death by 32% compared with placebo in the phase 3 PACIFIC trial.

With PACIFIC-2, AZ is trying to introduce immunotherapy even earlier for these stage 3 patients, the company’s oncology R&D chief, Susan Galbraith, Ph.D., explained in a statement Tuesday. After all, some patients might progress after initial chemoradiation and wouldn’t be eligible for Imfinzi under the original PACIFIC regimen.

Besides failing the primary endpoint of progression-free survival endpoint, PACIFIC-2 also showed an increased rate of infection during the treatment period for the Imfinzi-concurrent-chemoradiotherapy regimen, according to AZ.

About 1 in 3 patients with NSCLC are diagnosed at stage 3, and the majority of those cases have unresectable tumors. And AZ has other plans for Imfinzi in this patient population.

The PACIFIC-8 trial is evaluating Imfinzi with Gilead and Arcus Biosciences’ anti-TIGIT candidate domvanalimab following concurrent chemoradiotherapy in PD-L1-positive tumors. And with PACIFIC-9, AZ is trying to combine Imfinzi with its anti-CD73 antibody oleclumab or with Innate Pharma’s monalizumab also post-chemoradiation.

AZ has a broad portfolio in lung cancer, and the British pharma has a deep pipeline to expand its offerings across different disease subtypes and treatment lines.

AZ recently filed Imfinzi with the FDA for approval around surgery in resectable NSCLC based on the phase 3 AEGEAN trial. If approved, Imfinzi will face tough competition with Merck’s Keytruda and possibly Bristol Myers Squibb’s Opdivo in this early-stage setting.

The phase 3 PACIFIC-4 trial is testing Imfinzi in unresected stage 1/2 lymph node-negative NSCLC following stereotactic body radiation therapy. Imfinzi made just over $3 billion for the first nine months of the financial year. 

Also in early-stage lung cancer, AZ’s Tagrisso recently showed in the ADAURA trial an overall survival benefit against placebo when used after surgery in EGFR-mutated stage 1b to 3a NSCLC.

And in a similar regimen as Imfinzi’s PACIFIC, the phase 3 LAURA trial for Tagrisso as a maintenance therapy in unresectable, EGFR-mutant stage 3 NSCLC is expected to read out in the first half of 2024. But the market-leading EGFR inhibitor may come under threat from a Johnson & Johnson combination in the all-important first-line metastatic setting.

Elsewhere, AZ is about to file its Daiichi Sankyo-partnered Dato-DXd in previously treated NSCLC. The TROPION-Lung01 trial met its goal, but the magnitude of efficacy from the TROP2-targeted antibody-drug conjugate and its lung disease side effect worried investors.

For their first ADC program, Enhertu, AZ and Daiichi in 2022 won FDA approval for the HER2 agent in previously treated HER2-mutant NSCLC. The phase 3 DESTINTY-Lung04 trial is now evaluating Enhertu as a first-line treatment. And the two companies are in early testing of pairing Enhertu with Imfinzi in HER2-overexpressing NSCLC.

AZ also has high hopes for volrustomig, a bispecific molecule targeting PD-1 and CTLA-4. The company recently launched the phase 3 eVOLVE-Lung02 trial to see if volrustomib, combined with chemo, could topple Merck’s standard-of-care Keytruda-chemo regimen as first-line treatment in patients whose NSCLC tumors have PD-L1 expression below 50%.