AstraZeneca has reported positive phase 3 results from two separate non-small cell lung cancer trials, though the wins have done little to offset a significant setback elsewhere in its pipeline.
The British pharmaceutical giant, alongside partner Daiichi Sankyo, announced that Enhertu improved progression-free survival against Merck’s Keytruda and chemotherapy in first-line HER2-mutant nonsquamous NSCLC patients.
In a separate trial, AstraZeneca and Hutchmed’s Orpathys and Tagrisso combination outperformed platinum-based chemotherapy on both progression-free survival and overall survival in Tagrisso-pretreated EGFR-mutated NSCLC.
Both sets of data will be presented at a forthcoming medical meeting and shared with global regulatory authorities, AstraZeneca confirmed.
The positive readouts were overshadowed by the phase 3 failure of volrustomig, a PD-1/CTLA-4 bispecific antibody that failed to outperform Keytruda and chemotherapy in first-line NSCLC patients whose tumors express PD-L1 at below 50%.
The phase 3 Saffron trial could deliver Orpathys, also known as savolitinib, its first US approval, as the c-MET inhibitor has only been marketed in China since 2021.
Chinese authorities approved the Orpathys-Tagrisso combination last year for NSCLC patients with MET amplification following progression on a first-line EGFR inhibitor.
A separate phase 3 trial conducted solely in China, Sachi, linked the combination to a 66% reduction in patients’ risk of progression or death versus platinum-based chemotherapy.
Approximately 10% to 15% of NSCLC patients in Western populations and 30% to 40% in Asia have EGFR-mutated NSCLC, with about a third expected to develop high MET overexpression after treatment with a third-generation EGFR TKI like Tagrisso.
“By combining Orpathys and Tagrisso, with its established efficacy, safety profile and central nervous system protection, we aim to deliver the first biomarker-directed, all-oral option in this setting to patients across the globe,” said Susan Galbraith, Ph.D., AstraZeneca’s executive vice president of oncology hematology R&D.
The Destiny-Lung04 trial targets patients with HER2-mutated tumors, a group representing approximately 2% to 4% of the total NSCLC patient population.
Enhertu has already held FDA approval since 2022 for previously treated HER2-mutant NSCLC, and the latest trial could support its use in earlier lines of treatment.
Galbraith said the Destiny-Lung04 result marks “an important step forward in bringing additional effective therapies to patients at metastatic diagnosis when there is the greatest opportunity to improve outcomes.”
Volrustomig, Enhertu, and Orpathys all form part of AstraZeneca’s broader ambition to have medicines available for more than half of all lung cancer patients by 2030.
With volrustomig’s failure raising the pressure, attention now turns to next-generation candidates including PD-1/TIGIT bispecific rilvegostomig and Daiichi-partnered TROP2 ADC Datroway, whose phase 3 Avanzar trial readout in first-line NSCLC is expected this year.