AstraZeneca reported positive results from two non-small cell lung cancer trials for Enhertu and an Orpathys-Tagrisso combination, although the dual wins provided little cover for the company amid the failure of a PD-1/CTLA-4 bispecific antibody.
In a pair of phase 3 wins, AZ and Daiichi Sankyo’s Enhertu improved progression-free survival against Merck & Co.’s Keytruda and chemotherapy in first-line HER2-mutant nonsquamous NSCLC, and AZ and Hutchmed’s Orpathys and Tagrisso outperformed platinum-based chemotherapy on both PFS and overall survival in Tagrisso-pretreated EGFR-mutated NSCLC.
In both cases, AZ said the data will be presented at a medical meeting and shared with global regulatory authorities.
However, the two successes were overshadowed by the phase 3 crash of volrustomig, which failed to outdo Keytruda and chemo in first-line NSCLC patients whose tumors express PD-L1 at below 50%. The Enhertu and Orpathys-Tagrisso wins represent relatively niche populations.
Between the two positive readouts, the phase 3 Saffron trial could net Orpathys, also known as savolitinib, its first U.S. approval. The c-MET inhibitor has been marketed in China since 2021, initially as a treatment for NSCLC with MET exon 14 skipping alterations. Last year, Chinese authorities approved the Orpathys-Tagrisso regimen for NSCLC patients with MET amplification following progression on a first-line EGFR inhibitor. The phase 3 Sachi trial conducted solely in China linked the combo to a 66% reduction in patients’ risk of progression or death versus platinum-based chemo.
While both trials enrolled patients with MET amplification, Sachi allowed progression on various EGFR tyrosine kinase inhibitors (TKIs), whereas Saffron is only for post-Tagrisso patients. In a post-third-generation EGFR TKI subgroup in Sachi, the combo showed a PFS improvement of 68% compared with chemo.
Following a preliminary analysis midway into the phase 2 Savannah study that supported the advancement of Orpathys-Tagrisso into phase 3 tests, AZ and Hutchmed increased the level of MET expression cut-off to IHC3+ intensity in at least 90% of tumor cells and/or FISH 10+.
About 10% to 15% of NSCLC patients in Western populations and 30% to 40% of their peers in Asia have EGFR-mutated NSCLC. Among them, about a third of tumors are expected to develop high levels of MET overexpression or amplification after treatment with a third-generation EGFR TKI like Tagrisso, according to AZ’s estimates.
“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,” Susan Galbraith, Ph.D., AZ’s executive vice president of oncology hematology R&D, said in an Aug. 17 statement.
As for Enhertu, with the Destiny-Lung04 trial, AZ and Daiichi are aiming the HER2-targeted antibody-drug conjugate toward patients with HER2-mutated tumors who make up about 2% to 4% of the NSCLC population.
Prior to Monday’s announcement, Enhertu has been approved by the FDA since 2022 for previously treated HER2-mutant NSCLC.
Now, as the first phase 3 trial to improve PFS versus standard of care in this first-line setting, Destiny-Lung04 could support Enhertu's move earlier in the treatment of HER2-mutant NSCLC, Galbraith said in a separate statement. “This aggressive lung cancer often affects younger patients and has historically had limited first-line targeted treatment options, making these positive results 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 are part of AZ’s ambition to have medicines for more than half of all lung cancer patients by 2030. With volrustomig’s flop, the stakes are even higher for the British pharma’s next-generation lung cancer candidates, including its PD-1/TIGIT bispecific rilvegostomig and Daiichi-partnered TROP2 ADC Datroway, whose readout from the phase 3 Avanzar trial in first-line NSCLC is expected this year.