As AstraZeneca awaits an FDA decision for its Daiichi Sankyo-partnered Datroway in EGFR-mutated non-small cell lung cancer (NSCLC), the British pharma has rolled out early data from a trial combining the antibody-drug conjugate (ADC) with its old blockbuster Tagrisso.
A combination of Datroway and Tagrisso induced a response in 36% of patients with EGFR-mutant NSCLC who had progressed on first-line Tagrisso, new data show.
The data come from module 10 of the phase 2 Orchard trial, a platform study of novel combinations in the post-Tagrisso setting. The findings are part of an abstract set to be presented at the European Lung Cancer Congress (ELCC) next week.
The 36% objective response rate (ORR) was recorded among 33 evaluable patients who received Datroway at 6 milligrams per kilogram of body weight, which is the recommended dose for the TROP2-directed ADC’s FDA-approved indication in third-line HR-positive, HER2-negative breast cancer.
Among 35 patients who received Datroway at a lower 4 mg/kg dose, investigators recorded a 43% ORR for the combination. The two patient groups had similar follow-up times at about 13 months.
Considering the overall benefit-risk profiles of the two doses, investigators recommended the 6 mg/kg option, according to the abstract.
In October, AZ and Daiichi launched the phase 3 Tropion-Lung15 trial testing Datroway 6 mg/kg—either by itself or with Tagrisso—in post-Tagrisso EGFR-mutant NSCLC. The study bears an estimated primary completion date in June 2026.
Cancer that becomes resistant to Tagrisso may still have tumor cells that harbor EGFR mutations, an AstraZeneca spokesperson explained in offering the company’s rationale for adding Tagrisso to Datroway in second-line treatment.
“Continuing Tagrisso ensures ongoing inhibition against those EGFRm-driven tumor cells, while also receiving treatment to suppress the resistance and, ultimately, prolong patients’ responses to treatment,” the spokesperson said in a statement.
Besides the ORR measure, the higher dose of Datroway can trigger a response faster and keep tumors at bay longer, investigators found. The median time to onset of response was 1.4 months versus 2.7 months, respectively, for the two doses. Investigators estimated that only 15% of patients who received the lower dose would remain in response at nine months, whereas 64% on the preferred dose could enjoy that status.
Patients on the higher Datroway dose went a median 11.7 months without disease progression, compared with 9.5 months among recipients of the lower dose, the data show.
As expected, the combination with the higher dose was linked to more adverse events, although no new safety signals emerged.
Overall, 56% and 34% of patients given the high and low doses, respectively, experienced grade 3 or above treatment-related adverse events. Adverse events leading to Datroway dose reductions were recorded in 59% and 23% of patients in the two groups, respectively.
Interstitial lung disease or pneumonitis, a side effect that experts are watching closely for all ADCs based on Daiichi’s DXd platform, was seen in 15% of patients on the high dose, including 6% at grade 3 or above.
Before the latest Datroway-Tagrisso combo readout, AZ and Daiichi have applied for FDA approval of Datroway as a monotherapy in previously treated EGFR-mutated NSCLC. A decision from the agency is expected by July 12, 2025.
That submission was based on a pooled analysis of certain patients from the phase 3 Tropion-Lung01 and the phase 2 Tropion-Lung05 trials. Among 117 patients with EGFR-mutated NSCLC who had tried a median of three prior lines of therapy, Datroway alone achieved an ORR of 43% in the analysis, with the responses lasting for a median of seven months.
For years, Tagrisso has been the standard first-line treatment for EGFR-mutated NSCLC. But that status has recently come under attack from Johnson & Johnson’s combination of Rybrevant and Lazcluze. Rybrevant, an EGFRxMET bispecific antibody, is also approved in combination with chemotherapy following treatment with an EGFR inhibitor such as Tagrisso.
In the phase 3 Mariposa-2 trial conducted in post-Tagrisso patients, the Rybrevant-chemo regimen registered a 53% ORR, with a 6.9-month duration of response. The combo significantly reduced the risk of progression or death by 52% versus chemo alone. The median progression-free survival for the combo was 6.3 months.
The latest Orchard data for AZ’s Datroway-Tagrisso cocktail look competitive, with the inherent drawbacks of cross-trial comparisons in mind.
Other data at ELCC
Besides Orchard, AZ also shared the primary analysis of the phase 2 Savannah trial, which evaluated Tagrisso in tandem with Hutchmed-partnered MET inhibitor savolitinib, which is approved in China under the brand name Orpathys. The analyzed patients had EGFR-mutant NSCLC with high MET overexpression or amplification following treatment with first-line Tagrisso.
The combo logged a 56% ORR by investigator assessment or 55% by blinded central review among 80 patients who met a high MET expression criterion. The median duration of response was 7.1 months and 9.9 months, respectively, based on the separate types of review. And the median progression-free survival was 7.4 months and 7.5 months, respectively.
The primary efficacy analysis focused on a cohort of patients who received Orpathys doses more frequently than the regimen studied as part of a 2022 readout, in which AZ reported a 49% ORR.
Phase 3 results from the Saffron trial utilizing the more frequent, twice-a-day Orpathys regimen together with Tagrisso are expected in the second half of 2025. The trial includes patients who have progressed on either first- or second-line treatment with Tagrisso.
Editor's Note: The story has an updated statement from AstraZeneca.