AstraZeneca's Datroway-Tagrisso Combo Shows Promise in EGFR-Mutant NSCLC

AstraZeneca has unveiled encouraging early data from a trial combining its antibody-drug conjugate (ADC) Datroway with the established EGFR inhibitor Tagrisso in non-small cell lung cancer (NSCLC) patients with EGFR mutations. The results, set to be presented at the upcoming European Lung Cancer Congress (ELCC), offer new hope for patients who have progressed on first-line Tagrisso treatment.

Promising Efficacy in Post-Tagrisso Setting

The phase 2 Orchard trial's module 10 evaluated the Datroway-Tagrisso combination in patients with EGFR-mutant NSCLC who had progressed on first-line Tagrisso. The study explored two dosing regimens for Datroway:

• At 6 mg/kg (the FDA-approved dose for breast cancer), the combination achieved a 36% objective response rate (ORR) among 33 evaluable patients.
• A lower 4 mg/kg dose yielded a 43% ORR in 35 patients.

Despite the higher ORR at the lower dose, investigators recommended the 6 mg/kg option based on overall benefit-risk profiles. The higher dose demonstrated faster response onset (1.4 months vs. 2.7 months) and potentially longer-lasting benefits, with an estimated 64% of patients maintaining response at nine months compared to 15% at the lower dose.

Median progression-free survival reached 11.7 months for the higher dose cohort, surpassing the 9.5 months observed in the lower dose group.

Safety Profile and Ongoing Studies

As expected, the higher Datroway dose was associated with more adverse events. Grade 3 or above treatment-related adverse events occurred in 56% of patients at the higher dose, compared to 34% at the lower dose. Notably, interstitial lung disease or pneumonitis, a closely watched side effect for ADCs using Daiichi's DXd platform, was observed in 15% of high-dose patients, with 6% experiencing grade 3 or above events.

AstraZeneca and partner Daiichi Sankyo have already initiated the phase 3 Tropion-Lung15 trial, evaluating Datroway at 6 mg/kg alone or in combination with Tagrisso for post-Tagrisso EGFR-mutant NSCLC. This study is expected to reach its primary completion in June 2026.

Competitive Landscape in EGFR-Mutant NSCLC

The Datroway-Tagrisso combination enters a competitive field for post-Tagrisso treatment options. Johnson & Johnson's Rybrevant (amivantamab) plus chemotherapy recently demonstrated a 53% ORR and 6.9-month median duration of response in the phase 3 Mariposa-2 trial for this patient population.

AstraZeneca is also exploring other combination approaches, including the pairing of Tagrisso with the MET inhibitor savolitinib (Orpathys). In the phase 2 Savannah trial, this combination achieved a 56% ORR by investigator assessment in patients with high MET expression who had progressed on first-line Tagrisso.

As these various treatment strategies continue to evolve, the landscape for EGFR-mutant NSCLC patients is becoming increasingly complex and potentially more promising. The pharmaceutical industry eagerly awaits further data from ongoing trials to determine the optimal treatment sequencing and combinations for this patient population.