AstraZeneca has revealed a major lung cancer breakthrough as the U.S. Food and Drug Administration (FDA) approved Datroway (datopotamab deruxtecan) with accelerated approval. The first-in-class TROP2-targeted antibody drug conjugate (ADC) is now approved for adult patients with EGFR-mutated non-small cell lung cancer (NSCLC) who have already progressed on previous EGFR-directed therapy as well as platinum-based chemotherapy. This approval fulfills a significant unmet need for patients whose illness has developed resistance to current therapies.
Datroway Targeting TROP2 with Precision
Datroway is a new treatment paradigm in lung cancer, the first TROP2-targeted therapy to receive US approval for this indication. TROP2 (trophoblast cell surface antigen 2) is an overexpressed protein in most NSCLC tumors, rendering it an ideal target for therapeutic intervention. Datroway is a cleverly engineered antibody drug conjugate that takes advantage of this overexpression. It is made up of a humanized anti-TROP2 IgG1 monoclonal antibody, which serves as a “guided missile,” attached to a highly effective topoisomerase I inhibitor payload (an exatecan derivative, DXd) through a cleavable tetrapeptide-based linker. This advanced mechanism enables the antibody to bind uniquely to TROP2-expressing cancer cells. Upon internalization, the linker is degraded, releasing the cytotoxic DXd payload directly within the tumor cell. This targeted delivery has less harm to healthy tissues, targeting a stronger and more specific anti-cancer action than traditional chemotherapy.
Robust Clinical Evidence: TROPION-Lung05 and TROPION-Lung01 Trials
The FDA’s expedited approval is mainly based on strong evidence from a subgroup analysis of the worldwide, multicentre, single-arm, open-label Phase II TROPION-Lung05 trial and supplemented by evidence from the worldwide, randomized, multicentre, open-label Phase III TROPION-Lung01 trial.
In the combined analysis of 114 patients with previously treated locally advanced or metastatic EGFR-mutated NSCLC from both studies, Datroway showed a confirmed objective response rate (ORR) of 45% (95% confidence interval [CI]: 35-54), per blinded independent central review (BICR).
This significant response rate comprised complete response in 4.4% of the patients and partial response in 40%. The median response duration (DoR) was 6.5 months (95% CI: 4.2-8.4). The findings are especially significant for a patient group with few treatment alternatives after developing disease progression on accepted first-line therapy. The TROPION-Lung05 trial enrolled patients with assessable genomic changes, such as EGFR, ALK, ROS1, NTRK, BRAF, RET, or MET, who had previously progressed on one or more EGFR-targeted treatment and platinum-based chemotherapy. TROPION-Lung01 evaluated Datroway versus docetaxel in adults with advanced or metastatic NSCLC with or without assessable genomic changes who needed systemic therapy after prior therapy.
Safety Profile and Accelerated Approval Context
Safety profile of Datroway was assessed through pooled analysis of patients from the TROPION-Lung05, TROPION-Lung01, and TROPION-PanTumor01 trials. The major warnings and precautions with Datroway are interstitial lung disease (ILD)/pneumonitis, which is severe, life-threatening, or even fatal. In the NSCLC pooled safety data, ILD/pneumonitis in 7% of patients were reported, of which Grade 3 (0.6%), Grade 4 (0.4%), and fatal (1.7%) were seen. Median time to occurrence in ILD was 1.4 months.
Ocular adverse events were frequent (e.g., dry eye, keratitis, blurred vision) and sometimes included Grade 3 events. Stomatitis (mouth sores and ulcers) was frequent and usually could be managed with steroid mouthwash. Use of preservative-free lubricating eye drops and avoidance of contact lenses, unless advised by an eye care specialist, is recommended.
This fast-track approval is on the basis of objective response rate and response duration, which represents an encouraging clinical benefit. Ongoing approval for this indication could be dependent on confirmation and definition of clinical benefit in a confirmatory trial, as the TROPION-Lung15 trial, which is ongoing, will continue to study Datroway with or without Tagrisso compared with chemotherapy in second-line EGFR-mutated NSCLC.
This approval marks an important milestone in the personalized treatment of lung cancer, bringing new hope to individuals who have reached the end of existing standard treatments.
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Graduated from the University of Kerala with B.Sc. Botany and Biotechnology. Attained Post-Graduation in Biotechnology from the Kerala University of Fisheries and Ocean Science (KUFOS) with the third rank. Conducted various seminars and attended major Science conferences. Done 6 months of internship in ICMR – National Institute of Nutrition, Hyderabad. 5 years of tutoring experience.
