The landscape of TROP2-directed therapies, particularly antibody-drug conjugates (ADCs), is evolving in non-small cell lung cancer (NSCLC), marked by both progress and challenges. While fam-trastuzumab deruxtecan-nxki (Enhertu; T-DXd) has already gained approval, ongoing research focuses on existing ADCs like sacituzumab govitecan (Trodelvy) and novel ADCs in early-stage evaluations. Recent regulatory activities indicate a complex understanding of TROP2-directed therapies.
Datopotamab Deruxtecan (Dato-DXd): A Closer Look
AstraZeneca and Daiichi Sankyo have submitted a new biologics license application (BLA) for accelerated approval of datopotamab deruxtecan (Dato-DXd) for treating adult patients with locally advanced or metastatic EGFR-mutated NSCLC who have previously received systemic therapies, including EGFR-directed therapy. This submission follows a voluntary withdrawal of the BLA for advanced or metastatic nonsquamous NSCLC, based on the phase 3 TROPION-Lung01 trial (NCT04656652) results.
While the phase 1 TROPION-PanTumor01 trial (NCT03401385) showed durable responses in lung cancer patients treated with docetaxel, the TROPION-Lung01 trial presented mixed results regarding overall survival. In a post hoc analysis of patients with nonsquamous NSCLC and baseline brain metastases (data cutoff of March 29, 2023), Dato-DXd prolonged progression-free survival (PFS) compared to docetaxel. In patients with brain involvement, median PFS was 4.9 months with Dato-DXd vs 3.6 months with docetaxel (HR, 0.59; 95% CI, 0.35-1.00). For patients without brain involvement, PFS was 5.7 months vs 3.7 months, respectively (HR, 0.64; 95% CI, 0.50-0.81).
Melissa L. Johnson, MD, director of lung research at Sarah Cannon Research Institute in Nashville, Tennessee, emphasized the importance of understanding the ADC components: "As we consider ADCs in lung cancer, I want you to think about how the components [of the ADC], such as the linker, the target antibody, and the payload, are being [changed and substituted]." She noted that in the TROPION-Lung01 trial, overall survival was negative for the overall patient group initially treated with chemotherapy and immunotherapy.
When PFS was compared by histology, patients with nonsquamous histology treated with Dato-DXd had a median PFS of 5.6 months (95% CI, 4.4-7.0) vs 3.7 months (95% CI, 2.9-4.2) in those treated with docetaxel (HR, 0.43; 95% CI, 0.51-0.78). However, patients with squamous histology treated with Dato-DXd had a median PFS of 2.8 months (95% CI, 1.9-4.0) vs 3.9 months (95% CI, 2.8-4.5) in those treated with docetaxel (HR, 1.38; 95% CI, 0.94-2.02).
Sacituzumab Govitecan: Another ADC in the Spotlight
Sacituzumab govitecan, already indicated for triple-negative breast cancer (TNBC), is also under evaluation in NSCLC. The phase 3 EVOKE-01 study (NCT05089734) compared sacituzumab govitecan to docetaxel in patients with TNBC. While the primary endpoint of overall survival (OS) showed numerical improvement, it was not statistically significant. The ADC was better tolerated than docetaxel, with no new safety signals observed.
Johnson commented, "We can’t use this drug in all patients, so we probably need to dig deeper into the data to figure out who is truly benefiting."
The Future of TROP2-Directed ADCs
Other TROP2-directed ADCs in development include patritumab deruxtecan (HER3-DXd) in the phase 2 HERTHENA-Lung01 trial (NCT04619004); BL-B01D1, an ADC consisting of an EGFR×HER3 bispecific antibody bound to a novel TOP-I inhibitor payload via a cleavable linker, under study in a phase 1 trial (NCT05194982); sigvotatug vedotin in the phase 3 Be6A Lung-01 study (NCT06012435); and telisotuzumab vedotin in the phase 2 LUMINOSITY trial (NCT03539536).
Johnson concluded, "The sky is the limit when it comes to all these permutations... I hope I’ve shown you the importance of patient selection in the clinical trials that we conduct."
