The antibody-drug conjugate datopotamab deruxtecan demonstrated encouraging antitumor activity in patients with heavily pretreated non-small cell lung cancer (NSCLC), according to phase 1 study results published in the Journal of Clinical Oncology.

Although immunotherapy has greatly expanded the treatment landscape for patients with NSCLC, limited options remain for patients with progressive disease. Second-line therapies are also often associated with intolerable toxicities that negatively affect quality of life.

Datopotamab deruxtecan targets trophoblast cell-surface antigen 2 (TROP2), which is expressed commonly in adult solid tumors. The antibody-drug conjugate binds a TROP2-directed monoclonal antibody to a highly potent topoisomerase I inhibitor payload.

In a first-in-human dose-escalation and dose-expansion study, Toshio Shimizu, MD, professor of medicine at Wakayama Medical University Hospital, Japan, and colleagues enrolled patients with relapsed or progressive NSCLC. The population was heavily pretreated, with a median of three previous therapy lines (range, 1-13).

During the dose-escalation phase of the study, the researchers administered datopotamab deruxtecan intravenously at levels ranging from 0.27 mg/kg to 10 mg/kg once every 3 weeks, as they sought to determine a maximum tolerated dose. During the dose-expansion phase, patients received datopotamab deruxtecan once every 3 weeks at doses of 4 mg/kg, 6 mg/kg, or 8 mg/kg. Safety and tolerability served as the study’s primary endpoints. Antitumor activity, including objective response rate (ORR) and survival, served as secondary endpoints.

The dose-expansion cohort included data from 180 patients treated at the three dose points (4 mg/kg, n = 50; 6 mg/kg, n = 50; 8 mg/kg, n = 80). The researchers identified 6 mg/kg, given intravenously once every 3 weeks, as the recommended dose for further development. Among patients treated at the recommended dose (median age, 62.5 years; range, 38-76), the median time on study was 13.3 months, and the median exposure to datopotamab deruxtecan was 3.5 months.

Treatment was well tolerated, with common any-grade treatment-emergent adverse events including nausea (64%), stomatitis (60%), and alopecia (42%). Among patients treated at the recommended dose, 54% experienced grade 3 or higher treatment-emergent adverse events, and 48% experienced serious adverse events. Seven patients at this level discontinued treatment due to adverse events. Interstitial lung disease (ILD) occurred in 19 patients during the expansion phase, including in three patients treated at the recommended dose. Two cases of grade 2 ILD and one case of grade 4 ILD were considered related to datopotamab deruxtecan by the researchers.

In total, a confirmed partial response was seen in 42 patients, including 13 patients treated at the 6 mg/kg dose. One confirmed complete response occurred in a patient treated at the 8 mg/kg dose. The confirmed ORR for patients treated at the recommended dose was 26% (95% CI, 14.6-40.3). The median duration of response was 10.5 months (95% CI, 5.6-26.5). The median progression-free survival for patients treated at the recommended dose was 6.9 months (95% CI, 2.7-8.8), and the median overall survival was 11.4 months (95% CI, 7.1-20.6).

“Nearly all tumors expressed detectable TROP2 by immunohistochemistry, with 64 of 87 (73.6%) having high TROP2 expression (H-score >100),” Shimizu and colleagues noted. “No relationship was observed between TROP2 expression and antitumor response.”

Further studies of datopotamab deruxtecan as a combination therapy for first-line treatment of NSCLC and as monotherapy in the second line remain ongoing, according to the researchers.

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Disclosures: Shimizu declared financial ties to drugmakers. See full study for details. The study was supported by Daiichi Sankyo.

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