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A novel antibody-drug conjugate targeting TROP2 yielded durable responses in about a fourth of patients with heavily pretreated non-small cell lung cancer (NSCLC), updated results from a phase I dose-finding study showed.

In the cohort that received the datopotamab deruxtecan (Dato-DXd) dose selected for continued development, 28% of patients responded to the drug and an additional 40% had stable disease, reported Edward Garon, MD, MS, of the David Geffen School of Medicine at the University of California Los Angeles, during the virtual World Conference on Lung Cancer.

"Dato-DXd continued to demonstrate highly encouraging antitumor activity," said Garon, in presenting findings from the NSCLC cohorts of the TROPION trial. "The 6 mg/kg dose has been selected for further development due to promising antitumor activity along with a favorable safety profile."

Median duration of response (DOR) was 10.5 months in this cohort of patients -- the vast majority of whom had failed on both platinum-based chemotherapy and checkpoint inhibitors.

"Most responses were durable over time, with several responses in each cohort ongoing at the time of the data cutoff," said Garon, adding that "the 4 mg/kg cohort also yielded durable benefit, making it an active option for patients requiring dose reduction."

In that lower-dose cohort, 24% of patients responded to the antibody-drug conjugate and 50% had stable disease (median DOR was not evaluable).

Dato-DXd is an antibody-drug conjugate that includes three components: a monoclonal antibody that targets TROP2, a topoisomerase I inhibitor payload, and a stable tetrapeptide-based cleavable linker, explained Garon. The agent aims to eliminate target tumor cells, as well as surrounding "bystander" cells.

While TROP2 is highly expressed on NSCLC tumors and is associated with poor prognosis, patients in the study were unselected for TROP2 expression.

Discussant Giannis Mountzios, MD, MSc, PhD, of the Henry Dunant Hospital Center in Athens, Greece, called the median DOR reached in the selected cohort "clinically meaningful," but noted the substantial toxicity. In this cohort, 54% had grade 3 or higher treatment-emergent adverse events (TEAEs), 14% discontinued for toxicity, 30% had dose interruptions, and 10% required dose reductions.

In discussing the continued development of the drug, Mountzios questioned whether a biomarker would be needed for patient selection given the "modest activity" observed in all comers. He also asked about activity in the central nervous system, of which no data were presented despite the inclusion of patients with brain metastases.

The trial was restricted to those with an Eastern Cooperative Oncology Group (ECOG) performance status of 0-1, but heavily pretreated patients often have an ECOG performance status of 2, Mountzios pointed out.

"We need to know what to do with these patients," he said. "Another important concern is how to avoid severe interstitial lung disease. Does it correlate with previous immunotherapy or radiation? We need to know this data on antibody-drug conjugates to move on."

Three patients (6%) had interstitial lung disease (ILD) deemed related to the study drug in the 6 mg/kg cohort. And Mountzios drew attention to the three treatment-related deaths due to ILD in the higher-dose (8 mg/kg) cohort.

The NSCLC cohorts of the phase I TROPION trial included 180 previously treated patients with advanced or metastatic disease and tested three dosing levels for Dato-DXd: 4 mg/kg (n=50), 6 mg/kg (n=50), and 8 mg/kg (n=80). Patients had a median age of 61-64 across the three cohorts.

Most patients had received prior immunotherapy (74%-88%), nearly all had prior platinum-based chemotherapy (96%-98%), and about 20% had been treated with tyrosine kinase inhibitors, with 54%-64% of patients having received three or more prior lines of therapy in all. Most had nonsquamous tumors (82%-90%), and some patients had EGFR mutations (14%-19%).

Overall, the safety profile of the drug involved mostly mild to moderate toxicity, and hematologic events were uncommon, said Garon. Across dosing levels, the most frequent TEAEs (15% or higher) included nausea and vomiting, stomatitis, alopecia, fatigue, decreased appetite, constipation, infusion-related reactions, rash, anemia, dry eye, mucosal inflammation, cough, diarrhea, and dyspnea.

In the highest-dose cohort, which is no longer being evaluated due to the increased risk for ILD, 24% of patients responded (including one complete response), 53% had stable disease, and the median DOR was 9.4 months.

A previously reported study of Dato-DXd demonstrated promising antitumor activity in triple-negative breast cancer, and studies in other tumor types are underway. Along with other smaller trials in NSCLC, Dato-DXd is being evaluated in the phase III , which is testing the drug against docetaxel in previously treated advanced or metastatic patients who lack actionable genomic alterations.

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