according to Edward B. Garon, MD, of the University of California, Los Angeles. Prior results from TROPION-PanTumor01, have demonstrated similarly encouraging activity and a manageable safety profile for Dato-DXd, Dr. Garon said in a 2021 European Society for Medical Oncology Congress virtual oral presentation on Sept. 19 (abstract LBA49).
Limited benefit from existing treatments
Once tyrosine kinase inhibitors and platinum chemotherapy have failed, patients with advanced/metastatic NSCLC with AGAs (e.g., EGFR or ALK mutations) derive limited benefit from existing treatments, Dr. Garon observed. Datopotamab deruxtecan is an antibody-drug conjugate composed of a humanized anti-TROP2 monoclonal antibody conjugated to a potent topoisomerase I inhibitor payload via a stable tetrapeptide-based cleavable linker. TROP2 is highly expressed in NSCLC, regardless of genomic mutation status and has been associated with poor prognosis. Patients in TROPION-PanTumor01 were not selected based on TROP2 expression or AGA status, Dr. Garon noted.
TROPION-PanTumor01 (NCT03401385), an ongoing multicenter, open-label, dose-expansion study evaluating datopotamab deruxtecan in solid tumors, including NSCLC in 210 patients, is assessing safety, pharmacokinetics, antitumor activity, and biomarkers. All included patients (n = 180; median age, 62 years; 56% female) had progressed after standard treatment or had measurable disease and had no standard treatment available. Stable/treated brain metastases were permitted.
Subgroup with AGAs
The current report includes outcomes from the subgroup of 34 patients with AGAs, who were treated with 4 (n = 8), 6 (n = 10), and 8 mg/kg (n = 16) of datopotamab deruxtecan. AGAs were EGFR in 29 patients, ALK in 3, and ROS1 and RET in 1 each. Most patients (82%) had received three or more prior regimens; 85% had prior TKI, and among EGFR mutation patients, 69% had received osimertinib. Prior systemic treatment consisted of immunotherapy in 41%, platinum-based chemotherapy in 91%, and tyrosine kinase inhibitor in 85%. The primary objectives were to establish the maximum tolerated dose, safety, and tolerability. Efficacy was a secondary outcome.
Treatment-emergent adverse events were reported in all patients, with grade 3 or higher events in 53%. Most common were grade 1-2 nausea, stomatitis, fatigue, and alopecia. Drug-attributed events in 88% were grade 3 or higher in 38%. Treatment-emergent adverse events led to discontinuation in 15%, dose interruption in 27% and dose reductions in 15%. One case of grade 5 interstitial lung disease, in the 8-mg group, was adjudicated as drug related. “The safety profile of Dato-DXd was manageable and consistent with that observed in the overall NSCLC population in TROPION-PanTumor01,” Dr. Garon said, “and were primarily nonhematologic.”
The objective response rate was 35%, all partial responses. The stable disease rate was 41%; the progressive disease rate was 6%. Median duration of response was 9.5 months (95% confidence interval, 3.3-NE). Dr. Garon noted that clinical activity was observed in EGFR (Ex 19del, L858R) including after osimertinib and across other AGAs.
Further evaluation ongoing
Further evaluation of datopotamab deruxtecan is ongoing in the TROPION-Lung05 study among NSCLC patients with AGAs after targeted therapy and platinum-based chemotherapy options have been exhausted. Eligible AGAs include EGFR (including exon 20 insertions), ALK, ROS1, RET, BRAF, NTRK and MET exon 14 skipping.
Session moderator David Gandara, MD, University of California Davis Health, questioned the rationale for targeting oncogene driven cancers with this particular drug: “Is this just because this is felt to be an unmet need, or is there higher expression or some other biologic rationale?”
Dr. Garon responded, “Why are we looking at these driver mutation–positive patients? I think it has less to do with mechanism and more to do with the differences in treatment between these driver mutation positive patients and the rest of the population. This is a group of patients which has TROP2, but TROP2 expression is seen really across non–small cell lung cancer. But, in fact, one of the reasons it has been postulated that TROP2 is not a good biomarker for this class of drugs to date, is that its expression is so ubiquitous in the disease.”
The study was funded by Daiichi Sankyo. Dr. Garon disclosed numerous pharmaceutical-related financial interests.
This article was updated Sept. 24, 2021.