In Advanced NSCLC With Genomic Alterations, An Antibody Drug Conjugate May Lead to Antitumor Activity

In patients with advanced/metastatic non-small cell lung cancer (NSCLC) with actionable genomic alterations, datopotamab deruxtecan (Dato-DXd), an antibody drug conjugate, demonstrated safe antitumor activity, according to data from the TROPION-PanTumor01 trial (NCT03401385).

In this presentation at the 2021 ESMO Congress, results focused on 34 patients (median age, 62 years; 56% women) with advanced/metastatic NSCLC and actionable genomic alterations.

“For patients who have actionable genomic alterations such as EGFR mutations or ALK gene rearrangements, once patients have exhausted their tyrosine kinase inhibitor therapy as well as platinum-based chemotherapy, the options are not particularly good,” said Edward B. Garon, MD, MS, professor of medicine and director of the Thoracic Oncology Program at the David Geffen School of Medicine at the University of California, Los Angeles, during the presentation. “TROP2 is known to be highly expressed in non-small cell lung cancer including non-small cell lung cancer with actionable genomic mutations. Increased expression of TROP2 has been associated with poor outcomes.”

Patients were treated with Dato-DXd at doses of 4 mg/kg (n = 8), 6 mg/kg (n = 10) or 8 mg/kg (n = 16).

“[Dato-DXd] … is an antibody drug conjugate,” Garon said. “It’s composed of a humanized anti-TROP2 monoclonal antibody conjugated to a potent topoisomerase I inhibitor via a stable tetrapeptide-based cleavable linker.”

The actionable genomic alterations reported by investigators included ALK (n = 3), EGFR (n = 29) and ROS 1 and RET (both n = 1).

Most patients in this study received at least 3 prior regimens (82%) and were previously treated with tyrosine kinase inhibitors (85%). In addition, 69% of patients with EGFR mutations previously received osimertinib (Tagrisso). This study was conducted for a median of 13 months.

The overall response rate confirmed by blinded independent central review was 35% across all doses (95% CI, 19.7-53.5), with a median duration of response of 9.5 months (95% CI, 3.3-NE), “indicating a significant level of efficacy in [these] heavily previously treated advanced non-small cell lung cancer patients with actionable genomic alterations,” Garon explained.

The most common any-grade adverse events observed throughout the study included stomatitis (56%) and nausea (62%). Hematologic toxicities related to Dato-DXd were infrequent. Researchers reported one incidence of interstitial lung disease related to treatment with Dato-DXd, which was considered a grade 5 event at a dose of 8 mg/kg.

“One adverse event of particular concern with this agent is interstitial lung disease,” Garon said. “There was one case of fatal interstitial lung disease felt to be associated with the drug. That was at the 8 mg/kg dosing level, which has since been discontinued.”

Garon added earlier in the presentation that since the 8 mg/kg dose did not have a favorable efficacy-to-toxicity ratio, it is no longer being developed throughout this program.

Data from the phase 1 TROPION-PanTumor01 trial previously demonstrated that Dato-DXd led to encouraging antitumor activity in 210 patients with advanced/metastatic NSCLC who were previously heavily pretreated. In this ongoing multicenter, open-label, dose-expansion study, researchers focused on safety, antitumor activity, pharmacokinetics and biomarkers in patients with NSCLC whose disease progressed after standard treatment, or had measurable disease and no standard treatment available.

“Dato-DXd is being further evaluated in non-small cell lung cancer with actionable genomic alterations after both targeted therapy and platinum-based chemotherapy as part of the TROPION-Lung05 study (NCT04484142),” Garon said.

_Reference:

_{Garon EB, Johnson ML, Lisberg AE, et al. Efficacy of datopotamab deruxtecan (Dato-DXd) in patients (pts) with advanced/metastatic (adv/met) non-small cell lung cancer (NSCLC) and actionable genomic alterations (AGAs): Preliminary results from the phase I TROPION-PanTumor01 study. Presented at 2021 ESMO Congress; September 16-21, 2021; Virtual. LBA49}