Dato-DXd Shows Promising Early Efficacy in Advanced NSCLC

Cancer in the lungs | Image Credit: Axel Kock - www.stock.adobe.com

In patients with advanced or metastatic non–small cell lung cancer (NSCLC) treated in the phase 1b TROPION-Lung04 trial (NCT04612751), adding datopotamab deruxtecan (Dato-DXd) to durvalumab (Imfinzi), with or without carboplatin, led to favorable efficacy and safety.¹

According to a presentation given during the 2023 World Conference on Lung Cancer, investigators looked at the safety and efficacy profiles of Dato-DXd plus durvalumab with (cohort 2) or without (cohort 4) carboplatin of the 11-cohort trial of adult patients with treatment-naïve or previously treated disease. Responses and adverse events (AEs) were higher with the triplet combination.

The primary end points of safety and tolerability in TROPION-Lung04 showed there were no new safety signals with Dato-DXd therapy. Treatment-emergent AEs (TEAEs) related to the study treatment occurred in 100% of cohort 2 (n = 19) and cohort 4 (n = 14). Grade 3 or higher TEAEs were seen in 42.1% and 71.4% of patients in the doublet and triplet groups, respectively; however, only 31.6% and 35.7% were related to treatment. In cohort 2, 31.6% had serious AEs that were study treatment-related compared with 35.7% in cohort 4.

For patients in cohort 2, there were no dose-limiting toxicities (DLTs), but cohort 4 had 2 patients with DLTs. One patient had grade 3 febrile neutropenia and the other had grade 3 stomatitis and grade 3 maculopapular rash. There were no TEAEs associated with death in either cohort, however 21.1% and 21.4% discontinued any drug from cohorts 2 and 4, respectively, and 21.1% and 14.3% discontinued Dato-DXd.

Interstitial lung disease (ILD) adjudicated as drug-related at any grade was experienced by 15.8% of patients given the doublet and 7.1% of patients given triplet therapy. Grades 1, 2, and 3 or higher ILD were seen in 5.3% of patients each in cohort 2. Cohort 4 only had ILD of grade 2 in 7.1% of patients. There were no adjudicated ILD grade 5 events, and 1 grade 4 event in cohort 2.

In the doublet group, the most common grade 1/2 TEAEs observed in 15% or more of patients included constipation (58%), alopecia (53%), and stomatitis (42%). The most common grade 3 or higher events were pneumonia and stomatitis, both at 11%. For triplet therapy, stomatitis, alopecia, and nausea were the most common grade 1/2 events at 57% each. Anemia (36%), thrombocytopenia (21%), and lymphopenia and neutropenia (14% each) were the most common grade 3 or higher events for triplet therapy.

The key secondary end points of overall response rate (ORR) and disease control rate (DCR) were available for 14 patients in cohort 2 and 13 patients in cohort 4 in the first-line setting. The confirmed ORRs for cohorts 2 and 4 were 50.0% (95% CI, 23.0%-77.0%) and 76.9% (95% CI, 46.2%-95.0%), respectively. The best response in both cohort was partial response. There were 42.9% of patients with stable disease in cohort 2 and 15.4% in cohort 4. Only 1 patient in each cohort had progressive disease. The DCRs in cohort 2 and 4 were 92.9% (95% CI, 66.1%-99.8%) and 92.3% (95% CI, 64.0%-99.8%), respectively.

In the overall population, the ORR was 47.4% in cohort 2 (n = 19), and 71.4% in cohort 4 (n = 14). For patients receiving triplet therapy, responses were numerically higher than for those receiving doublet therapy. This was observed across all PD-L1 expression levels.

Dato-DXd is an antibody-drug conjugate “consisting of a humanized anti-TROP2 IgG1 monoclonal antibody covalently linked to a highly potent topoisomerase-I inhibitor payload via a plasma-stable, tumor-selective, tetrapeptide-based cleavable linker,” the study authors explained in their presentation slides. This drug previously enhanced antitumor response to PD-1 and PD-L1 inhibitors in preclinical data, and showed early clinical efficacy with a manageable safety profile in the phase 1 TROPION-PanTumor01 (NCT03401385) and phase 1 TROPION-Lung02 (NCT04526691) trials in advanced or metastatic NSCLC populations.

As monotherapy in other trials of previously-treated patients, Dato-DXd elicited a confirmed ORR of 26% in the TROPION-PanTumor01 trial and showed statistically significant improvement in the phase 3 TROPION-Lung01 trial (NCT04656652) vs docetaxel. Dato-DXd plus pembrolizumab (Keytruda) with or without platinum-based chemotherapy in treatment-naïve patients showed an ORR of 50% and 57%, respectively, in the TROPION-Lung02 trial.

In this phase 1b, multicenter, open-label, dose escalation/confirmation and expansion trial, no patients had actionable genomic alterations or ECOG performance status above 1. In cohort 2, patients were given Dato-DXd at 6 mg/kg plus durvalumab at 1120 mg every 3 weeks in both the sequential dose escalation part 1 (n = 3) and the dose expansion part 2 (n = 16). The dosage was the same in cohort 4, but included 4 cycles of carboplatin at area under the curve of 5 in part 1 (n = 6) and part 2 (n = 8)

According to the study authors, Dato-DXd will continue to be evaluated in upcoming phase 3 trials, including the AVANZAR (NCT05687266), TROPION-Lung07 (NCT05555732) and TROPION-Lung08 (NCT05215340) trials. These studies will investigate Dato-DXd as first-line treatment in patients with advanced or metastatic NSCLC combined with immune checkpoint inhibitors.

_References:

_{Papadopoulos KP, Bruno DS, Kitazono S, et al. Datopotamab deruxtecan (Dato-DXd) + durvalumab ± carboplatin in advanced/mNSCLC: Initial results from phase 1b TROPION-Lung04. Presented at: 2023 World Conference on Lung Cancer; September 10-12, 2023; Singapore. Abstract OA05.06.}