Interim Results Show Durable Response With Dato-DXd in Advanced NSCLC

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The addition of datopotamab deruxtecan (Dato-DXd) to durvalumab (Imfinzi), with or without carboplatin, demonstrated favorable efficacy and safety in patients with advanced or metastatic non–small cell lung cancer (NSCLC), according to an interim analysis of the phase 1b TROPION-Lung04 trial (NCT04612751) presented at the 2023 World Conference on Lung Cancer.¹

In the analysis, 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.

Reference

1. 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.