Dato-DXd Combination Is Effective in Post-TKI NSCLC

Xiuning Le, MD, PhD

Associate Professor

Department of Thoracic/Head and Neck Medical Oncology

The University of Texas MD Anderson Cancer Center

Houston, TX

For patients with EGFR-mutated non–small cell lung cancer (NSCLC) who have progressed on frontline osimertinib (Tagrisso), the combination of osimertinib plus datopotamab deruxtecan (Dato-DXd; Datroway) given at 4 or 6 mg/kg demonstrated encouraging efficacy with acceptable safety, according to an analysis of module 10 of the phase 2 ORCHARD study (NCT03944772).¹

The data, which were shared during the 2025 European Lung Cancer Congress (ELCC), indicated that the objective response rate (ORR) achieved in those who received osimertinib plus Dato-DXd at 4 mg/kg (n = 35) was 43% (80% CI, 31%-55%) at a median follow-up of 13.4 months.

In this group, the median time to response (TTR) was 2.7 months (range, 1.5-4.1), and the median duration of response (DOR) was 6.3 months (95% CI, 3.8-8.2). The DOR rates at 6 and 9 months were 60% (95% CI, 32%-80%) and 15% (95% CI, 2%-38%), respectively. Moreover, the median progression-free survival (PFS) was 9.5 months (95% CI, 7.2-9.8) and the respective PFS rates at 6, 9, and 12 months were 74% (95% CI, 56%85%), 50% (95% CI, 33%-65%), and 21% (95% CI, 9%-35%), respectively. In the group of patients who received osimertinib and Dato-DXd at 6 mg/kg (n = 33), the ORR was 36% (80% CI, 25%-49%) at a median follow-up of 13.8 months. The median TTR was 1.4 months (range, 1.2-2.1), and the median DOR was 20.5 months (95% CI, 6.2-not calculable [NC]); the 6-month DOR rate was 92% (95% CI, 54%-99%) and the 9-month DOR rate was 64% (95% CI, 30%85%). The median PFS was 11.7 months (95% CI, 8.3-NC), with PFS rates of 80% (95% CI, 61%-91%), 70% (95% CI, 49%-83%), and 39% (95% CI, 21%57%) at 6, 9, and 12 months, respectively.

Lung cancer: © maya2008 - stock.adobe.com

“Encouraging outcomes were observed with osimertinib plus Dato-DXd in patients with EGFR-mutated advanced NSCLC whose cancer had progressed on first-line treatment with osimertinib, warranting further investigation of this combination in phase 3 studies,” Xiuning Le, MD, PhD, associate professor in the Department of Thoracic/Head and Neck Medical Oncology, at The University of Texas MD Anderson Cancer Center in Houston, Texas, said in a presentation of the data.¹

^{Revisiting ORCHARD: A Biomarker-Directed Platform Study}

T he multicenter study enrolled patients with NSCLC and the following features: locally advanced or metastatic disease not amenable to curative surgery or radiation; confirmed adenocarcinoma of the lung with EGFR mutations linked with EGFR tyrosine kinase inhibitor sensitivity; 1 prior line of therapy with osimertinib monotherapy for advanced NSCLC with achieved clinical benefit; and evidence of radiological disease progression on frontline osimertinib given at 80 mg once daily.²

The study was comprised of 3 groups.¹ Group A received treatment based on the resistance mechanism detected; group B served as the nonmatched arm for those without a resistance mechanism detected; and group C represented the observational group for those whose optimal treatment involves medication not available within groups A or B.

Module 10 was part of group B, and these patients received osimertinib at 80 mg once daily paired with Dato-DXd at 4 or 6 mg/kg every 3 weeks. After disease progression, they were followed for overall survival (OS). The primary end point of the study was investigator-assessed ORR by RECIST 1.1 criteria, and key secondary end points included PFS, DOR, OS, adverse effects (AEs), and serious AEs.

Ranveer (lungs) - stock.adobe.com

Module 10: First Disclosure of Safety and Efficacy Data at ELCC

The analysis had a data cutoff date of October 12, 2024. The median patient age in the 4-mg/kg group was 62 years (range, 37-76) vs 64 years (range, 42-78) in the 6-mg/kg group. Most patients were female (69%; 65%, respectively) and White (60%; 65%).

In the 4-mg/kg group, 51% of patients had progressed on frontline osimertinib in under 12 months, 40% in more than 18 months, and 6% between 12 months and 18 months; in the 6-mg/kg group, these respective rates were 9%, 56%, and 35%.

In the 4-mg/kg group, 51% had a World Health Organization status of 0 and 49% had a status of 1; these respective rates were 44% and 56% in the 6-mg/kg group. Just under half of patients (46%) in the 4-mg/kg group had baseline central nervous system metastases vs 32% of those in the 6-mg/kg group; 37% and 12% of patients, respectively, had baseline liver metastases.

The median duration of treatment was comparable between the 4-mg/kg and 6-mg/kg cohorts, at 9.0 months and 9.8 months, respectively. In the 4-mg/kg group, 17%, 40%, and 80% of patients required osimertinib dose reduction, interruption, or discontinuation, respectively, and 23%, 29%, and 80% of patients required Dato-DXd dose reduction, interruption, or discontinuation. In the 6-mg/kg group, no patients needed osimertinib dose reduction, but 35% and 68% of patients needed osimertinib interruption or discontinuation; 62%, 32%, and 68% of patients needed Dato-DXd dose reduction, interruption, or discontinuation in this group.

“From cycle 4 onward, more than half of patients in the 6-mg/kg cohort reduced their Dato-DXd dose to 4 mg/kg,” Le said. “Similar proportions of patients in each cohort had osimertinib and Dato-DXd dose interruptions.”

PFS was higher in the 6-mg/kg cohort, and ORR was similar between the 2 cohorts, according to Le. “A faster time to response and greater target lesion shrinkage [was noted] in the 6-mg/kg cohort.” DOR was higher in the 6-mg/kg cohort.

Safety Spotlight

Treatment-related AEs were experienced by 97% of patients in the 4-mg/kg and 6-mg/kg groups; these effects were grade 3 or higher for 34% and 56% of patients, respectively. Any grade 3 or higher AE was experienced by 49% of those in the 4-mg/kg group and 74% of those in the 6-mg/kg group. One patient in the 4-mg/kg group experienced an AE that proved fatal.

The most common AEs experienced in the 4- and 6-mg/kg groups were nausea (57%; 74%, respectively), alopecia (51%; 68%), stomatitis (51%; 56%), constipation (46%; 41%), cough (26%; 53%), diarrhea (46%; 32%), decreased appetite (34%; 41%), vomiting (17%; 50%), fatigue (29%; 35%), paronychia (31%; 29%), and asthenia (11%; 29%).

The most common AEs of special interest (AESIs) in the 4-mg/kg group were stomatitis/oral mucositis (grade 1, 34%; grade 2, 17%; grade 3, 11%; grade 4, 0%), mucosal inflammation (6%; 9%; 3%; 0%, respectively), ocular surface event (9%; 6%; 0%; 0%), and interstitial lung disease (ILD)/pneumonitis (0%; 0%; 0%; 3%).

In the 6-mg/kg group, the most common AESIs were also stomatitis/oral mucositis (18%; 44%; 9%; 0%), mucosal inflammation (6%; 24%; 3%; 0%), ocular surface event (21%; 6%; 0%; 0%), and ILD/pneumonitis (3%; 6%; 6%; 0%).

“Considering the overall benefit/risk profile, 6 mg/kg is the preferred Dato-DXd starting dose for combination with osimertinib at 80 mg,” Le said.

Dato-DXd is under further exploration in patients with EGFR-mutated advanced NSCLC through the phase 3 TROPION-Lung14 (NCT06350097) and TROPION-Lung15 (NCT06417814) trials.

REFERENCES:

1. Le X, Hendriks L, Morabito A, et al. Osimertinib (osi) + datopotamab deruxtecan (Dato-DXd) in patients (pts) with EGFR-mutated (EGFRm) advanced NSCLC (aNSCLC) whose disease progressed on first-line (1L) osi: ORCHARD. J Thorac Oncol. 2025;20(3):S2-S4. doi:10.1016/S1556-0864(25)00196-0

2. Phase 2 platform study in patients with advanced non-small cell lung cancer who progressed on first-line osimertinib therapy (ORCHARD) (ORCHARD). ClinicalTrials. gov. Updated January 30, 2025. Accessed April 8, 2025. https://clinicaltrials.gov/study/NCT03944772