Osimertinib Plus Dato-DXd Shows Efficacy in Post-Osimertinib EGFR-Mutated Advanced NSCLC

Osimertinib Plus Dato-DXd in EGFR-Mutated

Advanced NSCLC | Image Credit:

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

The data, which were shared during the 2025 European Lung Cancer Congress, 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); 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%).

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.

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

Revisiting ORCHARD: A Biomarker-Directed Platform Study

The global, open-label, multicenter study enrolled patients with NSCLC and the following features: locally advanced or metastatic disease not amenable to curative surgery or radiation; histologically or cytologically confirmed adenocarcinoma of the lung with EGFR mutations linked with EGFR TKI sensitivity; receipt of only 1 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 non-matched 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 (SAEs).

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%) and White (60%; 65%). In the 4-mg/kg group, 51% of patients had progressed on frontline osimertinib in under 12 months, 40% in greater 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 (WHO) 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, 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 favored 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 also favored the 6-mg/kg cohort.

Safety Spotlight

Treatment-related AEs were experienced by 97% 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%), 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%), 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.

Disclosures: Dr Le disclosed receipt of research funding from ArriVent, Bayer AG, Boehringer Ingelheim, Dizal, Eli Lilly, EMD Serono, Janssen (J&J), Regeneron, Takeda, Teligene, and ThermoFisher. She serves as a consultant or advisor for AbbVie, Abion, Allist, ArriVent, AstraZeneca, Aviston, Bayer AG, BlossomHill, Blueprint Medicines, Boehringer Ingelheim, BioNTech, Bristol Myers Squibb, Daiichi-Sankyo, Dizal, Eli Lilly, EMD Serono (Meck KGaA), GuardantHealth, Hengrui Therapeutics, InnoVent, Janssen (J&J), Novartis, Pfizer, Regeneron, Roche/Genentech, Sensei Biotherapeutics, SystImmune, Teligene, and Taiho. Travel support was received by Allist, EMD Serono, and Janssen.

References

1. Le X, Hendriks L, Morabito A, et al. Osimertinib + datopotamab deruxtecan in patients with EGFR-mutated advanced NSCLC whose disease progressed on first-line osimertinib: ORCHARD. J Thorac Oncol. 2025;20(suppl 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