Dato-DXd Plus Durvalumab ± Carboplatin Delivers Antitumor Activity in Advanced NSCLC

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Frontline treatment with datopotamab deruxtecan-dlnk (Dato-DXd; Datroway) plus durvalumab (Imfinzi) with (cohort 4) or without (cohort 2) carboplatin elicited responses in patients with advanced or metastatic non–small cell lung cancer (NSCLC) regardless of histologic subtype or PD-L1 expression level, according to updated data from the phase 1b TROPION-Lung04 trial (NCT04612751).1

At a data cutoff of October 24, 2024, the confirmed objective response rate (ORR) in cohort 2 with the doublet (n = 15) was 53.3% (95% CI, 26.6%-78.7%) and the confirmed ORR was 56.8% (95% CI, 39.5%-72.9%) in cohort 4 with the triplet (n = 37). The respective disease control rates (DCRs) were 86.7% (95% CI, 59.5%-98.3%) and 89.2% (95% CI, 74.6%-97.0%). The median duration of response (DOR) was 15.0 months (95% CI, 4.5-28.8) in cohort 2 and 8.8 months (95% CI, 5.8-not evaluable) in cohort 4.

Additionally, the median progression-free survival (PFS) was 7.3 months (95% CI, 2.0-29.5) in cohort 2 with the doublet and 8.7 months (95% CI, 5.6-10.1) in cohort 4 with the triplet.

“The combination of Dato-DXd plus durvalumab with or without carboplatin had encouraging activity as frontline treatment for patients with advanced or metastatic NSCLC without actionable genomic alterations,” study author Ewa Kalinka, MD, PhD, of Polish Mother’s Memorial Hospital - Research Institute in Łódź, Poland, said in a presentation of the findings at the 2025 ESMO Targeted Anticancer Therapies Congress. “Responses were observed in both squamous and nonsquamous histologies and across all evaluated PD-L1 levels.”

Prior Findings and TROPION-Lung04 Enrollment

Previously reported data from the trial that had been presented with a data cutoff of March 6, 2023, demonstrated Dato-DXd’s efficacy in combination with durvalumab with or without carboplatin in treatment-naive patients and those who had received 1 prior line of chemotherapy for advanced or metastatic NSCLC.2

To be eligible for enrollment in the multi-center, open-label TROPION-Lung04 trial, patients needed to be at least 18 years of age with previously treated or treatment-naive advanced/metastatic squamous or nonsquamous NSCLC; they could not have actionable genomic alterations and must have had an ECOG performance status of 0 or 1.1 Cohorts 2 and 4 focused on patients who were treatment naive.

In cohort 2, patients received 6 mg/kg of Dato-DXd plus 1120 mg of durvalumab every 3 weeks as first-line treatment in both the dose-escalation (n = 1) and dose-expansion phase (n = 14). In cohort 4, patients received the same combination in the frontline setting plus 4 cycles of carboplatin with an area under the curve of 5 every 3 weeks as part of dose escalation (n = 6) and dose expansion (n = 31).

The primary end point of TROPION-Lung04 was safety and tolerability. Key secondary end points included DCR, DOR, ORR, and PFS by investigator assessment per RECIST 1.1 criteria.

In cohort 2 examining the doublet, the median age was 63.0 years (range, 49-75) and most patients were male (80.0%) and had nonsquamous histology (73.3%). Patients were either White (60.0%) or Asian (40.0%), and 20% had a history of brain metastases. PD-L1 expression was stratified by less than 1% (33.3%), between 1% and 49% (26.7%), and 50% or greater (40.0%), and all patients had stage IVA or IVB disease at study entry.

In cohort 4 with the triplet, the median age was 66.0 years (range, 38-86) and most patients were male (81.1%). Per the study design, an equal number of patients were enrolled with nonsquamous and squamous histology. Patients were either White (56.8%) or Asian (43.2%) and 13.5% had a history of brain metastases. PD-L1 expression was less than 1% (43.2%), between 1% and 49% (32.4%), and 50% or greater (24.3%). Further, 83.8% of patients had stage IVA or IVB disease at study entry compared with stage IIIA to IIIC disease (16.2%).

Diving Deeper Into Data Presented at ESMO

Additional findings revealed that when broken down by histology, in the doublet cohort of Dato-DXd plus durvalumab, the confirmed ORRs were 50.0% (95% CI, 6.8%-93.2%) in those with squamous (n = 4) histology and 54.5% (95% CI, 23.4%-83.3%) in those with nonsquamous (n = 11) histology. The DCRs were 75.0% (95% CI, 19.4%-99.4%) and 90.9% (95% CI, 58.7%-99.8%), respectively.

In the triplet cohort of Dato-DXd plus durvalumab and carboplatin, the confirmed ORRs were 47.4% (95% CI, 24.4%-71.1%) in those with squamous (n = 19) histology and 66.7% (95% CI, 41.0%-86.7%) in those with nonsquamous (n = 18) histology. The DCRs were 89.5% (95% CI, 66.9%-98.7%) and 88.9% (95% CI, 65.3%-98.6%), respectively.

With respect to safety, grade 3 or greater treatment-emergent adverse effects (TEAEs) occurred in 60.0% of patients in cohort 2 with the doublet and 70.3% of patients in cohort 4 with the triplet. Of those, 46.7% and 62.2% were treatment related, respectively.

Observed TEAEs in cohort 2 included constipation (grade 1/2, 53%; grade ≥ 3, 0%), nausea (47%; 0%), alopecia (47%; 0%), stomatitis (40%; 13%), fatigue (40%; 7%), rash (40%; 0%), pneumonia (33%; 7%), dry eye (27%; 0%), anemia (20%; 7%), COVID-19 (20%; 7%), pneumonitis (20%; 0%), decreased appetite (20%; 0%), abnormal hepatic function (20%; 0%), increased amylase levels (7%; 13%), neutropenia (7%; 7%), and leukopenia (7%; 0%).

In cohort 4 TEAEs included stomatitis (grade 1/2, 59%; grade ≥ 3, 8%), nausea (46%; 3%), alopecia (46%; 0%), constipation (43%; 0%), fatigue (41%; 5%), rash (32%; 3%), anemia (27%; 24%), thrombocytopenia (27%; 16%), decreased appetite (27%; 3%), abnormal hepatic function (22%; 5%), increased amylase levels (16%; 8%), leukopenia (16%; 8%), dry eye (16%; 0%), COVID-19 (14%; 0%), neutropenia (11%; 24%), pneumonia (11%; 0%), and pneumonitis (8%; 5%).

“At [the] updated cutoff, the safety profile for the combinations was consistent with previous reports and the individual safety profiles for each agent given as monotherapy, and no new safety findings were reported,” Kalinka stated.

In cohort 2, TEAEs leading to the discontinuation of any drug occurred in 26.7% of patients treated with the doublet and 24.3% of those in cohort 4 treated with the triplet. Most were related to Dato-DXd in both arms (cohort 2, 26.7%; cohort 4, 21.6%) with some occurring due to durvalumab (cohort 2, 13.3%; cohort 4, 18.9%) or carboplatin (cohort 4, 8.1%).

Two treatment-emergent deaths occurred in cohort 4 that were deemed related to Dato-DXd and durvalumab: pneumonitis and dyspnea.

“Dato-DXd and immune checkpoint inhibitor combinations with or without chemotherapy are currently being evaluated as potential frontline treatment options in patients with advanced or metastatic NSCLC without actionable genomic alterations in the phase 3 AVANZAR [NCT05687266], TROPION-Lung07 [NCT05555732], and TROPION-Lung08 [NCT05215340] trials,” Kalinka concluded.

Data-DXd is also currently under priority review from the FDA for an indication in locally advanced or metastatic EGFR-mutant NSCLC following receipt of prior systemic therapy.3

Disclosures: Kalinka cited having a consulting or advisory role with Bristol-Myers Squibb and Merck Sharp Dohme as well as serving as a speaker for AstraZeneca, Bristol-Myers Squibb, Eli Lilly, Gilead, Medison, Merck Sharp Dohme, Pfizer, and Roche. She is also a principal study investigator for Abbvie, AstraZeneca, Bristol-Myers Squibb, Celcuity, Daiichi Sankyo, Eli Lilly, Gilead, Merck Sharp Dohme, Pfizer, Regeneron, and Roche.

References

1. Cuppens K, Papadopoulos KP, Nishio M, et al. First-line (1L) datopotamab deruxtecan (Dato-DXd) + durvalumab ± carboplatin in advanced or metastatic non-small cell lung cancer (a/mNSCLC): results from TROPION-Lung04 (cohorts 2 and 4). ESMO Open. 2025;10(suppl 2):104164. doi:10.1016/j.esmoop.2025.104164
2. Datopotamab deruxtecan plus imfinzi showed promising clinical activity in the first-line advanced non-small cell lung cancer setting in TROPION-Lung04 Phase Ib trial. News release. September 10, 2023. Accessed March 10, 2025. bit.ly/3XAlF5G
3. Datopotamab deruxtecan granted priority review in the US for patients with previously treated advanced EGFR-mutated non-small cell lung cancer. News release. AstraZeneca. January 13, 2025. Accessed March 10, 2025. bit.ly/4j7USGF