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

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 of PD-L1 expression level, according to updated data from the phase 1b TROPION-Lung04 trial (NCT04612751) that were presented at the 2025 ESMO Targeted Anticancer Therapies Congress.1

At a data cutoff of October 24, 2024, the confirmed objective response rates (ORRs) in cohorts 2 (n = 15) and 4 (n = 37) were 53.3% (95% CI, 26.6%-78.7%) and 56.8% (95% CI, 39.5%-72.9%), respectively. 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) in cohort 2 was 15.0 months (95% CI, 4.5-28.8) vs 8.8 months (95% CI, 5.8-not evaluable) in cohort 4.

The median progression-free survival (PFS) in cohort 2 was 7.3 months (95% CI, 2.0-29.5) vs 8.7 months (95% CI, 5.6-10.1) in cohort 4.

“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,” lead study author Kristof Cuppens, MD, of Jessa Hospital in Hasselt, Belgium, said. “Responses were observed in both squamous and nonsquamous histologies and across all evaluated PD-L1 levels.”

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 disease.2

To be eligible for enrollment in the multi-center, open-label trial patients needed to be at least 18 years of age with previously treated or treatment-naive advanced or metastatic squamous or nonsquamous NSCLC without actionable genomic alterations and an ECOG performance status of 0 or 1. Cohorts 2 and 4 focused on patients who were treatment naive.1

In cohort 2, patients received 6 mg/kg of Dato-DXd plus 1120 mg of durvalumab every 3 weeks in the first-line setting in both the dose-escalation (n = 1) and dose-expansion phase (n = 14). In cohort 4, patients received the same combination in the first-line 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 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 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 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%), and 83.8% of patients had stage IVA or IVB disease at study entry compared with stage IIIA to IIIC disease (16.2%).

Additional findings revealed that when broken down by histology, in cohort 2, the confirmed ORRs were 50.0% (95% CI, 6.8%-93.2%) and 54.5% (95% CI, 23.4%-83.3%) in those with squamous (n = 4) and nonsquamous (n = 11) histology, respectively. The DCR was 75.0% (95% CI, 19.4%-99.4%) in those with squamous histology vs 90.9% (95% CI, 58.7%-99.8% in those with nonsquamous histology.

In cohort 4 the confirmed ORRs were 47.4% (95% CI, 24.4%-71.1%) and 66.7% (95% CI, 41.0%-86.7%) in those with squamous (n = 19) and nonsquamous (n = 18) histology, respectively. The DCR was 89.5% (95% CI, 66.9%-98.7%) in those with squamous histology vs 88.9% (95% CI, 65.3%-98.6%) in those with nonsquamous histology.

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

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

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

“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,” Cuppens stated.

In cohort 2 TEAEs leading to the discontinuation of any drug occurred in 26.7% of patients, vs 24.3% of those in cohort 4. Most were related to Dato-DXd in both arms (cohort 2, 26.7%; cohort 4, 21.6%) vs 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,” Cuppens concluded.

Data-DXd is 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: Cuppens did not list any disclosures.

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. Papadopoulos KP, Bruno DS, Kitazono S, et al. Datopotamab deruxtecan (Dato-DXd) + durvalumab ± carboplatin in advanced/metastatic NSCLC: initial results from the phase 1b TROPION-Lung04 study. Presented at: 2023 World Conference on Lung Cancer; September 10-12, 2023; Singapore. Abstract OA05.06.
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. https://www.astrazeneca.com/media-centre/press-releases/2025/datopotamab-deruxtecan-granted-priority-review-in-the-us-for-patients-with-previously-treated-advanced-egfr-mutated-non-small-cell-lung-cancer.html