T-DXd Plus Pembrolizumab Elicits Responses in IO-Naive HER2-Expressing or -Mutant NSCLC

Non–Small Cell Lung Cancer |
Image Credit: © Katsyarina –
stock.adobe.com

The combination of fam-trastuzumab deruxtecan-nxki (Enhertu; T-DXd) and pembrolizumab (Keytruda) demonstrated antitumor activity in patients with immune-oncology–naive, HER2-expressing or HER2-mutant non–small cell lung cancer (NSCLC), according to data from an interim analysis of the phase 1b DS8201-A-U106 study (NCT04042701) presented during the 2024 ESMO Immuno-Oncology Congress.

In all patients with HER2-expressing NSCLC (cohort 3; n = 22), the confirmed objective response rate (cORR) was 54.5% (95% CI, 32.2%-75.6%) by independent central review (ICR), which was comprised entirely of partial responses (PRs); 31.8% of patients achieved stable disease (SD) and 13.6% were not evaluable for response. In all patients with HER2-mutant NSCLC (cohort 4; n = 33), the cORR was 66.7% (95% CI, 48.2%-82.0%), which was comprised of a 6.1% complete response rate and a 60.6% PR rate; 24.2% of patients had SD and 9.1% were not evaluable.

Moreover, in those who were previously untreated and had HER2-expressing NSCLC (n = 8), the cORR by ICR was 62.5% (95% CI, 24.5%-91.5%), which was comprised entirely of PRs; 25.0% of patients had SD and 12.5% were not evaluable. In those who were previously untreated and had HER2-mutant NSCLC (n = 20), the cORR was 80.0% (95% CI, 56.3%-94.3%), which included a CR rate of 10.0% and a PR rate of 70.0%; 15.0% had SD and 5.0% were not evaluable.

“Combination therapy with T-DXd plus pembrolizumab showed preliminary antitumor activity in patients with IO-naive, HER2-expressing and HER2-mutant NSCLC,” Antoine Italiano, MD, PhD, of Institut Bergonié and University of Bordeaux, in Bordeaux, France, said in a presentation of the data. “Further research in a larger data set is necessary in this patient population.”

Preclinical data have indicated that T-DXd strengthened antitumor immunity, and when paired with a PD-1 antibody, proved to have more efficacy than either approach alone, Italiano said. “T-DXd has a potential additive effect with immune checkpoint inhibitors that target the PD-1/PD-L1 pathway to enhance tumor immunogenicity alongside tumor cell death,” he added.

The open-label, phase 1b study enrolled patients with pathologically documented HER2-expressing locally advanced or metastatic breast cancer, and HER2-expressing or HER2-mutated locally advanced or metastatic, IO-naive NSCLC. To be eligible for part 1, they needed to meet additional cohort-specific criteria of part 2. All patients had at least 1 measurable lesion by RECIST v1.1 criteria and an ECOG performance status of 0 or 1.

For part 1, or the dose-escalation phase, patients received 3.2 mg/kg of T-DXs plus 200 mg of pembrolizumab every 3 weeks (n = 3) or T-DXd at 5.4 mg/kg plus pembrolizumab at 200 mg every 3 weeks (n = 10). The latter dose was determined to be the recommended dose for expansion. For part 2, or the dose-expansion phase, there were 4 cohorts: those with HER2-positive breast cancer (cohort 1; n = 30), those with HER2-low breast cancer (cohort 2; n = 15), those with IO-naive HER2-expressing NSCLC (cohort 3; n = 30), and those with IO-naive HER2-mutant NSCLC (cohort 4; n = 30). A total of 22 patients were enrolled in cohort 3 and 33 patients were enrolled in cohort 4.

The primary end point for part 1 was to identify the maximum tolerated dose or the recommended dose expansion; for part 2, it was ORR by ICR. Secondary end points included duration of response (DOR), disease control rate (DCR), progression-free survival (PFS), time to response (TTR), and overall survival (OS). Investigators also evaluated serious and treatment-emergent adverse effects, as well as pharmacokinetics and pharmacodynamics.

The median patient age was 64.6 years and 63.6% of patients in cohort 3 and 30.4% of those in cohort 4 had prior systemic therapy.

Additional efficacy data showed that in all patients enrolled in cohort 3, the DCR was 86.4% (95% CI, 65.1%-97.1%). The median DOR of CR or PR was 20.2 months (95% CI, 4.2-not evaluable [NE]). The median PFS was 15.1 months (95% CI, 5.6-NE). In all patients enrolled in cohort 4, the DCR was 90.9% (95% CI, 75.5%-98.1%). The median DOR of CR or PR was 15.1 months (95% CI, 8.1-22.1). The median PFS was 11.3 months (95% CI, 5.8-21.3).

In previously untreated patients enrolled in cohort 3, the DCR was 87.5% (95% CI, 47.3%-99.7%). The median DOR of CR or PR was 20.2 months (95% CI, 6.9-NE), and the median PFS was 23.5 months (95% CI, 0.8-NE). In previously untreated patients enrolled in cohort 4, the DCR was 95.0% (95% CI, 75.1%-99.9%). The median DOR of CR or PR was 19.9 months (95% CI, 4.6-NE) and the median PFS was 21.3 months (95% CI, 5.8-NE).

“The preliminary safety profile was generally consistent with the known safety of the individual drugs and was generally manageable,” Italiano said.

The median duration of follow-up in all patients with NSCLC was 12.9 months (range, 0.3-35); in cohorts 3 and 4 the median follow-up was 5.9 months (range, 0.3-26) and 15.2 months (range, 0.5-35). The median treatment duration of T-DXd in all patients with NSCLC was 6.9 months (range, 1-33) and the median duration of pembrolizumab was also 6.9 months (range, 1-27). In cohort 3, the median duration of treatment with T-DXd was 5.2 months (range, 1-26), and with pembrolizumab was 5.2 months (range, 1-26). In cohort 4, the median duration of T-DXd was 9.7 months (range, 1-33) and of pembrolizumab was also 9.7 months (range, 1-27).

Grade 3 or higher drug-related treatment-emergent AEs (TEAEs) occurred in 38.2% of all patients with NSCLC; 22.7% of those in cohort 3 and 48.5% of those in cohort 4 experienced these effects. Serious drug-related TEAEs occurred in 25.5% of all patients with NSCLC; respective rates of these effects in cohorts 3 and 4 were 13.6% and 33.3%. Drug-related TEAEs were linked with death in 1 patient in cohort 4.

Of those in cohort 3, 9.1% experienced adjudicated drug-related interstitial lung disease (ILD) or pneumonitis; this was grade 2 in 1 patient and grade 3 in 1 patient. The median time to onset of first event was 212 days (range, 210-214). In cohort 4, 27.3% of patients had adjudicated drug-related ILD/pneumonitis; this was grade 2 in 8 patients and grade 5 for 1 patient. The median time to onset of first event was 70 days (range, 6-548).

“ILD remains an important risk associated with T-DXd treatment and patients should be monitored for signs and symptoms,” Italiano concluded.

Disclosures: Dr Italiano received grants or contracts from AstraZeneca, Bayer, Daiichi Sankyo, GSK, MSD, and Parthenon. Payment or honoraria for lectures, presentations, speakers’ bureaus, manuscript writing, or educational events were received from AstraZeneca, Bayer, Daiichi Sankyo, GSK, MSD, and Parthenon. He has participation on a drug safety monitoring board or advisory board for AstraZeneca, Bayer, Daiichi Sankyo, GSK, MSD, and Parthenon.

Reference

Italiano A, Besse B, Borghaei H, et al. Trastuzumab deruxtecan and pembrolizumab in immuno-oncology-naive HER2-expressing or HER2-mutant non–small cell lung cancer: interim analysis of a phase 1b study. Presented at: 2024 ESMO Immuno-Oncology Congress; December 11-13, 2024; Geneva, Switzerland. Abstract 118MO.