Nivolumab Plus T-DXd Under Study in HER2-Expressing Metastatic Breast Cancer

Get Permission

In the phase Ib DS8201-A-U105 trial, the addition of the PD-1 inhibitor nivolumab to the antibody-drug conjugate fam-trastuzumab deruxtecan-nxki (T-DXd) did not appear to improve outcomes over T-DXd alone (based on historical controls). However, it did establish the safety of the combination, according to Erika Hamilton, MD, Director of Breast Cancer and Gynecologic Cancer Research for Sarah Cannon Research Institute at Tennessee Oncology, Nashville.1

Erika Hamilton, MD

Erika Hamilton, MD

“T-DXd in combination with nivolumab demonstrated antitumor activity consistent with previously reported data for T-DXd monotherapy in patients with HER2-positive breast cancer. In this late-line setting, however, the addition of nivolumab did not show any discernible benefit,” Dr. Hamilton reported.

Invited discussant of this study, Rebecca A. Dent, MD, Head of the Department of Medical Oncology, Senior Consultant, and Chief of the Breast Medical Oncology Service at the National Cancer Center Singapore, commented on these findings: “I wouldn’t say this is negative. I think we need to evaluate this combination in a better context, potentially earlier and in different groups of patients…. And we needed to know whether it [nivolumab] adds to toxicity, and the bottom line is it does not appear to.”

Study Details

In DESTINY-Breast01, T-DXd showed efficacy and safety in patients with HER2-positive metastatic breast cancer with prior treatment with ado-trastuzumab emtansine (T-DM1),2 and preclinical models showed that T-DXd combined with an antibody targeting PD-1 had greater efficacy than either agent alone. Based on these findings, the investigators conducted an open-label, multicenter, phase Ib study of T-DXd with nivolumab in women with HER2-positive or HER2-low, immunotherapy-naive metastatic breast cancer; patients had previously received T-DM1 or, for patients with HER2-low disease, standard-of-care therapy. The study is also evaluating the therapy for urothelial cancer (not presented here).

At the European Society for Medical Oncology (ESMO) Breast Cancer Congress 2022, Dr. Hamilton presented the primary results of the treatment in 48 patients; this group included 32 with HER2-positive tumors and 16 with HER2-low tumors (ie, immunohistochemistry [IHC] 1+ or IHC 2+ and in situ hybridization–negative). Almost 70% of patients had hormone receptor–positive disease, and approximately 70% had received at least four prior lines of therapy.

Patients received T-DXd at 5.4 mg/kg and nivolumab at 360 mg every 3 weeks. Median duration of follow-up was 18.7 months for the HER2-positive cohort and 12.7 months for the HER2-low subset. The primary endpoint was objective response rate by independent review.

Outcomes With Combination Therapy

In the primary analysis, the confirmed response rate was 65.6% in the HER2-positive cohort, with three patients (9.4%) achieving complete responses; the response rate in the HER2-low cohort was 50.0%, and all were partial responses. Median best percentage change in tumor size was –53.0% and –35.0%, respectively.

“Most patients receiving T-DXd in combination with nivolumab experienced a reduction in tumor size…. Of note, one of three patients in the HER2-low cohort who had hormone receptor–negative disease did have a confirmed partial response. Furthermore, those patients receiving T-DXd with nivolumab in either cohort experienced a reduction in the sum of tumor diameters from baseline that was sustained over time,” she reported.

Median progression-free survival was 11.6 months and 7.0 months, respectively. Median duration of response was not yet evaluable in HER2-positive patients and was 5.5 months in the HER2-low cohort. Median overall survival also was not evaluable for HER2-positive patients and was 19.5% in the HER2-low subset.

Safety Profile

“Overall, safety was generally consistent with prior studies of T-DXd monotherapy. The addition of nivolumab did not appear to increase toxicity,” Dr. Hamilton said. “All patients experienced at least one treatment-emergent adverse event. Drug-related grade ≥ 3 treatment-emergent adverse events were attributed at similar rates to T-DXd and nivolumab.”

For nivolumab and T-DXd, respectively, treatment-emergent adverse events led to treatment discontinuation in 35.4% and 27.1%. There were five grade 5 (fatal) treatment-emergent adverse events, of which one was deemed drug-related.


  • The phase Ib DS8201-A-U105 trial evaluated the addition of nivolumab to fam-trastuzumab deruxtecan-nxki (T-DXd) in previously treated metastatic HER2-positive or HER2-low breast cancer.
  • The addition of the checkpoint inhibitor did not improve outcomes over historical controls treated with T-DXd monotherapy.
  • In the HER2-positive cohort, the confirmed response rate was 65.6%; median progression-free survival was 11.6 months.
  • Nivolumab did not add to the toxicity of the single agent.

Adverse events of special interest included interstitial lung disease or pneumonitis and left ventricular dysfunction. The former was observed in seven patients (14.6%) and was fatal in one (2.1%); all others were grade 2. One additional patient in part one of the study (not reflected in the summary) experienced grade 3 adjudicated drug-related interstitial lung disease. In the HER2-positive cohort, two patients (6.9%) experienced left ventricular dysfunction. The other grade ≥ 3 treatment-emergent toxicities included vomiting, increased liver enzymes, and blurred vision, which were recorded in one patient each.

Exploratory Biomarker Analysis

An exploratory biomarker analysis assessed response rates according to PD-L1 status in immune cells and tumor cells. High vs low PD-L1 expression was established at 1% for tumor cells and at 1% and 5% for immune cells. For both cohorts, using tumor cells or immune cells and 1% or 5% thresholds, no differences were revealed in objective response rates.

“Patients with HER2-positive and HER2-low breast cancer responded to treatment with T-DXd plus nivolumab, regardless of PD-L1 IHC status. However, given the limited sample numbers in these analyses, these biomarker results should be interpreted with caution,” Dr. Hamilton noted. 

DISCLOSURE: Dr. Hamilton has received institutional research funding from AbbVie, Acerta Pharma, Accutar Biotechnology, ADC Therapeutics, AKESOBIO, Amgen, Aravive, ArQule, Artios, Arvinas, AstraZeneca, AtlasMedx, Black Diamond, Bliss BioPharmaceuticals, Boehringer Ingelheim, Cascadian Therapeutics, Clovis, Compugen, Cullen-Florentine, Curis, CytomX, Daiichi Sankyo, Dana Farber Cancer Institute, Dantari, Deciphera, Duality Biologics, eFFECTOR Therapeutics, Ellipses Pharma, Elucida Oncology, EMD Serono, Fochon, Fujifilm, G1 Therapeutics, H3 Biomedicine, Harpoon, Hutchinson MediPharma, Immunogen, Immunomedics, Incyte, Infinity Pharmaceuticals, InvestisBio, Jacobio, Karyopharm, Leap Therapeutics, Lilly, Lycera, Mabspace Biosciences, Macrogenics, MedImmune, Merck, Mersana, Merus, Millennium, Molecular Templates, Myraid Genetic Laboratories, Novartis, Nucana, Olema, OncoMed, Onconova Therapeutics, ORIC Pharmaceuticals, Orinove, Pfizer, PharmaMar, Pieris Pharmaceuticals, Pionyr Immunotherapeutics, Plexxikon, Radius Health, Regeneron, Relay Therapeutics, Repertoire Immune Medicine, Rgenix, Roche/Genentech, SeaGen, Sermonix Pharmaceuticals, Shattuck Labs, Silverback, StemCentRx, Sutro, Syndax, Syros, Taiho, TapImmune, Tesaro, Tolmar, Torque Therapeutics, Treadwell Therapeutics, Verastem, Vincerx Pharma, Zenith Epigenetics, and Zymeworks; and has had a consulting or advisory role with Arcus, Arvinas, AstraZeneca, Black Diamond, Boehringer Ingelheim, CytomX, Daiichi Sankyo, Dantari, Deciphera Pharmaceuticals, Eisai, Greenwich LifeSciences, H3 Biomedicine, iTeos, Janssen, Lilly, Loxo, Merck, -Mersana, Novartis, Orum Therapeutics, Pfizer, Propella Therapeutics, Puma Biotechnology, Relay Therapeutics, Roche/Genentech, SeaGen, and Silverback.


1. Hamilton EP, Shapiro CL, Boni V, et al: Primary analysis from DS8201-A-U105: A 2-part, open label, phase 1b trial assessing trastuzumab deruxtecan with nivolumab in patients with HER2-expressing advanced breast cancer. ESMO Breast Cancer Congress 2022. Abstract 162O. Presented May 3, 2022.

2. Modi S, Saura C, Yamashita T, et al: Trastuzumab deruxtecan in previously treated HER2-positive breast cancer. N Engl J Med 382:610-621, 2020.

Related Articles

Expert Point of View: Rebecca A. Dent, MD

The invited discussant of the DS8201-A-U105 trial, Rebecca A. Dent, MD, Head of the Department of Medical Oncology, Senior Consultant, and Chief of the Breast Medical Oncology Service at the National Cancer Center Singapore, said the results were reassuring in terms of safety and may pave the way...