Nivolumab Plus Trastuzumab Deruxtecan Provides No Perceptible Clinical Benefit Over ADC Alone in Advanced HER2+ Breast Cancer

The addition of nivolumab to trastuzumab deruxtecan did not result in a marked clinical benefit in patients with locally advanced unresectable or metastatic HER2-positive breast cancer.

Erika Hamilton, MD

Erika Hamilton, MD

The addition of nivolumab (Opdivo) to fam-trastuzumab deruxtecan-nxki (Enhertu) did not result in a marked clinical benefit in patients with locally advanced unresectable or metastatic HER2-positive breast cancer, according to data from the phase 1 DS8201-A-U105 trial (NCT03523572).1 The regimen generated antitumor activity that proved to be consistent with what has been observed with the antibody-drug conjugate (ADC) alone in this population.

Results, which were presented during the 2022 ESMO Breast Cancer Congress, showed that the combination elicited an overall response rate (ORR) of 65.6% (95% CI, 46.8%-81.4%) in cohort 1, which was comprised of 32 patients with HER2-positive breast cancer who previously received ado-trastuzumab emtansine (T-DM1; Kadcyla); this included a complete response (CR) rate of 9.4% and a partial response (PR) rate of 56.3%. Additionally, 28.1% of patients in this cohort achieved stable disease, and 6.3% experienced disease progression.

The ORR achieved with the regimen in cohort 2, which was comprised of 16 patients with HER2-low breast cancer, was 50.0% (95% CI, 24.7%-75.3%), with all responders experiencing a PR. Twenty-five percent of these patients had stable disease, 12.5% experienced disease progression, and 12.5% were not evaluable (NE).

"In this late setting, the addition of nivolumab did not show any discernible benefit over trastuzumab deruxtecan alone,” lead study author Erika Hamilton, MD, of the Sarah Cannon Research Institute, said in a presentation on the data. “Furthermore, the small number of patients in the HER2-low breast cancer cohort is insufficient to determine the effects of anti–PD-1 therapy.”

In May 2022, the FDA granted regular approval to trastuzumab deruxtecan for the treatment of adult patients with unresectable or metastatic HER2-positive breast cancer who have previously received an anti–HER2-based regimen either in the metastatic setting, or in the neoadjuvant or adjuvant setting, and have developed disease recurrence during or within 6 months of therapy completion.2 The regulatory decision was supported by findings from the phase 3 DESTINY-Breast03 trial (NCT03529110), which showed that the ADC elicited an ORR of 82.7% (95% CI, 77.4%-87.2%) in this population.3

DS8201-A-U105 enrolled patients with centrally confirmed, HER2-expressing, locally advanced unresectable or metastatic breast cancer or urothelial cancer. To be eligible for enrollment, patients were required to have an ECOG performance status of 0 or 1, at least 1 measurable lesion per RECIST v1.1 criteria, and could not have previously received trastuzumab deruxtecan or immunotherapy.

The trial was comprised of 2 parts. In the dose-escalation portion of the study, investigators examined the use of trastuzumab deruxtecan given at a dose of 3.2 mg/kg (n = 4) or 5.4 mg/kg (n = 3) in combination with 360 mg of nivolumab every 3 weeks. In part 2 of the study, referred to as the dose-expansion phase of the research, these agents were evaluated in 4 cohorts.

Those in cohort 1 needed to have HER2-positive breast cancer, defined as having an immunohistochemistry (IHC) score of 3+, or IHC 2+/in-situ hybridization (ISH) positivity, and have received prior treatment with T-DM1. In cohort 2, patients needed to have HER2-low breast cancer, defined as an IHC score of 1+ or IHC 2+/ISH negativity, and have received prior standard therapy. Cohort 3 included patients with HER2-high urothelial cancer who received prior chemotherapy (n = 30), and cohort 4 comprised those with HER2-low urothelial cancer who previously received chemotherapy (n = 4).

Results from cohorts 1 and 2 were presented during the 2022 ESMO Breast Cancer Congress.

Following the dose-escalation portion of the trial, patients in part 2 went on to receive 5.4 mg/kg of trastuzumab deruxtecan and 360 mg of nivolumab every 3 weeks.

The primary end point of part 2 of the study was ORR by independent central review (ICR). Secondary end points included duration of response (DOR), disease control rate, progression-free survival (PFS), and time to treatment response (TTR), all by ICR. Other secondary end points included investigator-assessed ORR and overall survival (OS), as well as pharmacokinetics, pharmacodynamics, safety, tolerability.

The median age of all participants in cohorts 1 and 2 was 53.6 years (range, 34.4-76.2), and all were female. Patients had an ECOG performance status of either 0 (43.8%) or 1 (56.3%), and 68.8% of patients had hormone receptor–positive disease. The majority of patients (70.8%) received 4 or more prior lines of treatment; 2.1% of patients received 1 prior line, 8.3% received 2 prior lines, and 12.5% received 3 prior lines. Moreover, the median number of prior lines of unique therapies received was 4.5 (range, 0-14). Notably, 20.8% of patients had a history of brain metastases.

At the time of the presentation, 16.7% of patients overall were still receiving trastuzumab deruxtecan, and 83.3% had discontinued treatment. The most common reason for discontinuation across the cohorts was disease progression (41.7%), followed by toxicity (22.9%), clinical progression (10.4%), patient withdrawal (4.2%), physician decision (2.1%), or another unspecified reason (2.1%).

Additionally, 12.5% of patients were still receiving nivolumab, and 87.5% had discontinued treatment with the immunotherapy. The most common primary reason cited for nivolumab discontinuation was progressive disease (39.6%), followed by toxicity (31.3%), clinical progression (8.3%), patient withdrawal (4.2%), and physician decision (4.2%).

The median duration of follow-up for cohorts 1 and 2 were 18.7 months (range, 1.7-26.9) and 12.7 months (range, 1.7-21.4), respectively. The median treatment duration for trastuzumab deruxtecan was 8.9 months (range, 1-23) and 6.9 months (range, 1-21) in cohort 1 and cohort 2, respectively. In these cohorts, the median treatment duration for nivolumab was 5.5 months (range, 1-23) and 5.9 months (range, 1-14), respectively.

Additional data from cohort 1 showed that the combination resulted in a median DOR that was NE (95% CI, 7.9-NE). In this cohort, the median PFS was 11.6 months (95% CI, 6.9-NE), the median TTR was 1.6 months (range, 1.2-5.5), and the median OS was NE (95% CI, 20.8-NE).

In cohort 2, the median DOR was 5.5 months (95% CI, 2.8-8.0), the median PFS was 7.0 months (95% CI, 2.3-10.8), the median TTR was 3.7 months (range, 2.6-9.8), and the median OS was 19.5 months (95% CI, 2.7-NE).

Among 31 evaluable patients in cohort 1, the median change in tumor size was -57% (range, negative-100% to 13%). Notably, all 3 patients who had a CR experienced a -100% reduction in tumor size. Among 15 patients in cohort 2, the median chance in tumor size was -35% (range, -68% to 54%).

An exploratory biomarker analysis revealed the combination generated antitumor activity regardless of PD-L1 status. “Due to the limited sample numbers in these analyses, these biomarker results should be interpreted with caution,” Hamilton noted.

All patients in both cohorts experienced at least 1 any-grade treatment-emergent adverse effect (TEAE). Specifically, 87.5% of patients experienced a TEAE of any grade related to trastuzumab deruxtecan, and 83.3% of patients experienced a TEAE of any grade related to nivolumab. Grade 3 or higher TEAEs were reported in 50% of patients; 22.9% of these were due to trastuzumab deruxtecan and 22.9% were because of nivolumab. Serious TEAEs were reported in 37.5% of patients, 2.1% of which were related to trastuzumab deruxtecan and 6.3% of which were related to nivolumab.

AEs of special interest included interstitial lung disease (ILD) and pneumonitis; 14.6% of patients experienced these effects at any grade. Specifically, 6 patients (12.5%) had grade 2 ILD/pneumonitis, and 1 patient (2.5%) experienced a grade 5 AE.

The median time to adjudicated onset was 168 days (range, 40-250). Notably, 1 patient who received 3.2 mg/kg of trastuzumab deruxtecan with nivolumab in part 1 of the trial experienced grade 3 ILD/pneumonitis. Additionally, in cohort 1, 2 patients experienced a left ventricular dysfunction event; this toxicity did not occur in any patients in cohort 2.

TEAEs led to any study treatment discontinuation in 37.5% of patients total; 25% of these discontinuations were associated with trastuzumab deruxtecan and 20.8% were related to nivolumab. Additionally, 8.3% of patients experienced a TEAE that required a dose reduction of trastuzumab deruxtecan. Notably, 47.9% of patients experienced TEAEs that required study drug interruptions; 25% were related to trastuzumab deruxtecan and 27.1% were related to nivolumab.

Notably, 5 patients experienced TEAEs associated with death, although only 1 death in cohort 1 was related to study treatment.


  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 (T-DXd) with nivolumab (nivo) in patients (pts) with HER2-expressing advanced breast cancer. Ann Oncol. 2022;33(suppl 3):S194-S223. doi:10.1016/annonc/annonc894
  2. FDA grants regular approval to fam-trastuzumab deruxtecan-nxki for breast cancer. News release. FDA. May 4, 2022. Accessed May 4, 2022.
  3. Cortés J, Kim S-B, Chung W-P, et al. Trastuzumab deruxtecan versus trastuzumab emtansine for breast cancer. N Engl J Med. 2022;386(12):1143-1154. doi:10.1056/NEJMoa2115022
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