In an interim analysis of the first immunotherapy combination phase 1b trial with trastuzumab deruxtecan, safety results showed nivolumab with trastuzumab deruxtecan was well tolerated in patients with HER2-positive or HER2-low metastatic breast cancer. Physician’s Weekly interviews lead study author Erika Hamilton, MD, a medical oncologist and  the Director of the Breast Cancer and Gynecologic Cancer Research Program at the Sarah Cannon Research Institute at Tennessee Oncology in Nashville, TN, who presented these results during the virtual 2020 San Antonio Breast Cancer Symposium [1].

Dr Hamilton presented the preliminary results from 2 cohorts of a 4 cohort phase 1b trial evaluating the efficacy and safety of trastuzumab deruxtecan in combination with nivolumab, a programmed death-1 (PD-1) immune checkpoint inhibitor, in patients with previously treated HER2-positive (88%) a or HER2-low (75%) metastatic breast cancer. Trastuzumab deruxtecan is an antibody-drug conjugate (ADC) composed of an anti-HER2 (human epidermal growth factor receptor 2) antibody, a cleavable tetrapeptide-based linker, and a cytotoxic topoisomerase I inhibitor. The FDA granted accelerated approval to trastuzumab deruxtecan in December 2019 for the treatment of unresectable/metastatic HER2-positive breast cancer already treated with at least 2 prior anti–HER2 regimens, based on initial results from the DESTINY-Breast01 study (NCT03248492). Participants in the current multicenter phase 1b study (n=48) received a combination of trastuzumab deruxtecan (5.4 mg/kg) and nivolumab (360 mg), administered every 3 weeks. The majority of patients had received at least 4 prior therapies.

The primary endpoint for this analysis was overall safety and tolerability of trastuzumab deruxtecan and nivolumab combination therapy. No new safety signals were observed; adverse events were similar to those seen with trastuzumab deruxtecan monotherapy in patients with HER2-positive metastatic breast cancer and nivolumab monotherapy across many tumor types. However, the rate of treatment-emergent adverse events leading to treatment discontinuation (18.8%) was numerically higher with the combination than historical comparator cohorts treated with either monotherapy alone. Overall, 43.8% of patients experienced a grade 3 or higher treatment-emergent adverse event, with 18.8% identified as events related to trastuzumab deruxtecan and 18.8% related to nivolumab. The most common any-grade treatment-emergent adverse events were nausea (54.2%), fatigue (45.8%), and alopecia (41.7%). There were 5 cases (10.4%, all HER2-positive) of treatment-related interstitial lung disease (ILD) or pneumonitis, determined by an independent adjudication committee, including one death (grade 5). The remaining 4 cases were grade 2.

After a median follow-up of 7 months, preliminary efficacy results for the 48 evaluable patients found that patients in the HER2-positive cohort (n=32) and the HER2-low cohort (n=16) showed a confirmed objective response rate of 59% and 38%, respectively. Disease control rates of 91% and 75% were observed in the HER2-positive and HER2-low cohorts, respectively. Median duration of response has not yet been reached in either cohort, and follow-up is ongoing.

Median duration of treatment with trastuzumab deruxtecan was 6.5 months (range 1.4-14.0 months) in the HER2-positive cohort and 6.3 months (range 0.7-10.4 months) in the HER2-low cohort. The median duration of treatment with nivolumab was 5.2 months (range, 1.3-11.3 months) and 4.9 months (range 0.7-10.4 months) in the HER2-positive and HER2-low cohorts, respectively.

The investigators concluded that the combination was well tolerated in patients with HER2-positive or HER2-low metastatic breast cancer, providing the first data showing that trastuzumab deruxtecan may be safely combined with an immunotherapy agent, at therapeutic doses of both agents and for a meaningful treatment duration.

Physician’s Weekly asked Dr Hamilton for her perspectives:

What did you learn at SABCS2020 that was practice-changing?

“This year at SABCS, it was reassuring to experience that we continue to make progress in breast cancer. There were a lot of good presentations coming out of San Antonio, we saw update to the phase 3 monarchE trial (adjuvant abemaciclib, NCT03155997). We saw a striking benefit of adjuvant CDK 4/6 inhibitor for those patients with high-risk node-positive, ER-positive disease in the adjuvant setting and also some updates about immunotherapy, in the neoadjuvant setting in particular. So, I think those were encouraging and I think we continue to make progress and hopefully, we get COVID under control and make even more progress.”

“After seeing the data, I do feel that the adjuvant CDK4/6 inhibitor data from monarchE was strong, even stronger than the neoadjuvant immunotherapy data. I think the neoadjuvant immunotherapy is really for all-comers, and immunotherapy is not without real side effects, whether that is pneumonitis, colitis, permanent diabetes. I will be excited to see that reduction in recurrence rate translate into cure before I think I would feel comfortable in offering that across the board. Conversely, for the CDK4/6 inhibitors, that was a very select population that was ultra-high risk, less serious side effects with that and so I am pretty excited to adopt that and I hope that we do not see the curves come back together like we did in PENELOPE-B (NCT01864746).”

Take home messages from your presentation?

“As HER2-positive metastatic breast cancer continues to progress, and multiple lines of HER2-directed therapy have been exhausted, consideration needs to be given to evaluating a combination of medicines with different mechanisms of action. These preliminary data provide a promising signal that trastuzumab deruxtecan, a HER2-directed antibody drug conjugate, may be combined with nivolumab, an immune checkpoint inhibitor. Longer follow-up and more research is needed to determine whether adding immunotherapy to trastuzumab deruxtecan to treat HER2-positive or HER2-low metastatic breast cancer may provide further clinical benefit than receiving trastuzumab deruxtecan alone.”

“We tested a combination of trastuzumab deruxtecan with nivolumab, both given every 3 weeks. Patients were allowed with both HER2-positive breast cancer, as well as HER2-low breast cancer. it was a typical phase 1; patients were pretty heavily pretreated, had either 5 or 4 median priors for HER2-positive or HER2-low disease, respectively. The interim and immature overall response rates were pretty much in line with what we have seen previously;  59% for HER2-positive disease, which was 61% in DESTINY-Breast01 study (NCT03248492), or 38% ORR for the HER2-low disease compared with 37% in J101 (NCT02564900). ”

New or important safety signals?

“We saw the expected adverse events (AEs), of which neutropenia was the most common, in about 50% of patients, all grade. In addition 40% subjects had alopecia, and between 30- 50% had fatigue, but there were no grade 3 or grade 4 AE’s for those categories. Overall, the subjects tolerated the combination pretty well. The big question that everybody had was whether pneumonitis might be a problem, that the combination might exacerbate that AE. There were 8 events that led to trastuzumab deruxtecan being discontinued, only 4 of those were attributable to interstitial lung disease, three grade 2s and one grade 5 (death). Nevertheless, this was the first study combining trastuzumab deruxtecan with immunotherapy, and the safety was reasonably within the expectations of single-agent therapy. We are going to see more of this combination therapy with immune-oncology agents in the breast realm, in HER2-positive disease earlier on. Similar immunotherapy combinations with trastuzumab deruxtecan are also being tested for bladder cancer.”

“Happily, nothing new. The interstitial lung disease or pneumonitis seems pretty on par with the control arm. The other side effects were pretty similar. The one thing that looked like it could be a little bit higher than we see with single-agent therapy was hypothyroidism. There were more discontinuations of both trastuzumab deruxtecan and nivolumab than we typically see in the later-line trials, but the reason why that is happening is hard to tease out with only 48 patients on that trial.”

How do you place in the regimen in context with others?

“Importantly, we did not see an improved overall response rate and we certainly did not see longer progression-free survival. I would anticipate that immunotherapy in combination with deruxtecan to provide a higher response rate, or other clinical benefits. I mean really it is the tail of the curve, the long-term responders, that I would be curious about.”

“The purpose of the study was really to enable the safety data that we did not see increase pneumonitis ILD to move this into other lines, first-line trials, et cetera and in other places like bladder cancer, where they are looking to combine trastuzumab deruxtecan with immunotherapy.”

What are the next steps?

“The next steps are really DESTINY-Breast07 (NCT04538742) and 08 (NCT04556773), which are combinations of trastuzumab deruxtecan either with chemo or with targeted agents or with immuno-oncology, for both HER2-positive and HER2-low breast cancer. ”

“Another important study we saw at San Antonio regarding HER2-positive disease, was the breakdown of HER2CLIMB (NCT02614794) results by hormone receptor type. As previously reported by HER2CLIMB investigators, the addition of tucatinib to trastuzumab and capecitabine resulted in clinically meaningful improvements in overall survival, progression-free survival and objective response rate compared to the addition of placebo. The new exploratory analyses presented at SABCS demonstrated that the PFS, OS, and ORR improvements with tucatinib were observed consistently across hormone receptor status subgroups, including in patients with brain metastases, across the board. Some of the hormone receptor-positive subsets were not statistically significant but again, progression-free survival across the board being prolonged by the addition of tucatinib. These data suggest that adding tucatinib to trastuzumab is the other new guy on the stage for HER2-positive disease.”


  1. Hamilton EP et al. Presented at: 2020 San Antonio Breast Cancer Symposium; December 8-11; 2020; Virtual. Poster Spotlight PD3-07.