HER2+ BC: A Year in Review and Updates from SABCS - Episode 10

Promising Data for Trastuzumab Deruxtecan Combination

Experts in breast oncology discuss the evolving role of trastuzumab deruxtecan for metastatic HER2-positive breast cancer.

Hatem Soliman, MD: There were updated results from the DESTINY-Breast01 study with trastuzumab deruxtecan; Shanu [Modi, MD,] presented some of those data.

Andrew Seidman, MD: With longer follow-up now, for those 184 patients getting 5.4 mg/kg every 3 weeks of trastuzumab deruxtecan, the response rate is around the same, at 61%. The prior median duration of response was 14.8 months; it’s now 20.8 months. The median PFS [progression-free survival], which was 16.4 months, is now 19.4 months. There’s an immature survival analysis, of which exceeds 2 years. These are patients who had 2 or more prior HER2-targeted regimens. They weren’t quite as heavily pretreated as that Japanese cohort, but these data do compare quite favorably to the real-world outcomes that were reported by that group.

Hatem Soliman, MD: There were some intriguing data that had been a subject of much interest over time. There’s an evolving story around the combination of cytotoxic agents and systemic agents that we use routinely to treat patients with breast cancer, and what potential interplay there may be with immunotherapy [IO] agents that are in development and are available.

Erika Hamilton, [MD,] was able to present some initial findings from a trial, the phase 1b multicenter OPALINE study, looking at trastuzumab deruxtecan in combination with nivolumab, an anti–PD-L1 monoclonal antibody inhibitor. The thought is that trastuzumab deruxtecan and drugs like it, can potentially induce immunogenic cell death in some patients where the tumor, in its essence is triggered to have an inflammatory response that will attract killer T cells into the vicinity of the tumor. By combining this treatment with nivolumab, you may be able to rescue those infiltrating T cells within the tumor microenvironment and allow them to work better against the killing tumor cells and potentially have an additive or synergistic effect.

This was a small study that looked at taking patients who had HER2-expressing advanced metastatic disease. They could have been HER2-positive, IHC3+ [immunohistochemistry score of 3+], or they could have been IHC2+ and FISH [fluorescence in situ hybridization]-positive. There were a couple of different levels of HER2 expression by IHC, and the usual criteria in terms of performance status and measurable disease, and they couldn’t have seen either drug previously. These were patients who were naïve to both drugs.

There was a 3+3 design for dose escalation that had a couple of dose levels of looking at the 3.2 mg/kg dose of trastuzumab deruxtecan and 5.4 mg in combination with a standard 3-week dose of nivolumab at 360 mg. That was followed by a dose expansion into 4 cohorts that had HER2-positive disease. There also was HER2-low IHC, which was 1+, or IHC2+ and FISH-negative, which is an appealing population to investigate regarding the activity of trastuzumab deruxtecan for some of these patients who may not be strictly HER2+ by standard criteria.

There are also a couple of other criteria, looking at HER2 high-expressing and also low-expressing urinary cancer as well. But these cohorts were looked at in the sample, about 32 patients who were HER2+ and about 16 patients who were HER2-low. When looking at the number of prior lines of therapy for this population that were included, they were quite heavily pretreated, about 88% in the HER2+ group and 75% in the HER2-low group had 4 or more lines of prior therapy. This is in keeping with the heavily pretreated population that we see with trastuzumab deruxtecan get treated and have significant activity. Looking at the efficacy numbers, the overall response rate for the HER2+ subset was 59%, and then in the HER2-low, we saw an interesting signal there, with a response rate of 38% as well.

We didn’t see many CRs [complete remissions], but the bulk of them were largely PRs [partial remissions], and there was a significant stabilization of disease, about 30% in either group. This showed that there was a good disease control rate of 91% in the HER2+ group and about 75% in the HER2-low. When you look at the waterfall plots, impressive activity as we’ve come to expect from T-DXd [trastuzumab deruxtecan]. If you look at some of the safety signals that we would see with the drug, overall the discontinuation rate was not too far off from what we would see, but there were about 46% who had a treatment-emergent adverse event [TEAE] that was grade 3 or higher. A few TEAEs were associated with death; 1 was study drug related in the HER2+ setting, too. It’s not that the treatment was completely without potential issues there. When you look at some of the other toxicities here, it didn’t appear that there were a lot of significant immune-related adverse events that were out of line with what we’d expect with nivolumab. There were a lot of the same [adverse] effects you’d expect with the drug, in terms of nausea and fatigue.

The ILD [interstitial lung disease] pneumonitis issue does need to be continually monitored in this setting because about 10% of the patients in the HER2+ group had ILD pneumonitis, and 1 of those was fatal. We do have to continue to follow those patients closely and optimize our monitoring for them. Overall this is showing interesting activity early on. It’s not enough to really be able to say that there’s a significant difference with the combination IO and T-DXd [trastuzumab deruxtecan] compared to trastuzumab deruxtecan alone. But it’s still a small study in its early days, so we need to stay tuned to these kinds of combinations going forward.

Transcript edited for clarity.