Dr. Galsky discusses combo of nivolumab plus trastuzumab deruxtecan in urothelial carcinoma

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In a recent interview, Matthew Galsky, MD, discussed the phase 1b DS8201-A-U105 trial, in which the combination of the antibody-drug conjugate trastuzumab deruxtecan (T-DXd; Enhertu) and the immunotherapy nivolumab (Opdivo) demonstrated antitumor activity in patients with HER2-expressing urothelial carcinoma (UC).1

Galsky is a professor of medicine and director of genitourinary medical oncology at the Icahn School of Medicine, Mount Sinai, and the co-director of the Center of Excellence for Bladder Cancer and associate director for translational research at the Tisch Cancer Institute in New York City, New York.

Can you explain HER2 overexpression and its impact on patient prognosis?

Galsky: HER2 overexpression in urothelial cancer has been noted for quite a long time. HER2 is overexpressed in a subset of urothelial cancers at the protein level, and we know that it links to HER2 gene amplification in a subset of patients. HER2 mutations are also found in your local cancer. There are a range of HER2 alterations in urothelial cancer that have been attempted to be targeted with therapeutics over the years. Unfortunately, to date, there haven't been successes in translating HER2 overexpression, HER2 gene amplifications, HER2 genomic alterations at the level of the tumor with treatments, and that's changing recently.

What prior safety and efficacy results have been observed with nivolumab alone in this patient population?

Nivolumab is approved by the FDA for the treatment of metastatic urothelial cancers in patients who have progressed, despite prior platinum-based chemotherapy, and it is now approved in the adjuvant setting as well after surgery, cystectomy, or nephroureterectomy for patients at high risk for recurrence. In patients with metastatic urothelial cancer who have progressed despite prior platinum-based chemotherapy, nivolumab and other PD-1 and PD-L1 inhibitors in that space have been associated with objective response rates between about the 15-30% range depending on the study.

What's been observed in preclinical studies examining trastuzumab deruxtecan plus nivolumab for these patients?

We know that antibody-drug conjugates in model systems of cancer, and this includes several different antibody-drug conjugates in different model systems of cancer, we know that those seem to have some pro immunogenic effects that has potentially caused what's been referred to as immunogenic cell death. This is a specific form of cell death that leads to the release of dangerous signals that might result in activation of innate immune response and subsequently potentiate an adaptive immune response. There seems to be some evidence that that occurs in model systems with antibody-drug conjugates.

Of course, it occurs with a range of treatments and a range of chemotherapies, but there seems maybe to be something specific about antibody-drug conjugates that potentiates this effect. In combination with immune checkpoint blockade in model systems, there seems to be potentially at least additive effects and potentially synergistic effects combining that class of therapies with immune checkpoint inhibitors.

Can you discuss the design of the DS8201-A-U105 trial?

This was a phase 1B study and explored the combination of trastuzumab deruxtecan plus nivolumab in patients with metastatic breast cancer and in patients with metastatic urothelial cancer. Those were the 2 expansion cohorts in this study. The rationale for pursuing this in breast cancer is that anti HER2 therapies have a long track record of activity and breast cancer are standard treatments. This antibody-drug conjugate is explored extensively in breast cancer and has been approved in breast cancer so there was a rationale combining that class of drugs with immune checkpoint blockade in urothelial cancer is sort of the flip side.

We know that immune checkpoint blockade has activity in this patient population, and we know that HER2 is overexpressed, but there really haven't been anti-HER2 strategies that have shown activity in the clinic. Those were the 2 tumor types that were included in this phase 1B study for those reasons.

There was a small dose escalation in part 1 of this study, and then part 2 of this study explored the combination at the recommended phase 2 dose in those 2 different patient populations, but in four cohorts. Two of the cohorts enrolled patients with metastatic urothelial cancer, both of those cohorts enrolled patients who had progressed despite prior platinum based chemotherapy with metastatic urothelial cancer. But the difference between the 2 cohorts was that cohort 3 enrolled patients who had HER2 overexpression by immunohistochemistry at the 2+ or 3+ level, and the cohort for enrolled patients with HER2 overexpression at the 1+ level by immunohistochemistry.

What were the overall findings of the study?

The cohort of patients who had tumors with HER2 overexpression at the 2+ or 3+ level and enrolled 30 patients, cohort 3, interestingly showed that the cohort that enrolled patients with lower to expression that is 1+ overexpression enrolled only 4 patients, so that cohort was closed due to poor accrual. I say interestingly, because we think the HER2 1+ expression may be even more common than 2+/3+. Potentially, that reflected enthusiasm is on the part of investigators or your patients in terms of enrolling patients with lower levels of HER2 expression.

Now we know as the data have evolved with this antibody-drug conjugate in with some other antibody-drug conjugates that are similarly directed against HER2, we know that even with low HER2 expression, patients can benefit from treatment. Even though we only have a small cohort in this study, the same signal is being seen. Specifically, in cohort 4, which only enrolled for patients with HER2 1+ overexpression, 2 of the 4 patients had an objective response.

In cohort 3 that enrolled 30 patients with HER2 2+ or 3+ overexpression, the objective response rate was 36%. Even though I just said patients with HER2 1+ overexpression can benefit from treatment and can respond. When you look at the expression level of HER2, there does seem to be some association between the level of expression and the activity of the therapy in that in the small cohort of patients with HER2 3+ overexpression. Of the 8 patients enrolled in cohort 3, 5 of those 8 patients had an objective response, so small numbers, but there seems to be some relationship between the level of expression and likelihood of response even though patients with lower levels of expression can respond to treatment.

What treatment emergent adverse events were seen in patients and how are they managed?

The most common adverse events were fatigue, nausea, vomiting, diarrhea, and poor appetite. Side effects that we see in a lot of studies with cytotoxic therapy and that we also see in a lot of studies in patients with metastatic cancer that are potentially unique to this combination or to the individual components of the of the combination of trastuzumab deruxtecan can has been associated with interstitial lung disease or pneumonitis. Immune checkpoint inhibitors, PD-1 inhibitors, can also cause pneumonitis. That was an adverse event that particular attention to those events were centrally adjudicated. If there was concern about 1 of those side effects, it was reviewed centrally by a team, including review of the imaging.

There was interstitial lung disease or pneumonitis seen in this study. Among the 34 patients in combined cohorts 3 and 4, it occurred in 8 patients. Six of those 8 events were grade 1 or 2 in severity. There were very conservative guidelines in terms of management of those adverse events, including stopping treatment.

The other potential adverse event of interest with anti-HER2 strategies is a decrease in the cardiac ejection fraction. That was only seen in 1 patient of the 34 patients who were enrolled in cohorts 3 and 4. That event occurred after the patient had already been off treatment with trastuzumab deruxtecan, and they were continuing nivolumab as a single agent. That event occurred later and was somewhat atypical, but only occurred in that 1 patient.

Are there any ongoing clinical trials to further explore the role of T-DXd in this population right now?

In the study, this combination was pursued based on compelling scientific rationale. Prior to there being studies of single agent trastuzumab deruxtecan in this patient population so now there's actually a large basket study with trastuzumab deruxtecan that is enrolling patients with metastatic urothelial cancer, that study will establish the single Legion activity of this therapy.

What unmet needs would you hope that research focuses on in the near future?

We are seeing a couple of strategies directed against HER2 in urothelial cancer that are showing activity in the clinic. Therapies directed against HER2 have been explored for a couple of decades now in urothelial cancer without a lot of activity and without a lot of promise. I think we are now seeing that this target is credentialed in urothelial cancer, and it is a relevant therapeutic target. I think we will start to see a biomarker defined population of patients with urothelial cancer for whom treatment is directed against HER2.

Reference

1. Galsky MD, Del Conte G, Foti S, et al. Primary analysis from DS8201-A-U105: A phase 1b, two-part, open-label study of trastuzumab deruxtecan (T-DXd) with nivolumab (nivo) in patients (pts) with HER2-expressing urothelial carcinoma (UC). J Clin Oncol. 2022;40(6):438-438. doi: 10.1200/JCO.2022.40.6_suppl.438

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