Combination active in HER2-expressing urothelial carcinoma
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SAN FRANCISCO — The combination of fam-trastuzumab deruxtecan-nxki and nivolumab demonstrated antitumor activity among patients with HER2-expressing urothelial carcinoma, according to results presented at ASCO Genitourinary Cancers Symposium.
Researchers observed no new safety signals with either agent.
“I think trastuzumab deruxtecan can play a potentially important role in the treatment armamentarium for patients with HER2-expressing urothelial cancers in the future,” Matthew D. Galsky, MD, professor of medicine (hematology and medical oncology) and professor of urology at Icahn School of Medicine at Mount Sinai, told Healio. “Earlier-generation HER2 antibody-drug conjugates did not show marked activity in urothelial cancer, so this emerging data is important and — along with other trials — are really validating HER2 as an important target in urothelial cancer.”
HER2 overexpression has been identified in a large subset of urothelial cancers; however, there are no approved therapies for urothelial cancer that target this protein, Galsky said.
“Antibody-drug conjugates have played a key role in the recent transformation in the treatment landscape in urothelial cancer, as have immune checkpoint inhibitors. In fact, the combination of these drug classes seems to have particularly impressive activity, and this has been shown now in a few different trials with a few different regimens,” Galsky said. “This study combines those concepts, using an antibody-drug conjugate directed at HER2 alone with a PD-1 inhibitor.”
Trastuzumab deruxtecan (Enhertu; AstraZeneca, Daiichi Sankyo) is a novel antibody-drug conjugate with three components: a humanized anti-HER2 immunoglobulin G1 monoclonal antibody with the same amino acid sequence as trastuzumab; a topoisomerase 1 inhibitor payload; and a tetrapeptide-based cleavable linker.
Preclinical models suggested greater efficacy with the combination of trastuzumab deruxtecan and an anti-PD-1 antibody than either agent alone.
Galsky and colleagues conducted the phase 1B DS8201-A-U105 study to assess trastuzumab deruxtecan in combination with the anti-PD-1 antibody nivolumab (Opdivo, Bristol Myers Squibb) for adults with HER2-expressing advanced or metastatic urothelial cancer or breast cancer.
The study included dose escalation and dose expansion stages.
At ASCO GU, Galsky reported results from two groups of patients (n = 34; median age, 70.9 years; range, 41.4-80.5; 88.2% male) with urothelial cancer — Cohort 3 and Cohort 4 — from the dose expansion stage.
Cohort 3 included 30 patients with high HER2 expression (immunohistochemistry 2+/3+) after chemotherapy, and cohort 4 included four patients with low HER expression (immunohistochemistry 1+) after chemotherapy.
All patients experienced documented progression after prior platinum-based therapy, had ECOG performance status of 0 or 1, had received no prior trastuzumab deruxtecan or immunotherapy treatment, and had measurable metastatic disease.
More than half (61.8%) of evaluated patients had received at least one prior regimen for locally advanced or metastatic disease, and one-quarter (26.5%) had a history of liver metastases.
Patients received 5.4 mg/kg trastuzumab deruxtecan and 360 mg nivolumab via IV every 3 weeks.
Confirmed objective response rate assessed by independent central review served as the primary endpoint.
Secondary endpoints included duration of response, disease control rate, PFS, time to response, OS, pharmacokinetics/pharmacodynamics, safety and tolerability.
Median treatment duration was 3.9 months (range, 1-21) for trastuzumab deruxtecan and 4.1 months (range, 1-20) for nivolumab.
In cohort 3, researchers reported an ORR of 36.7% (95% CI, 19.9-56.1), with a 13.3% complete response rate and 23.3% partial response rate.
Median time to response was 1.9 months (range, 1.2-6.9) and median duration of response was 13.1 months (95% CI, 4.1-not estimable).
Researchers reported median PFS of 6.9 months (95% CI, 2.7-14.4) and median OS of 11 months (95% CI, 7.2-not estimable).
Five (62.8%) of eight patients with immunohistochemistry 3+ achieved confirmed objective response, including two (25%) with complete response. Six (27.3%) of 22 patients with immunohistochemistry 2+ achieved confirmed objective response, including two (9.1%) with complete response.
In cohort 4, two patients achieved partial response, one demonstrated stable disease and one had progressive disease.
“The regimen led to at least some tumor regression in the majority of patients,” Galsky told Healio. “Although the sample size is small, there does seem to be some association between the depth of response and the expression level of the HER2 protein. Most of the responses were relatively durable, with at least a few patients having responses maintained long after treatment was discontinued.”
In both cohorts, nearly three-quarters (73.5%) of patients experienced grade 3 or higher treatment-emergent adverse events (44.1% related to trastuzumab deruxtecan and 26.5% related to nivolumab).
The most common any-grade treatment-emergent adverse events included nausea (73.5%), fatigue (52.9%) and vomiting (44.1%).
About one-third (32.4%) of patients experienced treatment-emergent adverse events that led to drug discontinuation.
Slightly less than one-quarter (23.5%) of patients developed adjudicated drug-related interstitial lung disease or pneumonitis. Median time to adjudicated onset was 129 days.
The majority of cases were grade 1 (n = 2) or grade 2 (n = 4). Researchers reported one grade 3 case and one grade 5 case.
“Pneumonitis can occur with trastuzumab deruxtecan and with PD-1 blockade,” Galsky said. “However, the rates of pneumonitis with this combination seem relatively similar to what has been described with trastuzumab deruxtecan alone in other tumor types.”
An exploratory biomarker analysis showed patients with higher PD-L1 expression levels or higher blood tumor mutation burden achieved a numerically higher rate of response, Galsky said.
Other clinical trials are ongoing to further explore trastuzumab deruxtecan for this patient population.
“There is currently a basket study with trastuzumab deruxtecan as a single agent in several different tumor types, including urothelial cancer,” Galsky said. “This study will be very important in highlighting the activity of trastuzumab deruxtecan alone.”
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Galsky MD, et al. Abstract 438. Presented at: ASCO Genitourinary Cancers Symposium; Feb. 17-19, 2022; San Francisco.
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