SAN JUAN, Puerto Rico – Nearly 70% of patients with advanced/metastatic HER2-expressing endometrial cancer (EC) responded to an investigational antibody-drug conjugate (ADC), according to phase II data.
Response to trastuzumab pamirtecan (T-Pam) increased with HER2 expression, reaching a maximum of 73.1% in patients with HER2 3+ expression by immunohistochemistry (IHC). About one third of patients with HER2 1+ expression responded, as did 40–45% of patients with HER2 2+. Response rates assessed at local and central levels were highly consistent. Median progression-free survival (PFS) in patients with or without prior exposure to immune checkpoint inhibitors (ICIs) was 7–8 months.
Nearly half of the patients had grade ≥3 treatment-related adverse events (TREES), but the overall safety profile was considered manageable, with no unexpected AEs, although seven patients developed interstitial lung disease (ILD)/pneumonitis, Bhavana Pothuri, MD, of NYU Langone Health and Perlmutter Cancer Center in New York City, reported at the Society of Gynecologic Oncology (SGO) meeting.
“T-PAM has demonstrated promising activity in a large cohort of 145 patients with HER2-expressing, recurrent EC and FDA Breakthrough Designation,” Pothuri said. “The ORR (overall response rate) in patients with centrally confirmed HER2 IHC who had previously progressed on platinum and ICI treatment was 49.3% with a median response duration of 9.9 months.”
“With respect to safety, GI toxicities were mostly low-grade and manageable,” he said. “ILD/pneumonitis is a clinically significant adverse event for these patients, and proactive education and surveillance and management strategies are important to ensure patient safety.”
The results support continued clinical development, Pothuri said, and enrollment in a Phase 3 trial of the ADC in recurrent EC has begun.
The trial did not include patients with prior exposure to HER2-targeted ADCs — but allowed other HER2-targeted agents — which is noteworthy in the context of the current treatment landscape, said SGO invited discussant Bradley Core, MD, of the University of Colorado Cancer Center in Aurora.
“This study did not include patients with prior T-DXD (trastuzumab deruxtecan, Enhertu),” Core said. “T-DXD is already listed in (National Comprehensive Cancer Network) guidelines for recurrent endometrial cancer and demonstrates similar efficacy, although notably, there is no current approval for 1+ expression.”
The EC data came from a larger trial of ADCs in several types of solid tumors, and the local and central trials for HER2 expression were for gastric and/or breast cancer trials, Core continued. The greatest discrepancy between local and central testing was seen in low (IHC 1+) expression, while local and central testing results demonstrated good agreement for IHC 3+ expression.
“Expression levels are important details to help us communicate with our patients regarding expected outcomes,” he said.
“These are unprecedented results to behold,” Corr said. “Response rates are exceptional across the board, but are consistent with better responses with higher expression.”
The long-term prognosis of recurrent/metastatic EC is poor, Pothuri said, and treatment options are limited beyond first-line. HER2 overexpression or gene amplification is common in EC, and anti-HER2 therapy has demonstrated efficacy in patients with HER2-expressing EC.
T-Palm was evaluated Global Phase I/II Trial This included patients with HER2-expressing EC and a median of two prior systemic therapies (and a maximum of five). Patients receive ADCs every 3 weeks, continuing until disease progression or toxicity. The primary endpoint was ORR as determined by independent review and safety.
Data analysis included 145 patients with a distribution of HER2 expression according to local review, including IHC 1+ in 40.7%, IHC 2+ in 40.7%, and IHC 3+ in 17.9%. Central review showed the distribution of IHC 0 was 26.2%, IHC 1+ was 20.0%, IHC 2+ was 29.7%, and IHC 3+ was 17.2%.
The primary analysis showed an ORR of 44.1% in all patients by locoregional testing, including disease control rates (DCR) of 45.9% and 81.8% in patients with prior ICI treatment (n = 109) and 78.9% in all patients and those at ICI risk. The median duration of response was approximately 10 months and the median PFS was 8 months.
Analysis of response by central trial results showed an ORR of 48% in all patients and 49.3% in the ICI-exposed subgroup (n = 73), median duration of response 10-11 months, DCR 80-83%, and median PFS 7-8 months.
Response rates by IHC score with local and central testing were 33.9% and 34.5% for IHC 1+, 40.4% and 44.2% for IHC 2+, and 73.1% and 70.8% for IHC 3+, respectively.
Safety analysis showed that 29% of patients discontinued treatment due to TRAE, and three patients died due to TRAE. The most common treatment-emergent AEs (any grade) included nausea (62.8%), anemia (48.0%), platelet count decreased (38.6%), fatigue (38.6%), vomiting (33.8%), alanine aminotransferase increased (29.0%), and decreased appetite (27.6%).
