Encouraging Activity in Poor-Risk Endometrial Cancer With HER2-Targeted Novel Drug

SAN JUAN, PUERTO RICO — As many as 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 a third of patients with HER2 1+ expression responded, as did 40-45% of those with HER2 2+. Locally and centrally assessed response rates were highly concordant. Median progression-free survival (PFS) was 7-8 months in patients with and without prior exposure to immune checkpoint inhibitors (ICIs).

Almost half of the patients had grade ≥3 treatment-related adverse events (TRAEs), but the overall safety profile was considered management, with no unexpected AEs, though seven patients developed interstitial lung disease (ILD)/pneumonitis, reported Bhavana Pothuri, MD, of NYU Langone Health and Perlmutter Cancer Center in New York City, at the Society of Gynecologic Oncology (SGO) meeting.

“T-Pam demonstrated encouraging activity in a large cohort of 145 patients with HER2-expressing, recurrent EC and has received FDA breakthrough designation,” said Pothuri. “Confirmed ORR [overall response rate] in patients with centrally confirmed HER2 IHC who had progressed on prior platinum and ICI treatment was 49.3% with a duration of response of 9.9 months.”

“With regard to safety, GI toxicities were mostly low grade and manageable,” she added. “ILD/pneumonitis is a clinically important adverse event for these patients, and proactive education and monitoring and management strategies are critical to ensure patient safety.”

The results supported continued clinical development, and a phase III trial of the ADC in recurrent EC has begun enrollment, said Pothuri.

The trial excluded patients with prior exposure to a HER2-targeted ADC — but did allow other HER2-targeted agents — which is noteworthy within the context of the current treatment landscape, said SGO invited discussant Bradley Corr, MD, of the University of Colorado Cancer Center in Aurora.

“This study did not include patients with prior T-DXd [trastuzumab deruxtecan, Enhertu],” said Corr. “T-DXd is already listed in the [National Comprehensive Cancer Network] guidelines for recurrent endometrial cancer and demonstrates similar efficacies, though notably, does not have current approval for 1+ expression.”

The EC data came from a larger trial of the ADC in several types of solid tumors, and that local and central testing for HER2 expression were for gastric and/or breast cancer testing, Corr continued. The largest discrepancy between local and central testing was seen in low (IHC 1+) expression, whereas local and central testing results exhibited good concordance for IHC 3+ expression.

“Expression levels are important details to understand to help us communicate with our patients in regard to expected outcomes,” he said.

“These are phenomenal outcomes to see,” Corr added. “The response rates are exceptional across the board, but congruent with better responses with higher expression.”

Recurrent/metastatic EC has a poor long-term prognosis, and treatment options are limited beyond first line, said Pothuri. HER2 overexpression or gene amplification is common in EC, and anti-HER2 therapy has demonstrated efficacy in patients with HER2-expressing EC.

T-Pam was evaluated in a global phase I/II trial involving patients with HER2-expressing EC and a median of two prior systemic therapies (and as many as five). Patients received the ADC every 3 weeks, continued until disease progression or toxicity. The primary endpoints were ORR as determined by independent review and safety.

Data analysis included 145 patients with a distribution of HER2 expression by local review consisting of IHC 1+ in 40.7%, IHC 2+ in 40.7%, and IHC 3+ in 17.9%. Central review showed a distribution of IHC 0 in 26.2%, IHC 1+ in 20.0%, IHC 2+ in 29.7%, and IHC 3+ in 17.2%.

The primary analysis showed an ORR of 44.1% in all patients by local testing, including 45.9% in patients with prior ICI treatment (n=109) and disease control rate (DCR) of 81.8% and 78.9% in all patients and those with ICI exposure. Median duration of response was about 10 months and median PFS of 8 months.

Analysis of response by central testing results showed an ORR of 48% in all patients and 49.3% in the ICI-exposed subgroup (n=73), median duration of response of 10-11 months, DCR of 80-83%, and median PFS of 7-8 months.

Response rates by IHC score were 33.9% and 34.5% for IHC 1+ with local and central testing, respectively, 40.4% and 44.2% for IHC 2+, and 73.1% and 70.8% for IHC 3+.

The safety analysis showed that 29% of patients discontinued treatment because of TRAEs, and three patients died of TRAEs. The most common treatment-emergent AEs (any grade) were nausea (62.8%), anemia (48.0%), decreased platelet count (38.6%), fatigue (38.6%), vomiting (33.8%), increased alanine aminotransferase (29.0%), and decreased appetite (27.6%).