Trastuzumab Deruxtecan Brings Encouraging Responses in HER2-Expressing Cancers Across Multiple Tumor Types

Editor's note: This article has been updated.

Trastuzumab deruxtecan, already used in to treat patients with breast, gastric, and lung cancers whose tumors express HER2, may potentially be used across a range of cancers, based on early data being presented today at annual meeting of the American Society of Clinical Oncology (ASCO) in Chicago, Illinois.

DESTINY-PanTumor02 (NCT04482309) highlights the versality of trastuzumab deruxtecan (Enhertu), and may be the most important study yet for the antibody drug conjugate. Early phase 2 findings show the drug’s potential to receive a tumor-agnostic indication, which would be a first in this class and could offer an option for patients with rarer cancers expressing HER2. Often, patients in small cancer populations have unmet need, as their numbers are insufficient to make up a tumor-specific study.

“For these patients there are no approved or targeted treatments, and often the disease is refractory to standard of care therapies,” said lead study author Funda Meric-Bernstam, MD, chair of the Department of Investigational Cancer Therapeutics at the University of Texas MD Anderson Cancer Center.

trastuzumab deruxtecan

After a median of 9.7 months of follow-up, trastuzumab deruxtecan brought strong responses in endometrial, cervical, ovarian, and urothelial cancers, especially for patients with HER2+ tumors with immunohistochemistry (IHC) scores of 3+.

In DESTINY-PanTumor02, only pancreatic tumors with HER2+ expression had poor responses, and Meric-Bernstam said that cohort has been closed.

“These results advance our clinical understanding of HER2 expression, reaffirm HER2 as an actionable biomarker across a broad range of tumor types, and show that trastuzumab deruxtecan could potentially provide a new treatment option for patients with advanced disease across these tumors, especially in patients with HER2 IHC 3+ or 2+ expression,” she said.

Methods and results. At the time of data cutoff, 267 patients had been treated with 5.4 mg/kg of trastuzumab deruxtecan every 3 weeks. Patients had a median of 2 prior lines of therapy; 75 were IHC 3+ and 125 were IHC 2+ by central testing.

The primary endpoint was investigator-assessed confirmed objective response rate (ORR). Secondary endpoints included duration of response (DOR), disease control rate, progression-free and overall survival, and safety. By tumor type, ORRs were as follows:

• Endometrial cancer: 57.5% overall; 84.6% for IHC 3+, and 47.1% for IHC 2+
• Cervical cancer: 50% overall; 75% for IHC 3+, 40% for IHC 2+
• Ovarian cancer: 45% overall; 63.6% for IHC 3+, 36.8% for IHC 2+
• Urothelial cancer: 39% overall; 56.3% for IHC 3+, 35% for IHC 2+
• Biliary tract cancer: 22% overall; 56.3% for IHC 3+, 0% for IHC 2+
• Pancreatic cancer: 4% overall; 0% for IHC 3+, 5.3% for IHC 2+

The median duration of response (DOR) was 11.8 months. Among patients with IHC 3+ expression, the ORR was 61.3% and median DOR was 22.1 months.

Adverse events (AEs) of grade 3 or higher were seen 58.4% of patients; 11.6% discontinued therapy due to AEs. Adjudicated drug-related interstitial lung disease/pneumonitis occurred in 18 patients (6.7%), with 1 death.

During the press briefing, ASCO commentator Bradley Alexander McGregor, MD, pointed to the potential for trastuzumab deruxtecan to address unmet need. “This is really, really compelling data,” he said. The ADC mechanism of delivering therapy “right to the source” yielded encouraging results aside from pancreatic cancer.

“So, while early, I think this is really exciting and represents a shift in how we think about cancer care,” he said.

Investigators said the study is ongoing and data on progression-free survival (PFS) and overall survival (OS) will be presented at a later date.

Is IHC the right test? Evidence-Based Oncology asked Andrew Hertler, MD, who advises payers and major employers in his role as chief medicalofficer for New Century Health, for his observations on the DESTINY-PanTumor02 findings. EBO had discussed the DESTINY-Breast04 results involving trastuzumab deruxtecan with Hertler earlier this year, after that trial identified a new classification of HER2-low breast cancer when it was presented at ASCO 2022.

“It is interesting that response rates were superior in patients with HER2 scores of 3+ by IHC over 2+ which seems somewhat discordant with the activity of [trastuzumab dertuxtecan] in HER2-low breast cancer,” Hertler said in an email.

He also noted that, “The rate of drug-related treatment-emergent adverse events (TEAEs) was high (84.3%) with 38.6% of patients experiencing grade 3 or higher TEAEs.”

The data presented, Hertler observed, only involved response rate and DOR. “Given that response rate correlates with overall survival improvement less than 50% of the time, I anxiously await these results to determine ultimate patient benefit,” he said. If trastuzumab deruxtecan “shows clinically meaningful OS and PFS benefits, it could be practice changing and an improvement over available options for these patients.”

However, Hertler asked, “We need to resolve whether IHC is the best test for a tumor-agnostic approach, given the fact that discordant results have been seen when the same specimen is tested in different laboratories. Would next-generation sequencing be a superior test?”

AstraZeneca and Daiichi-Sankyo funded the study.

Reference

Meric-Bernstam F, Makker V, Oaknin A. Efficacy and safety of trastuzumab deruxtecan (T-DXd) in patients (pts) with HER2-expressing solid tumors: DESTINY-PanTumor02 (DP-02) interim results. Presented at: American Society of Clinical Oncology, Chicago, IL: June 2-6, 2023; Abstract LBA3000: