Fam-trastuzumab deruxtecan-nxki (T-DXd) may prove to be beneficial in a variety of treatment-refractory solid tumors that express HER2, according to findings from the international phase II DESTINY-PanTumor02 trial presented at the 2023 ASCO Annual Meeting.¹ For patients with the highest HER2 expression, the objective response rate to this antibody-drug conjugate was 61.3%, and the median duration of response was 22.1 months.

“The activity we’ve seen is quite compelling…. DESTINY-PanTumor02 shows T-DXd to be a potential new treatment option for patients with HER2-expressing solid tumors,” said Funda Meric-Bernstam, MD, Chair of the Department of Investigational Cancer Therapeutics at The University of Texas MD Anderson Cancer Center, Houston. She said that “meaningful activity” was shown even in cancers that are “difficult to treat.”

“The activity we’ve seen is quite compelling…. DESTINY-PanTumor02 shows T-DXd to be a potential new treatment option for patients with HER2-expressing solid tumors.”

— Funda Meric-Bernstam, MD

Tweet this quote

T-DXd is a HER2-targeting antibody-drug conjugate that is currently approved for tumors that are metastatic or unresectable that are HER2-expressing in breast, HER2-positive gastric or gastroesophageal junction, and HER2-mutant non–small cell lung cancers. DESTINY-PanTumor02 asked whether its efficacy would also extend to other HER2-expressing tumor types. It is the first global study of tumor-agnostic applications for T-DXd across a broad range of HER2-expressing solid tumors.

About DESTINY-PanTumor02

The study enrolled 267 patients with HER2-expressing biliary tract, bladder, cervical, endometrial, ovarian, pancreatic, and a few other tumor types. It excluded breast, gastric, colorectal, and non–small cell lung cancers. Patients had shown disease progression following prior therapy or were not eligible for curative therapy. Patients had locally advanced or metastatic disease that had worsened after at least one systemic treatment or that had no treatment options. By HER2 expression level based on local or central assessment at enrollment, 40% had immunohistochemistry (IHC) 3+; 57% had IHC 2+ expression; 3% had IHC 1+ or unknown status. By central testing, 28.1% had IHC 3+ and 26.8% were IHC 2+ and 20.6% were 1+ or nonexpressing.

Key Findings

For the overall population of patients receiving at least one dose of T-DXd and followed for a median of 9.7 months, T-DXd resulted in an objective response rate of 37.1%, and a median duration of response of 11.8 months. In patients with higher levels of HER2 expression (IHC 3+), the antibody-drug conjugate was even more effective, resulting in an objective response rate of 61.3% and a median duration of response of 22.1 months. A total of 15 patients (5.6%) achieved a complete response. Seven patients who had a complete response had endometrial cancer.

Response by Disease Site

Across different disease sites, treatment with T-DXd resulted in the following objective response rates:

• Endometrial cancer: 57.5% for all patients (84.6% for IHC 3+ and 47.1% for IHC 2+)
• Cervical cancer: 50.0% for all patients (75.0% for IHC 3+ and 40.0% for IHC 2+)
• Ovarian cancer: 45.0% for all patients (63.6% for IHC 3+ and 36.8% for IHC 2+)
• Urothelial cancer: 39.0% for all patients (56.3% for IHC 3+ and 35.0% for IHC 2+)
• Biliary tract cancer: 22.0% for all patients (56.3% for IHC 3+ and 0% for IHC 2+)
• Pancreatic cancer: 4.0% for all patients (0% for IHC 3+ and 5.3% for IHC 2+).

Among patients who had a response, the Kaplan-Meier estimate of continued response at 12 months was 72.3% in endometrial cancer, 47.6% in cervical cancer, 45.8% in ovarian cancer, 23.2% in urothelial cancer, 41.7% in biliary tract cancer, and 0% in pancreatic cancer. Because no responses were observed in the first 15 patients, said Dr. Meric-Bernstam, the pancreatic cohort was closed early after 25 patients had been enrolled. At the time of the current analysis there was one response among the patients by investigator assessment and three responses (12%) by independent central review in the pancreatic cohort.

“The safety of T-DXd was consistent with the known safety profile of the drug,” she reported. Grade ≥ 3 adverse events occurred in 38.6% of patients, most commonly neutropenia, in 19.1%. Interstitial lung disease of any grade occurred in 7.5% of patients; it was grade 3 in one patient, and one patient died of this toxicity. Left-ventricular dysfunction and cardiac failure were rare (3%).

Dr. Meric-Bernstam said the findings advance the clinical understanding of HER2 expression and reaffirm HER2 as an actionable biomarker across a broad range of tumor types. The results position T-DXd as a potential treatment option for tumors beyond the approved indications, especially in patients with HER2 IHC 3+ or 2+ expression.

Detection of HER2 Expression by Cell-Free DNA

Also, at the 2023 ASCO Annual Meeting, Japanese investigators reported results from the phase II HERALD/EPOC1806 trial. This study included 62 patients with 17 different types of solid tumors who underwent testing for HER2 amplification by plasma cell-free DNA (DNA).² Those with HER2-expressing tumors were treated with T-DXd.

“T-DXd achieved a high objective response rate and durable response with a manageable safety profile in patients with advanced solid tumors and HER2 amplification detected in cell-free DNA,” said Hiroya Taniguchi, MD, PhD, head physician in the Department of Clinical Oncology at the Aichi Cancer Center Hospital in Nagoya, Japan.

Hiroya Taniguchi, MD, PhD

At a median follow-up of 8.9 months, the objective response rate by investigator assessment was 56.5% (58.1% by independent central review), all partial; stable disease was achieved by 33.9%, and the disease control rate was 90.3%. The median duration of response was 8.8 months, and the median progression-free survival was 7.0 months, Dr. Taniguchi reported in a poster.

In addition, responses were observed in 13 types of cancer, with the highest rates in salivary gland cancer (100%) and endometrial cancer (83.3%). As was seen in DESTINY-PanTumor02, response with T-DXd was limited in patients with pancreatic cancer. Clearance of HER2 in cell-free DNA was an early predictor of response: response rates were 88.0% for those with HER2 clearance and 22.7% for those without HER2 clearance. 

DISCLOSURE: Dr. Meric-Bernstam reported financial relationships with AbbVie, Apeiron Biologics, AstraZeneca, Biovica, Black Diamond Therapeutics, Debiopharm Group, EcoR1 Capital, eFFECTOR Therapeutics, Eisai, Infinity Pharmaceuticals, Karyopharm Therapeutics, Lengo Therapeutics, Loxo, Menarini Group, OnCusp Therapeutics, PACT Pharmaceuticals, Roche, Seagen, Silverback Therapeutics, Tallac Therapeutics, Theratechnologies, Tyra Biosciences, Xencor, Zetalis, and Zymeworks. Dr. Taniguchi reported financial relationships with Bayer, Bristol Myers Squibb Japan, Daiichi Sankyo, Chugai Pharma, Lilly Japan, Medical & Biological Laboratories Co, LTD, Merck Serono, Mitsubishi Tanabe Pharma, MSD KK, Nippon Kayaku, Novartis, Ono Yakuhin, Sanofi, Taiho Pharmaceutical, Takeda, and Yakult Honsha.

REFERENCES

1. Meric-Bernstam F, Makker V, Oaknin A, et al: Efficacy and safety of trastuzumab deruxtecan (T-DXd) in patients with HER2-expressing solid tumors: DESTINY-PanTumor02 interim results. 2023 ASCO Annual Meeting. Abstract LBA3000. Presented June 5, 2023.

2. Taniguchi H, Yagisawa M, Satoh T, et al: Tissue-agnostic efficacy of trastuzumab-deruxtecan (T-DXd) in advanced solid tumors with HER2 amplification identified by plasma cell-free DNA testing: Results from a phase 2 basket trial (HERALD/EPOC1806). 2023 ASCO Annual Meeting. Abstract 3014. Presented June 3, 2023.