Daiichi Sankyo and AstraZeneca’s ENHERTU® (fam-trastuzumab deruxtecan-nxki) has been approved in the U.S. for the treatment of adult patients with unresectable or metastatic HER2 positive (immunohistochemistry [IHC] 3+) solid tumors who have received prior systemic treatment and have no satisfactory alternative treatment options. This indication is approved under accelerated approval based on objective response rate (ORR) and duration of response (DOR). Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial.
ENHERTU is a specifically engineered HER2 directed antibody drug conjugate (ADC) discovered by Daiichi Sankyo and being jointly developed and commercialized by Daiichi Sankyo and AstraZeneca.
The first tumor agnostic approval of a HER2 directed therapy and ADC was based on efficacy data in 192 adult patients with previously treated unresectable or metastatic HER2 positive (IHC 3+) solid tumors who were enrolled in one of three multicenter phase 2 trials from the DESTINY clinical development program, including DESTINY-PanTumor02, DESTINY-Lung01 or DESTINY-CRC02. The major efficacy outcome measure in all three of the studies was confirmed ORR and an additional efficacy outcome measure was DOR. In DESTINY-PanTumor02, efficacy was assessed in a subgroup of previously treated patients (n=111) with centrally or locally assessed HER2 positive (IHC 3+) solid tumors including either biliary tract, bladder, cervical, endometrial, ovarian, pancreatic or other tumors. Confirmed ORR was 51.4% (95% confidence interval [CI]: 41.7-61.0) and median DOR range was 19.4 months (range: 1.3, 27.9+ [‘+’ denotes ongoing responses at data cutoff]).
In DESTINY-Lung01, efficacy was assessed in a subgroup of patients (n=17) with centrally confirmed HER2 positive (IHC 3+) non-small cell lung cancer (NSCLC). A confirmed ORR of 2 52.9% (95% CI: 27.8-77.0) and median DOR range of 6.9 months (range: 4.0, 11.7+) was seen. In DESTINY-CRC02, efficacy was assessed in the subgroup of patients (n=64) with centrally confirmed HER2 positive (IHC 3+) colorectal cancer. Confirmed ORR was 46.9% (95% CI: 34.3-59.8) and median DOR range was 5.5 months (range: 1.3+, 9.7+).
The approval was received following the U.S. Food and Drug Administration’s (FDA) review of the application using the Real-Time Oncology Review (RTOR) program and under Priority Review and Breakthrough Therapy Designation. The submission was reviewed under Project Orbis, which provides a framework for concurrent submission and review of oncology medicines among participating international partners. As part of Project Orbis, ENHERTU also is under regulatory review for the same indication by regulatory authorities in Australia, Brazil and Singapore.
“Until the approval of trastuzumab deruxtecan, patients with metastatic HER2 positive solid tumors have had limited treatment options,” said Funda Meric-Bernstam, MD, Chair of Investigational Cancer Therapeutics at The University of Texas MD Anderson Cancer Center. “Based on the clinically meaningful response rates seen across clinical trials, this tumor-agnostic approval means that patients may now be treated with a HER2 directed medicine.”
ENHERTU is approved with Boxed WARNINGS for interstitial lung disease (ILD)/pneumonitis and Embryo-Fetal toxicity. The safety of ENHERTU was evaluated in 347 adult patients with unresectable or metastatic HER2 positive (IHC 3+) solid tumors who received ENHERTU (5.4 mg/kg) in DESTINYBreast01, DESTINY-PanTumor02, DESTINY-Lung01 and DESTINY-CRC02. The most common adverse reactions (frequency ≥20%), including laboratory abnormalities, were decreased white blood cell count, nausea, decreased hemoglobin, decreased neutrophil count, fatigue, decreased lymphocyte count, decreased platelet count, increased aspartate aminotransferase, increased alanine aminotransferase, increased blood alkaline phosphatase, vomiting, decreased appetite, alopecia, diarrhea, decreased blood potassium, constipation, decreased sodium, stomatitis, and upper respiratory tract infection. Serious adverse reactions occurred in 34% of patients receiving ENHERTU. Serious adverse reactions in >1% of patients who received ENHERTU were sepsis, pneumonia, vomiting, urinary tract infection, abdominal pain, nausea, pneumonitis, pleural effusion, hemorrhage, COVID-19, fatigue, acute kidney injury, anemia, cellulitis, and dyspnea. Fatalities due to adverse reactions occurred in 6.3% of patients including ILD/pneumonitis (2.3%), cardiac arrest (0.6%), COVID-19 (0.6%), and sepsis (0.6%). The following events occurred in one patient each (0.3%): acute kidney injury, cerebrovascular accident, general physical health deterioration, pneumonia, and hemorrhagic shock.
“This fifth indication in the U.S. is a significant milestone as eligible patients with previously treated metastatic HER2 positive solid tumors may now be treated with ENHERTU,” said Ken Keller, Global Head of Oncology Business, and President and CEO, Daiichi Sankyo, Inc. “The accelerated approval by the FDA for this tumor agnostic indication is based on the clinically meaningful efficacy seen with ENHERTU across numerous types of metastatic cancers.”
“As the first antibody drug conjugate to be granted a tumor agnostic indication, ENHERTU is truly delivering on its potential across metastatic HER2 targetable tumors,” said Dave Fredrickson, Executive Vice President, Oncology Business Unit, AstraZeneca. “This approval also elevates the importance of testing for biomarkers, including HER2, across a broad range of tumors to ensure these patients with advanced cancer who have few options know whether a targeted medicine might be right for them.”
👉 https://www.daiichisankyo.com/files/news/pressrelease/pdf/202404/20240405_E.pdf
