US FDA Approves First Tumor-agnostic HER2-directed Therapy

The US FDA has approved AstraZeneca and Daiichi Sankyo’s Enhertu (trastuzumab deruxtecan) as the first tumor-agnostic HER2-directed therapy for the treatment of adult patients with unresectable or metastatic HER2-positive (IHC 3+) solid tumors who have received prior systemic treatment and have no satisfactory alternative treatment options.

The approval, granted under accelerated approval, underscores the efficacy of Enhertu based on objective response rate (ORR) and duration of response (DoR). It represents a beacon of hope for patients facing limited treatment alternatives. However, continued approval for this indication is subject to confirmation of clinical benefit in ongoing trials.

Enhertu stands out as a specifically crafted HER2-directed antibody drug conjugate (ADC), a testament to the collaborative efforts of Daiichi Sankyo and AstraZeneca in its discovery, development, and commercialization.

The first-ever FDA approved Tumor-agnostic HER2-directed therapy

Of particular note is the pioneering aspect of this approval, marking the first-ever approved tumor-agnostic HER2-directed therapy and ADC by the FDA. The decision was grounded in the compelling data derived from the subset of patients with HER2-positive IHC 3+ tumors across multiple Phase II trials, including DESTINY-PanTumor02, DESTINY-Lung01, and DESTINY-CRC02.

Funda Meric-Bernstam, MD, Chair of Investigational Cancer Therapeutics at The University of Texas MD Anderson Cancer Center, US, said:

“Until the approval of trastuzumab deruxtecan, patients with metastatic HER2-positive solid tumours have had limited treatment options. Based on the clinically meaningful response rates seen across clinical trials, this tumour-agnostic approval means that patients may now be treated with a HER2-directed medicine.”

Dave Fredrickson, Executive Vice President, Oncology Business Unit, AstraZeneca, said:

“As the first antibody drug conjugate to be granted a tumour-agnostic indication, Enhertu is truly delivering on its potential across metastatic HER2-targetable tumours. This approval also elevates the importance of testing for biomarkers, including HER2, across a broad range of tumours to ensure these patients with advanced cancer who have few options know whether a targeted medicine might be right for them.”

Ken Keller, Global Head of Oncology Business, and President and CEO, Daiichi Sankyo, Inc., said:

“This fifth indication in the US is a significant milestone as eligible patients with previously treated metastatic HER2-positive solid tumours may now be treated with Enhertu. The accelerated approval by the FDA for this tumour-agnostic indication is based on the clinically meaningful efficacy seen with Enhertu across numerous types of metastatic cancers.”

In the landmark DESTINY-PanTumor02 Phase II trial, which enrolled patients with centrally or locally assessed HER2-positive (IHC 3+) solid tumors spanning various types such as biliary tract, bladder, cervical, endometrial, ovarian, pancreatic, and other malignancies, Enhertu exhibited compelling efficacy. Patients treated with Enhertu demonstrated a confirmed objective response rate (ORR) of 51.4% (95% confidence interval [CI] 41.7-61.0) and a median duration of response (DoR) ranging from 19.4 months (with ongoing responses at data cutoff [+]). Similarly, in the DESTINY-Lung01 trial focusing on centrally confirmed HER2-positive (IHC 3+) non-small cell lung cancer (NSCLC), Enhertu showcased a confirmed ORR of 52.9% (95% CI 27.8-77.0) and a median DoR range of 6.9 months (range 4.0-11.7+). Notably, in the DESTINY-CRC02 trial involving patients with centrally confirmed HER2-positive (IHC 3+) colorectal cancer, Enhertu displayed a confirmed ORR of 46.9% (95% CI 34.3-59.8) and a median DoR range of 5.5 months (range 1.3+-9.7+).

Ensuring patient safety remains paramount. The safety profile of Enhertu was assessed in 347 patients with unresectable or metastatic HER2-positive (IHC 3+) solid tumors across multiple trials, including DESTINY-Breast01, DESTINY-PanTumor02, DESTINY-Lung01, and DESTINY-CRC02. Encouragingly, the observed safety profile was consistent with prior clinical trials of Enhertu, with no new safety concerns identified.

The remarkable efficacy and safety profile of Enhertu have led to its inclusion in the prestigious NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) as a treatment option for various metastatic tumors. This recognition underscores the significant clinical impact of Enhertu across diverse cancer types.

The approval process for Enhertu was expedited under the FDA’s Real-Time Oncology Review program, reflecting its potential to address critical unmet medical needs. Garnering Priority Review and Breakthrough Therapy Designation further underscored the urgency of bringing this innovative therapy to patients in need.

Moreover, Enhertu’s regulatory journey extends beyond the borders of the United States. Under Project Orbis, which facilitates concurrent submission and review of oncology medicines among participating international partners, Enhertu is currently under regulatory review for the same indication by authorities in Australia, Brazil, and Singapore. This global collaboration underscores the collective commitment to accelerating access to transformative cancer treatments worldwide.

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