Enhertu, Datroway Approvals Start Off A Big Year For Daiichi

On the heels of the US Food and Drug Administration approval of AstraZeneca and Daiichi Sankyo’s Datroway (datopotamab deruxtecan) for breast cancer, the partners have notched another FDA win with the approval of the marketed antibody drug conjugate (ADC) Enhertu in a potentially large new indication. The companies announced on 27 of January that Enhertu (trastuzumab deruxtecan) was approved by FDA for the treatment of unresectable, metastatic HR+, HER2 low or HER2 ultralow breast cancer that has progressed on one or more endocrine therapies.

The back-to-back approvals are a positive development for Daiichi Sankyo, which is bracing for a busy year, with multiple trial readouts expected from registration studies across the company’s ADC portfolio. Ken Keller, CEO of Daiichi Sankyo Ltd., the US subsidiary of Japan-based Daiichi Sankyo Co. Ltd., talked to Scrip in an interview at the J.P. Morgan Healthcare Conference about the catalyst-rich year ahead.

“Last year was a good year, not a perfect year, but this year, we’ve got eight different top-line results that are going to read out in our registration trials, so we’re looking at a fast start to the year,” Keller said.

Daiichi’s imperfect 2024 involved some setbacks within the company’s ADC portfolio, both with AstraZeneca and with its other big collaborator, Merck & Co. The bigger one arguably was with the TROP2-targeting ADC Datroway, which the companies had filed initially with FDA for advanced or metastatic non-squamous non-small cell lung cancer (NSCLC) based on a modest progression-free survival (PFS) benefit in the TROPION-Lung01 study, but the companies withdrew the application later in the year after discussions with FDA.

Recovering In Lung Cancer

The companies refiled at the end of the year in a smaller subset of patients, those with EGFR-mutated NSCLC who have received prior systemic therapies, but the revision cuts the commercial prospects for Datroway. The application has been accepted with a priority review and has a 12 July FDA action date, the companies confirmed at J.P. Morgan.

“Obviously, the revenue will not be as big as quickly as we wanted it to be,” Keller said. “But I think most importantly…this is going to help a nice group of patients,” Keller said. EGFR mutations only occur in about 10%-15% of NSCLC in the US and Europe, though the numbers are higher in Asia, about 25%-30%, he said.

“What will really be telling is we’ve got the first-line NSCLC studies, three of them. The first one reads out later this year, and that will really dictate how successful the product is,” Keller said.

The first Phase III first-line NSCLC study to read out will be the closely watched AVANZAR trial, which is studying Datroway in combination with AstraZeneca’s PD-L1 inhibitor Imfinzi (durvalumab) and carboplatin versus Merck & Co.’s Keytruda (pembrolizumab) and platinum-based chemotherapy.

Datroway’s first indication in breast cancer is also not expected to be a big commercial winner. It was approved on 17 January for adults with unresectable or metastatic HR+, HER2-negative breast cancer who have received prior endocrine-based therapy and chemotherapy, though the market opportunity is likely to be eclipsed by Enhertu, especially given the newest approval of that drug.

Daiichi faced another setback last year with a different ADC, the HER3-targeting ADC patritumab deruxtecan in development with Merck. The companies received a complete response letter in June from FDA related to an application for approval in advanced or metastatic EGFR-mutated NSCLC previously treated with two or more systemic therapies. The problem was related to third-party manufacturing issue.

“We will solve it, but we haven’t updated the timing on when we will solve it,” Keller said.

Daiichi Sankyo’s oncology growth strategy is built almost entirely on ADCs, a hot area of oncology drug development, where the Japanese pharma has emerged as an early leader. The company signed multiple massive licensing deals with big pharma partners spanning five ADC programs, the first with AstraZeneca in 2019 for Enhertu and a second in 2020 for Datroway and then a third in 2023 with Merck & Co. for three ADCs including patritumab deruxtecan.

Enhertu: A Growth Engine Delivering

Enhertu remains the company’s commercial backbone for now and Daiichi has yet to prove it can build another ADC blockbuster. Enhertu is on track to generate $4bn in revenue in the current fiscal year, Keller said.

Enhertu was first granted accelerated approval in 2019 for HER2-postive breast cancer in the third-line setting and has moved up in the treatment paradigm to the second line since and added new indications including: HER2-low breast cancer, NSCLC in tumors with activating HER2 mutations and HER2-positive gastric or gastroesophageal junction adenocarcinoma. It was the first ADC to gain a tumor-agnostic indication for metastatic HER2-positive tumors in 2024.

The approval in HR+, HER2 low or HER2 ultralow breast cancer marks a new frontier for Enhertu as HR+ patients have generally not been treated with HER2 targeting drugs. The drug was previously approved in HR-, HER2-low breast cancer, but the addition of HR+ patients greatly expands the commercial opportunity, especially because Enhertu outperformed chemotherapy in Phase III.

The approval is based on the results of the Phase III DESTINY-Breast06 study, in which Enhertu demonstrated a 36% reduction in the risk of disease progression or death versus chemotherapy in the overall trial population, which enrolled patients with chemotherapy naïve HR+, HER2 low or HER2 ultra-low metastatic breast cancer. A median PFS of 13.2 months was seen in patients treated with Enhertu compared to 8.1 months in patients treated with chemotherapy.

The company is expecting even more expansion for Enhertu including into earlier-lines of treatment. Among the late-stage trials reading out later this year are several for Enhertu, including DESTINY-Breast09 in first-line metastatic HER2-positive breast cancer versus standard of care (taxane/traztuzumab/pertuzumab), DESTINY-Breast05 in the adjuvant setting and DESTINY-Breast11 in the neoadjuvant setting.

“In terms of population, the early- stage studies for breast cancer, the 09, 05, and 11, that would more than double the population that we could help,” Keller said.