Daiichi Sankyo’s development of antibody-drug conjugates continues to hit turbulence. Despite the success of Enhertu, the company has experienced two latest hiccups: the discontinuation of internal development of a next-wave candidate featuring its second ADC platform, and yet another delay for a highly anticipated phase 3 readout for AstraZeneca-partnered Datroway.
Daiichi has ended internal development of DS-9606, a CLDN6-directed ADC “following a strategic portfolio review,” Daiichi’s R&D head Yuki Abe said during the company’s quarterly investor call Jan. 30.
Abe suggested that “there is room for development” of DS-9606 with potential partners, given it has generated good results in germ cell tumor.
DS-9606 is the first candidate using Daiichi’s modified pyrrolobenzodiazepine (mPBD) payload. Daiichi management argued that the decision was not about the mPBD platform but instead stems from “a business and portfolio perspective.”
The data Daiichi gathered so far “confirmed the utility of this mPBD technology,” Abe said. Therefore, Daiichi plans to explore different targets and antibodies based on mPBD, he added.
CLDN6 is expressed in several tumor types including endometrial, ovarian and gastric cancers, germ cell tumors and non-small cell lung cancer (NSCLC), according to Daiichi. Roche recently axed an anti-CLDN6 trispecific antibody developed by its Japanese subsidiary Chugai.
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Daiichi made a name in the ADC world with its DXd platform, which is used in both Enhertu and Datroway. But following the success of Enhertu, development of other DXd ADCs has been far from smooth sailing. Disappointing overall survival (OS) results forced AZ and Daiichi to withdraw their initial FDA application for Datroway in 2024 in a broad second-line nonsquamous NSCLC population.
Friday, Daiichi further pushed back a closely watched readout from the phase 3 Avanzar trial for a combination of Datroway and AZ’s Imfinzi in first-line NSCLC. The partners now expect to report top-line data in the second half of 2026 rather than the first half, a delay from the original projection of 2025. The postponed timeline is the result of slower than expected event occurrence, according to Daiichi.
The Avanzar study became complicated after AZ, based on second-line data, devised a new TROP2-based biomarker to select patients for Datroway. Progression-free survival (PFS) and OS for both the biomarker-defined population and all nonsquamous patients are the study’s primary endpoints.
The trial is important because it’s the first for a TROP2 ADC in the first-line NSCLC setting, and it’ll help validate AZ’s biomarker strategy.
In its quarterly update, Daiichi said it has added PFS and OS in TROP2-positive population as primary endpoints for the Tropion-Lung07 trial. The trial is combining Datroway with Merck & Co.’s Keytruda—rather than Imfinzi—in first-line nonsquamous NSCLC with PD-L1 expression below 50%. And the company plans to adopt “a similar strategy” for Tropion-Lung08, which is testing the Datroway-Keytruda combo in PD-L1-high patients and has a readout slated for the second half of 2026.
Because the biomarker was developed to increase the probability of success for Datroway regimens, one analyst on the call questioned whether using it would be necessary for a Keytruda combination.
“This was actually a topic of considerable internal discussion,” Abe said. “At one point, I personally thought that perhaps it was not necessary to add the biomarker.”
However, Daiichi learned from experience that patients are “highly heterogeneous” in lung cancer, and it believes “the presence of this biomarker can offer significant benefits to patients,” Abe said.
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In another update, Daiichi said patient recruitment has been stopped for Tropion-Lung12 “due to complexity of study operation.” The study was an adjuvant therapy trial for stage 1 NSCLC with ctDNA-positive or high-risk features evaluating Datroway in combination with AZ’s PD-1/TIGIT bispecific rilvegostomig.
In another setback, Daiichi and partner Merck were recently hit with a clinical hold for their B7-H3-directed ADC ifinatamab deruxtecan (I-DXd) after logging an unexpected number of deaths of interstitial lung disease (ILD). The FDA has since lifted the hold, and the two companies have implemented a stricter risk management protocol, including exclusion of patients with high ILD risks and additional training of investigators and clinical trial staff.
