Merck-Daiichi ADC Deal Faces FDA Rejection

The FDA has declined the approval of patritumab deruxtecan, an investigational antibody-drug conjugate developed by Merck and Daiichi Sankyo, intended for the treatment of locally advanced or metastatic non-small cell lung cancer (NSCLC) with specific genetic mutations. This decision, communicated via a complete response letter (CRL), highlighted issues tied to a third-party manufacturing facility. Importantly, the rejection did not stem from concerns about the drug's efficacy or safety, as clarified by the companies.

Ken Takeshita, global head of R&D at Daiichi Sankyo, expressed the companies' commitment to promptly address the FDA's feedback in collaboration with the third-party manufacturer. The collaboration between Merck and Daiichi Sankyo was formalized in October 2023, with Merck investing over $4 billion upfront and committing up to $18 billion in subsequent payments. This partnership grants Merck the rights to co-develop and commercialize patritumab deruxtecan globally, with the exception of Japan, where Daiichi Sankyo retains exclusive rights.

The partnership also extends Merck's access to two other Daiichi antibody-drug conjugates (ADCs)—ifinatamab deruxtecan, aimed at extensive-stage small cell lung cancer, and raludotatug deruxtecan, currently being tested for advanced ovarian cancer.

Patritumab deruxtecan leverages Daiichi Sankyo’s proprietary DXd ADC platform. The drug targets the HER3 protein, associated with various malignancies, including breast and lung cancer. Once patritumab deruxtecan binds to HER3, it penetrates tumor cells and releases a toxic payload—an exatecan derivative topoisomerase I inhibitor—that induces cell death. The FDA had previously granted patritumab deruxtecan a Breakthrough Therapy designation for treating NSCLC with EGFR mutations.

The Biologics License Application for patritumab deruxtecan was supported by data from the HERTHENA-Lung01 study, a pivotal Phase II trial involving 225 patients whose disease had progressed after treatment with an EGFR tyrosine kinase inhibitor and platinum-based chemotherapy. The trial reported an objective response rate of 29.8%, with one patient achieving complete response and 66 patients showing partial responses. However, nearly 65% of participants experienced grade 3 or higher treatment-emergent adverse events, leading to a 7.1% dropout rate due to side effects. There was also a fatal case of interstitial lung disease documented in the study.

In December 2023, the FDA accepted patritumab deruxtecan’s application and granted it Priority Review status, underscoring the urgency and potential impact of the therapy. Despite the recent setback, Merck and Daiichi Sankyo remain focused on resolving the manufacturing issues in hopes of securing future approval.