Learn how Loxo leveraged Genomenon’s custom genomic services to ensure the actionability of all mutations included on their CDx submission to the PMDA
Retevmo® (selpercatinib) is a highly selective RET inhibitor used in the treatment of RET-mutation positive Medullary Thyroid Carcinoma (MTC) and RET-fusion positive Non-Small Cell Lung Cancer (NSCLC) or advanced thyroid cancer that was developed by Loxo Oncology, now a subsidiary of Eli Lilly. The Oncomine Dx Target Test (ODxTT), developed by Thermo Fisher Scientific, was chosen as the companion diagnostic (CDx) for Retevmo.
Loxo sought co-approval of Retevmo and the ODxTT by the Pharmaceuticals and Medical Devices Agency (PMDA) in Japan. Co-approval was achieved first for NSCLC. The submission for thyroid cancer was more complex and the PMDA requested that Loxo provide rationale for every mutation detected and reported by the ODxTT, including evidence that those mutations were activating and that patients with those mutations would respond to Retevmo.
Objective
Loxo sought to evaluate each of the 97 RET mutations reported by the ODxTT to respond to the request from the PMDA and progress the submission for Retevmo.
Challenges
- Minimizing time investment – Creating a comprehensive database of RET mutations would require a significant time investment and the PMDA was requesting a response within weeks, a significantly shorter time frame than Loxo had expected.
- Developing expertise – The request from the PMDA for evidence of activation was a first for Loxo; they did not have the requisite expertise in genetic data curation that would ensure a rapid, dependable result and a smooth review process by the PMDA.
The Solution
Loxo partnered with Genomenon to overcome these challenges and rapidly develop a comprehensive set of evidence for the 97 RET mutations detected by the ODxTT.
- Variant Landscape for RET - Genomenon used a unique combination of AI-driven indexing and expert curation to rapidly deliver a Variant Landscape for RET. This included all published variants interpreted according to clinical guidelines with reference-cited evidence from the literature and other databases.
- Regulatory Support - Genomenon remained available post-data delivery to support Loxo through the review process by the PMDA, including providing further clarification of the evidence where necessary.
Results
- Inactivating mutations removed – Following review of published evidence from the Variant Landscape combined with re-analysis of response data from the LIBRETTO-001 trial, Loxo removed 8 mutations with evidence of inactivation/lack of response to Retevmo.
- Submission deadlines met on time – Genomenon developed the Variant Landscape for RET within only a few weeks and responded within hours to questions that arose from the PMDA.
- CDx co-approved with therapy – The ODxTT and Retevmo were successfully co-approved by the PMDA in 2022
By leveraging Genomenon’s AI technology and expertise in genetic data curation, Loxo achieved an on-time co-approval of Retevmo and the ODxTT for the treatment of thyroid cancer in Japan.
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