Clinical development in oncology has historically focused on the identification of cancer-dependent targets and over the last 20 years, multiple treatment modalities have been developed to target a broad range of molecular signatures in cancer. Elucidation of the genetic landscape of tissue-specific cancers facilitated the introduction of mutation-specific targeted therapies. This allowed the realistic aspiration for targeted therapies which were tailored to the specific genetic aberrations found in an individual’s tumour. This year at ASCO 2020 revealed a shift away from this paradigm, specifically for targeting rare cancers, moving from tissue-specific to tissue-agnostic drug development.

This shift is clearly demonstrated by the approval of Roche’s Rozlytrek (entrectinib), Bayer’s Vitrakvi (larotrectinib), Lilly’s Retevmo (selpercatinib) and the late-stage clinical development of Blueprint Medicine’s pralsetinib. These agents target NTRK gene fusions (Rolzytrek and Vitrakvi) or RET alterations (Retevmo and pralsetinib). The commercialisation of these agents differs from conventional tissue-specific drug development as these agents are approved in multiple tumour types. Specifically, Rozlytek and Vitrakvi are approved for all solid tumours harbouring an NTRK gene fusion and the pivotal trials included multiple tumour types; including breast, cholangiocarcinoma, colorectal, gynaecological, neuroendocrine, non-small cell lung cancer, amongst many others. Although the NTRK fusion is rare in individual cancer, 1500-5000 are detected in the US per year across multiple tumour types. As NTRK gene fusion testing increases globally, a greater commercial opportunity for pharmaceutical manufacturers arises as target patient population increases. GlobalData, therefore, expects this strategy of targeting niche genetic aberrations with a broad label across multiple solid cancers to be effective as the utility of next-generation sequencing and broad molecular profiles increases in diagnostic labs. RET fusions are oncogenic drivers in multiple tumour types, most commonly found in thyroid cancers and less commonly found in breast, lung, ovarian and pancreatic cancers. Standard therapies provide limited benefits for patients with RET fusion-positive tumours. Alike, agents targeting NTRK gene fusions, the development of highly specific RET inhibitors represents a shift away from developers concentrating on organ/histology specific indications to biomarker-guided tumour-agnostic approaches. Lilly’s Retevmo was FDA approved in May and an NDA has been recently submitted for Blueprint’s pralsetinib.

This paradigm shift in drug development gives rise to new considerations for pharmaceutical developers. In terms of patient population, estimation of patient population depends on the prevalence of a specific molecular aberration across multiple tumour types and the understanding of tissue-specific differences to targeted treatments. There may also be opportunities for re-purposing existing drugs through label expansions to other cancer types harbouring specific mutations, which might lead to a greater impetus to deeply understand the genetic landscape of various malignancies. This represents a positive development for patients and physicians, allowing another evolution in the development of personalised medicine and greater availability of therapeutic options for patients with rare forms of disease.