While the use of basket trials to test therapies in tissue agnostic, biomarker-based cancer indications is increasing, the long-term implications rely on a handful of factors, many of which may affect postmarket uptake of agents approved via this route, according to a white paper from Trinity Partners (Waltham, Mass.) published Tuesday.
For example, tissue-agnostic therapies would often require next-generation sequencing to identify patients with the mutations studied in basket trials. Universal testing for rare biomarkers may receive pushback from payers due to costs and the biomarkers may not be included in commonly used NGS panel.
Trinity said another major hurdle tissue-agnostic therapies may face is an unwillingness by doctors and payers to support the drugs outside of their most efficacious tumor types when presented with efficacy by tumor type on the product label, which FDA requires. Clinicians and payers may choose to prescribe or include in formularies only the tumor types in which the therapy is most efficacious, while avoiding tumor types for which only a small sample size was included in the registrational data package.
The authors identified 37 ongoing basket trials collectively evaluating 31 therapies across over 16 types of biomarkers.
Of those trials, only two are registrational, defined by Trinity as an industry-led, named trial and/or one publicly referred to as registrational. The group found no Phase III basket trials. The authors characterized nine of the trials as potentially registrational, meaning they did not fit the criteria for registrational, but could potentially support a regulatory filing if data read out is positive.
Keytruda pembrolizumab, which received FDA's first tissue-agnostic approval, did not encounter the brunt of these challenges because its efficacy was already widely established in a range of FDA-approved tumor types. The PD-1 mAb from Merck & Co. Inc. (NYSE:MRK) was approved last year to treat advanced microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) solid tumors.
Despite its evaluation in many cancers, even Keytruda's use for all MSI-H tumor types has been questioned, according to Trinity. The National Comprehensive Cancer Network (NCCN) (Fort Washington, Pa.) recommended its use only "for tumors with large sample sizes in its registrational trial, and tumors associated with Lynch Syndrome, which has long been linked to the MSI-H biomarker," Trinity said.
In March, Loxo Oncology Inc. (NASDAQ:LOXO) completed submission of a rolling NDA to FDA for larotrectinib (LOXO-101) to treat locally advanced or metastatic solid tumors with neurotrophic tyrosine kinase receptor (Trk) fusion-proteins, regardless of tissue of origin.
Larotrectinib is a small molecule inhibitor of neurotrophic tyrosine kinase receptor 1 (TrkA; NTRK1), TrkB (NTRK2) and TrkC (NTRK3). It has breakthrough therapy, Orphan Drug and rare pediatric disease designations from FDA.
Loxo did not respond to inquiries regarding how it may approach potential payer hurdles outlined by Trinity.