Blog October 7, 2019

New Approvals for Tumor-Agnostic Cancer Treatments — and the Questions They Raise

entrectinibOn August 15, the U.S. Food and Drug Administration granted accelerated approval to Genentech/Roche’s Rozlytrek (entrectinib) for the treatment of adult and adolescent patients with solid tumors that exhibit neurotrophic tyrosine receptor kinase (NTRK) fusions and for whom there are no existing effective treatments. While NTRK fusions are rare, appearing in about 1% of solid tumors (about 2,500 – 3,000 patients in the United States), they occur in a variety of cancers including lung, salivary gland, breast, thyroid and colon/rectum.


This is the third FDA approval of a “tumor-agnostic” therapy. The first approval came in May 2017, when the FDA granted an accelerated approval to Merck’s Keytruda (pembrolizumab) for patients with unresectable or metastatic  microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) tumors.  The second, Bayer’s Vitrakvi (larotrectinib), another treatment targeting NTRK fusions that was originally developed by Loxo Oncology, gained FDA approval in November 2018. In late July, Viktrakvi also gained marketing authorization from the European Medicines Agency, making it the first tissue-agnostic cancer drug to be approved in Europe. 


Tumor-agnostic treatments have the potential to become a major focus of cancer drug development. Today, 31 therapies are reportedly being evaluated in “basket trials” — studies that test the effect of a drug on a single mutation in a variety of tumor types at the same time — that are in Phase 2 or later development. However, a number of challenges could limit these drugs’ widespread use.


Genetic heterogeneity between tumors and within an individual tumor may greatly impact the drug’s efficacy. Given oncology care’s current tumor-centric approach to treatment, it remains to be seen how readily these drugs will be accepted without more outcomes data on their real-world use and long-term effects. From the perspectives of access to treatment and willingness to prescribe tissue-agnostic therapies, notable efficacy and/or considerable unmet need may be a requirement to encourage both wider adoption and willingness of payers to reimburse high treatment costs. 


In addition, there are a few potential hurdles with respect to patient identification and biomarker testing. The NGS-based methods used to identify patients with these rare biomarkers are primarily available in major academic centers, rather than in the community, and the cost of such sequencing — while greatly reduced from a few years ago — remains high. Additionally, not all of the molecular targets being explored are currently included in commonly used NGS test panels. As a result, labs and private insurers may be resistant to adopt and cover a costly test for a rare biomarker that affects 1% or less of patients.


The growing number of tumor-agnostic treatments raises other potential questions. How will these drugs affect clinical practice and guidelines, which are currently centered on tumor-specific therapies? How will these treatments be integrated in the patient journey – and at what point? How will they be used together with other treatments in patients who, for example, express mutations that can be simultaneously targeted by different drugs? How will payers manage a growing pool of tissue-agnostic therapies and compare benefits across different tumor types? And will there be a need for new services to help manage these treatments, such as personalized genetic marker maps, machine-assisted treatment algorithms, etc.?