The first accelerated approval for a tumor-agnostic drug was granted by the FDA in May 2017, enabling patients with any locally advanced or metastatic solid tumor expressing particular biomarkers for either microsatellite instability or mismatch repair to receive treatment with Merck & Co’s checkpoint inhibitor, Keytruda. This approval was seen as groundbreaking at the time and has contributed to a shift from consideration of tumor classification by tissue specificity, to that of biomarker-defined types, independent of tissue of origin. By eliminating the tissue restriction of tumor type, this approach may serve to usher in a new chapter in precision medicine, which in the past has been geared towards tailored therapies that were both biomarker- as well as tissue-type–restricted. Given the potentially low patient populations within cancer indications containing particular biomarkers, these approaches have generally seen slower adoption by developers. However, the tissue-agnostic approach is not without issues to be considered.

The accelerated approval for Keytruda in the tissue-agnostic setting, which will require post-market data to be converted to a full approval, was granted based on the results of five non-randomized, single-arm studies. Considering the nature of the patient population, which harbor rare mutations in refractory cancers, this type of trial design is considered acceptable for conditional approval status. The fact that randomized, controlled trials are not entirely feasible in this setting does, however, raise the issue of how to approach trial design for future tumor-agnostic studies. Many of these rare mutations occur in recurrent settings or in tumors for which there is no standard of care that could be used in the control arm. Other issues that warrant examination include how to best choose and evaluate disease endpoints across heterogeneous cancer types.

The FDA is supportive of this emerging approach, having appointed a lead medical officer, Steven Lemery, MD, for regulatory considerations regarding tissue-agnostic approaches, as well as recently holding a public workshop, on May 9 of this year, to discuss the regulatory considerations of this approach for orphan drug designation. Subsequently, on June 4, FDA commissioner Scott Gottlieb, MD, stated that as part of the FDA’s initiative of modernizing and streamlining the drug review process, adaptive approaches to drug clinical development including tissue-agnostic approvals have been adopted. The FDA acknowledges that introduction of newer approaches to drug approvals requires the development and support of additional technologies and processes for data collection and review. GlobalData believes that increased adoption of the use of real-world evidence during the pre-approval and post-marketing phases could serve to facilitate drug approvals as well as market uptake in this setting.

With the first tissue-agnostic oncology drug approval having occurred last year, what is next on the horizon for this approach? In May of this year, the FDA granted fast track priority review, with a decision date of November 26, to larotrectinib for NTRK fusion-positive cancers. The drug is under development by Loxo, which recently partnered with Bayer. Furthermore, just one year prior, in May 2017, the FDA granted breakthrough therapy designation in the tissue-agnostic setting for NTRK-positive tumors to a competing drug, Ignyta’s entrectinib, followed by orphan drug designation in July of that year. Ignyta’s success in securing these designations for entrectinib, a multi-kinase inhibitor with activity against ROS1 and ALK in addition to TRK, was a triggering factor in its acquisition by Roche at the end of 2017.

According to a recent analysis of the state of tissue-agnostic drug development, published in the March 9, 2018 issue of Nature Reviews Drug Discovery, while the approach may not be completely viable for all biomarkers due to tissue-specific differences, there is a fairly robust pipeline currently under development for tissue-agnostic approval status. With renewed support from regulatory authorities and interest from big pharma, additional resources are becoming available for validating these biomarkers and developing more refined and accurate biomarker testing protocols, which should increase the likelihood of success in the tissue-agnostic setting. Increased biomarker testing, coupled with tissue-agnostic trials such as TAPUR and NCI-MATCH, designed to study responses for different biomarkers across various tumor types, will provide data to help expand the potential populations of patients available for treatment. In addition, continued investment by large pharma in the candidates under development by small companies, similar to Bayer’s partnership with Loxo and Roche’s acquisition of Ignyta, will serve to fuel further development and translate into accelerated progress in precision medicine approaches.

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