Zai Lab

Hua Gong

Precision medicine focuses on finding the right therapies for the right patients based on their genetic profiles, with targeted therapy serving as the foundation to treat genetic mutations in cancer. The development of targeted therapies has significantly improved cancer treatment over the years, especially for patients harboring specific genetic aberrations. Due to the low prevalence of these genetic alterations, the current clinical development model for targeted therapies is time-consuming and costly, highlighting the need for an efficient way to develop such therapies. Results from multiple clinical studies have demonstrated that it is possible to have the same pharmaceutical agents targeting a wide range of mutated malignancies. Histology-agnostic clinical trials, also known as “basket studies” that target biomarker-defined populations in multiple tumor types, may represent an important research strategy to further improve the efficiency of oncology drug development.

Recent FDA approvals have supported the premise of histology-agnostic clinical trials. These early successes have supported the importance of a flexible regulatory approach to facilitate the development and commercialization of new cancer treatments, however, there still remains significant intrinsic complexities facing drug developers. For histology-agnostic clinical trials, common challenges may include:

1) Master protocol trial design

2) Predictive biomarkers

3) Requirement of robust clinical evidence

It is important to understand and navigate these challenges posed by histology-agnostic clinical trial design.

Key considerations for a well-designed basket study

A master basket study protocol should include a coordinated effort to evaluate investigational therapies in multiple tumor types among biomarker defined populations within the same trial structure. The overarching protocol should be designed to answer multiple questions, constituting a collection of trials and cohorts that share key design components for better coordination than that of individual trials conducted independently. The selection of endpoints, comparators and statistical analysis are critical to define for different tumor types in each of the trial arms or cohorts.

Another key consideration is to preselect patients for therapies using a predictive biomarker.

Novel discoveries have led to the development of drugs tailored to the molecular profile, thus increasing a demand for finding appropriate biomarker-selected patients.Histology-agnostic trial design has greatly facilitated the evaluation and approval of new drugs within small cohorts of orphan cancers which previously challenged the design of histology-dependent molecular trials. The emergence of mutational signature allows for tailoring of therapy treatment to target the patients’ genetic aberrant and their independent tumor types. The biomarker test then needs to be analytically validated and its clinical utility established in order to be applied to patient selection.

The FDA requires substantial evidence of efficacy and safety based on direct or surrogate markers of clinical benefit. For example, in the case of larotrectinib and entrectinib, the rarity of the NTRK fusions resulted in a lack of feasibility for a standalone analysis, thus necessitating a larger, pooled analysis. While randomized clinical trials may not be feasible for enrolling multiple tumor types, larger confirmatory post-marketing studies are likely required to confirm tissue-agnostic activity for approval. The lack of a comparator group prevents a survival-based efficacy assessment, necessitating the use of surrogate endpoints like objective response rate (ORR). Future approvals should pay heed to strong scientific rationale and consistent clinical response for all studied tumor types, as well as follow up on the accelerated approval of the large confirmatory, non-randomized clinical trials.

Tissue-agnostic drug approvals represent a paradigm shift in drug development, and agnostic-histology approvals will continue to increase and improve with an enhanced understanding of cancer biology and therapeutics development, along with improved technology. Clinical investigators and regulators should be prepared to address potential challenges to support the development of new promising agents to treat cancer.