In an important first, the FDA recently granted accelerated approval to Keytruda® for an indication that is based on a common biomarker rather than a tumor type. This approval signals a new phase in precision medicine and a potential major shift in the approach to cancer treatment, in which physicians base treatment decisions on a tumor signature rather than tumor type. The treatment indication for Keytruda is for solid tumors that are microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR). In an FDA press release announcing the approval, Dr Richard Pazdur, director of the Office of Hematology and Oncology Products at CDER, noted that “this is an important first for the cancer community.”
This approval provides an additional signal of the FDA’s willingness to accept novel—and potentially more agile—therapeutic/diagnostic development approaches, including basket clinical trial designs. Basket clinical trials enroll patients for treatment based on biology, not tumor type, allowing for the measurement of treatment safety and efficacy across multiple tumor types. In the 5 clinical trials that supported the Keytruda approval, a total of 15 MSI-H or dMMR cancer types (colorectal cancer being the most common type; n = 98) were identified among 149 enrolled patients. While this type of development approach may not be appropriate for all targets, the approval will likely propel the adoption of basket clinical trial designs in precision medicine investigations.
In the clinical trials supporting the Keytruda approval, the tumor status for MSI-H or dMMR tumors was determined by polymerase chain reaction (PCR) or immunohistochemistry (IHC) routine laboratory developed tests, respectively. The approval was not accompanied by an FDA-approved companion diagnostic (CDx), but the postmarketing commitments for the approval are to support the development of CDx tests for the detection of dMMR or MSI-H tumors (another sign of a more agile approach to development). In this new era of basing therapeutic selection on a tumor and immune system signature rather than a tumor type, diagnostics are likely to play a more integral role in cancer treatment. In an ASCO 2017 annual meeting presentation discussing tumor-agnostic approaches, Dr Steven Lemery, the lead medical officer of the Office of Hematology and Oncology Products at CDER, stressed that “[you] cannot identify patients if tumors [are] not tested.”
The Keytruda approval demonstrates that immunotherapies have the potential to be impactful for a tumor agnostic approach. As part of a presentation to investors at the ASCO 2017 annual meeting, David Feltquate, the vice president of Immuno-oncology Development at Bristol-Myers Squibb, discussed the intricacies of the interaction of the immune system with cancer and noted, “This is the phase where we have to be really creative, start to build and create regimens that are more active for broader patients, but be selective in who these patients are that we’re applying to these regimens.” The development of diagnostics that are used to predict patient responsiveness to immunotherapies, alone and in combination, will likely require the application of novel technologies and methods to support elucidation of a patient’s individual tumor biology. These technologies and methods will provide a more comprehensive examination of the entire tumor signature, including the genomic and immune microenvironment profiles, which will be needed to appropriately select for patients who will benefit from treatment initially as well as over time.