Neoadjuvant Endpoints, Response Criteria Proposed

Historically, pathologists have judged responses to neoadjuvant treatment by counting viable cancer cells in subsequently resected tumor tissue. If those cells comprise less than 10% of the bulk tumor, the outcome is a major pathologic response (mPR); having no viable tumor cells is a pathologic complete response (pCR).

However, these response criteria, originally developed for neoadjuvant chemotherapy trials, don't seem to capture what pathologists are seeing under the microscope in neoadjuvant testing of PD-1 inhibitors. A new set of evaluation criteria, researchers say, might better gauge immune-related responses.

Evidence for the proposed “immune-related pathologic response criteria” (irPRC) comes from a retrospective analysis of trial data from 20 patients with early-stage non–small cell lung cancer (NSCLC) who received neoadjuvant nivolumab (Opdivo; Bristol-Myers Squibb). According to trial investigator Janis Taube, MD, of Johns Hopkins University in Baltimore, MD, the tumors displayed a number of unique histopathologic features such as scarring and inflammation around the site of the tumor bed. They also show signs of immune cell activation, tumor cell death, and tissue repair. “It's an immune-mediated cell death rather than a cytotoxic one,” Taube explains.

Taube and her Hopkins colleague Tricia Cottrell, MD, PhD, incorporated aspects of both immune-mediated tumor regression and residual viability into one unified score to create the irPRC. As they reported this month at the American Association for Cancer Research Annual Meeting 2018 in Chicago, IL, irPRC yielded more consistent and reproducible scoring of pathologic response among independent physicians than residual viable tumor estimates using traditional criteria.

Bristol-Myers Squibb executives say that the proposed criteria more accurately address immunotherapy's mechanism of action. “This looks like something we should study further and test in a rigorous, statistically powered fashion,” says Robin Edwards, MD, the company's group director of pathology.

The criteria might also prove applicable to other cancers. According to Taube, pathologists have seen similar histopathologic features in neoadjuvant immunotherapy trials in melanoma, renal cancer, Merkel cell carcinoma, and other tumor types. “Our hope,” she says, “is that there could someday be pan-tumor criteria for immune-related pathologic response.”

However, the adoption of irPRC, at least in neoadjuvant lung cancer trials, is somewhat contingent on a larger debate about which surrogate endpoint should become standard for neoadjuvant trials of all types of drugs—immunotherapies, chemotherapies, and targeted therapies alike.

Last month, at a workshop convened by the FDA and the International Association for the Study of Lung Cancer (IASLC), experts gathered to discuss whether to rely on pCR as a surrogate endpoint for accelerated approval, as is currently the standard for studies of neoadjuvant breast cancer therapy, or, given the rarity of pCR in lung cancer, to use other measures such as event-free survival or mPR—the latter having been strongly linked to patient survival in neoadjuvant chemotherapy trials. Early nivolumab data suggest that mPR is predictive of robust immune responses as well.

Gideon Blumenthal, MD, acting deputy director of the FDA's Office of Hematology and Oncology Products, says the agency is “very supportive” of mPR as a surrogate readout. However, “we're not ready to endorse any of these endpoints for neoadjuvant lung cancer [trials] at this point.”

“It's too soon for any of these endpoints,” he says, arguing that greater standardization in evaluation criteria is still needed. To that end, the IASLC Pathology Committee is developing recommendations for evaluating resected lung tissue following neoadjuvant therapy. According to emeritus panel member Bill Travis, MD, of Memorial Sloan Kettering Cancer Center in New York, NY, these “will probably be completed in the next few months.”

Perhaps more importantly, says Blumenthal, “we just need to see more data.” –Elie Dolgin