麻豆传媒

CHICAGO -- FDA researchers found that when evaluating outcomes observed with immunotherapy drugs used in advanced melanoma, the depth of response (i.e., how much of the cancer is eliminated by treatment) was a more accurate predictor of survival than the current reliance on Response Evaluation Criteria in Solid Tumors (RECIST).

Among patients treated with anti-PD-1 or anti-CTLA-4 immunotherapies, survival at 3 years was about 95% in patients who had achieved a complete response, 90% for those who achieved a 76% to less-than 100% reduction in tumor burden, and about 80% for those who had a 51-75% reduction in tumor burden, reported Christy Osgood, MD, a pediatric oncologist and medical officer with the FDA in Silver Spring, Maryland.

But patients who achieved smaller reductions in tumor burden fared worse: Those whose tumor burden was reduced by 26-50% had a 3-year survival rate of about 60%; those with a reduction of 25% or less had a 3-year survival rate of about 50%, and those who did not show any reduction in tumor burden had a 3-year survival rate of less than 25%, Osgood reported in an oral presentation here at the American Society of Clinical Oncology annual meeting.

"Depth of response correlates with a longer progression-free survival and overall survival regardless of therapy type," she said.

For targeted agents in the BRAF- and MEK-inhibitor classes, a greater than 75% depth of response was associated with greater chance of 2-year survival compared with patients who achieved lower levels of elimination of tumor burden, Osgood reported. A complete response with the agents translated to an 80% survival rate at 2 years; a 76% or greater response translated to a 70% survival rate. Less of a reduction in tumor burden resulted in a 2-year survival that was 50% or less, with lower reduction resulting in a lower chance of being alive at 2 years.

Study discussant Paul Chapman, MD, of Memorial Sloan Kettering Cancer Center in New York City, said, "Until today, we have been using RECIST criteria in evaluating patients. RECIST was never meant to be a tool for managing patients, although we have migrated to using RECIST as a surrogate for survival, although it doesn't correlate very well."

"This study shows us that depth of response does seem to correlate with survival, and this may be a new metric for us," he said.

Osgood noted in her presentation that RECIST basically had three levels:

• Less than 30% reduction in tumor size -- generally considered a non-response

• 30% to less than 100% reduction -- generally considered a partial response

• 100% reduction -- a complete response

"RECIST does not provide any granular response between 30% reduction and 100%," she said. "Thus the current system may not capture the full spectrum of benefit derived for more recently developed targeted kinase inhibitors or immunotherapies."

Osgood and her colleagues gathered randomized trial data in marketing applications to the FDA from 2011 through 2018, evaluating drugs in patients with previously untreated advanced or metastatic melanoma. The team excluded trials of intralesional therapies and identified 10 randomized trials that included a total of 4,826 patients. After culling patients with incomplete data or those who did not receive trial drugs, the researchers evaluated outcomes in 4,278 patients.

Treatments were stratified by targeted kinase inhibitors, immunotherapy, and chemotherapy, mainly dacarbazine and paclitaxel.

Similarly, the depth of response was stratified as follows:

• Patients in whom no decrease in tumor burden occurred

• Patients with a response of 25% of less

• Patients with a response of 26-50%

• Patients with a response of 51-75%

• Patients with a response of 76% to less than 100%

• Patients with a 100% complete response

About 59% of the patients in the studies were men, their mean age was 57 (range of 17-93), about 95% were white, about 72% were in ECOG stage 0, 93% were diagnosed as having stage IV disease, 34% had elevated lactase dehydrogenase levels (considered a sign of cancer-mediated cell damage), and BRAF mutations were found in 68% of patients.

Overall, the 2-year survival rate was highest in patients who received immunotherapy, 70% of whom were alive at that time point, compared with about 50% for patients treated with targeted therapies; there were no 2-year survivors among the advanced melanoma patients treated with chemotherapy, Osgood reported.