Checkpoint therapy with PD-(L)1 and CTLA4-directed monoclonal antibodies has shown to be extremely effective for many patients with a variety of tumors. PD-1 testing, alone, however, are lacking in selecting patients for therapy – up to 17% of patients who do not meet criteria for PD-1 positivity respond to treatment, and many patients with PD-1 tumors do not respond well to checkpoint therapy.
Also, PD-1 testing requires tumor biopsies, which is not convenient or possible after initial surgery. A blood test that could predict response to checkpoint, as well as other immunological therapies, would be ideal because it could be performed repeatedly and would provide insight into the current status of patients’ tumors following rounds of therapy, as opposed to the initial biopsies or surgical samples, which may have been obtained several years and many therapies previously.
We may be getting closer – researchers reported on a blood test that uses next generation sequencing to measure hypermutated blood-derived circulating tumor DNA (ctDNA) 54 to 70 genes. The results of analyses in sixty-nine patients for which blood samples and follow-up data were available demonstrated that those with more mutations (greater than three “variants of unknown significance) had a 45% response rate and a progression-free survival (PFS) of 23 months compared with those who had a low mutational – 15% response rate and PFS of 2.3 months. Median overall survival was not achieved yet in the group with high mutational burden, while those with low mutational burden had an 11 month overall survival.
“Patients whose tumors harbored more alterations progressed slower, lived longer, and responded more favorably to checkpoint inhibitor-based immune therapy,” Khagi (lead author) said. “The alteration number that predicted response in our study was not arbitrary, but defined as six or more total circulating tumor DNA alterations or more than three VUS alterations. These bright-line cutoffs might allow clinicians to use the objective results of this simple blood test to make determinations about whether to use checkpoint inhibitor-based immune therapy in a variety of tumor types.
This study further reinforces the importance of neo-antigens in precipitating prolonged and effective anti-cancer immune responses, and further supports the findings that patients with mismatch repair deficiency perform better on checkpoint therapy because their tumors mutate at a high rate.