Over 95% of the ongoing Phase III trials in the US featuring an immune checkpoint modulator involve either a PD-1 or PD-L1-targeting drug. Given the proven efficacy of these targets this is not necessarily surprising. However, for patients unable to tolerate, or refractory to these drugs, this lack of innovation is disappointing, says GlobalData, a leading data and analytics company.

Considering immune checkpoint modulating drugs in development (Phase II or III) globally for any oncology indication the picture is slightly better. PD-1 inhibitors account for 27% of the pipeline (this includes marketed drugs if they are being tested in a new indication), while PD-L1 accounts for a further 18% (there is also one bispecific targeting both PD-1 and PD-L1).

The next most common targets are CTLA4, with 15 drugs targeting this alone, and nine targeting CTLA4 in combination with a second target, LAG3 (10 single, 6 double), TIGIT (9 single, 2 double), CD47 (8 single, 5 double), CD40 (6 single, 1 double), and TIM3 (6 single, 3 double).

Jessica McCormack, PhD, Oncology & Hematology Analyst at GlobalData, comments: “Even though the pipeline for immune checkpoint modulating drugs is relatively diverse, there is still a huge emphasis on PD-1/L1. This makes sense since these targets have been validated in multiple indications. However, this is not encouraging for those patients who cannot receive or are refractory for PD-1/L1s.”

It is hoped that combining an additional agent with a PD-1/L1 inhibitor can increase efficacy of the PD-1/L1 inhibitor as well, and there is some evidence for this. However, while it is important to pursue this avenue, it would also be beneficial to explore entirely new targets that may be effective in these harder-to-treat patients. On this front, although considerable investment has gone into finding and validating new targets, there is relatively little to show for it.

McCormack continues: “The addition of both CTLA-4 inhibitor Yervoy, or LAG3 inhibitor relatlimab, to Opdivo in front-line melanoma have been shown to significantly increase overall survival. But there is less data in PD-1 refractory patients. It is also unclear how patients who have previously been treated with adjuvant PD-1/L1 inhibitors and then progress, should be treated.”

Retreatment with the same agent in combination with another drug may be effective, but there is not a huge amount of data available to support any firm conclusions. Intuitively it seems like these patients might benefit from novel therapies.

McCormack concludes: “TIGIT inhibitors figure in just 7% of Phase III US trials featuring an immune checkpoint modulating drug, but this represents the highest percentage of any novel target. However, several reports of disappointing data from TIGIT inhibitors have lowered confidence in this target. There is a worry that if TIGIT should fail there will be increased reluctance on the part of pharmaceutical companies to back these novel, riskier targets. This will be very unfortunate for patients.”