Immunotherapy using checkpoint inhibitors
Currently, the most exciting area of cancer research revolves around harnessing our own immune system to combat cancer. There are now several “checkpoint inhibitors” on the market, with the most common being nivolumab (Opdivo), pembrolizumab (Keytruda), and ipilimumab (Yervoy). Despite the commonly exaggerated efficacy reported with checkpoint inhibitors, unfortunately, only approximately 20% of patients respond positively when this therapy is used as the sole treatment, with most of the responses limited to patients with melanoma.
Checkpoint inhibitors, although sometimes beneficial, when used according to the recommended dosing guidelines, may be associated with significant toxicity. The question that many cancer scientists are asking, as well as a few oncologists who have reviewed the published literature, is why are we using such high doses of these drugs? An article published on Oct 1, 2019 expounds upon this issue: Immune Checkpoint Inhibitor Dosing: Can We Go Lower Without Compromising Clinical Efficacy?
There is a large amount of data showing that checkpoint inhibitors have significant activity at doses much lower than those currently approved. Using high or maximum tolerated dose (MTD) immunotherapy is analogous to using MTD chemotherapy for solid tumors. It is certainly not clear that MTD chemotherapy is optimal for solid tumors, nor is it clear that MTD immunotherapy is optimal for solid tumors. Apparently, one does not need high doses of checkpoint inhibitors in order to get a therapeutic effect. The efficacy of low doses could be explained because the programmed death-1 [PD-1] receptor [the molecular target of both Opdivo and Keytruda] reaches maximum occupancy at low doses for these agents, translating into a flat exposure-response curve, where increasing the dosage does not lead to an increase in tumor response.
Another article was published in 2018 demonstrating similar findings, and was entitled, “Impact of immune checkpoint inhibitor dose on toxicity, response rate, and survival: A pooled analysis of dose escalation phase 1 trials.” The investigators analyzed clinical data from patients treated in phase 1 immune checkpoint inhibitor dose escalation trials at MD Anderson Center for Targeted Therapy. Patients were stratified into a low-dose [LDG] ( < 33% of maximum tolerated dose), medium dose [MDG] (34-66% of maximum tolerated dose), high dose [HDG] (67-100% of maximum tolerated dose), or very high dose [VHDG] ( > 100% of maximum tolerated dose) group. Groups were compared for immune related adverse events (irAE), progression-free survival (PFS), overall survival (OS), overall response rate (ORR – those who had a complete response or partial response), and disease control rate (DCR -those who had a complete response, partial response, or stable disease for > 6 months).
Conclusions: Despite a dose-dependent increase in irAE, we identify no improvement in PFS, OS, or DCR with escalating doses of checkpoint inhibitors administered in phase I trials. Lower doses may reduce toxicity and cost without compromising disease control or survival.
Based on the available data, the current guidelines for checkpoint inhibitor dosing are causing significant financial and immunological toxicity, without improving PFS or OS.
Cancer scientists have been evaluating methods to improve the efficacy of checkpoint inhibitors; Strategies to Improve Cancer Immune Checkpoint Inhibitors Efficacy, Other Than Abscopal Effect: A Systematic Review.
The data reveals that combining checkpoint inhibitors with modalities, such as radiation, chemotherapy, angiogenesis inhibitors, and targeted drugs, improves the response.
At Advanced Medical Therapeutics, we recommend combining low dose combination checkpoint inhibitors with other modalities which release tumor antigens and improve the tumor microenvironment, thereby increasing the chances of an optimal immune response to cancer.