Dosing immunotherapy combinations: Analysis of 3,526 patients for toxicity and response patterns

Abstract

Immunotherapy combinations are used to improve outcomes in metastatic cancer, but evidence-based knowledge of appropriate starting doses for novel combinations is lacking. Phase I-III adult combination clinical trials (≥ 1 drug was immunotherapy; anti-PD-1, PD-L1, or CTLA-4) were reviewed (PubMed Jan 1, 2010 to Sep 1, 2016; ASCO 2014-2016, ASH/ESMO 2014-2015 abstracts). The safe dose for each drug used in each combination was divided by the single-agent recommended dose to calculate dose percentage. Additive dose percentage was the sum of each dose percentage. Overall, 84 studies (N = 3,526 patients, 59 combinations) were analyzed. In 50% of studies, all drugs could be administered at full dose; 63%, in the presence of anti-PD-1/PD-L1 and 36% with anti-CTLA-4. The lowest safe starting dose for a doublet combination including a second immunotherapy was 50% of each drug; 60%, for a targeted agent. Most doublet/triplets combining anti-PD-1/PD-L1 with cytotoxics were tolerable at full doses. Response rates (median [interquartile range]) were higher for 3-drug than 2-drug combinations (53% [33-63%] (N = 23 studies) vs. 23% [14-39%]) (N = 60 studies) (p < 0.0001) with similar rates seen for targeted, cytotoxic, biologic, or additional immunotherapy combinations (p = 0.35). In conclusion, anti-PD-1/PD-L1 checkpoint inhibitors can be safely given with a variety of other immunotherapy and targeted agents, albeit at about half dose. Doublet and triplet combinations with cytotoxics could mostly be given at full doses. Anti-CTLA-4 agents compromised dosing more than anti-PD-1/PD-L1 agents. Response rates were significantly higher for 3- versus 2-drug combinations.

Relationship between protein biomarkers of chemotherapy response and microsatellite status, tumor mutational burden and PD‐L1 expression in cancer patients

“…However, recent advances in NGS and molecular profiling have demonstrated that each tumor has a unique molecular profile, which mandates a more personalized approach . Recent studies have explored dosing of novel combinations of targeted agents, cytotoxics and immunotherapies . The FDA recently approved pembrolizumab in a tissue‐agnostic manner for use in all patients with MSI‐H status or mismatch gene alterations, which signifies a major shift in drug approval practice.…”

“…Combinations of immunotherapy and cytotoxic chemotherapy are increasingly being used and tested in clinical trials . Chemotherapy has the potential to enhance antitumor immune responses by several mechanisms including activation of immune effectors such as monocytic‐derived dendritic cells and sensitizing tumor cells to lysis .…”

“…Combinations of immunotherapy and cytotoxic chemotherapy are increasingly being used and tested in clinical trials. [1][2][3] Chemotherapy has the potential to enhance antitumor immune responses 4 by several mechanisms including activation of immune effectors such as monocytic-derived dendritic cells 5 and sensitizing tumor cells to lysis. 6,7 However, preclinical studies have shown that chemotherapy can also deplete immunosuppressive cells, including myeloid-derived suppressor cells 8 and T-regulatory cells.…”

Trial watch: Immunogenic cell death induction by anticancer chemotherapeutics

“…[301][302][303] Thus, current anticancer drugs have been developed in immunodeficient preclinical models and in clinical trials devoid of any form of immunomonitoring, mainly most often aimed at identifying maximum tolerated doses (MTDs). 298,304 Nonetheless, a majority of currently available anticancer agents mediate on-target or off-target immunostimulatory effects, which strongly argues against an irrelevant role for the immune system in the therapeutic effects of these treatments. [305][306][307][308] Moreover, in various cases, chemotherapeutics applied through multiple treatment cycles may negatively affect the immune system, by causing lymphopenia or leucopenia, thereby further compromising antitumor immune responses.…”

“…However, the widespread use of these treatments has been implemented mostly on empirical (rather than immunological) grounds. 200,[296][297][298][299][300] Indeed, the possibility that chemotherapy and other forms of treatment (including radiotherapy and photodynamic therapy) might promote an immunogenic form of cancer cell death has been overlooked for several decades. [301][302][303] Thus, current anticancer drugs have been developed in immunodeficient preclinical models and in clinical trials devoid of any form of immunomonitoring, mainly most often aimed at identifying maximum tolerated doses (MTDs).…”