Are anti-PD1 and anti-PD-L1 alike? The non-small-cell lung cancer paradigm

Abstract

Anti-PD1 and anti-PD-L1 agents may have intrinsic and clinically relevant differences in the treatment of non-small cell lung cancer (NSCLC) patients. By reviewing currently available indirect evidence on these agents for NSCLC treatment, highlighting possible inter- and intra-class dissimilarities, anti-PD1 agents showed a higher response rate and a better outcome when combined with chemotherapy for the first-line treatment of patients with squamous and PD-L1 low advanced NSCLC, as compared to anti-PD-L1 agents. Conversely, anti-PD-L1 agents were responsible for less severe adverse events (AEs), particularly, immunerelated AEs. These differences could be explained by their different specific properties. Considering possible differences between anti-PD1 and anti-PD-L1 agents could be clinically relevant for treatment tailoring and inspiring new investigational approaches.

Keywords: Immune-checkpoint inhibitor; PD-L1; PD1; immune-related adverse events; lung cancer.

Figure 1.

Indirect comparisons between anti-PD1 and anti-PD-L1 exploring possible clinical efficacy differences: A, indirect comparison of difference (Delta) in median months of OS and PFS between anti-PD1 and anti-PD-L1 agents and chemotherapy in the secondand beyond line treatment of aNSCLC by available phase III randomized trials; B, indirect comparison of ORR percentage between anti-PD1 and anti-PD-L1 agents and of gain in ORR (Delta) percentage between them and chemotherapy in the second- and beyond line treatment of aNSCLC by available phase III randomized trials; C, indirect comparison of median months of OS and PFS between anti-PD1 and anti-PD-L1 agents plus chemotherapy and of gain in OS and PFS (Delta) months between them and chemotherapy alone in the first-line treatment of squamous aNSCLC by available phase III randomized trials; D, indirect comparison of median months of OS and PFS between anti-PD1 and anti-PD-L1 agents and of gain in OS and PFS (Delta) months between them and chemotherapy in the first-line treatment of PD-L1 high aNSCLC by available phase III randomized trials. aNSCLC, advanced nonsmall-cell lung cancer; ADCC, antibody-dependent cell-mediated cytotoxicity (ADCC); Atezo, atezolizumab; CM, checkmate; G, grade; KN, keynote; Ig, immunoglobulin; ImP, ImPower; moAbs, monoclonal antibodies; Nivo, nivolumab; ORR, overall response rate; OS, overall survival; PD1, programmed cell death 1; PD-L1, programmed cell death ligand 1; Pembro, pembrolizumab; PFS, progressionfree survival; Sq, squamous.

Figure 2.

Indirect comparison between anti-PD1 and anti-PD-L1 exploring possible toxicity differences: A, indirect comparison of led to discontinuation, ≥ grade 3 and all grade toxicity percentages between anti-PD1 and anti-PD-L1 agents in the second- and beyond line treatment of aNSCLC by available phase III randomized trials; B, indirect comparison of immune-related adverse events percentages between anti-PD1 and anti-PD-L1 agents in the second- and beyond line treatment of aNSCLC by available phase III randomized trials. aNSCLC, advanced nonsmall-cell lung cancer; ADCC, antibody-dependent cell-mediated cytotoxicity (ADCC); Atezo, atezolizumab; CM, checkmate; G, grade; KN, keynote; Ig, immunoglobulin; ImP, ImPower; moAbs, monoclonal antibodies; Nivo, nivolumab; ORR, overall response rate; OS, overall survival; PD1, programmed cell death 1; PD-L1, programmed cell death ligand 1; Pembro, pembrolizumab; PFS, progressionfree survival; Sq, squamous.

Figure 3.

Anti-PD-1/PD-L1 isotypes. IgG1-moAbs containing an Fc region, which can bind cognate receptors on immune effector cells, could induce tumor cell lysis mediated by ADCC as compared to those with IgG4 or a mutated Fc region. aNSCLC, advanced nonsmall- cell lung cancer; ADCC, antibody-dependent cell-mediated cytotoxicity (ADCC); Atezo, atezolizumab; CM, checkmate; G, grade; KN, keynote; Ig, immunoglobulin; ImP, ImPower; moAbs, monoclonal antibodies; Nivo, nivolumab; ORR, overall response rate; OS, overall survival; PD1, programmed cell death 1; PD-L1, programmed cell death ligand 1; Pembro, pembrolizumab; PFS, progressionfree survival; Sq, squamous.