[HTML][HTML] A new addition to the PD-1 checkpoint inhibitors for non-small cell lung cancer—the anti-PDL1 antibody—MEDI4736

SM Lee, LQ Chow - Translational lung cancer research, 2014 - ncbi.nlm.nih.gov
SM Lee, LQ Chow
Translational lung cancer research, 2014ncbi.nlm.nih.gov
© Translational lung cancer research. All rights reserved. Transl Lung Cancer Res 2014; 3
(6): 408-410 www. tlcr. org competitors: activity across multiple tumor types, rapidity of
response with many tumor regressions observed at the first 6-week restaging study, and—
most importantly—durability of response, lasting as long as 67 weeks without ongoing
treatment. While the PD-L1 status correlated with higher response rates in a variety of tumor
types, there were also meaningful responses observed in PD-L1 negative patients, as has …
© Translational lung cancer research. All rights reserved. Transl Lung Cancer Res 2014; 3 (6): 408-410 www. tlcr. org competitors: activity across multiple tumor types, rapidity of response with many tumor regressions observed at the first 6-week restaging study, and—most importantly—durability of response, lasting as long as 67 weeks without ongoing treatment. While the PD-L1 status correlated with higher response rates in a variety of tumor types, there were also meaningful responses observed in PD-L1 negative patients, as has been seen in other trials with different PD-1 inhibitors, limiting the reliability of PD-L1 status to determine who should be treated with these agents. It is not yet known if this is due primarily to heterogeneity and nonstandardized methods of immunohistochemical and molecular methods for the current testing for PDL1 (varying cut-off criteria for positivity, PDL1 status of infiltrating tumor lymphocytes, stromal or tumor cells and specific antibodies used), or if this is due to the unreliability of PD-L1 status itself, which may change in vivo in response to different environmental contexts as well as vary across different tumor sites in the same patient (10). MEDI4736 may distinguish itself slightly from the other anti-PD-1 agents by its tolerability. Although it is difficult to draw meaningful conclusions from differences across separate trials of the various PD-1 drugs, the toxicities of MEDI4736 were minimally lower than what has been reported with other agents, with only 6% grade 3/4 adverse events in the expansion cohorts, notably no colitis, and only one event of grade 2 pneumonitis, which was reversible (7). MEDI4736 also demonstrated low immunogenicity, with only a 3% incidence (1 in 32 patients) of positive anti-drug antibodies that impacted pharmacokinetic and pharmacodynamics levels (11). This may be a result of MEDI4736 being a fully human antibody, compared to other PD-1 antibodies that contain humanized murine regions which can contribute to variations in affinity and immunogenicity among the PD-1 antibodies. Moreover, it is not known whether the use of an IgG1 or IgG4 backbone elicits any differences in efficacy or tolerability.
The differences between anti-PD-1 antibodies versus those of the anti-PD-L1 antibodies are not well elucidated either. As antibodies specifically targeting PD-L1 such as MPDL3280A and MEDI4736 only block the PD-1: PDL1 interaction, these agents could theoretically lead to less toxicity than the anti-PD-1 drugs which block both PD-1: PD-L1 and PD-1: PD-L2 binding (12, 13). Seemingly minor differences in toxicity patterns become very relevant when considering the distinct tumor types and patient populations that are being targeted for PD-1 development. The toxicity of pneumonitis, for example, can be particularly life threatening in lung cancer where patients often already have compromised lung function from smoking, COPD, radiation history, as well as the cancer itself. However, there is also evidence that some tumors, such as esophageal, hepatocellular and ovarian, express PD-L2, in which case an anti-PD-1 antibody that binds to both PD-L1 and PDL2 may prove to be more toxic but also more effective (14). It appears some of these antibodies may demonstrate greater efficacy in specific tumor types as opposed to others. For example, MPDL3280A has distinguished itself by its tolerability and efficacy in NSCLC and bladder cancer. It is currently in phase II and III registration trials in lung cancer (NCT02031458, NCT02008227) and in phase II trials in bladder cancer (NCT02108652).
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