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Exploring novel immune-related toxicities and endpoints with immune-checkpoint inhibitors in non-small cell lung
1From the Department of Medicine, Division of Medical Oncology, University of Washington, Seattle, WA.
Abstract:
Because of dramatic tumor regressions reported with the anti-programmed death-1 (PD-1) and anti-programmed death ligand-1 (PDL-1) antibodies inhibiting the PD-1 immune checkpoint, non-small cell lung cancer (NSCLC) is now recognized as an immune-modifiable disease. As responses were observed in smaller numbers in phase I trials, the immunologic profiles and unique toxicities of these agents have not been fully established in NSCLC. Moreover, PD-1 checkpoint inhibitors in development by different companies may demonstrate diverse spectrums of activity and toxicity. Although the cytotoxic T-lymphocyte antigen-4 (CTLA-4) checkpoint inhibitors in earlier phase studies appeared to have less impressive responses in NSCLC, their safety profile has been more broadly defined. The anti-CTLA-4 antibody, ipilimumab, has the best characterized immune-related toxicities (predominantly skin, gastrointestinal, hepatic, and endocrine) and management strategies in melanoma. Despite the lack of studies directly comparing these agents, toxicities from PD-1 inhibition seem milder than those of CTLA-4 inhibition, with distinct toxicities of pneumonitis infrequently observed with the BMS-936558 anti-PD-1 antibody, nivolumamb, and frequent mild infusion reactions reported with the BMS-936559 anti-PDL-1 antibody. As lungs are critical organs often already compromised in NSCLC patients, immune-mediated pneumonitis can cause worrisome morbidity and mortality. Even though immune checkpoint inhibitors are being rapidly developed in a multitude of trials, optimal immune-mediated toxicity management has not been determined, is evolving, and will be further explored. Early diagnosis and symptom management with corticosteroids form the basis of treatment. Assessment of new immune-response criteria and use of primary endpoints of overall survival (OS) will be important in the development of these immunotherapies in NSCLC.
Insights
Non-small cell lung cancer is now immune-modifiable. Anti-PD-1/PD-L1 antibodies show promise, but their unique toxicities, like pneumonitis, require careful management in NSCLC patients.
Area of Science:
- Oncology
- Immunology
- Pharmacology
Background:
- Non-small cell lung cancer (NSCLC) is increasingly recognized as an immune-modifiable disease due to responses to anti-programmed death-1 (PD-1) and anti-programmed death ligand-1 (PDL-1) antibodies.
- While PD-1/PD-L1 inhibitors show promise, their immunologic profiles and unique toxicities in NSCLC are not fully established.
- Cytotoxic T-lymphocyte antigen-4 (CTLA-4) inhibitors have a more defined safety profile, though with less impressive responses in NSCLC compared to PD-1/PD-L1 agents.
Purpose of the Study:
- To review the immunologic profiles and toxicities of immune checkpoint inhibitors (ICIs) in non-small cell lung cancer (NSCLC).
- To compare the toxicity profiles of anti-PD-1/PD-L1 agents with anti-CTLA-4 agents.
- To discuss the implications of immune-mediated toxicities, particularly pneumonitis, in NSCLC and their management.
Main Methods:
- Review of existing clinical trial data and literature on PD-1, PD-L1, and CTLA-4 inhibitors in NSCLC.
- Comparison of reported activity and toxicity profiles of different immune checkpoint inhibitors.
- Discussion of management strategies for immune-related adverse events.
Main Results:
- Anti-PD-1/PD-L1 antibodies demonstrate significant tumor regressions in NSCLC, establishing it as an immune-modifiable disease.
- Toxicities from PD-1 inhibition appear milder than CTLA-4 inhibition, with notable exceptions like infrequent pneumonitis with nivolumab and infusion reactions with atezolizumab.
- Anti-CTLA-4 antibody ipilimumab has well-characterized toxicities (skin, GI, hepatic, endocrine) primarily established in melanoma.
Conclusions:
- Optimal management of immune-mediated toxicities in NSCLC is evolving, with early diagnosis and corticosteroid use forming the current basis of treatment.
- Immune-mediated pneumonitis is a significant concern in NSCLC patients due to compromised lung function, necessitating careful monitoring and management.
- Further research focusing on immune-response criteria and overall survival as primary endpoints is crucial for the development of immunotherapies in NSCLC.
