Defining unique clinical hallmarks for immune checkpoint inhibitor-based therapies

Abstract

IntroductionImmuno-oncology therapies, including immune checkpoint inhibitors (ICIs), have transformed cancer care and have brought into question whether classic oncology efficacy assessments adequately describe the distinctive responses observed with these agents. With more ICI-based therapies being approved across multiple tumor types, it is essential to define unique clinical hallmarks of these agents and their associated assessments to better reflect the therapeutic impact for both patients and physicians. Long-term survival and objective responses, such as depth and durability of responses, treatment-free survival, efficacy in brain metastases, improved health-related quality of life, and unique safety profiles, are among the hallmarks that have emerged for ICI therapies. An established clinical hallmark is a sustained long-term survival, as evidenced by a delayed separation of Kaplan-Meier survival curves, and a plateau at ~3 years. Combination ICI therapies provide the opportunity to raise this plateau, thereby affording durable survival benefits to more patients. Deepening of responses over time is a unique clinical ICI hallmark, with patients responding long term and with more durable complete responses. Depth of response has demonstrated prognostic value for long-term survival in some cancers, and several ICI studies have shown sustained responses even after discontinuing ICI therapy, offering the potential for treatment-free intervals. Although clinical evidence supporting efficacy in brain metastases is limited, favorable ICI intracranial responses have been seen that are largely concordant with extracranial responses. While patient outcomes can be significantly improved with ICIs, they are associated with unique immune-mediated adverse reactions (IMARs), including delayed ICI toxicities, and may require multidisciplinary management for optimal care. Interestingly, patients discontinuing ICIs for IMARs may maintain responses similar to patients who did not discontinue for an IMAR, whether they restarted ICI therapy or not.ConclusionHerein, we comprehensively review and refine the clinical hallmarks uniquely associated with ICI therapies, which not only will rejuvenate our assessment of ICI therapeutic outcomes but also will lead to a greater appreciation of the effectiveness of ICI therapies.

Keywords: CTLA-4 antigen; combination; drug therapy; immunotherapy; programmed cell death 1 receptor; review.

Figure 1

Clinical hallmarks of ICI-based therapies and representative studies. CR, complete response; CRC, colorectal cancer; HCC, hepatocellular carcinoma; HRQOL, health-related quality of life; ICI, immune checkpoint inhibitor; IMAR, immune-mediated adverse reaction; NSCLC, non-small cell lung cancer; RCC, renal cell carcinoma.

Figure 2

Cancer immunity cycle and therapy targets. Adapted from Chen and Mellman, with permission from Elsevier. A2AR, adenosine A2A receptor; CAR-T, chimeric antigen receptor T cell therapy; CD, cluster of differentiation; CTLA-4, cytotoxic T-lymphocyte antigen 4; DC, dendritic cell; ICI, immune checkpoint inhibitor; IFN-α, interferon alpha; IL, interleukin; LAG-3, lymphocyte-activation gene three protein; PD-1, programmed death-1; PD-L1, programmed death ligand 1; STING, stimulator of interferon genes; TIM-3, T-cell immunoglobulin domain and mucin domain-3; TLR, toll-like receptor; TME, tumor microenvironment.

Figure 3

Long-term OS in clinical trials with immune checkpoint inhibitor and targeted therapies in patients with advanced melanoma. Data presented represent first-line treatment options, with the exception of those for IL-2 and pooled ipilimumab, for patients with melanoma; results will vary by tumor type. Permissions to use figures: licensed under the Creative Commons Attribution V.4.0 License (CC BY-NC 4.0) (https://creativecommons.org/licenses/by/4.0/). IL, interleukin; OS, overall survival.

Figure 4

Patients with melanoma in CR over time. CR rates among patients undergoing immune checkpoint inhibitor therapy steadily increased, indicating that the best response can improve over time. CR, complete response; IPI, ipilimumab; NIVO, nivolumab.

Figure 5

(A) Illustration of TFS assessment and OS curve partitioning. TFS estimates for (B) NIVO plus IPI, (C) nivolumab, and (D) ipilimumab in patients with melanoma in CheckMate 067 and 069. Data labels represent the mean number of months and the percentage of time in a treatment state during the 60-month period. Areas are restricted mean times. ^aTime after cessation of protocol therapy without toxicity before initiation of subsequent systemic anticancer therapy or death. ^bTime after cessation of protocol therapy with toxicity while treatment-free. Permissions to use figures: licensed under the Creative Commons Attribution V.4.0 License (CC BY 4.0) (https://creativecommonsorg/licenses/by/40/). IPI, ipilimumab; NIVO, nivolumab; OS, overall survival; TFS, treatment-free survival.

Figure 6

Safety profiles of ICI therapies in patients with non-small cell lung cancer (cross-trial comparisons cannot be made due to differences in dosing and methods used to assess TRAEs across studies). ^aData for grade 3–4 TRAEs also includes grade 5 TRAEs. ^bRepresents total adverse events, not just TRAEs. ATEZO, atezolizumab; CEMIP, cemiplimab; chemo, chemotherapy; ICI, immune checkpoint inhibitor; IPI, ipilimumab; NIVO, nivolumab; PEMBRO, pembrolizumab; QxW, every x weeks; TRAE, treatment-related adverse event.