Abstract
This cohort study analyzed the safety and efficacy of immune checkpoint inhibitors in patients with cancer and autoimmune disease, and examined whether immune-related toxic effects were associated with outcomes.
Immune checkpoint inhibitors (ICIs) carry risks of immune-related adverse events (irAEs).1 Given similarities between irAEs and autoimmunity, patients with autoimmune disease (AID) are often excluded from clinical trials of ICI drugs.2 We analyzed the safety and efficacy of ICIs in patients with cancer and AID, and examined whether immune-related toxic effects were associated with outcomes in a large pancancer cohort.
Methods
We reviewed the records of 1822 patients with solid tumors diagnosed from January 1, 2015, to December 31, 2018, who received anti—programmed cell death 1/ligand 1 monotherapy or combination therapy at our center. Active AID was defined as disease requiring systemic immunosuppression at ICI initiation. Disease flare was defined as worsening of AID, and irAEs were inflammatory events unrelated to AID.1 We defined immune-related toxic effects as the presence of disease flare, irAE, or both, which were graded using the Common Terminology Criteria for Adverse Events (version 5.0). Response to ICIs was categorized using Response Evaluation Criteria in Solid Tumors (version 1.1).3 Owing to possible immortal time bias, the association of immune toxic effects with survival was assessed with multivariable Cox regression including toxic effects as a time-varying covariate. This study was approved by the Memorial Sloan Kettering Cancer Center institutional review board. All patients provided written informed consent. Additional methods are available in the eMethods in the Supplement.
Results
Of 1822 patients with 18 cancer types treated with ICIs, 147 patients (8.1%) had AID, with no significant differences between the AID and non-AID cohorts. The most common diagnoses were psoriasis (n = 38) and rheumatoid arthritis (n = 18); 25 (16.9%) patients with AID had active disease requiring systemic immunosuppression at ICI initiation. Rates of tumor response (28.6% vs 25.7%, P = .43) and overall survival (HR = 0.95; 95% CI, 0.76-1.17; P = .61) were similar in the AID and non-AID cohorts (Table 1).
Table 1. Baseline Characteristics of Patients Treated With Immune Checkpoint Inhibitor Therapy With and Without Preexisting Autoimmune Disease.
| Characteristic | No. (%) | P value | |
|---|---|---|---|
| AID (n = 147) | No AID (n = 1675) | ||
| Sex | .34 | ||
| Male | 74 (50.3) | 917 (54.5) | |
| Female | 73 (49.7) | 765 (45.5) | |
| Age at ICI start, median (IQR), y | 66.43 (57.5-74) | 63.54 (54.4-71) | .06 |
| Duration of follow-up, median (IQR), y | 10.7 (4.5-21.4) | 10.9 (4.4-19) | .94 |
| Cancer type | .21 | ||
| Non–small cell lung cancer | 62 (42.2) | 613 (36.6) | |
| Melanoma | 20 (13.6) | 196 (11.7) | |
| Kidney | 8 (5.4) | 84 (5) | |
| Othera | 57 (38.8) | 789 (47.1) | |
| Stage at diagnosis | .19 | ||
| I-III | 53 (36.1) | 503 (30) | |
| IV | 87 (59.18) | 1048 (62.7) | |
| Unknown/not applicable | 7 (4.76) | 124 (7.4) | |
| Stage at ICI start | .82 | ||
| I-III | 8 (5.4) | 82 (4.9) | |
| IV | 132 (89.8) | 1473 (87.9) | |
| Unknown/not applicable | 7 (4.8) | 120 (7.2) | |
| ICI drug class | .41 | ||
| Anti-PD-1/L1 | 128 (87.1) | 1407 (83.7) | |
| Combination therapyb | 19 (12.9) | 268 (15.9) | |
| ECOG performance status | .53 | ||
| 0 | 42 (28.6) | 584 (34.9) | |
| 1 | 74 (50.3) | 838 (50) | |
| ≥2 | 13 (8.8) | 139 (8.3) | |
| Unknown | 18 (12.2) | 114 (6.8) | |
| Interval from diagnosis to ICI start, median (IQR), d | 334 (163.5-544.5) | 267 (112-484) | .08 |
| Presence of distant metastases | .67 | ||
| No | 23 (15.7) | 285 (17) | |
| Yes | 124 (84.4) | 1388 (82.9) | |
| Unknown | 0 (0) | 2 (.1) | |
| Presence of brain metastases | .51 | ||
| No | 129 (87.8) | 1437 (85.8) | |
| Yes | 18 (12.2) | 238 (14.2) | |
| Objective response rate | 42 (28.6) | 431 (25.7) | .43 |
| Overall survival rate at 1 y [using Kaplan-Meier method], % (95% CI) | 45.6 (40.7-50.5) | 46 (44.9-47.1) | .61 |
Abbreviations: AID, autoimmune disease; ECOG, Eastern Cooperative Oncology Group; ICI, immune checkpoint inhibitor; PD-1/L1, programmed cell death 1/ligand 1.
Other cancer types include sarcoma, bladder, central nervous system, head and neck, gastric, colorectal, endometrial, hepatobiliary, small cell lung cancer, esophageal, pancreatic, mesothelioma, ovarian, unknown primary, breast.
Combination therapy included ipilimumab + nivolumab and durvalumab + tremelimumab.
Of 147 patients with AID, 87 (59.1%) experienced ICI toxicity: 20 (13.6%) with disease flare, 45 (30.6%) with irAE, and 22 (14.9%) with both. Most disease flares were mild, with 81% (34/42) grade 1 to 2 and 19% (8/42), grade 3; 33% (14/42) of patients with disease flare required treatment with immunosuppressive agents. Most patients experienced irAEs of highest grade 1 to 2 (76%; 51/67), 19% (13/67) grade 3, and 3% (2/67) grade 4; overall, 37.7% (40/106) of all irAEs were treated with immunosuppression. Patients with active AID experienced disease flare more often than those with latent disease (60.0% vs 22.1%, P < .001).
Patients with AID who experienced immune-associated toxic effects had higher ICI response rates (42.5% vs 8.3%, P < .001). In multivariable Cox regression including toxic effects as a time-varying covariate, patients with AID who experienced toxic effects had significantly improved overall survival compared with those without/before toxic effects (HR = 0.55; 95% CI, 0.32-.95; P = .03; Table 2). Although patients with active AID had similar response rates (24.0% vs 29.5%, P = .64), they had poorer overall survival (HR = 2.81; 95% CI, 1.41-5.58; P = .003).
Table 2. Factors Associated With Overall Survival in 147 Participants in the Autoimmune Disease Cohort.
| Variable | Univariate analysis | Multivariable analysis | ||
|---|---|---|---|---|
| HR (95% CI) | P value | HR (95% CI) | P value | |
| Tumor mutational burden (continuous) | .98 (.97-1.00) | .06 | 0.98 (.96-1.01) | .13 |
| Sex | ||||
| Female | 1 [Reference] | |||
| Male | .98 (.65-1.47) | .90 | ||
| Age (continuous) | .99 (.98-1.01) | .44 | ||
| Body mass indexa | .96 (.92-1.00) | .06 | 0.97 (.93-1.02) | .26 |
| Metastasis | ||||
| Distant | 2.18 (1.13-4.22) | .02 | 1.81 (.55-5.92) | .33 |
| Brain | 1.64 (.91-2.96) | .10 | 2.27 (1.12-4.61) | .02 |
| Stage at diagnosis | ||||
| I-III | 1 [Reference] | |||
| IV | 1.41 (.90-2.22) | .13 | ||
| Stage at ICI start | ||||
| I-III | 1 [Reference] | |||
| IV | 8.83 (1.23-63.57) | .03 | 2.29 (.20-26.20) | .50 |
| Cancer type | ||||
| Otherb | 1 [Reference] | |||
| Non-small cell lung cancer | .83 (.54-1.28) | .41 | 0.35 (.46-1.11) | .11 |
| Melanoma | .44 (.21-.89) | .02 | 0.68 (.26-1.73) | .42 |
| ICI drug class | ||||
| Monotherapy (anti-PD-1/L1) | 1 [Reference] | |||
| Combination therapy | .84 (.45-1.58) | .59 | ||
| ECOG performance status | ||||
| 0 | 1 [Reference] | |||
| 1 | 2.46 (1.42-4.27) | .001 | 2.05 (1.11-3.78) | .02 |
| 2-4 | 3.50 (1.63-7.51) | .001 | 2.62 (1.09-6.31) | .03 |
| Neutrophil-lymphocyte ratio | 1.05 (1.03-1.08) | .000 | 1.06 (1.03-1.09) | <.001 |
| Active autoimmune disease | 1.18 (.70-2.00) | .53 | 2.81 (1.41-5.58) | .003 |
| Any gradec | ||||
| Toxic effect | .53 (.33-.84) | .006 | 0.55 (.32-.95) | .03 |
| Flare | .65 (.38-1.09) | .10 | ||
| irAE | .70 (.44-1.10) | .12 | ||
Abbreviations: ECOG, Eastern Cooperative Oncology Group; ICI, immune checkpoint inhibitor; irAE, immune-related adverse event; PD-1/L1, programmed cell death 1/ligand 1.
Calculated as weight in kilograms divided by height in meters squared.
Other cancer types include sarcoma, bladder, central nervous system, head and neck, gastric, colorectal, endometrial, hepatobiliary, small cell lung cancer, esophageal, pancreatic, mesothelioma, ovarian, unknown primary, breast.
Modeled as a time-varying covariate.
Discussion
We analyzed the outcomes of patients with AID treated with ICIs for cancer and describe a protective association between immune-related toxic effects and survival in this patient population.
Patients with AID experienced equivalent rates of response and survival as patients without AID. Disease flares were generally mild, and required systemic immunosuppression in 33% of cases. However, patients with active AID had poorer outcomes, possibly attributable to impaired T-cell activation owing to systemic immunosuppression.4,5
It has been previously observed that when patients are treated with ICI drugs for cancer, irAEs appear to be associated with longer survival. This suggests that immune-associated toxic effects may be a manifestation of successful activation of T cells by ICIs.6 Our data on patients with AID show that autoimmune flare has a similar association and may also suggest superior ICI efficacy.
Limitations of this retrospective study are that the AID cohort represented patients in whom ICIs were deemed safe, and this pancancer cohort may not generalize to all cancer types.
Conclusions
The findings of this cohort study suggest that safety and efficacy of ICIs are similar between patients with cancer with and without concurrent AID diagnoses. Immune-associated toxic effects in patients with AID appear to be associated with superior immunotherapy efficacy, with the caveat that patients with active AID had poorer outcomes.
eMethods
References
- 1.Postow MA, Sidlow R, Hellmann MD. Immune-related adverse events associated with immune checkpoint blockade. N Engl J Med. 2018;378(2):158-168. doi: 10.1056/NEJMra1703481 [DOI] [PubMed] [Google Scholar]
- 2.Coureau M, Meert AP, Berghmans T, Grigoriu B. Efficacy and toxicity of immune -checkpoint inhibitors in patients with preexisting autoimmune disorders. Front Med (Lausanne). 2020;7:137. doi: 10.3389/fmed.2020.00137 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 3.Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer. 2009;45(2):228-247. doi: 10.1016/j.ejca.2008.10.026 [DOI] [PubMed] [Google Scholar]
- 4.Tison A, Quéré G, Misery L, et al. ; Groupe de Cancérologie Cutanée, Groupe Français de Pneumo-Cancérologie, and Club Rhumatismes et Inflammations . Safety and efficacy of immune checkpoint inhibitors in patients with cancer and preexisting autoimmune disease: a nationwide, multicenter cohort study. Arthritis Rheumatol. 2019;71(12):2100-2111. doi: 10.1002/art.41068 [DOI] [PubMed] [Google Scholar]
- 5.Menzies AM, Johnson DB, Ramanujam S, et al. Anti-PD-1 therapy in patients with advanced melanoma and preexisting autoimmune disorders or major toxicity with ipilimumab. Ann Oncol. 2017;28(2):368-376. doi: 10.1093/annonc/mdw443 [DOI] [PubMed] [Google Scholar]
- 6.Eggermont AMM, Kicinski M, Blank CU, et al. Association between immune-related adverse events and recurrence-free survival among patients with stage III melanoma randomized to receive pembrolizumab or placebo: a secondary analysis of a randomized clinical trial. JAMA Oncol. 2020;6(4):519-527. doi: 10.1001/jamaoncol.2019.5570 [DOI] [PMC free article] [PubMed] [Google Scholar]
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
eMethods