Immune checkpoint inhibitors (ICPi) cause various immune-related adverse events (irAE) with thyroid dysfunction as a commonly reported abnormality. There is increasing evidence showing positive association with development of irAE and survival. However, prior trials with ICPi had underrepresentation of minorities with < 5% African Americans.

To evaluate the association between development of irAE and survival outcomes among a racially diverse patient population.

Data on patients with stage IV solid malignancies treated with programmed cell death-protein 1/programmed death ligand 1 blockers between January 2013 and December 2018 across MedStar Georgetown Cancer Institute facilities were retrospectively reviewed. Patients treated with cytotoxic T-lymphocyte-associated protein 4 inhibitors were excluded. Progression free survival (PFS) and overall survival (OS) were primary endpoints and were calculated using Kaplan-Meier methods and Wilcoxon rank sum test for comparison.

Out of 293 patients who met eligibility criteria, 91 pts (31%) had any grade irAE; most common AE were endocrine (40.7%) specifically TSH elevation, dermatological (23.1%) and rheumatologic (18.7%). Proportion of irAE was significantly higher in Caucasians vs African Americans (60.4% vs 30.8%), in patients with low programmed death ligand 1, lower LDH, older age, and those who had more treatment cycles with ICPi. Rate of progression was lower in patients with irAE (30.8% vs 46.0%, P = 0.0140). Median PFS (5.8 vs 3.0 mo, P = 0.0204) and OS (17.1 vs 7.2 mo, P < 0.0001) were higher with irAE. Statistically significant difference in OS (17.1 vs 8.6 mo, P = 0.0002) but not in PFS (5.8 vs 3.3 mo, P = 0.0545) was noted with endocrine irAE. No differences in survival were observed among other commonly reported irAE. Differences in survival among subgroups of patients with irAE are described.

Development of irAE positively correlated with improved PFS and OS as reported in previous studies. To our knowledge, this is the first study observing differences in OS favoring endocrine AE and Caucasian race. These factors may be potential surrogate markers of prognosis pending replication of these results in large-scale studies.

Emergence of immune checkpoint inhibitors (ICPi) has revolutionized standard of care treatment in a wide spectrum of cancer subtypes resulting in increased survival[1,2]. These agents up regulate activity of the immune system by blocking intrinsic down regulators of immunity such as cytotoxic T-lymphocyte-associated protein 4 and programmed cell death-protein 1 (PD-1)[1]. This amplified immune activity can also result in off target autoimmune inflammation of healthy organs resulting in immune-related adverse effects (irAE)[1,3].

Various mechanisms contribute to the irAE affecting several organ systems, with effect on the endocrine glands noted as one of the most common and often irreversible irAE[1,4-7]. Correlation with the development of these adverse effects on outcomes is controversial, however, there is a growing body of evidence that the development of these adverse events may be associated with improved outcomes[1,8-13].

In this retrospective analysis, we aim to describe the association of development of irAEs to survival outcomes in patients treated with ICPi for advanced stage solid malignancies. We also specifically underscore the effects of endocrine irAEs on survival. More importantly, we sought to address differences in survival outcomes across different racial groups given the significant underrepresentation of minority racial groups in pivotal immunotherapy trials[14].

We hypothesize that development of irAEs will have a positive correlation with progression free survival (PFS) and overall survival (OS) in patients treated with ICPi. We also anticipate that there will be differences in outcomes among various racial groups. There is very limited data on efficacy outcomes in racially diverse patients who receive immunotherapy and develop irAEs making our study unique and clinically relevant.

This is a retrospective analysis of patients with a diagnosis of stage IV solid malignancy who were treated with PD-1 or programmed death ligand 1 (PDL1) blocker between January 1, 2013 and December 31, 2018 across MedStar Georgetown Cancer Institute facilities. This study was approved by the MedStar institutional review board and a waiver of HIPAA authorization was obtained given its retrospective nature.

Development of irAE in patients treated with ICPi is not uncommon and is an off-target effect of increased immune activity[1]. Several studies done in specific tumor types using various anti-PD-1 and anti-PDL1 agents confirmed the association of irAE development with improved outcomes[8-12,16]. Our study similarly concluded a positive correlation of irAE development with increased probability of survival. The inclusion of a racially diverse population of patients in our study is unique and has not been previously reported to the best of our knowledge. Moreover, we also noted important associations with development of endocrine irAE with survival outcomes.

Median PFS and OS were significantly improved in patients who developed irAE in our study. Moreover, positive correlation in median OS was also seen in patients who had endocrine adverse events. A study by Grangeon et al[17] assessing similar survival endpoints in patients with advanced stage non-small cell lung cancer (NSCLC) concluded improved objective response rates, PFS and OS in patients who received ICPi therapy. Moreover, in patients who had thyroid dysfunction PFS and OS were significantly improved. Other studies reported similar outcomes in patients with NSCLC who had thyroid AE following treatment with immunotherapy[9,10,18]. A preliminary study from our group also addressed this issue with a systematic literature review and meta-analysis of patients with lung cancer and head and neck cancer on immune checkpoint inhibitor therapy across twelve randomized-controlled trials comprising of 7060 patients with 3815 patients using ICPi[19]. In that study, at a mean follow-up of 12.2 mo, the OS (hazard ratio: 0.75; 95% credibility interval: 0.70-0.80) and PFS (hazard ratio: 0.77; 95% credibility interval: 0.72-0.81) in the ICPi arm were significantly improved. Endocrine irAE, specifically hypothyroidism, was the most common adverse event with a prevalence of 9% (P = 0.019). However, none of these studies accounted for differences among various racial groups and outcomes in all cancer subtypes is sparse.

Minority patient enrollment, specifically African American patients, in immunotherapy trials across various tumor types was less than 5%[14]. This raises an important gap in the understanding of clinical outcomes in these patients with the use of ICPi. A study done in 136 metastatic NSCLC patients who received immunotherapy at our institutions did not show a difference in efficacy or safety among Caucasians and AA races (unpublished results). Out of the 293 patients in our study with various stage IV solid malignancies, 41.6% of patients were AA. The incidence of irAE was significantly higher in Caucasians vs AA 60.4% and 30.8% respectively, P = 0.0141. Moreover, a higher median OS was also seen with Caucasian race vs AA in patients with irAE (20.6 vs 12.9 mo, P = 0.0237) and in those with endocrine irAEs (21.8 vs 15.8 mo, P = 0.0356). Although this did not translate to a better probability of survival, our study adds important real-world data in this under-represented group of patients.

A major limitation to our study is the significant heterogeneity in baseline patient characteristics including tumor subtype, type of immunotherapy used, and line of treatment. Despite these limitations, our study confirmed our primary endpoint of improved survival outcomes in patients who develop irAE during treatment. In other subgroups of interest such as Caucasian race and patients with endocrine irAE, there was a positive correlation with median OS however this was not translated to increased rate of survival due to discordant results between the two statistical tests. Prospective studies in similar patients with pre-specified multivariate analyses accounting for tumor type, type of ICPi and line of treatment may further elicit important patterns and could lead to definitive conclusions in these subgroups.

Development of irAEs improves PFS and OS in patients with advanced stage solid malignancies treated with ICPi. Our study also underscored two important factors, race and endocrine irAEs, as possible surrogate markers for improved survival given the noted positive correlation with median overall survival.