Treatment-Related Adverse Events Predict Improved Clinical Outcome in NSCLC Patients on KEYNOTE-001 at a Single Center

Abstract

We retrospectively analyzed non-small cell lung cancer (NSCLC) patients from a single center treated with pembrolizumab on the KEYNOTE-001 trial and evaluated the association between treatment-related adverse events (trAEs) and clinical outcomes. Investigators reported AEs on trial and graded them according to Common Terminology Criteria for Adverse Events v4.0, labeling them as unlikely, possibly, or probably treatment-related. AEs labeled as possibly/probably related were considered trAEs for this analysis. The relationship between the incidence of a trAE and clinical outcomes was evaluated. Ninety-seven NSCLC patients treated on KEYNOTE-001 at the University of California, Los Angeles were evaluated. Ten percent (85/826) of AEs were trAEs, occurring in 40% (39/97) of patients. The most frequent trAEs were rash (21% patients), fatigue (6% patients), and hypothyroidism (6% patients). The 39 patients that experienced a trAE had increased objective response rate (ORR, 38.5%), progression-free survival (PFS: median, 248 days), and overall survival (OS: median, 493 days), compared with the 58 patients that did not (ORR: 8.9%, PFS: median 60 days, OS: median 144.5 days). The observed association between trAEs and improved clinical outcome persisted when using Cox proportional hazards regression models to assess the confounding effect of covariates and mitigate guarantee-time bias. The association also remained when data were substratified by grade, degree of association, and treatment-related select AE designation. This single-center analysis revealed that trAEs predicted for improved clinical outcome with pembrolizumab, and when controlling for guarantee-time bias and plausible confounders, this association remained. This observed relationship adds to our understanding of anti-PD-1 therapy and could aid clinicians in identifying patients most likely to benefit from therapy.

Are immune-related adverse events associated with the efficacy of immune checkpoint inhibitors in patients with cancer? A systematic review and meta-analysis

“…A number of recent studies has supported this hypothesis by showing favorable outcomes for patients with non-small cell lung cancer (NSCLC) and melanoma who developed various irAEs in response to immune checkpoint inhibition [4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20][21][22]. However, a definite conclusion has not been drawn based on the findings from each single study, as contradictory results exist [23][24][25][26][27][28][29][30][31][32][33][34][35]. A systemic review included 16 studies and reported that irAEs such as pneumonitis, thyroid disorders, myalgias, and mucosal toxicity did not show a significant correlation with overall survival (OS) [36].…”

Putative Abscopal Effect in Three Patients Treated by Combined Radiotherapy and Modulated Electrohyperthermia

“…As the use of immunotherapy becomes more popular, irAE is emerging as an issue (35). irAEs from ICP inhibitors are generally regarded as a "toxicity, " however, a number of reports are beginning to appear in the literature claiming that patients with higher irAEs may have a higher response rate (36,37). In addition, patients with irAE have longer treatment durations and more time to develop autoimmune toxicities (35).…”

A multidisciplinary toxicity team for cancer immunotherapy-related adverse events.

“…Electronic or in-person IR-tox teams could serve as independent adjudicators of irAE attributions, and resolve relative discrepancies in irAE attribution between study sites, noted in irAE publications. 17 One limitation of this study was the lack of a control group (ie, patients for which the IR-tox team was not available for consultation). Future studies might aim to evaluate time to referral, time to irAE treatment, or time to irAE resolution in patients referred to the IR-tox team versus not.…”