Pembrolizumab's lack of efficacy in TKI naïve, PD-L1+, EGFR-mutant patients with advanced NSCLC, including those with PD-L1 expression ≥50%, suggests that it is not an appropriate therapeutic choice in this setting.
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.
Background
Clinical trials in lung cancer increasingly require subjects to provide fresh tumor tissue as a prerequisite to enrollment. The effects of this requirement on enrollment rates, enrollment durations, and subject selection have not been fully elucidated.
Methods
We retrospectively reviewed data generated by patients who consented to one or more interventional lung cancer clinical trials the UCLA Jonsson Comprehensive Cancer Center between January 2013 and December 2014. Trials were considered to require a biopsy when enrollment was conditional on the procurement of tissue without intervening therapy between procurement and enrollment.
Results:
311 patients underwent 368 screening incidents for one or more of 19 trials. Trials that required a new biopsy had a longer median screening duration (34 vs. 14 days) than trials that did not require a biopsy (p<0.001). Trials requiring a biopsy had a greater screen failure rate (49.1% v. 26.5%, p<0.001), largely driven by patients who did not undergo the required biopsy or lacked the required biomarker. Worsening performance status led to the majority of screen failures (56.5%) among biomarker-eligible patients.
Conclusions:
Although the scientific benefits of obtaining a new biopsy and requiring specific results for trial enrollment are clear, it leads to a lengthening of the screening period, which, in some cases, is associated with clinical decline prior to enrollment. Implications for the interpretation of data from studies of this design should be explored.
After decades without promising new treatments for advanced and metastatic melanoma, ipilimumab was the first systemic therapy approved for use in this patient population. A fully human monoclonal antibody that blocks cytotoxic T-lymphocyte antigen 4 (CTLA-4) to augment antitumor T-cell responses, ipilimumab significantly extended overall survival in clinical trials. Because ipilimumab is associated with a set of immune-related adverse events that likely reflect the agent’s mechanism of action, a management guide has been established. Nurses play a significant role in initially identifying these adverse reactions and assisting in patient education, treatment, and follow-up. Herein, we discuss commonly asked questions related to ipilimumab therapy and treatment of adverse events, and how nurses can be prepared to answer these questions as they arise from patients and caregivers.
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