|The following article features coverage from the American Society of Clinical Oncology 2019 meeting. Click here to read more of Cancer Therapy Advisor‘s conference coverage.|
A pooled analysis of all anti–PD-1/anti–PD-L1 trials across cancer types identified several potential risk factors for the higher early mortality rates observed in patients receiving immunotherapy, but confounding factors prevent establishing a definitive answer for this unexplained phenomenon, according to a poster presented at the 2019 American Society of Clinical Oncology (ASCO) Annual Meeting in Chicago, Illinois.1
A high early mortality rate has been noted in multiple trials evaluating PD-1/PD-L1 inhibitors, regardless of tumor type, which results in a crossing over of the overall survival Kaplan-Meier curves. Hypotheses proposed to explain this phenomenon include disease progression before a response to immunotherapy can occur or immunotherapy-associated toxicities. The purpose of this exploratory analysis by the US Food and Drug Administration (FDA) was to characterize factors associated with the high early mortality rate associated with PD-1/PD-L1 inhibitors.
The analysis included data from 18 randomized, controlled trials that had been submitted to the FDA, including single-agent and immunotherapy plus chemotherapy experimental arms, of patients with head and neck squamous cell carcinoma (HNSCC), melanoma, non-small cell lung cancer (NSCLC), renal cell carcinoma (RCC), and urothelial carcinoma (UC).
In a piecewise analysis, pooled trials of NSCLC demonstrated a hazard ratio (HR) greater than 1 for up to 90 days after treatment initiation, though most were not significant. This changed to 0.68 (95% CI, 0.63-0.74) at greater than 90 days. This pattern was not observed in the pooled analysis of the melanoma trials.
The study identified several potential risk factors for early mortality. In the NSCLC trials, there was a greater proportion of early mortality among patients with no PD-L1 expression with high baseline tumor burden and an ECOG performance status of 1 in the single-agent immunotherapy arm compared with the control arm. This pattern was not observed in the immunotherapy plus chemotherapy arm. Patients with nonsquamous histology demonstrated early mortality with single-agent or combination immunotherapy.
In the melanoma trials, poor ECOG performance status, elevated lactate dehydrogenase levels, and high baseline tumor burden were associated with early mortality with single-agent immunotherapy compared with the control arm. In addition, a greater proportion of early mortality occurred among patients with melanoma with a high baseline tumor burden and ECOG performance status of 1 whose disease was PD-L1 negative with immunotherapy compared with the control regimen.
The investigators concluded that although several potential risk factors were identified, “these high-risk subgroups do not fully explain the early mortality pattern observed in the immunotherapy-treated patients.” They also noted that the results are confounded by differences in trial design, such as whether the immunotherapy arms were being evaluated as first- or second-line treatment.
Read more of Cancer Therapy Advisor‘s coverage of ASCO’s annual meeting by visiting the conference page.
- Mulkey F, By K, Theoret MR, et al. Analysis of early mortality in randomized clinical trials evaluating anti-PD-1/PD-L1 antibodies: a systematic analysis by the United States Food and Drug Administration (FDA). Presented at: 2019 American Society of Clinical Oncology (ASCO) Annual Meeting; May 31-June 4, 2019; Chicago, IL. Abstract 2516.