Predicting Responses to PD-1/PD-L1 Immunotherapies Just Got Easier

According to results from a recent systematic review and meta-analysis, diminished responses to anti-programmed cell death 1/programmed cell death ligand 1 (PD-1/PD-L1) immunotherapies in patients with metastatic clear cell renal cell carcinoma (ccRCC) are associated with older age, lower levels of PD-L1 expression, favorable to intermediate Memorial Sloan Kettering Cancer Center (MSKCC) risk score, and the absence of sarcomatoid tumor differentiation.

The findings from a recent systematic review and meta-analysis were published in JAMA Network Open.

Researchers, led by senior author Paul Arora, MSc, PhD, of Cytel Inc. in Toronto, theorized that the identification of these baseline factors may help guide clinicians in the delivery of anti-PD-1/PD-L1 immunotherapies for these patients.

Activated T cells express the PD-1 receptor, while dendritic cell express PD-L1. The interplay between these proteins controls inflammation in the body and thus minimizes tissue damage. Because tumor cells are capable of expressing PD-L1, tumor cells with PD-L1 positivity can escape the body’s immune response via the PD-L1 pathway. Anti-PD-1/PD-L1 agents work to block the signaling pathway between PD-1 and PD-L1, thus putting into motion T-cell inhibitory processes and boosting antitumor activity.

“Pembrolizumab and nivolumab are examples of anti–PD-1 drugs; avelumab, atezolizumab, and durvalumab are examples of anti–PD-L1 drugs. However, large interpatient variability exists in treatment efficacy and safety and resistance to blockade therapy. Identifying which characteristics are associated with response to PD-1/PD-L1 inhibitors is therefore an important task. Specifically, the targeting of ICIs to patients who are most likely to respond to these therapies could lead to cost savings. Research on the effect modification of ICIs is limited,” they wrote.

In this systematic review, Arora and colleagues searched MEDLINE and the Cochrane Register of Trials databases for studies focused on factors associated with differential response to PD-1/PD-L1 inhibitors in patients with metastatic ccRCC to elucidate the degree to which each factor affected responses to PD-1/PD-L1 inhibitors.

They identified 662 phase II and phase III randomized clinical trials. Of these, seven were eligible for their analysis, in which they found that responses to PD-1/PD-L1 inhibitors were significantly associated with the following factors:

• Age: Patients ages 75 years or older had a significantly diminished response to treatment with anti-PD-1/PD-L1 agents compared with those who were less than 65 years old (HR ratio: 1.51; 95% CI: 1.01-2.26; 95% PI: 1.01-2.26; I²=0%; P=0.04).
• MSKCC risk score: Patients in the intermediate MSKCC risk group at baseline demonstrated a significantly reduced response to PD-1/PD-L1 inhibitors compared with those in the poor risk group (HR ratio: 1.62; 95% CI: 1.14-2.29; 95% PI: 1.14-2.29; I²=0%; P=0.01). In addition, researchers found that patients in the favorable MSKCC subgroup had a reduced response compared with those in the poor subgroup, but this difference was not statistically significant (HR ratio: 1.53; 95% CI: 1.00-2.34; 95% PI: 1.00-2.34; I²=0%; 005). They found no differences in response in comparisons of the favorable and intermediate groups (HR ratio: 0.96; 95% CI: 0.70-1.30; 95% PI: 0.70-1.30; I²=0%; P=0.77).
• PD-L1 expression: In patients with a baseline PD-L1 response of less than 1%, response to treatment was significantly reduced compared with those who expressed PD-L1 of 1% or greater (HR ratio: 1.36; 95% CI: 1.10-1.68; 95% PI; 1.10-1.68; I²=0%; P=0.004). In addition, in two of the studies, patients who expressed a baseline PD-L1 of less than 1% demonstrated a reduced response compared with those who expressed PD-L1 of 10% or greater (HR ratio: 2.21; 95% CI: 1.14-4.27; 95% PI: 1.11-4.39; I²=2.26; P=0.02).
• Sarcomatoid differentiation: Patients without sarcomatoid tumor differentiation had a poor response to ICIs compared with those with sarcomatoid tumors (HR ratio: 1.54; 95% CI: 1.07-2.21; 95% PI: 1.07-2.21; I²=0%; P=0.02).

“Within this investigation, subgroups of patients who may have a diminished response to anti–PD-1/PD-L1 therapies were identified. However, it is important to recognize that such subgroups may still benefit from PD-1/PD-L1 inhibitors. Although the efficacy of these immunotherapies may be diminished, such therapies may still be more efficacious than the prior standard therapies within these subgroups,” they wrote.

“The treatment landscape for patients with metastatic ccRCC is rapidly evolving. Because there are currently 15 US Food and Drug Administration–approved therapies for metastatic ccRCC, patients often cycle through multiple regimens. Without biomarker-informed strategies, this empirical sequential treatment selection exposes patients to maximal toxic effects but does not optimize clinical benefit. Especially for PD-1/ PD-L1–directed therapies, which can require many months to achieve maximal response, biomarkers are being sought to estimate clinical benefit,” wrote Alice C. Fan, MD, and John T. Leppert, MD, MS, both of Stanford University School of Medicine in Stanford, California, in their invited commentary.

They stressed the importance of the findings centered on patient age but urged caution in their interpretation.

“Strikingly, in the study by Sati et al, age was the sole clinical factor associated with improved overall survival: Patients younger than 65 years had improved overall survival compared with patients aged 75 years or older. It is important to note that younger age did not meet statistical significance thresholds in any of the 3 included trials, and the relative effect in this meta-analysis was modest. Moreover, younger age was associated with improved overall survival, but not progression-free survival. Thus, it is not clear whether age is an effect modifier of response to PD-1/PD-L1–based CPI therapies, because it could also be functioning as a measure of overall health.”

Fan and Leppert also noted that these findings are of great import in correctly and specifically identifying optimal treatments for patients with metastatic ccRCC.

“The current state of biomarkers to estimate response to PD-1/PD-L1–based CPI therapy is wanting. [The researchers] identified candidate cohorts that may be preferentially selected for receipt of PD-1/PD-L1–based CPI therapy. Research efforts will continue to focus on ways to personalize treatment selection for individual patients by identifying which treatments are associated with improved overall survival, result in complete responses, and are associated with immune-related adverse events, as well as strategies that inform appropriate sequencing of individual agents or combinations of therapies. We remain optimistic that a combination of clinical characteristics, molecular biomarkers, and imaging approaches will yield biomarkers to identify treatments and significantly improve outcomes for patients with metastatic ccRCC,” they concluded.

Limitations of this systemic review and meta-analysis include an underrepresentation of older patients, the assumption that the magnitude of differences is similar across differing ICI regimens, the possibility of exploratory subgroup analyses underreporting, and the small number of clinical trials and sample sizes included.

1. In a systematic review and meta-analysis of subgroup findings from seven randomized clinical trials, researchers found that diminished responses to anti–PD-1/PD-L1 treatments were associated with older age, low levels of PD-L1 expression, intermediate Memorial Sloan Kettering Cancer Center risk scores, and the absence of sarcomatoid differentiation.

2. Researchers hope that the identification of these baseline factors may help guide clinicians in the delivery of anti-PD-1/PD-L1 immunotherapies for these patients.

E.C. Meszaros, Contributing Writer, BreakingMED™

Cat ID: 127

Topic ID: 81,127,730,835,127,192,241,925