Several factors associated with a diminished response to immune checkpoint inhibitor (ICI) drugs among patients with metastatic clear cell renal cell carcinoma (ccRCC) have been identified.
They include the patient being aged 75 years or older, being assessed as intermediate on the Memorial Sloan Kettering Cancer Center (MSKCC) risk score, and having tumors with a PD-L1 expression below 1% and with a lack of sarcomatoid differentiation.
“These baseline factors may help to guide the delivery of anti–PD-1/ PD-L1 immunotherapy” metastatic ccRCC, said investigator and medical oncologist Winson Cheung, MD, MPH, a professor at the University of Calgary, Alberta, Canada, and colleagues.
The findings come from a meta-analysis of seven phase 2/3 trials, which was published January 26 in JAMA Open Network.
However, experts writing in an accompanying editorial say these findings from pooled trial data “should be interpreted with caution.”
Identifying Patients Likely to Respond
The team was addressing the large variability in response to ICIs that is seen among patients with ccRCC — and they were hoping to find predictive biomarkers. “Identifying which characteristics are associated with response to PD-1/PD-L1 inhibitors is an important task,” they write. “Specifically, the targeting of ICIs to patients who are most likely to respond…could lead to cost savings.”
However, although efficacy may be lower among some groups, “it is important to recognize” that ICIs “may still be more efficacious than the prior standard therapies,” they note.
The team pooled data from six trials that pitted immunotherapy with pembrolizumab, nivolumab, avelumab, or atezolizumab — either alone or in combination with antiangiogenesis agents — against the kinase inhibitors sunitinib or everolimus for metastatic ccRCC, as well as a nivolumab study without a comparator.
The outcome of interest was the ratio of subgroup-specific hazard ratios, with a value of 1 indicating that the hazard ratios of the compared groups were equal in magnitude, but values other than 1 indicating that one group had an advantage.
Overall survival was longer in patients younger than 65 years compared with those 75 years or older (HR ratio older to younger, 1.51).
Progression-free survival (PFS) was longer among subjects with a PD-L1 expression of at least 10% (ratio lower to higher expression 2.21) or at least 1% (ratio lower to higher expression, 1.36) vs subjects with expression below 1%.
PFS was also longer in subjects with a poor MSKCC risk score vs an intermediate score (ratio intermediate to poor score HR, 1.62), and among subjects whose tumors exhibited sarcomatoid differentiation vs those who did not (ratio no differentiation to differentiation, 1.54).
Interpret With Caution
“There is a tremendous clinical need to identify factors associated with response” in metastatic ccRCC, say urologic oncologist Alice Fan, MD, and urologist/nephrologist John Leppert, MD, both at Stanford University, Stanford, California, in the editorial.
Currently, patients cycle through multiple regimens searching for the best outcome, an approach that exposes them “to maximal toxic effects but does not optimize clinical benefit,” Fan and Leppert say. The need is especially pressing for checkpoint inhibitors, which can take months to show maximal response.
However, although the study identified groups of individuals “that may be preferentially selected” for ICI treatment, reliance on pooled data from trials with different designs, inclusion criteria, and treatment regimens “is challenging,” they comment.
Older patients “can exhibit dramatic responses” to checkpoint inhibition, Fan and Leppert note. Response can be good even without sarcomatoid differentiation, and PD-L1 expression is not always associated with response, they caution.
Link to MSKCC Score a Mystery
There are many possible explanations for the study findings. The diminished overall survival among older patients could simply be a result of age-related comorbidities, chronic inflammation, or reduced T-cell activation, among other possibilities. The team agreed that the age finding can’t be taken at face value because of the underrepresentation of older patients in clinical trials.
However, diminished PFS with lower PD-L1 expression makes sense because “tumors that have an increased dependence on immunosuppression via PD-L1 are more likely to be affected by the inhibition of the PD-1/PD-L1 pathway,” the researchers comment.
Similarly, sarcomatoid RRC also has higher expression of PD-L1, which likely accounts for better PFS with sarcomatoid features.
The finding of diminished PFS with intermediate MSKCC risk scores, vs poor scores, is more of a mystery. Response was also diminished among patients with favorable scores, although not significantly so. Meanwhile, there was no differential response based on International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) risk scores.
The team didn’t offer an explanation, but noted that the MSKCC score “may be better suited to targeting the delivery of ICIs…These findings align with the Society for Immunotherapy of Cancer consensus statement wherein 76% of subcommittee members believed that the IMDC categories could not be used to guide the delivery of anti–PD-1/tyrosine kinase inhibitor combination therapy.”
Study limitations include the small number of trials in the meta-analysis and the inability to adjust for patient-level factors. It was also assumed that the magnitude of difference between subgroups would be similar across across ICIs. “In support of this hypothesis, there was little to no heterogeneity in these meta-analyses,” the investigators note.
The hunt for predictors of response will continue. “We remain optimistic,” editorialists Fan and Leppert write, “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.”
A funding source was not reported. Three of the five investigators are employees of Cytel, a provider of statistical software and analytics for clinical trial design and execution. The investigators and editorialists have disclosed no relevant financial relationships.
M. Alexander Otto is a physician assistant with a master’s degree in medical science, and an award-winning medical journalist who has worked for several major news outlets before joining Medscape, including McClatchy and Bloomberg. He is an MIT Knight Science Journalism fellow. Email: [email protected]