Among treatment-naive patients with metastatic renal cell carcinoma (RCC), exceptional response to immunotherapy were noted in patients with higher clonal neoantigen load, strong enrichment of B-cell receptor signaling-related pathways, tertiary lymphoid structure (TLS) signatures and evidence of increased metabolic activity, according to research published in Nature Cancer.
In a cohort of treatment-naive patients who were treated with dual immunotherapy-based standard-of-care treatment, an analysis of genomic and transcriptomic data revealed that patients with higher clonal neoantigen load were more likely to exhibit exceptional responses to treatment. Similarly, in the immunotherapy and VEGF combination cohort, patients with exceptional responses demonstrated enrichment of B-cell receptor signaling pathways, robust TLS signatures and evidence of heightened metabolic activity.
“There really are truly a set of patients that today who might have exceptional long-term benefit from immune therapy, and that has to factor into our thinking and their thinking, though we don't have a perfect way of saying [who] in a clinical test upfront right now,” Dr. David A. Braun, said in an interview with CURE®. “The hope is that in the coming years, many groups… nationwide and internationally will push the field forward.”
Braun is an Assistant Professor of Medicine, Medical Oncology, and a Louis Goodman and Alfred Gilman Yale Scholar, at the Yale School of Medicine, and currently serves as a member of the Center of Molecular and Cellular Oncology at Yale Cancer Center, in New Haven Connecticut.
Breaking Down the Methods of Research
With over 80,000 new cases yearly in the United States alone, RCC is among the most common malignancies. Advances in metastatic disease, including the use of immune checkpoint inhibitors, have improved patient's 5-year survival rate from less than 10% in the early 2000s to nearly 50% present day. However, predicting tumor response to this treatment method remains challenging, as RCC does not follow the common paradigm linking higher tumor mutational burden (TMB) to better immunotherapy outcomes.
A subset of patients, known as "exceptional responders," achieves deep, prolonged responses to immune checkpoint inhibitors, but the clinical and molecular determinants of these outcomes remain unclear. In order to better understand these extreme phenotypes, researchers evaluated pre-treatment tumor and germline samples from patients with advanced clear cell RCC treated with immunotherapy-based combinations, identifying genomic and transcriptomic drivers of exceptional responses.
In the study, investigators evaluated genomic features linked to immunotherapy responses in clear cell RCC using whole-exome sequencing and RNA sequencing from pre-treatment tumor specimens and matched germline samples of patients enrolled onto the phase 3 JAVELIN RENAL 101 and CheckMate 214 clinical trials. The study population reflected the broader trial population with comparable survival outcomes. Exceptional response, on the trial, was defined by stringent criteria, including complete or partial response with prolonged progression-free survival (PFS), while intermediate response included responses not meeting effectiveness thresholds.
“How can we learn from [our study]? [We want] to make [these responses] not so exceptional [and a more widely accepted standard], so that we may understand the factors that lead to long-term, durable responses; the ones that patients are really hoping for and asking for. How can we rationally design our next set of experiments and ultimately clinical trials to move towards those exceptional responses? That is the goal of this kind of research,” Braun emphasized in the interview with CURE.
Delving into Additional Study Data
In the evaluation of data, investigators shared in the Nature Cancer journal article that exceptional outcome rates were comparable in trial (6.3%) and real-world (10.3%) cohorts for those who received immunotherapy and VEGF treatment; however, these outcomes were higher in trials (24.9%) versus the real-world settings (5.7%) for those who received an immunotherapy doublet. Furthermore, the median overall survival (OS) was longest in exceptional responders compared with intermediate response and progressive disease across trial and real-world settings. Subsequently, exceptional responders had a significantly improved PFS and OS across treatment regimens
Additionally, clonal neoantigen load was an independent predictor of exceptional response, and study authors noted that it was associated with longer PFS in immunotherapy-based regimens. Lower intratumoral heterogeneity correlated with exceptional responses, as well. Additionally, traditional biomarkers, such as TMB or frameshift mutations, showed limited association with these types of responses, except for higher tumor ploidy in exceptional responders to TKIs.
Additional insights derived from this research showed that exceptional responses to immunotherapy and VEGF combinations were associated with higher TLS gene expression, including adaptive immunity and plasma/memory B-cell infiltration, as well as that TLS signatures were enriched in exceptional responder group. Additionally, higher metabolic signature was an independent predictor of exceptional responses and improved PFS and OS.
“We think very deeply about what is it that patients are sort of ultimately looking for, and to [get the] best answer, you have to go to the patients themselves,” Braun explained. “The [most important] things to them are trying to get to long term durable responses, and in an ideal world, cures. [We are] trying to get to a point where patients have long term disease control…
“It is hoped that we take lessons like these and [change] exceptional responders from just a small fraction, [to a] large one. That's the lesson I hope to take from [the study]. I always want to be honest and practical about where we are today, that [these exceptional responses are] still not the majority of patients, but hopefully with the lessons learned, we can begin to move towards that,” he concluded.
Reference:
“Immunogenomic determinants of exceptional response to immune checkpoint inhibition in renal cell carcinoma” by Dr. Tejas Jammihal, et al., Nature Cancer.
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