For more than two decades, the clinical experience with high dose (HD) IL-2 has provided proof of principle that immunotherapy can produce durable responses in a small percentage of patients with clear cell RCC (ccRCC) and obviate the need for subsequent therapy. However, its toxicity and limited efficacy has severely narrowed its application. Agents that induce a high proportion of durable tumor responses with acceptable toxicity remain a critical unmet need for mRCC patients. Ongoing clinical trials evaluating immune checkpoint blockade with CTLA-4 and PD-1/PD-L1 antibodies have demonstrated impressive clinical efficacy in many tumors and seem poised to shift the cancer treatment paradigm.
This edition of the Kidney Cancer Journal describes the results of the first, large randomized trial of PD-1 blockade in ccRCC patients who had failed prior therapy (Checkmate-025) (Motzer et al., NEJM 2015). In this pivotal trial, nivolumab produced clinically meaningful improvements in overall survival and quality of life, while displaying a favorable toxicity profile. Importantly, PD-1 pathway blockade led to a durable benefit without the toxicity associated with HD IL-2.
At the recent International Symposium of the Kidney Cancer Association, investigators debated ways in which we could build upon this new standard of care and optimize the therapeutic potential of PD-1 blockade based immunotherapy. Given the recent FDA approval of nivolumab (BMS) in RCC, several critical unanswered questions will likely pose an immediate challenge to patient management. For example, when can PD-1 blockade by safely discontinued? Does it need to be given for two years, indefinitely, or can some patient stop early and still achieve treatment-free survival?
Currently available data suggest that the answer may vary in different patients. Since most responses to PD-1 blockade occur early (< 6 months) and treatment can last for two years or beyond, it is likely that we are “over-treating” a subset of patients. But how do we identify those patients? This may require considering novel trial designs with novel endpoints, such as the sorafenib randomized discontinuation study that confirmed its clinical activity in RCC patients with stable disease.
While published response rates are encouraging, how many are durable when immune checkpoint blockade is discontinued? In melanoma patients, the survival curve for patients treated with CTLA-4 blockade (ipilimumab) begins to plateau at 2 years at over 20%, even though the treatment may only last 12 weeks. But emerging evidence suggests that the plateau in the OS curve may not be as firm with PD-1 blockade. For example, in melanoma patients treated with nivolumab, the overall survival rate at 2 years was an impressive 48%, and yet, when patients are followed further, the OS rate trended downward, leading to the question, where will the curve plateau? Identifying the patients who can stop therapy early and those that need maintenance will be essential to improving outcomes for our patients.
During this important discussion at the IKCA meeting, questions that are the subject of ongoing translational research efforts arose, including: What are the mechanisms of innate resistance to PD-1 pathway blockade and what factors, in addition to PD-L1 expression, can reliably predict durable benefit? Preliminary correlative studies were presented that demonstrate that while PD-L1 expression on the tumor or infiltrating immune cells may increase the likelihood of benefit with PD-1 blockade, it fails to reliably identify all responders.
Accumulating evidence was presented that suggests that responsiveness to immune checkpoint blockade may correlate with infiltration of cytotoxic T-cells, tumor grade and mutational/neo-antigen burden. Tumor heterogeneity, which complicates most predictive biomarker discovery efforts in RCC, will almost certainly pose a challenge to investigators. Given the robust antitumor activity of VEGF pathway inhibitors, the application of single agent PD-1 blockade in the treatment naïve setting will likely require the development of a biomarker model that incorporates multiple factors and provides greater positive predictive value.
While many patients do not respond to single agent immunotherapy, the tolerability of these agents makes them ideal backbones for combination treatment regimens designed to overcome resistance. For example, combined inhibition of both CTLA-4 and PD-1 induces impressive antitumor activity, albeit with significant toxicity, in patients with melanoma and is being explored in ccRCC (e.g. NCT02231749). With this approach, tumor responses seem to occur with equal frequency in PD-L1 positive and negative tumors suggesting that the addition of anti-CTLA-4 alters factors in the tumor microenvironment, making PD-L1 negative tumors more susceptible to anti-PD-1 blockade.
Given their additive toxicity and cost, combination approaches need to be rationally designed and used. Pre-clinical models suggest that several other methods of modifying the tumor microenvironment (e.g. binding VEGF, blocking IDO or inhibiting MDSC) enhance the activity of PD-1 pathway blockade, supporting their exploration in randomized trials (e.g. NCT02420821).
Over the last decade, an improved understanding of kidney cancer tumor biology has led to major advancements in the treatment of patients with metastatic disease. While agents that target the VEGF and mTOR pathways prolong survival, resistance develops for most patients within the first year of therapy. Agents that lead to durable remissions are of urgent need to patients living with this disease. To optimize the therapeutic potential of PD-1 blockade, integrated studies that combine clinico-pathologic assessment, genomics, immunology and immunocompetent murine models of kidney cancer will be essential. Emerging data from ongoing basic and translational research studies should help answer many of the important questions that remain.
David F. McDermott, MD
Leader, Kidney Cancer Program
Dana-Farber/Harvard Cancer Center
Director, Biologic Therapy and Cutaneous Oncology Programs
Beth Israel Deaconess Medical Center
Associate Professor of Medicine,
Harvard Medical School