When I tell people that I am a resident in urology, they often ask me why I chose this field. There are many reasons, but one of my primary motivations was to treat renal cancer, a disease that has affected several people close to me. With early detection, surgery can be curative. Unfortunately, a third of patients have metastatic disease at the time of presentation. These patients rely on systemic therapy.
Treatment for advanced clear-cell carcinoma, the most common variant of renal cancer, starts with inhibitors of vascular endothelial growth factor receptor (VEGFR). These are the “-nibs”: sunitinib, sorafenib, pazopanib, and axitinib. If one agent fails, another can be tried. Almost all patients treated with these drugs will develop drug resistance and disease progression within a year. After that, the next line of therapy typically is an inhibitor of the mammalian target of rapamycin (mTOR) – everolimus or temsirolimus. Studies have linked everolimus to longer progression-free-survival compared to placebo.
Two trials, published recently in NEJM, suggest there may be more effective alternatives. One is nivolumab, a drug that works by a differerent mechanism. Nivolumab inhibits an immune checkpoint regulator called programmed death 1 (PD-1); by disrupting signaling between PD-1 and ligands expressed on tumor cells, which would otherwise result in immunosuppression, it restores anti-tumor immunity. The CheckMate trial randomized over 800 patients with advanced clear-cell carcinoma whose disease had progressed after one or two regimens of anti-angiogenic therapy to receive either nivolumab or everolimus. The primary endpoint was overall survival.
The study found much better results with nivolumab than everolimus. The median overall survival was 25 months with nivolumab, as compared to under 20 months with everolimus, translating to a hazard ratio for death of 0.73 (P=0.002). The objective response rate, defined as the number of patients with complete or partial response divided by the total number of randomized patients, was also higher: 25% with nivolumab versus 5% with everolimus, for an odds ratio of nearly six. Meanwhile, the rate of grade 3 or 4 adverse events was lower by almost half.
A second promising agent is cabozantinib, a multikinase inhibitor that, in addition to inhibiting VEGFR, hits other targets that have been implicated in advanced renal cell cancer. The METEOR trial randomized over 650 patients to receive either cabozantinib or everolimus. Inclusion criteria were similar to that of the CheckMate trial, except there was no limit to the number of previously attempted therapies. The primary endpoint was progression-free survival (overall survival was a secondary endpoint).
Cabozantinib was found to be associated with longer median progression-free survival than everolimus – greater than 7 months, as compared to less than 3 months. That translated to a 42% lower rate of progression or death (hazard ratio 0.58). The objective response rate was 21% with cabozantinib, versus 5% with everolimus. There was also a trend toward improved overall survival (hazard ratio for death of 0.67, P=0.005), although this did not meet the requirement for statistical significance at the pre-specified interim analysis.
But cabozantinib also had its problems. Adverse events necessitated a dose reduction in 60% of patients receiving cabozantinib, as compared to only 25% of patients receiving everolimus. The rate of grade 3 or 4 adverse events was higher — 68% with cabozantinib (the most common being hypertension and diarrhea), versus 58% with everolimus (the most common being anemia and fatigue). Approximately 10% of both treatment groups had to discontinue therapy because of adverse events.
In an accompanying editorial, Drs. David Quinn and Primo Lara of the University of Southern California and University of California Davis, respectively, write: “Given the overall survival advantage it confers and its relatively good side-effect profile, nivolumab is the choice for patients who have disease progression while they are receiving VEGF-targeted therapy.” They continue, “Cabozantinib is a salvage treatment for patients whose tumors progress during VEGF therapy; however, without a significant overall survival benefit and with significant side effects…it will not precede nivolumab in the therapeutic sequence.” Both agents, they conclude, offer clinical benefit over everolimus that is “unequivocal.”
Clinical benefit and value aren’t necessarily the same. Quinn and Lara raise concern about the price of these new treatment options, which may put them out of affordable range for many patients. And with increasing scrutiny over health care spending, it’s unclear to what extent we can, or should, expect insurance to subsidize expensive therapies that prolong survival for a few months. Calculating cost is one thing. Determining value – to patients and their loved ones, to the doctors who care for them, and to the communities that surround them – is something else entirely.