News releases from academic centers can fall victim to the hyperbole and excessive optimism often seen in the commercial realm. This release from MD Anderson Cancer Center avoids the worst excesses and we liked much of what was written, including the description of the study design and quantification of the survival benefit. But some important omissions are evident. We can perhaps forgive the release for not including a discussion of cost. But there were other significant deficiencies, including lack of a meaningful discussion on potential harms of the treatment, no mention of the study funding source, and no disclosure that the principal investigator (quoted extensively in the release) is a consultant to the manufacturer of nivolumab. These are important elements to help readers understand the true extent of this “breakthrough.”
Although a somewhat uncommon form of cancer, renal cell carcinoma (RCC) is an important topic. As is noted by the news release, a significant number of patients with the disease present with metastases making treatment difficult. Existing therapies are not ideal with only moderate improvements in survival. The demonstration of an immunotherapy for RCC that is more effective than existing treatments is encouraging. We should note that the “breakthrough designation” from the FDA is “… intended to expedite the development and review of medicines with early signals of potential clinical benefit in serious diseases to help ensure patients have access to new therapies as soon as possible” (our emphasis added).
Cancer treatments are very (some would same ridiculously) expensive and the two treatments highlighted in this release are no exception. To put it into perspective, we calculate the monthly cost of nivolumab to be in the vicinity of $12,600 (not including administration fees) and of everolimus at $11,500 month.
nivolumab = 3mg/kg x 70kg = 210mg @$30/mg=$6,300 x 2 = $12,600
everolimus = $11,500 for 30 tablets
The primary outcome measure for the study was median survival. The news release notes, “In the randomized phase III clinical trial, patients whose disease progressed on antiangiogenic therapies were treated with either nivolumab or everolimus. Median overall survival was 5.4 months longer with nivolumab (25 months) compared with everolimus (19.6 months).” We are also told, “More than 12 months later, 31% and 27% of patients treated with nivolumab and everolimus, respectively, continued to show a response.”
If one is discerning, it becomes clear that this new treatment buys a patient about 5 months of survival time. That’s certainly valuable time, but it’s debatable whether that amounts to the kind of benefit patients associate with the term “breakthrough.”
The release says only that there were “fewer treatment-related adverse events, including fatigue and nausea, and improved quality of life with nivolumab.” But that’s not really a satisfactory accounting of the harms of treatment. As the article in the NEJM notes, “Treatment related adverse events of any grade occurred in 319 of the 406 patients (79%) treated with nivolumab and in 349 of the 397 (88%) treated with everolimus.” The release should have given readers more insight into what these harms are and how often they occur.
The release provides a good deal of information on the study design, number of subjects treated in each arm and provides additional comments on secondary outcome measures.
The release appropriately notes the number of cases of RCC diagnosed worldwide and the frequency on metastatic disease on presentation. We would have preferred it if the prevalence of the disease had been described as a rate (per 100,000), so we could appreciate how rare it is.
The news release fails to note that the study was funded by the manufacturer of nivolumab (Bristol Myers Squibb) and that Dr. Sharma is a consultant to the company. This is important context.
Although not named specifically, other therapies are mentioned: ” A number of targeted therapies have been approved in recent years for the treatment of advanced RCC, with five antiangiogenic and two mTOR inhibitors (including everolimus; these drugs block a protein that regulates cell growth, proliferation, survival, etc.), showing benefits in pivotal phase III trials”
To be sure, this is not really a true comparison of options, just a listing. But since the main alternative is the treatment used in the trial, this may be a moot point. We’ll give the benefit of the doubt on the rating.
The release makes it clear that “Nivolumab, marketed as Opdivo, is currently used to treat metastatic melanoma and advanced non-small cell lung cancer.” However it is silent on the availability of everolimus (Afinitor). The release also did not mention insurance coverage for these treatments.
The release establishes novelty in the lead sentence: “For the first time, an immune checkpoint inhibitor has been proven to increase survival among patients with advanced renal cell carcinoma (RCC), a patient population for whom treatment options are currently limited.” It also establishes that the drug “is currently used to treat metastatic melanoma and advanced non-small cell lung cancer.”
The language of the release is somewhat hyperbolic given the small magnitude of the benefit. Examples: “breakthrough” … “this is a new way forward” … “this study sets a new benchmark for therapeutic strategies for advanced RCC patients” … “portends paradigm change.” However, the term “breakthrough” is technically consistent with the FDA designation of nivolumab as a “Breakthrough Therapy.” We’ve been critical of that designation because we think it skews patient expectations and may set them up for disappointment. But we’ll give the benefit of the doubt on the rating. We remind readers, as the release does, that the “Breakthrough Therapy designation is intended to expedite the development and review of medicines with early signals of clinical benefit in serious diseases to help ensure patients have access to new therapies as soon as possible.”