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More context would be helpful on kidney cancer “breakthrough”

CheckMate-025 study led by the University of Texas MD Anderson Cancer Center portends paradigm change in standard of care treatment

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IMAGE: This is Padmanee Sharma, M.D., Ph.D. view more

Credit: MD Anderson Cancer Center

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.

Researchers at The University of Texas MD Anderson Cancer Center demonstrated a median overall survival benefit of 25 months with nivolumab, a Food and Drug Administration (FDA)-approved immunotherapy agent, compared with 19.6 months for everolimus, a current standard of care for patients with metastatic kidney cancer.

Published online by the New England Journal of Medicine and being presented this week at a Presidential session of the European Cancer Congress (ECC), the findings of CheckMate-025 provide definitive evidence that an immune checkpoint inhibitor is a valid treatment strategy for patients with advanced RCC, and supports a paradigm change in the standard of care treatment, according to the authors.

Nivolumab, marketed as Opdivo, is currently used to treat metastatic melanoma and advanced non-small cell lung cancer. CheckMate-025 is an example of how investigators are examining approved immunotherapy drugs to determine potential impact on other tumor types.

“Immunotherapy has long been believed to have the potential to make an impact in kidney cancer, but until now we had not been able to demonstrate such a significant survival benefit. We have a real opportunity to change clinical practice for patients when other therapies have failed,” said principal investigator Padmanee Sharma, MD, PhD, professor, Departments of Genitourinary Medical Oncology and Immunology and scientific director of the Immunotherapy Platform, part of MD Anderson’s Moon Shots Program.

“Through studies such as CheckMate-025, we are learning to target the patients’ immune systems to fight cancer rather than targeting the tumor itself. This is a new way forward.”

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).

The study included 821 patients with advanced RCC across 151 sites in 24 countries in North America, Europe, Australia, South America and Asia. All had previously been treated with one or two antiangiogenic therapies, drugs that inhibit the growth of new blood vessels, a critical component of cancer development. The median duration of treatment was 5.5 months with nivolumab and 3.7 months with everolimus.

In addition to demonstrating increased overall survival, the researchers showed a higher objective response rate – the number of patients who respond to the treatment – with nivolumab. Of the 821 patients enrolled, 25% responded to nivolumab versus 5% of those treated with everolimus.

Among these patients, partial responses were observed in 24% of those treated with nivolumab and 5% of patients treated with everolimus; complete responses were observed in 1% (four patients) treated with nivolumab and fewer than 1% (two patients) treated with everolimus.

Further, among patients who showed a response, the impact was “durable,” according to Sharma. While median progression-free survival appeared similar between treatments (4.6 months and 4.4 months with nivolumab and everolimus, respectively), when researchers explored a delayed progression-free survival benefit at six months, they reported 15.6 months with nivolumab and 11.7 months with everolimus. This ongoing response was observed among 44% of those treated with nivolumab and 36% of those treated with everolimus. More than 12 months later, 31% and 27% of patients treated with nivolumab and everolimus, respectively, continued to show a response.

For some patients, even after treatment with nivolumab ended, response to the drug continued. “The immune system has a memory, so even when treatment has stopped, the body continues to exhibit a long-term response – meaning these patients can live normal lives without progressive disease.”

Finally, the investigators observed fewer treatment-related adverse events, including fatigue and nausea, and improved quality of life with nivolumab.

Trial halted early; breakthrough therapy designation granted by FDA

These results led the trial to be halted early in July 2015 when an assessment conducted by the independent Data Monitoring Committee (DMC) concluded that the study met its primary endpoint, demonstrating superior overall survival in patients receiving nivolumab.

Nivolumab blocks a T cell inhibitory signaling pathway known as PD-1 that controls the immune response and can prevent the immune system from attacking cancerous cells. The drug is approved for metastatic melanoma patients who show no response to other treatments and for advanced squamous non-small cell lung cancer (NSCLC) with progression on or after chemotherapy. Based on the CheckMate-025 findings, earlier this month (September 16) the FDA granted Breakthrough Therapy Designation to nivolumab for the potential indication of metastatic RCC. 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.

“The next questions are, ‘how do we increase the number of patients who respond?’ and ‘how do we move immune checkpoint agents into the frontline setting?’ – not just using them when other therapies have failed but intervening earlier,” said Sharma. “We’re studying combination therapies to answer these questions and believe these studies will change the way we treat many cancers.”

Each year, there are 338,000 new cases of RCC diagnosed worldwide; it is the most common type of kidney cancer among adults and approximately 30% of patients present with metastatic disease at diagnosis, according to the scientific literature. 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.

“While these treatments have changed the therapeutic landscape for RCC, they are associated with limited survival following emerging resistance to therapy,” said Sharma. “The overall survival benefit shown in this study sets a new benchmark for therapeutic strategies for advanced RCC patients in need of a second-line therapy.”

Sharma is scientific director of MD Anderson’s immunotherapy platform, which provides immune monitoring expertise to MD Anderson’s 85 clinical trials of immunotherapy drugs as single agents or in combinations. Platform investigators conduct research to understand which patients will benefit from immunotherapy, to evaluate effective drug combinations and to identify new molecules that block or stimulate immune response.

The platform is part of MD Anderson’s Moon Shots Program, which is designed to harness scientific knowledge and develop new technologies that will dramatically reduce cancer deaths through prevention, early detection and treatment.

Rating

3 Star

Breakthrough study demonstrates survival advantage with immune checkpoint inhibitor for advanced kidney cancer patients

Our Review Summary

Breakthrough 410x410News 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.”

 

Why This Matters

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).

Criteria

Does the news release adequately discuss the costs of the intervention?

Not Satisfactory

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.

calculation

nivolumab = 3mg/kg x 70kg = 210mg @$30/mg=$6,300 x 2 = $12,600
everolimus = $11,500 for 30 tablets

Does the news release adequately quantify the benefits of the treatment/test/product/procedure?

Satisfactory

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.”

Does the news release adequately explain/quantify the harms of the intervention?

Not Satisfactory

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.

Does the news release seem to grasp the quality of the evidence?

Satisfactory

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.

Does the news release commit disease-mongering?

Satisfactory

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.

Does the news release identify funding sources & disclose conflicts of interest?

Not Satisfactory

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.

Does the news release compare the new approach with existing alternatives?

Satisfactory

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.

Does the news release establish the availability of the treatment/test/product/procedure?

Not Satisfactory

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.

Does the news release establish the true novelty of the approach?

Satisfactory

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.”

Does the news release include unjustifiable, sensational language, including in the quotes of researchers?

Satisfactory

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.”

Total Score: 6 of 10 Satisfactory

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