Finally, Drug Improves Survival in Pretreated Kidney Cancer

Zosia Chustecka

September 25, 2015

UPDATED September 26, 2015 // VIENNA ― The past few years have seen seven new drugs receive approval for the treatment of renal cell carcinoma, but they may all have to move over now that immunotherapy has arrived on the scene.

New results released today for nivolumab (Opdivo, Bristol-Myers Squibb Company) show that pretreated patients lived for nearly 6 months longer on the immunotherapy compared with the standard treatment, everolimus (Afinitor, Novartis Pharmaceuticals Corporation).

This is the first time that a benefit in overall survival benefit has been seen in a clinical trial of second-line treatment for renal cell carcinoma ― all previous trials, which have been used for drug approvals, have shown only an improvement in progression-free survival.

"Nivolumab has set a new benchmark," said Cora Sternberg, MD, from the San Camillo Forlanini Hospital, in Rome, who discussed the results here at European Cancer Congress (ECC) 2015.

The new results with nivolumab "are significant and clinically meaningful" and "are likely to change the treatment of patients with advanced kidney cancer whose disease has progressed on prior treatment," said senior author Padmanee Sharma, MD, professor of genitourinary medical oncology and immunology at the MD Anderson Cancer Center, Houston, Texas.

Dr Padmanee Sharma

The results come from a phase 3 trial (CheckMate 025) conducted in 821 patients with renal cell carcinoma who had stopped responding to antiangiogenic therapies.

The median overall survival was 25 months with nivolumab vs 19.6 months with everolimus (hazard ratio, 0.73; P = .002).

In addition, more patients responded to the immunotherapy ― the objective response rate was 25% for nivolumab vs 5.4% for everolimus (P < .001).

"We hope that this study will quickly lead to approval of nivolumab as a standard-of-care therapy for these patients," Dr Sharma commented in a statement.

Nivolumab is already approved for use in melanoma and in lung cancer, having been shown to improve in survival in comparison with standard therapies in both tumor types. Now kidney cancer looks as if it could be the next indication to be approved.

Nivolumab Is Now "The Drug of Choice"

The new results were presented by Dr Sharma at a presidential session and have been published online in the New England Journal of Medicine.

Another presentation at the same session featured another trial in pretreated renal cell carcinoma (the METEOR trial), in which improved progression-free survival (PFS) was seen with cabozantinib (Cometriq, Exelixis, Inc) in comparison with everolimus, as reported by Medscape Medical News. These two presentations are "definitely among the highlights of this congress," commented Peter Naredi, MD, PhD, the European CanCer Organisation (ECCO) scientific co-chair for the meeting. Dr Naredi, who is also professor of surgery at Sahlgrenska University Hospital, in Gothenburg, Sweden, was not involved with either trial.

"For patients with advanced kidney cancer who have progressed on earlier treatment, we now get two novel treatment options, both with different mechanisms of action," he said.

But nivolumab is the clear winner here, suggests a New England Journal of Medicine editorial that accompanies the publication of both trials. The editorial was written by David I. Quinn, MB, PhD, University of Southern California Norris Comprehensive Cancer Center, Los Angeles, and Primo N. Lara, Jr, MD, from the University of California Davis Comprehensive Cancer Center, Sacramento .

"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 write, whereas "cabozantinib is a salvage treatment for patients whose tumors progress during VEGF therapy."

They note that cabozantinib has not shown a significant overall survival benefit and had significant side effects that necessitated a dose reduction in 60% or more of patients ― for these reasons, they say, it "will not precede nivolumab in the therapeutic sequence."

First Trial in Second Line to Show Survival Benefit

Dr Sharma emphasized to Medscape Medical News that this trial is the first in the second-line setting in kidney cancer to show a survival benefit.

The drugs currently used were all approved on the basis of an improvement in PFS, the authors note in their paper. Interestingly, nivolumab did not improve PFS; there was no significant difference in PFS between it and everolimus. But this has been seen previously with immunotherapy in the treatment of other cancers, Dr Parma said, for example, in melanoma.

In her discussion, Dr Sternberg said that the PFS results do not reflect the significant tumor shrinkage that was seen with nivolumab.

Dr Sharma also emphasized the novel mechanism of action of nivolumab.

The other drugs for kidney cancer all act on the tumor itself, either by targeting vascular endothelial growth factor, as does bevacizumab (Avastin, Genentech, Inc); or its receptors, as do sunitinib (Sutent, Pfizer Inc), sorafenib (Nexavar, Bayer HealthCare Pharmaceuticals), pazopanib (Votrient, Novartis Pharmaceuticals Inc), and axitinib (Inlyta, Pfizer Inc); or by targeting the mammalian target of rapamicin (MTOR), as do everolimus and temsirolimus (Torisel, PF Prism CV).

In contrast, nivolumab acts on the immune system, where it works by creating memory in T cells. These novel immunotherapy approaches have already shown long-lasting responses, Dr Sharma said.

As an example, she cited the long-term responses seen in metastatic melanoma patients with another immune checkpoint inhibitor, ipilimumab (Yervoy, Bristol-Myers Squibb Company). Some patients are still alive after 10 years, whereas in the past, these patients would have been dead within months.

"We are not there yet," she commented, but noted that the kidney cancer patients who responded to nivolumab are continuing to respond. Even some of the patients who have stopped taking nivolumab are still responding, she added..

These are patients with metastatic disease, and they have a dismal prognosis, she added. The 5-year survival is only 8%, she said at the press briefing.

Although applauding the results, Martine Piccart, MD, president of ECCO, added a sober note to the discussion. The new immunotherapy drugs are very expensive, and there are countries in Europe that will not be able to afford them, she said, especially in this palliative setting. Already for several of the drugs approved for metastatic kidney cancer, including everolimus, drug costs are not reimbursable in the United Kingdom.

In addition, there is a question of how long patients receiving nivolumab would need to continue with therapy, noted Dr Piccart. This point was also raised by Dr Sternberg in her discussion: the duration of therapy would also have an impact on cost, especially if patients do survive for years and have to continue to take these expensive drugs.

This issue was also noted in the NEJM editorial by Dr Quinn and Dr Lara, who raise the "practical question of whether these new therapies provide sufficient value in resource-constrained health care environments."

“Effective treatments will work only if they are accessible to the patients they are designed to help,”’ they add..

PDL1 Expression Not a Marker

Previous studies with nivolumab and related agents, which work as inhibitors of the cell programmed death pathway, have explored various biological features that could be used to indicate which patients are most likely to respond. A front-runner among these has been the measure of programmed death ligand 1 (PDL1) expression.

However, the results from this trial suggest that PDL1 expression cannot be used as a marker.

"The finding that overall survival was higher among patients treated with nivolumab, irrespective of PDL1 expression, suggests that PDL1 expression should not be used to determine which patients might respond to the therapy and whether or not to offer it to them," Dr Sharma commented.

"PDL1 is a dynamic biomarker that changes over time as a result of evolving immune responses," she explained. "So it is not surprising that PDL1 measured in tumor samples before treatment does not capture the true expression of PDL1 and how it may correlate to responses to treatment. I would expect that tumor samples taken while patients were on treatment, as opposed to pretreatment, might indicate that PDL1 expression, as well as other markers of immune response, has a correlation with response to treatment."

The study was funded by Bristol-Myers Squibb. Dr Sharma reported consultancy for Amgen , Bristol-Myers Squibb , GlaxoSmithKline, and AstraZeneca/MedImmune and also consultancy and stock ownership in Jounce Therapeutics. Dr Corenberg was an investigator in the trial.

European Cancer Congress (ECC) 2015. Abstract LBA. To be presented September 26, 2015.


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