'Exciting Times' With Immunotherapy for Kidney Cancer

San Francisco — Two new combination regimens are set to become new standards of care for the treatment of metastatic renal cell carcinoma (mRCC).

The new combinations contain an immunotherapy and a targeted agent.

New results with these combinations were presented here at the Genitourinary Cancers Symposium (GUCS) 2019 and were simultaneously published in the New England Journal of Medicine.

One combination is the immunotherapy pembrolizumab (Keytruda, Merck) and the vascular endothelial growth factor (VEGF)–targeted tyrosine-kinase inhibitor (TKI) axitinib (Inlyta, Pfizer). In the KEYNOTE-426 trial, the combination therapy yielded superior outcomes to the current standard of care, sunitinib (Sutent, Pfizer). As reported by Medscape Medical News, these results showed a significantly extended overall and progression-free survival for patients with previously untreated mRCC.

The other combination is the immunotherapy avelumab (Bavencio, Merck KGaA and Pfizer) and axitinib. Previously reported results from the JAVELIN Renal 101 trial showed that the combination significantly extended progression-free survival in the first-line setting in patients with advanced RCC, as compared to sunitinib. Updated results now show superior overall survival, with a 12-month rate of 89.9% vs 78.3% with sunitinib.

"These are exciting times" in the treatment of kidney cancer, commented Lori Wood, MD, associate professor in the Division of Medical Oncology at Dalhousie University and senior scientist at the Beatrice Hunter Cancer Research Institute, both in Halifax, Nova Scotia, Canada.

At the meeting, while discussing the new data with the immunotherapy and axitinib combinations, she said, "The results speak for themselves, and these are practice changing studies.

"A new standard of care in 2019 is present, and the majority of patients will be eligible to receive combination therapy, and it should be checkpoint inhibitors with axitinib," she said.

A new standard of care in 2019 is present...checkpoint inhibitors with axitinib. Dr Lori Wood

"Both combinations are expected to become new standards of care and to be incorporated into future guidelines," writes Bernard Escudier MD, from the Gustave Roussy Cancer Campus, Villejuif, France, in an NEJM editorial published alongside the studies.

However, both commentators noted that several questions still need to be answered about these new data.

Immunotherapy in Kidney Care

In his editorial, Escudier points out that sunitinib became the standard of care in the first-line setting in 2007 after showing superiority to interferon alfa, the original immunotherapy used in the treatment of kidney cancer.

But the new immunotherapies that act on programmed cell death pathways soon made an impact.

In 2015, nivolumab (Opvido, Bristol-Myesr Squibb) was shown to be more efficacious than everolimus (Afitinor, Novartis) and quickly became the standard of care as second-line therapy after failure of first-line VEGF inhibitors.

In 2018, the combination of two immune checkpoint inhibitors, nivolumab and ipilimumab (Yervoy, Bristol-Myers Squibb), was found to be superior to sunitinib (N Engl J Med. 2018;378:1277-1290).

The combination of nivolumab and ipilimumab was approved by the US Food and Drug Administration, and after some consideration, also by the European Medicines Agency. It is now the standard of care, primarily for intermediate- and poor-risk patients.

Long-term follow-up from CheckMate-214, also presented here (abstract 547), now indicates that combination nivolumab and ipilimumab resulted in a durable survival benefit as a first-line treatment for patients with advanced RCC.

Now come the published results for the combinations of immunotherapy with a targeted agent — pembrolizumab plus axitinib, and avelumab plus axitinib.

Escudier predicts that these two combinations will also become standards of care but cautions that the trials with the combinations "raise three questions."

Questions, Questions

The first question that these new trials raise, writes Escudier, is "whether inhibition of PD-1 [programmed cell death protein–1] and PD-L1 [programmed cell death–ligand-1] synergizes with axitinib and what the role of axitinib is in these combinations."

Axitinib is active when used alone, he points out. A previous large phase 2 trial showed that axitinib was a potent and selective VEGF inhibitor with excellent antitumor activity. It yielded a median progression-free survival of 14.5 months and an objective response rate of 48% (Lancet Oncol. 2013;14:1233-1242).

"It would have been very informative to have a control group with axitinib monotherapy in the current trials to ensure that avelumab and pembrolizumab made a clinically significant contribution to the observed results," he points out.

Second, it is unclear which combination will be used in the future. All of the trials so far — pembrolizumab plus axitinib, avleumab plus axitinib, and nivolumab plus ipilimumab — used sunitinib as the control, he notes.

A comparison of the results of the pembrolizumab plus axitinib trial and the avelumab plus axitinib trial showed very similar rates of progression-free survival and objective response, he says, although the pembrolizumab trial included a higher percentage of favorable-risk patients.

Although the follow-up data from the two trials were similar, Escudier notes that patients in the pembrolizumab trial achieved a significantly longer overall survival than those in the avelumab trial.

"It will be of great interest to see whether the rate of overall survival will increase in the avelumab trial with longer follow-up," he says.

The third question is whether subgroup analyses from all three trials can help oncologists in selecting the best combination.

There is work ongoing into biomarkers in mRCC, and recent data suggest that factors such as angiogenesis, the T-cell effector response, the interferon-γ response, and myeloid inflammatory gene–expression signatures may be predictive of response to inhibitors of VEGF, PD-1, and PD-L1.

"Previously, it had been suggested that PD-L1 positivity might also predict the increased efficacy of immune checkpoint inhibitors," he writes, although he notes that the methods used to assess positivity differed in each of the three trials.

"The rate of efficacy of nivolumab plus ipilimumab in PD-L1–positive metastatic renal-cell carcinoma was very high and will have to be confirmed prospectively," he adds. However, "the efficacy rate of this same combination among favorable-risk patients was disappointing," and this was not seen with the combinations of immunotherapy with axitinib, he notes.

Logistics and "Things to Ponder"

In her discussion of the new data at the meeting, Wood also commented that there are logistics and technicalities to consider and "things to ponder."

One is that decisions will need to be made as to which treatment to choose: there are two combinations of immunotherapy with axitinib, as well as the combination of two immunotherapies together.

Another important issue is cost, she said. As an example, she noted that two cost analyses of combination ipilimumab and nivolumab showed a cost of $85,506 to $125,739 per quality-adjusted life year.

"We need to consider not only drug costs but the cost of resources, such as clinic space, nursing visits, and infusion time," she said.

In addition, treatment with the new combinations is very time intensive compared to treatment with sunitinib, which for years has been the standard of care in this disease.

A patient taking sunitinib may have nine physician/registered nurse visits a year, with no time spent at the clinic for infusions. Moreover, problems can often be discussed over the telephone, Wood noted. In contrast, the combination of avelumab plus axitinib is given every 2 weeks, requires 26 physician/nurse visits a year, 26 infusions, and can lead to many unscheduled office visits, because patients usually need to be seen by a healthcare provider if problems arise, Wood emphasized.

Another issue is in regard to patient selection, she noted. In "real-world settings," checkpoint inhibitors will be contraindicated for some patients, such as those taking high doses of steroids. "Compliance with therapy is another issue, and patients need to have the ability to return for extra unscheduled visits," she said.

Wood also pointed out that, owing to logistics, these new therapies will be unavailable to many patients. "In the big picture, we have to remember the majority of patients worldwide do not have access and will not have access to VEGF targeted therapy or checkpoint inhibitors," she said.

Where available, these new combinations will be first-line treatment for mRCC patients with favorable-, intermediate-, and poor-risk disease, and they will be a new standard of care in many parts of the world, she predicted. "For intermediate/poor-risk patients, there is no clear winner between ipilimumab/nivolumab or checkpoint inhbitor/axitinib," she added.

"Decisions on treatment may be based on overall survival, complete response rates, toxicities, practical aspects, like number of visits and infusions, and cost, in a full discussion with patients," Wood concluded. "But we cannot safely and effectively deliver the new standard of care without infrastructure and system changes to accommodate it."

Much to Be Learned

Approached for an independent comment by Medscape Medical News, Robert Dreicer, MD, deputy director of the University of Virginia Cancer Center, Charlottesville, explained that currently, the standard of care regarding treatments such as the combination nivolumab and ipilimumab is based on risk group.

"But what these two studies are showing us is that there is a benefit for all risk groups with a tyrosine kinase inhibitor and a checkpoint inhibitor," he said. "Once they obtain regulatory approval, these combinations will become the standard of care — the comparator in the studies was the standard of care, so it's very straightforward."

Dreicer explained that there is going to be an "evolution of therapies used, and it's probably not going to be one or the other. This is where follow-up work will come into play."

He emphasized that other combinations will be coming down the pipeline as well. "Clinicians will need to look at the data, and there are a lot of issues that clinicians will need to work through," he said. "One is how the drugs are administered, and we will also need to see which group of patients may have a better likelihood of benefiting from one combination or the other, and we don't know that yet."

Dreicer predicted that there will not be head-to-head comparisons of these different combinations, and "we are going to have to learn more about these therapies, and we need longer follow-up — there is much yet to be learned."

KEYNOTE-426 was funded by Merck Sharp & Dohme. Checkmate 214 was funded by Bristol-Myers Squibb. JAVELIN Renal 101 was funded by Pfizer and is part of an alliance between Pfizer and Merck KGaA, Darmstadt, Germany. Escudier has received grants and personal fees from Aveo and BMS and personal fees from Pfizer, Ipsen, Roche, Novartis, and EUSA outside the submitted work. Dreicer has relationships with Astellas Pharma, AstraZeneca, Genentech/Roche, EMD Serono, Incyte, Pfizer, Seattle Genetics, Rainier Therapeutics, Janssen, and Merck. Wood has received institutional research funding from Aragon Pharmaceuticals, AstraZeneca, Bristol-Myers Squibb, Exelixis, Merck, Novartis, Pfizer, Roche Canada.

New Engl J Med. Published online February 16, 2019. Pembrolizumab plus axitinib study, Full text; avelumab plus axitinib study, Full text; Editorial

Genitourinary Cancers Symposium (GUCS) 2019: Abstracts 547, 543, and 544. Presented February 16, 2019.

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