Despite promising new regimens, search for cure is ‘highest priority’ in advanced renal cell carcinoma
With approximately 73,820 diagnoses and 14,770 deaths expected this year in the U.S., renal cell carcinoma remains a cancer in need of new treatment options.
The disease is among the 10 most common cancers diagnosed among older adults, with an average age at diagnosis of 64 years. Historically, only 11% of patients with stage IV disease have achieved 5-year OS.
“The biggest challenge in advanced renal cell carcinoma is that most patients cannot be cured with current medical therapy,” David F. McDermott, MD, professor of medicine at Harvard Medical School, and director of biologic therapy and cutaneous oncology programs at the Beth Israel Deaconess Medical Center, told HemOnc Today. “Developing treatments that induce disease remission and eventually lead to cure is the highest priority for these patients.”
Up to 30% of patients have advanced disease at the time of diagnosis. Within the last few years, several promising first-line treatment options have emerged for this group.
Two studies presented at this year’s Genitourinary Cancers Symposium asserted avelumab (Bavencio; EMD Serono, Pfizer) plus axitinib (Inlyta, Pfizer) and pembrolizumab (Keytruda, Merck) plus axitinib should be the new standard frontline regimens for advanced renal cell carcinoma. Both combinations have since received FDA approval for that setting.
However, these studies did not compare the combinations with ipilimumab (Yervoy, Bristol-Myers Squibb) plus nivolumab (Opdivo, Bristol-Myers Squibb) — deemed the new standard of care last year — because that combination received approval after the studies were designed. Instead, they were compared against the old standard, sunitinib (Sutent, Pfizer), and neither trial had an axitinib-alone arm.
“There are pluses and minuses for each of these combinations, but it is safe to say that PD-1 pathway-based combination therapy will become the frontline standard of care,” McDermott said. “PD-1 plus CTLA-4 blockade with ipilimumab plus nivolumab clearly improves survival for patients with intermediate- and poor-risk disease and it is certainly active in good-risk patients as well. The complete response rate with this regimen also is encouraging.”
HemOnc Today spoke with experts about the persistent challenges in treating advanced renal cell carcinoma, whether there really is one new standard of care for first-line treatment, and the next steps for research.
Need for curative treatment
The goal of treatment for advanced renal cell carcinoma has been to extend survival, with little hope for a cure.
“Unlike for certain other cancer types, treatment for advanced renal cell carcinoma is not always for curative intent,” Toni K. Choueiri, MD, director of the Lank Center for Genitourinary Oncology and co-leader of the Kidney Cancer Program at Dana-Farber/Harvard Cancer Center, told HemOnc Today. “These patients are now living longer, but the vast majority cannot be cured of their disease.”
Thus, research has focused on developing therapies that extend the quantity and quality of life.
“Advanced renal cell carcinoma is something that we currently have to tell patients that we cannot cure, but we can treat,” Elizabeth Plimack, MD, MS, chief of the division of genitourinary medical oncology, associate professor in the department of hematology and oncology, and director of genitourinary clinical research at Fox Chase Cancer Center, told HemOnc Today. “As inspiration, we have had a handful of patients in our practices who have achieved a durable response to treatment and even some for whom treatment eradicated all disease.
“These patients enter into long-term follow-up doing quite well, which is what we want to achieve,” she said. “If we can achieve long-term DFS in a reliable percentage of patients, then we can start to talk about things like remission or cure in advanced renal cell carcinoma, but we will need very long-term follow-up and better treatment options ultimately in order to see this.”
Brian I. Rini, MD, professor of medicine at Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, staff member of the department of solid tumor oncology at Cleveland Clinic, and a HemOnc Today Editorial Board Member, said that although the field has made quantum leaps in median survival, “the leaps are not enough for the vast majority of patients.”
“Historically, median survival was between 12 and 14 months with low-dose cytokines. Later, survival increased to nearly 2 years with VEGF-targeted therapy, and the most recent median survival with sunitinib from the CheckMate 214 study is more than 3 years,” Rini said. “When median survival is reached for the newer active combinations, this will probably increase to more than 4 years.”
Last year, the combination of ipilimumab and nivolumab received FDA approval for intermediate- or poor-risk patients with previously untreated advanced renal cell carcinoma, based on data from the CheckMate 214 trial.
After a minimum follow-up of 17.5 months, results showed improved OS (not reached vs. 26 months; HR = 0.63; P < .001), objective response rate (42% vs. 27%; P < .001) and PFS (11.6 months vs. 8.4 months) over sunitinib, leading to a new frontline treatment standard.
Speaking at International Kidney Cancer Symposium in 2017, Rini explained the rationale for the new standard.
“Ipilimumab-nivolumab is a standard of care in frontline metastatic renal cell carcinoma, in part because of the higher complete and partial response rates with durability, which achieves the goal of what we are trying to do: cure and control the disease over the long term,” he said.
More patients who received the combination vs. sunitinib achieved complete response (9% vs. 1%) or partial response (32% vs. 25%).
“We don’t really talk in kidney cancer about very good partial responses or some of the other terms that are often used in other malignancies. But, certainly in my clinical experience, some of these partial responses will be significant,” Rini said. “This means they will be deep and durable, with 80% to 90% tumor shrinkage and minor residual abnormalities. One of the things we will need to do with this data set is look into how many of these partial responses are deep and durable. And, how do we identify which patients can achieve this milestone?”
Despite the improvements that have been seen, there is more work to be done, McDermott said.
“Overall prognosis for patients with renal cell carcinoma has improved dramatically within the past decade, and survival outcomes for certain patients are threefold higher than they were a decade ago, but they are still not 100%,” he said.
Redefining the standard
Within a year of approval of ipilimumab-nivolumab for advanced renal cell carcinoma, data presented at European Society for Medical Oncology Congress in 2018, followed by presentations at this year’s Genitourinary Cancers Symposium, revealed two additional options for frontline treatment: avelumab-axitinib and pembrolizumab-axitinib.
In the ongoing phase 3 JAVELIN Renal 101 trial, Choueiri and colleagues evaluated PFS and OS among 886 treatment-naive patients with advanced renal cell carcinoma assigned 1:1 to receive 10 mg/kg IV avelumab every 2 weeks plus 5 mg twice-daily oral axitinib (n = 442; median age, 62 years; 72% men) or 50 mg oral sunitinib once daily for 4 weeks of a 6-week cycle (n = 444; median age, 61 years; 78% men). Sixty-three percent of patients had PD-L1-positive tumors, defined as expression on at least 1% of immune cells.
Results showed benefit with avelumab — a human anti-PD-L1 immunoglobulin G1 monoclonal antibody — and axitinib, a highly potent VEGF receptor tyrosine kinase inhibitor, across all prognostic risk groups and PD-L1 subgroups.
After a minimum follow-up of 6 months, patients who received the combination showed a 4-month (95% CI, 2.9-5.1) longer mean duration of response.
“Given the durable responses observed and the more-than-double responses for the combination treatment, it’s reasonable to believe that there will be more improvement in mean duration of response vs. sunitinib with a longer follow-up time,” Choueiri said. “The results support avelumab plus axitinib as a new first-line standard of care for all patients with advanced renal cell carcinoma.”
Based on these data, FDA approved the combination for frontline advanced renal cell carcinoma last month.
Results of the randomized phase 3 KEYNOTE-426 clinical trial, also presented at Genitourinary Cancers Symposium, showed another axitinib combination — with the PD-1 inhibitor pembrolizumab — extended OS and PFS compared with sunitinib as first-line treatment for patients with advanced or metastatic clear-cell renal cell carcinoma.
In the study, researchers randomly assigned 861 patients (median age, 62 years; 73% men) 1:1 to 200 mg IV pembrolizumab every 3 weeks for a maximum for 35 cycles plus 5 mg oral axitinib twice daily (n = 432) or 50 mg oral sunitinib daily in a 4-week-on, 2-week-off schedule (n = 429).
More patients assigned pembrolizumab-axitinib achieved 12-month OS (89.9% vs. 78.3%) and 18-month OS (82.3% vs. 72.1%). Although median OS was not reached in either arm, the data showed pembrolizumab-axitinib significantly improved OS (HR = 0.53; 95% CI, 0.38-0.74).
“The fact that the pembrolizumab-axitinib data showed a benefit in OS, which has not yet been shown with avelumab-axitinib, gives the combination a bit of an edge,” said Plimack, who served as a study researcher on KEYNOTE-426. “The toxicity profiles, however, were pretty good relatively speaking for both combinations. The key, again, will be durability of response and treatment-free response. What we do not know with either of these combinations is when we can stop treatment, so ongoing chronic therapy is blended into all of these trials.”
In April, FDA approved pembrolizumab-axitinib for this patient population.
“We are really happy about this approval because we have seen firsthand how effective this combination can be,” Plimack told HemOnc Today at the time of the approval. “We still can’t promise patients that they can be cured, but we know this combination shrinks tumors in the vast majority of patients who take it. What we don’t know yet — and time will tell — is how long patients are going to do well on this combination. We hope it’s for many years, and we hope their cancer control persists even after we stop treatment.”
Michael B. Atkins, MD, deputy director of the Lombardi Comprehensive Cancer Center at Georgetown University Medical Center, said it is difficult to compare pembrolizumab-axitinib with ipilimumab-nivolumab because long-term follow-up data are not available for the newer combination.
“I want to see what the complete remission rate is going to be with pembrolizumab plus axitinib, how durable responses will be, whether there is a ‘tail’ on the survival curve, and whether the benefit will persist even after treatment is stopped,” Atkins told HemOnc Today. “I would not jump on the pembrolizumab-plus-axitinib bandwagon until we see more data.”
The cross-trial comparison is challenging because the ipilimumab-nivolumab study was conducted years before the pembrolizumab-axitinib study, according to Plimack.
“I would argue that pembrolizumab plus axitinib should be the frontline standard of care for all patients based upon the totality of data,” she said. “This has been debated recently and those who favor ipilimumab plus nivolumab cite the long-term data on outcomes, which we do not yet have for pembrolizumab plus axitinib.”
Clinicians will need to study the data closely to choose among these three frontline options, Bernard Escudier, MD, of Gustave Roussy Cancer Campus in Villejuif, France, wrote in an editorial that accompanied publication of the JAVELIN Renal 101 and KEYNOTE-426 trials in The New England Journal of Medicine. This is particularly important because all the trials used sunitinib as the control.
“Comparisons between the pembrolizumab-plus-axitinib and the avelumab-plus-axitinib trials show that the rates of PFS and ORR were very similar, although there was a higher percentage of favorable-risk patients in the pembrolizumab trial,” Escudier wrote. “The difference in risk between the patients in the pembrolizumab trial and those in the avelumab trial is also reflected in the longer PFS among patients receiving sunitinib in the former trial than in the latter trial (11.1 months vs. 8.4 months). However, although the follow-up in the two trials was similar, patients in the pembrolizumab trial had a significantly longer OS than those in the avelumab trial; this might have been attributable to the long-term effect of PD-1 inhibition.”
Whether OS increases with avelumab is key, Escudier added.
“In contrast to these two current trials, the trial of nivolumab plus ipilimumab did not show a significant increase in PFS, although OS was significantly increased and, more importantly, the complete response rate among patients in that trial was high,” he wrote.
Also unclear is the role of axitinib.
“Axitinib was shown to be a potent and selective VEGF inhibitor with excellent antitumor activity in a large phase 2 trial involving 213 patients with metastatic renal cell carcinoma,” Escudier wrote. “In that trial, [published in 2014 in The Lancet Oncology,] the median PFS was 14.5 months and the ORR was 48%. 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.”
Lastly, it remains to be seen whether subgroup analyses will be helpful in distinguishing among the three trials. Biomarkers under investigation include angiogenesis, the T-cell effector response, interferon-gamma response and myeloid inflammatory gene expression signatures, Escudier wrote.
‘Intense’ search for biomarkers
Echoing Escudier’s comments, experts with whom HemOnc Today spoke said the absence of reliable biomarkers to determine which patients will benefit most from each of these combinations remains a key challenge.
“We have a whole array of therapies for renal cell carcinoma fortunately, but no good predictive markers to identify which treatment individual patients should receive,” Dror Michaelson, MD, PhD, director of the Hematology/Oncology Fellowship Program at Massachusetts General Hospital Cancer Center, told HemOnc Today. “We are lagging behind our colleagues who treat lung or breast cancer, for example, who are able to identify tumor characteristics in individual patients to guide therapy. We do not have anything like this yet for renal cell carcinoma. We place patients into risk groups, but this does not speak to the individual tumor characteristics. The search for biomarkers has been intense during the past couple of years and continues to be an active area of investigation.”
There is a need for biomarkers to predict which patients will respond to a treatment for two main reasons, Plimack said.
“For one, a biomarker could be used for patient selection as has been done with lung cancer, for example,” she said. “Two, if we knew what biological components of a tumor were required to have it be susceptible to treatment, then this could allow us to develop new treatments for patients.”
Choueiri said there is always a need for new biomarkers in renal cell carcinoma.
“We have been working on this for the past 10 to 15 years,” he said. “However, it is not easy to find a biomarker in renal cell carcinoma, because there does not always seem to be a single contributor characterizing patients into ‘no response’ vs. ‘great response’ groups. Overall, it is a work in progress and each biomarker has to be developed more and additionally validated in clinical trials.”
Earlier this month at ASCO Annual Meeting, Choueiri presented biomarker analyses from the JAVELIN Renal 101 study. Researchers found that PD-L1 expression did not distinguish PFS benefit in the avelumab-plus-axitinib group; however, patients with PD-L1-positive tumors in the sunitinib group showed shorter PFS. Further, a higher number of CD8-positive cells in tumors appeared associated with extended PFS in the combination group, but shorter PFS in the sunitinib group.
A 26-gene signature — composed of genes associated with T-cell receptor signaling; T-cell activation, proliferation and differentiation; natural killer cell-mediated cytotoxicity; chemokines; and other immune-response genes — appeared most significantly associated with PFS in the avelumab-axitinib group. Researchers also observed significant differences in PFS related to mutations in CD163L1, DNMT1 or PTEN genes.
“I cannot stress enough how important it is to come up with new targets for patients with advanced renal cell carcinoma,” Choueiri said. “It is not easy to do, but it is very important.”
As with any combination, the price of therapy increases as additional agents are added to the regimen.
In a study published this year in JAMA Oncology, Wan and colleagues pooled outcome data from the CheckMate 214 trial and evaluated the cost-effectiveness of nivolumab plus ipilimumab vs. sunitinib in the first-line setting from the U.S. payer perspective.
Researchers created a model in which 1,096 patients (median age, 62 years) received sunitinib or nivolumab-ipilimumab for four doses followed by nivolumab monotherapy.
Results showed nivolumab-ipilimumab cost $108,363 per additional quality-adjusted life-year (QALY) gained compared with sunitinib. The probabilistic sensitivity analyses suggested a high likelihood that nivolumab plus ipilimumab would be considered cost-effective at a willingness-to-pay threshold of $100,000 to $150,000 per QALY.
“I would not say that cost-effectiveness is the best feature of combination therapies, but as a patient, I would want the best treatment,” Rini said. “We have to remember that these treatments will hopefully not have to be continued indefinitely. The big academic focus is on how we can limit treatment to limit toxicities and financial burdens, which is not yet sorted out. If patients are cured and can stop treatment, then a lot of money will be saved.”
Treatment duration for advanced renal cell carcinoma has varied from trial to trial, and in some ways is arbitrary, McDermott said.
“For the common patient who is on treatment with stable disease or for the patient who has achieved a partial response, the exact amount of time that those patients need on treatment is not yet clearly defined,” McDermott said. “There may be certain patients who can come off treatment sooner than we take them off treatment, and there may be others who require chronic long-term therapy. This needs to be looked at in randomized trials.”
However, these trials are not easy to conduct, he said.
“Often patients want to stay on treatment, which is in large part because the majority of toxicities associated with treatment for advanced renal cell carcinoma occur within the first 6 months,” McDermott said. “So, if a patient is on treatment for more than 6 months and they are benefiting from treatment, they are less likely to experience a new side effect. Long-term toxicity is something that we do not have enough data on and we have to continue to follow.”
‘Continuing to fight’
Experts agree that next steps for research should include further assessment of novel biomarkers, establishing optimal treatment duration and ultimately identifying a cure.
“Patients with renal cell carcinoma are living longer today than they did years ago,” Plimack said. “Many patients will ultimately progress on current therapies and will need another treatment. We, therefore, need to continue to evolve treatment options for these patients using different mechanisms of action.”
In an ongoing phase 2 trial, researchers are assessing the safety and efficacy of an oral small molecule inhibitor, PT2977 (Peloton Therapeutics) — which impairs hypoxic and pseudohypoxia signaling in cancer cells — in patients with clear-cell renal cell carcinoma.
In April, Choueiri presented data at European International Kidney Cancer Symposium showing 12 of 55 patients (22%) achieved a confirmed partial response to PT2977. At a median follow-up of 9 months, median PFS was not reached, and 36% of patients remained on study.
The agent also appeared well-tolerated, with anemia occurring most frequently.
“The data from this trial indicate that hypoxia-inducible factor 2-alpha inhibition has the potential to become a promising new treatment option for patients with renal cancer,” Choueiri said in a press release. “The data show that PT2977 can provide clinically meaningful responses in heavily pretreated patients with a favorable safety and tolerability profile.”
McDermott said there should not be a “one-size-fits-all” approach to treatment.
“We need combination approaches that are individualized based upon an assessment of the tumor microenvironment and, ideally, we would not be giving patients more therapy than they need,” McDermott said. “We need to look at other combination regimens, because even with the advances that we have, most patients will eventually fail on these combinations. What works after failure on a PD-1 combination therapy will be an area of active exploration for future research. We do not have trials in this space, but this will be very important going forward.”
Choueiri said that at the end of the day, new targets are still needed.
“This is extremely important, and we along with other investigators are working on this now,” he said. “We are continuing the fight and the field is moving fast.” – by Jennifer Southall
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For more information:
Michael B. Atkins, MD, can be reached at Georgetown University, 37th and O Streets, NW, Washington, D.C. 20057; email: firstname.lastname@example.org.
Toni K. Choueiri, MD, can be reached at Dana-Farber Cancer Institute, 450 Brookline Ave., Boston, MA 02215; email: email@example.com.
David F. McDermott, MD, can be reached at Beth Israel Deaconess Medical Center, 330 Brookline Ave., Shapiro 9, Boston, MA 02215; email: firstname.lastname@example.org.
Dror Michaelson, MD, PhD, can be reached at Massachusetts General Hospital Cancer Center, 55 Fruit St., Yawkey 7E, Boston, MA 02114; email: email@example.com.
Elizabeth Plimack, MD, MS, can be reached at Fox Chase Cancer Center, 333 Cottman Ave., Philadelphia, PA 19111; email: firstname.lastname@example.org.
Brian I. Rini, MD, can be reached at Cleveland Clinic Taussig Cancer Institute, 9500 Euclid Ave., Desk CA60, Cleveland, OH 44195; email: email@example.com.
Disclosures: Atkins reports consultant/advisory roles with Acceleron Pharma, Aduro Biotech, Agenus, Array BioPharma, Arrowhead Pharmaceuticals, Boehringer Ingelheim, Bristol-Myers Squibb, Eisai, Exelixis, Genentech, Glactone Pharma, Immunocore, Iovance Biotherapeutics, Merck, Newlink Genetics/Pharmatech, Novartis, Oncolys BioPharma, Pfizer, Surface, Werewolf Pharma and X4 Pharma, as well as institutional research funding from Bristol-Myers Squibb. Choueiri reports consultant/advisory roles with or institutional research funding or honoraria from Agensys, Alexion Pharmaceuticals, Alligent, Analysis Group, AstraZeneca, Bayer, Bristol-Myers Squibb, Calithera Biosciences, Celldex, Cerulean Pharma, Clinical Care Options, Corvus Pharmaceuticals, Eisai, Eli Lilly, EMD Serono, Exelixis, Foundation Medicine, Genentech/Roche, GlaxoSmithKline, Harborside Press, HERON, Ipsen, Lpath, Merck, Michael J. Hennessy Associates, Navinata Health, Novartis, Peloton Therapeutics, Pfizer, PlatformQ Health, Peloton Therapeutics, Pfizer Prometheus, Roche/Genentech, Sanofi/Aventis, Takeda, TRACON Pharma and UpToDate. McDermott reports consultant/advisory roles with or institutional research funding from Alkermes, Array BioPharma, Bristol-Myers Squibb, Eli Lilly, EMD Serono, Exelixis, Genentech/Roche, Jounce Therapeutics, Merck, Novartis, Peloton Therapeutics, Pfizer, Prometheus Laboratories and X4 Pharma. Plimack reports consultant/advisory roles with or institutional research funding from Astellas Pharma, AstraZeneca/MedImmune, Bristol-Myers Squibb, Clovis Oncology, Exelixis, Genentech/Roche, Horizon Pharma, Incyte, Inovio Pharmaceuticals, Janssen, Merck, Novartis, Peloton Therapeutics and Pfizer. Rini reports consultant/advisory roles with, or institution research funding or travel expenses from AstraZeneca/MedImmune, Bristol-Myers Squibb, Merck, Novartis, Peloton Therapeutics, Pfizer, Roche/Genentech and Synthorx. Michaelson reports no relevant financial disclosures.