A Whirlwind of Changes in Kidney Cancer Brings Optimism

Robert A. Figlin, MD

The pharmacologic treatment for advanced renal cell carcinoma (RCC) has evolved considerably since the FDA approved interleukin-2 as the first systemic therapy for the tumor type in 1992.¹ The next drug the agency approved was sorafenib (Nexavar), which was the first targeted therapy for RCC. Since then, the FDA has approved more than 20 drugs for RCC in the past 12 years. At a recent OncLive^® Peer Exchange^®, a panel of experts in genitourinary malignancies talked about how the treatment paradigm for patients with advanced RCC has changed and is likely to continue changing.

Robert A. Figlin, MD, who moderated the Peer Exchange® panel, said the rapid pace of drug approvals for RCC leaves oncologists with many unanswered questions about the optimal way to use the new agents. The panelists reviewed data from clinical trials that can help guide treatment decisions for the first-line setting and beyond.

Changing Landscape

“New data continue to emerge to help us navigate a pathway for each individual patient, often through multiple lines of therapy,” Figlin said. The basic goal of treatment remains the same: find a way to cure the patient’s cancer while preserving the quality of life. Panelist Eric Jonasch, MD, suggested progress is being made on that front, with the recent approval of immunooncology agents that prolong overall survival (OS) and even cure RCC in a subset of patients.As the number of available drugs has grown, the patient population with RCC also has changed, Figlin observed. Toni K. Choueiri, MD, agreed and noted that they are now seeing a growing population of patients who had progression on multiple lines of therapy, including immunooncology drugs. Figlin expressed concern that some clinicians might be discontinuing traditional VEGF-targeted tyrosine kinase inhibitors (TKIs) too quickly—that instead of using dose adjustments to manage tolerance issues, there is a rush to switch patients to immuno-oncology drugs.

Choueiri said when the TKIs were first introduced, the treatments were quickly discontinued due to adverse events (AEs). As clinicians learned to manage the AEs of TKIs, however, patients could continue taking the drugs until their disease progressed. “I have to be honest with you, I see the movement going back to where we were—with the patient being taken off quickly from agents like sunitinib or pazopanib [Votrient] who sometimes could have stayed on the drug for a longer period of time, had the side effect been managed in a different way,” Choueiri said.

Michael R. Harrison, MD, said decisions about what therapy to use or when to discontinue a therapy should consider the patient’s goals of care. “If you ask patients what is their goal, different patients have a different balance between prioritizing qualify of life versus tumor response variables or outcomes,” he said.

One of the emerging debates concerns when to start treatment. Figlin said, “Over the years, everybody thought ‘once you find [RCC], you treat it.’ And we’re learning now that may not be necessary. There are some patients whom we can observe, which is different than a decade ago.” He asked the panelists what they thought about the concept of active surveillance after nephrectomy in patients with slow-growing disease.

“We do have data at this point in time that suggests it’s probably safe to wait, especially if you have an individual who has perhaps a small number of lesions, who has slowly growing disease, who has excellent performance status,” said Jonasch. “This is a strategy that I certainly employ with some of my patients,” he added.

David I. Quinn, MBBS, PhD, pointed to data from a phase II trial published in 2016 that showed active surveillance was a successful approach for a subset of patients with metastatic RCC.² “What was clear was that patients who were particularly good risk or intermediate risk based on Motzer or Heng criteria could do well, especially if they had pulmonary metastases as their major site of disease,” he said.

First-Line Therapy

Quinn said a study presented at the 2017 Genitourinary Cancers Symposium also supported the use of active surveillance for patients with metastatic RCC who had a good or intermediate International Metastatic Renal Cell Carcinoma Database Consortium prognostic score.³ Median time on surveillance in the study was 17 months, and surveillance did not compromise OS or the effectiveness of subsequent therapy. Quinn said he would not use active surveillance for patients with liver metastases or lymph node-predominant disease, and considered it a riskier option for patients with solitary brain or bone metastases that had been treated.The panel suggested that the choice of first-line therapy after nephrectomy for patients with poorrisk criteria was more straightforward. Choueiri said he starts with temsirolimus (Torisel) if the patient is hospitalized. “But if you’re managing this patient as an outpatient, you have the time to start with an oral VEGF-targeted agent,” he said. In cases where the extent of metastatic disease is greater than the volume of disease in the kidney, Choueiri said he would consider systemic therapy first and cytoreductive nephrectomy afterward.

Jonasch said sunitinib (Sutent) and pazopanib are equally viable options for first-line systemic therapy. “If you look at the phase III data, there really isn’t a big difference,” he said. The greatest differences are in tolerability. Jonasch said head-to-head trials of sunitinib versus pazopanib associated sunitinib with higher rates of fatigue, taste changes, and hand-foot syndrome, whereas pazopanib was associated with a higher risk of hair loss, elevated transaminase levels, and nausea.^4,5

Jonasch also noted that clinicians are increasingly deviating from the standard 4-weekson/2-weeks-off schedule for sunitinib to minimize toxicity. A recent study showed that extending the number of weeks off sunitinib for patients with a reduction in tumor burden ≥10% was feasible and did not compromise treatment efficacy. He said the strategies are allowing patients to take sunitinib longer, which is translating into improved survival outcomes.

Figlin suggested that although the choice of firstline therapy may be clear, knowing when to switch to another therapy is not. “We see many patients who may have had their therapies prematurely stopped and went on to a second-line treatment when they may have still been able to benefit with some modulation from the first-line therapy,” he said. Harrison agreed, and said that when he has reviewed the files of patients referred to him, it is not always clear whether they discontinued a VEGF TKI due to progression or because tolerance issues were not optimally managed. In those cases, he said he sometimes successfully rechallenges them with a VEGF TKI.

Progression After First-Line Therapy

Quinn said one issue is that scans may be misleading. “We need to be aware that there’s an oscillation in the disease that should not be confused with progression,” he advised. Jonasch agreed that there is a need for better biomarkers of progression, whether via imaging or looking at the circulating microenvironment (eg, circulating cytokines and angiogenesis factors).Figlin said that although many drugs have been approved for second-line therapy, data to guide clinicians in choosing between them are scarce. “[They have] never been compared in the secondline setting,” he said. Harrison said his choice for patients with progression after a VEGF TKI is generally between cabozantinib (Cabometyx), an inhibitor of MET, AXL, VEGF, and RET, or nivolumab (Opdivo), a PD-1 inhibitor. He said his choice is guided by the patient’s symptoms, quality-of-life concerns, how long the patient sustained therapy with a VEGF TKI, what AEs they experienced, and whether they need a break from that profile.

“If a patient is symptomatic, especially those patients who have sites of disease in the bone or the liver, I’m thinking a little bit more about cabozantinib. If [it is] a patient who has clear progression but maybe it’s just in the lung or maybe in other sites like lymph nodes, then I’m probably thinking more about nivolumab,” Harrison explained. Quinn said although cabozantinib is “a great drug,” he typically uses nivolumab in the second-line because “it’s well tolerated, and I think [patients] want a break from VEGF toxicities.” He said he typically reserves cabozantinib for patients who have contraindications to immunotherapy, such as an organ transplant or autoimmune disease.

Choueiri said he uses cabozantinib for patients who have faster progression, especially if they have visceral metastases. He said studies have shown a low rate of progressive disease and significant tumor shrinking with cabozantinib. “I do not want to lose the battle—I want something to hold the patient quickly and effectively,” he said. Choueiri concurred with the other panelists that nivolumab is a good option for patients who struggled with the AEs of a VEGF TKI, for whom there is no immediate urgency to treat, and who are willing to come to the clinic for treatment.

Clinical trials compared nivolumab and cabozantinib with everolimus (Afinitor) in patients who were previously treated with a VEGF TKI. In the phase III CheckMate-025 trial, nivolumab significantly improved OS compared with everolimus (25 months vs 19.6 months, respectively).⁷ Choueiri said the response rate in the nivolumab arm was also higher and that the drug was well tolerated.

In METEOR, another phase III trial, final data associated cabozantinib with significantly longer OS than everolimus (21.4 months vs 16.5 months, respectively), significantly better median progression-free survival (7.4 months vs 3.9 months), and objective response rate (17% vs 3%, respectively).⁸ “The adverse effects were quite similar to what we’re used to with a VEGF TKI,” Choueiri, who helped conduct the study, said.

Future Directions

Lenvatinib (Lenvima), which inhibits VEGF receptors and fibroblast growth factor receptors, was approved last year in combination with everolimus as a second-line option for patients with advanced RCC. Approval was based on results from a randomized phase II study, which showed the addition of lenvatinib to everolimus significantly prolonged median OS compared with everolimus alone (25.5 months vs 15.4 months, respectively).⁹ Choueiri said nivolumab, cabozantinib, and lenvatinib have never been compared in head-tohead trials, “and my guess is they will never be compared head to head.”Although nivolumab, cabozantinib, and lenvatinib are not approved for first-line treatment, the panelists discussed the possibility that they eventually could be. “First-line immunotherapy may be worth pursuing,” said Quinn, who noted that several trials of first-line immunotherapy are expected to report data soon. He said any changes would depend on whether the trials show an OS benefit. Quinn said other first-line options that may emerge are immuno-oncology agents combined with a VEGF TKI, or a vaccine combined with a VEGF TKI.

Jonasch said studies are also looking at combining new and older agents, such as the PD-L1 inhibitor atezolizumab (Tecentriq) with bevacizumab (Avastin). Several studies are looking at adjuvant therapy with sunitinib, pazopanib, or other agents in populations with a high risk of recurrence. Limited data show promise, but Jonasch said the trials need to show a survival benefit and that confirmatory studies are needed.

Harrison expressed his hope for biomarker discoveries. “Basically, [we need to be] moving toward precision medicine to develop biomarkers to find the right drug for the right patient at the right time,” he said.

Figlin agreed they do not have all the answers they would like. He encouraged patients and physicians never to hesitate “to get another opinion from someone who spends their life—like my colleagues—thinking about kidney cancer and how to address, answer, and ask the right questions for the individual patient.”

References

1. American Society of Clinical Oncology. CancerProgress.net website. www.cancerprogress.net/timeline-date/first-fda-approval-targeted-drug-kidney-cancer-0?category=103#7. Published 2016. Accessed April 25, 2017.
2. Rini BI, Dorff TB, Elson P, et al. Active surveillance in metastatic renal-cell carcinoma: a prospective, phase 2 trial. Lancet Oncol. 2016;17(9):1317-1324. doi: 10.1016/S1470-2045(16)30196-6.
3. Bimbatti D, Sava T, Massari F, et al. Changes in tumor burden and IMDC class after active surveillance (AS) for metastatic renal cell carcinoma (mRCC). Paper presented at: 2017 Genitourinary Cancers Symposium; February 16-18, 2017; Orlando, FL. Abstract 435. http://meetinglibrary.asco.org/content/179412-197.
4. Motzer RJ, Hutson TE, Cella D, et al. Pazopanib versus sunitinib in metastatic renal-cell carcinoma. N Engl J Med. 2013;369(8):722-731. doi: 10.1056/NEJMoa1303989.
5. Escudier B, Porta C, Bono P, et al. Randomized, controlled, double-blind, cross-over trial assessing treatment preferences for pazopanib versus sunitinib in patients with metastatic renal cell carcinoma: PISCES Study. J Clin Oncol. 2014;32(14):1412-1418. doi: 10.1200/JCO.2013.50.8267.
6. Ornstein M, Wood LS, Elson P, et al. A phase II study of intermittent sunitinib in previously untreated patients with metastatic renal cell carcinoma [published online January 23, 2017]. J Clin Oncol. 2017. doi: 10.1200/JCO.2016.71.1184.
7. Motzer RJ, Escudier B, McDermott DF, et al. Nivolumab versus everolimus in advanced renal-cell carcinoma. N Engl J Med. 2015;373(19):1803-1813. doi: 10.1056/NEJMoa1510665.
8. Choueiri TK, Escudier B, Powles T, et al. Cabozantinib versus everolimus in advanced renal cell carcinoma (METEOR): final results from a randomised, open-label, phase 3 trial. Lancet Oncol. 2016;17(7):917-927. doi: 10.1016/S1470-2045(16)30107-3.
9. Motzer RJ, Hutson TE, Glen H, et al. Lenvatinib, everolimus, and the combination in patients with metastatic renal cell carcinoma: a randomised, phase 2, open-label, multicenter trial. Lancet Oncol. 2015;16(15):1473-1482. doi: 10.1016/S1470-2045(15)00290-9.