A New Front Line Is Taking Shape in Metastatic Renal Cell Carcinoma

Daniel J. George, MD

The dismal prognosis for patients with metastatic renal cell carcinoma (mRCC) has fueled an earnest quest for more effective treatments, culminating in a better understanding of the disease and regulatory approval of several new drugs and therapeutic combinations. “The busy oncologist treating a patient with metastatic disease now has a plethora of choices for both newly diagnosed and relapsed kidney cancer,” Daniel J. George, MD, said during a recent OncLive Peer Exchange^® panel. George moderated the panel of kidney cancer experts, whose discussion touched on recent drug approvals and practice-changing data presented at this year’s American Society of Clinical Oncology (ASCO 2018) Annual Meeting in June.

CABOZANTINIB AND THE CABOSUN STUDY

Renal cell carcinoma (RCC) is clinically silent in the beginning, and between 25% and 30% of patients will have metastatic disease at diagnosis.^1,2 Although median overall survival (OS) for individuals with mRCC has more than doubled since the introduction of tyrosine kinase inhibitors (TKIs) and antiangiogenic agents,³ less than 20% of patients survive more than 5 years.²In December 2017, the FDA expanded approved indications for cabozantinib (Cabometyx) to include previously untreated advanced RCC.⁴ Cabozantinib is a TKI that blocks VEGFR, MET, and AXL and was initially approved in the RCC setting for patients with advanced disease who previously received an antiangiogenic agent.4 The FDA based its expanded approval on positive findings from the phase II CABOSUN trial (NCT01835158), a collaborative effort between the Alliance for Clinical Trials in Oncology and the National Cancer Institute.⁵ Toni K. Choueiri, MD, a leading CABOSUN investigator, said the purpose of the randomized, open-label study was “to answer the question of whether cabozantinib is superior to sunitinib [Sutent], a long-standing standard of care in RCC.” Investigators randomly assigned 157 previously untreated patients with intermediate- or poor-risk advanced RCC to receive sunitinib 50 mg/day (4 weeks on, 2 weeks off) or cabozantinib 60 mg/day.5 Median progression-free survival (PFS) per the independent review committee (IRC) was 8.6 months in the cabozantinib arm versus 5.3 months in the sunitinib arm (HR, 0.48; 95% CI, 0.31-0.74; 2-sided P = .0008); investigator-assessed PFS was similar.⁵ “Progression-free survival was met, both by investigator assessment and IRC,” Choueiri said. The overall response rate (ORR) per IRC was also greater in the cabozantinib arm than in the sunitinib arm (20% vs 9%, respectively).⁵ Although those data prompted the FDA to approve cabozantinib for all treatment-naïve patients with advanced RCC, Choueiri noted that European regulatory bodies have restricted approval to intermediate- or poor-risk patients⁶ because “CABOSUN data did not include patients with good risk and, essentially, these patients with clear cell component.”

Toni K. Choueiri, MD

George, another CABOSUN investigator, was lead author for a subgroup analysis presented at the 2018 Genitourinary Cancers Symposium.⁷ The authors analyzed PFS and ORR outcomes by sex, age (≥ or <65 years), risk group, baseline ECOG performance status, MET tumor expression, and bone metastases. Cabozantinib was associated with superior PFS and ORR across all subgroups but showed the greatest advantage over sunitinib in poor-risk patients and patients who were MET positive.⁷

Richard W. Joseph, MD, described cabozantinib as a great drug but expressed concern about an increased risk of toxicity compared with pazopanib (Votrient), a VEGFR inhibitor also approved for patients with advanced RCC. Although rates of overall and grade 3/4 adverse events were similar between the cabozantinib and sunitinib arms in CABOSUN,⁵ panelist Walter M. Stadler, MD, said the phase III COMPARZ trial found pazopanib to be far better tolerated than sunitinib.⁸ He therefore questioned whether cabozantinib was advisable for patients with a good prognosis, a population CABOSUN excluded.

IMMUNOTHERAPY AND THE CHECKMATE-214 TRIAL

Stadler also said he would like to see whether the improved PFS associated with cabozantinib translates into improved OS, a secondary endpoint that CABOSUN was not powered to establish.The FDA approved a regimen that combines the immune checkpoint inhibitors nivolumab (Opdivo) and ipilimumab (Yervoy) as frontline therapy for patients with intermediate- and poor-risk advanced RCC in April 2018.⁹ The approval was based on findings from CheckMate-214, a randomized phase III trial that compared the doublet with single-agent sunitinib for clear cell advanced RCC (N = 1096).¹⁰ Stadler said the study, which observed significant improvement in OS with nivolumab/ ipilimumab compared with sunitinib (HR, 0.63; P <.001), has had “a major impact on the field.” He pointed out that the combination’s superiority was limited to the intermediate- and poor-risk populations and an exploratory analysis of OS, ORR, and PFS in the 249 favorable-risk patients favored sunitinib.10 “Certainly, [the combination of] ipilimumab and nivolumab is not the better choice [for favorable-risk patients], and I think that’s been a little bit underrecognized,” he said.

George said complete response (CR) rate has always been an important goal of RCC trials and was significantly higher in CheckMate-214 with the nivolumab/ipilimumab combination than with sunitinib. In the intermediate- and poor-risk cohorts, 9% of patients in the combination arm achieved a CR compared with 1% in the sunitinib arm (P <.001).¹⁰ In the favorable-risk cohort, the CR rate was 11% in the combination arm compared with 6% in the sunitinib arm.

Richard W. Joseph, MD

On several endpoints, the magnitude of benefit associated with nivolumab/ipilimumab was greater for patients with a PD-L1 expression level ≥1% than for those with a level <1%.10 Robert J. Amato, DO, suggested the results underscore the importance of an individualized approach to treatment. He said his institution attempts to use markers such as PD-L1 for recommending immunotherapy and “other pathways we look at from an omics perspective—whether it’s proteomics or genomics…to select the agent that’s suited for the individual.” Alternatively, they consider toxicity data and a patient’s comorbidities. He said some patients were referred to him from community oncologists who said they were not candidates for immunotherapy because of their comorbidities.

“We have to recognize that this combination immunotherapy leads to very severe toxicities in 5% to 10% of patients,” Stadler said. CheckMate-214 reported 8 treatment-related deaths in the combination arm compared with 4 in the sunitinib arm, an increase he described as significant.¹⁰ “My statement has always been that, listen, a well-trained oncologist knows how to give cisplatin, which is probably the most toxic drug that I know, and so oncologists will learn how to do this,” he said.

Amato brought up pseudoprogression, a phenomenon that occurs in 5% to 15% of patients with RCC treated with PD-1/PD-L1 inhibitors.¹¹ “How do we teach the community oncologist who doesn’t see RCC every day and gets this report from the radiologist [showing pseudoprogression] that it’s OK to stay on [immunotherapy]?” he wondered.

SUNITINIB WITH OR WITHOUT NEPHRECTOMY IN CARMENA TRIAL

“A little common sense goes a long way,” Stadler said. He recommended looking at the computed tomography scan and the patient simultaneously. He said if the scan shows a lymph node grew 0.3 cm but the patient is feeling better, it is probably pseudoprogression; however, a lung mass that doubled from 4 to 8 cm in a patient who is feeling worse is likely real progression.Data from the phase III CARMENA trial were presented at a plenary session at ASCO 2018 and recently published in the New England Journal of Medicine.^12,13 CARMENA was a noninferiority study conducted by French investigators that randomly assigned 450 patients with intermediate- or poor-risk clear cell mRCC to cytoreductive nephrectomy and adjuvant sunitinib versus sunitinib alone.12

Walter M. Stadler, MD

Stadler said the noninferiority margin was an HR of 1.2 or less, which was met in the study. The results from the study showed no significant difference in median OS, ORR, or disease-control rate between the arms, although these outcomes trended better in the sunitinib-only arm. Sunitinib alone was also associated with a significantly higher clinical benefit rate than nephrectomy plus sunitinib (47.9% vs 36.6%; P = .02). “It did look surprisingly like the patients who received the sunitinib without nephrectomy did better,” Stadler said. In light of the findings, he said physicians who want to perform upfront nephrectomy should be ready to defend their choice to patients.

Choueiri disagreed with the notion that CARMENA takes nephrectomy off the table for most patients with newly diagnosed disease. “A patient with intermediate risk, great performance status, and young—who can get through surgery quickly and who has a limited disease burden outside the kidney—should be considered strongly for an upfront cytoreductive nephrectomy,” he said. He added that investigators may want to conduct trials like CARMENA using agents or combinations shown to be more effective than sunitinib in the frontline.

Robert J. Amato, DO

Joseph said he was not sure CARMENA’s results would affect his practice. He noted that 40 patients in CARMENA’s surgery arm never received adjuvant sunitinib, which he said indicated they were very sick, poor-risk patients whom he never would have sent for upfront nephrectomy. “I almost always have a trial of some systemic therapy, wait a period of time, whether it be 3 to 6 months, and then kind of pick the patients who are doing well who you think can withstand a nephrectomy,” Joseph explained. He said CARMENA “answers some questions, but it leaves a lot to be asked.”

Despite the panelists’ divergent perspectives on the applicability of CARMENA’s findings to practice, they generally agreed CARMENA was an important trial and that additional studies should seek to validate its findings. They also agreed it was an exciting time in kidney cancer and expressed the shared hope that future studies would go beyond incremental improvements in survival and identify new biomarkers or capitalize on existing ones. “This might be a very different talk even in 2019,” Joseph concluded.

References

1. Gupta K, Miller JD, Li JZ, Russell MW, Charbonneau C. Epidemiologic and socioeconomic burden of metastatic renal cell carcinoma (mRCC): a literature review. Cancer Treat Rev. 2008;34(3):193-205. doi: 10.1016/j.ctrv.2007.12.001.
2. Kalra S, Atkinson BJ, Matrana MR, et al. Prognosis of patients with metastatic renal cell carcinoma and pancreatic metastases. BJU Int. 2016;117(5):761-765. doi: 10.1111/bju.13185.
3. Rodriguez-Vida A, Hutson TE, Bellmunt J, Strijbos MH. New treatment options for metastatic renal cell carcinoma. ESMO Open. 2017;2(2):e000185. doi: 10.1136/esmoopen-2017-000185.
4. FDA grants regular approval to Cabometyx for first-line treatment of advanced renal cell carcinoma [press release]. US Food and Drug Adminsitration: Silver Spring, MD; December 19, 2017. www.fda.gov/drugs/informationondrugs/approveddrugs/ucm589842.htm. Accessed August 29, 2018.
5. Choueiri TK, Hessel C, Halabi S, et al. Cabozantinib versus sunitinib as initial therapy for metastatic renal cell carcinoma of intermediate or poor risk (Alliance A031203 CABOSUN randomised trial): progression-free survival by independent review and overall survival update. Eur J Cancer. 2018;94:115-125. doi: 10.1016/j.ejca.2018.02.012.
6. Summary of opinion (post authorisation): Cabometyx: cabozantinib [press release]. European Medicines Agency: London, United Kingdom; March 22, 2018. ema.europa.eu/docs/en_GB/document_library/Summary_of_opinion/human/004163/WC500246393.pdf. Accessed August 29, 2018.
7. George DJ, Hessel C, Halabi S, et al. Cabozantinib versus sunitinib for previously untreated patients with advanced renal cell carcinoma (RCC) of intermediate or poor risk: subgroup analysis of progression-free survival (PFS) and objective response rate (ORR) in the Alliance A031203 CABOSUN trial. Presented at: 2018 Genitourinary Cancers Symposium; February 8-10, 2018; San Francisco, CA. Abstract 582. meetinglibrary.asco.org/record/156873/abstract.
8. Beaumont JL, Salsman JM, Diaz J, et al. Quality-adjusted time without symptoms or toxicity analysis of pazopanib versus sunitinib in patients with renal cell carcinoma. Cancer. 2016;122(7):1108-1115. doi: 10.1002/cncr.29888.
9. FDA approves nivolumab plus ipilimumab combination for intermediate or poor-risk advanced renal cell carcinoma [press release]. US Food and Drug Administration: Silver Spring, MD; April 16, 2018. www.fda.gov/drugs/informationondrugs/approveddrugs/ucm604685.htm. Accessed August 29, 2018.
10. Motzer RJ, Tannir NM, McDermott DF, et al. Nivolumab plus ipilimumab versus sunitinib in advanced renal-cell carcinoma. N Engl J Med. 2018;378(14):1277-1290. doi: 10.1056/NEJMoa1712126.
11. Soria F, Beleni AI, D’Andrea D, et al. Pseudoprogression and hyperprogression during immune checkpoint inhibitor therapy for urothelial and kidney cancer [published online March 16, 2018]. World J Urol. doi: 10.1007/s00345-018-2264-0.
12. Méjean A, Escudier B, Thezenas S, et al. CARMENA: cytoreductive nephrectomy followed by sunitinib versus sunitinib alone in metastatic renal cell carcinoma—results of a phase III noninferiority trial. Presented at: 2018 ASCO Annual Meeting; June 1-5, 2018; Chicago, IL. Abstact LBA3. meetinglibrary.asco.org/record/161512/abstract.
13. Méjean A, Ravaud A, Thezenas S, et al. Sunitinib alone or after nephrectomy in metastatic renal- cell carcinoma. N Engl J Med. 2018;379(5):417-427. doi: 10.1056/NEJMoa1803675.