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

Christin Melton, ELS
Published: Wednesday, Oct 03, 2018
Daniel J. George, MD
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.

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.2

CABOZANTINIB AND THE CABOSUN STUDY

In 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
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.


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Community Practice Connections™: New Directions in Advanced Cutaneous Squamous Cell Carcinoma: Emerging Evidence of ImmunotherapyAug 13, 20191.5
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