Cabozantinib may be new standard for metastatic papillary kidney cancer
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Cabozantinib conferred a significant and meaningful extension of PFS compared with sunitinib in metastatic papillary renal cell carcinoma, according to results of a phase 2 randomized trial presented at Genitourinary Cancers Symposium.
Other small-molecule inhibitors evaluated in the multiarm SWOG 1500 study, crizotinib (Xalkori, Pfizer) and savolitinib (HMPL-504/AZD6094; AstraZeneca, Chi-Med), did not demonstrate a benefit compared with the existing standard, sunitinib (Sutent, Pfizer).
“I was thrilled to see that cabozantinib [Cabometyx/Cometriq, Exelixis] resulted in this really dramatic improvement in PFS and response rate,” Sumanta (Monty) K. Pal, MD, clinical professor of medical oncology at City of Hope, SWOG Cancer Research Network investigator and a HemOnc Today Editorial Board Member, told Healio. “These data suggests that, for the first time, we have an agent that benefits outcomes in this rare population of patients. Previously there was no real, true standard of care.”
Pal added that this finding will change the way oncologists treat this rare form of kidney cancer “right away.”
“It’s definitely going to influence things, without a doubt,” he said.
Based on the understanding that MET signaling is a key molecular driver in papillary renal cell carcinoma, Pal and colleagues decided to compare sunitinib with MET kinase inhibitors.
“We set out to show that any one of these three drugs could delay tumor growth and, ironically, a drug I was involved in the phase 1 development of, cabozantinib, is the one that made the mark and improved outcomes for these patients,” Pal said.
Pal and colleagues collected data of 147 patients (median age, 66 years; 76% men) who had pathologically verified papillary renal cell carcinoma, Zubrod performance status of 0 to 1 and measurable metastatic disease. Patients may have received up to one prior systemic therapy, excluding VEGF- or MET-directed therapy; the majority of patients (92%) had no prior therapy.
Researchers randomly assigned patients to receive 50 mg daily sunitinib in a 4-weeks-on, 2-weeks-off schedule (n = 46), 60 mg daily cabozantinib (n = 44), 250 mg twice-daily crizotinib (n = 28) or 600 mg daily savolitinib (n = 29).
PFS for each experimental group vs. sunitinib served as the study’s primary endpoint. Secondary endpoints included OS, response rate and adverse events.
Experimental groups with at HR greater than 1 for PFS at a prespecified futility analysis —occurring after 15 PFS events in each of the experimental groups and 20 events in the sunitinib group — would be recommend for closure.
Based on those criteria, researchers halted accrual for the crizotinib (median PFS, 2.8 months) and savolitinib (median PFS, 3 months) groups early for futility.
Accrual continued to completion for sunitinib and cabozantinib, with resulting showing significantly prolonged median PFS with cabozantinib compared with sunitinib (9 months vs. 5.6 months; HR = 0.6; 95% CI, 0.37-0.97).
Researchers also evaluated outcomes based on histologic subtype. Local pathologic review determined 18% of patients had type I histology, 54% had type II histology and 28% of patients had mixed/other histology, with corresponding frequencies per central review of 30%, 45% and 25%.
Benefit with cabozantinib persisted for patients with type I (local assessment, HR = 0.26; 95% CI, 0.07-1.01; central assessment, HR = 0.56; 95% CI, 0.22-1.45) and type II (local assessment, HR = 0.57; 95% CI, 0.3-1.06; central assessment, HR = 0.62; 95% CI, 0.31-1.24) histology.
“Although discordances were observed in subtype classifications, it did appear that cabozantinib had a homogenous effect across treatment groups,” Pal said during his presentation. “With this in mind, cabozantinib should be considered the new reference standard for systemic therapy in patients with metastatic renal cell carcinoma.”
The confirmed overall response rate of 23% (complete response, 5%) with cabozantinib was significantly higher than the 4% ORR (complete response, 0%) with sunitinib (P = .01), with few responses occurring in the crizotinib and savolitinib groups.
Preliminary OS results showed a slight trend toward improvement with cabozantinib (median, 20 months; 95% CI, 11-not reached) relative to the sunitinib group (median, 16.4 months; 95% CI, 13-22), but, overall, there were no significant differences. Median OS was 19.9 months (95% CI, 11-not reached) with crizotinib and 11.7 months (95% CI, 7-29) with savolitinib.
Pal and colleagues noted grade 3 to grade 4 adverse events occurred among 68% of the sunitinib group, 74% of the cabozantinib group, 37% of the crizotinib group and 39% of the savolitinib group, with one grade 5 adverse event occurring with cabozantinib.
Rate of treatment discontinuation due to adverse events was highest with sunitinib (24%), followed by cabozantinib (23%), crizotinib (16%) and savolitinib (10%).
A follow-up study that will evaluate the addition of cabozantinib to immunotherapy is currently in the planning stages, Pal told Healio.
“There are rare subtypes of any cancer and it’s important that they be tackled independently from other diseases and from the broader disease, perhaps,” Pal said. “Understanding the biology in rare cancers, whether it’s a rare type of kidney cancer or breast cancer or ovarian cancer, is really critical.
“Developing trials around that biology is challenging, but as we’ve demonstrated in SWOG 1500, it is doable and necessary if we’re going to move the needle for these patients,” he added.
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Pal SK, et al. Abstract 270. Presented at: Genitourinary Cancers Symposium (virtual meeting); Feb. 11-13, 2021.
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