There were numerous notable presentations at the 2019 Genitourinary Cancers Symposium, many of which were covered in The ASCO Post over the past few months. To add to our continued coverage of this meeting, here are some highlights from studies focusing on novel therapeutics in renal cell carcinoma and prostate cancer.
Pembrolizumab/Cabozantinib in Renal Cell Carcinoma
The combination of pembrolizumab and cabozantinib, an oral tyrosine kinase inhibitor, demonstrated antitumor activity in patients with previously treated metastatic renal cell carcinoma, and both drugs were tolerated at their approved doses, according to data from a dose-escalation cohort of a phase I study.2
Among eight patients with renal cell carcinoma of any histology, the best objective response was a partial response in two patients and stable disease in five patients; two patients experienced progressive disease. The maximum tolerated dose was identified as pembrolizumab at 200 mg every 3 weeks plus oral cabozantinib at 60 mg daily. No dose-limiting toxicities were observed with cabozantinib at 40 mg when used in combination with pembrolizumab in evaluable patients. One patient required a dose reduction from 60 mg of cabozantinib to 40 mg after cycle 5.
The side effects of cabozantinib were as expected. The most common treatment-emergent adverse events of any grade at either cabozantinib dosage were fatigue (75%), diarrhea (62.5%), weight loss (62.5%), and dysgeusia (50%).
Patients in the study were not selected for PD-L1 expression. No correlation with PD-L1 status and response was seen in the tumor samples tested.
Molika E. Keeler, MS
“These data suggest encouraging early efficacy, and we will proceed with a phase II trial,” said lead author Molika E. Keeler, MS, of the University of Colorado, Aurora.
Based on these findings, a two-stage phase II study with a planned enrollment of 20 treatment-naive or previously treated patients has been initiated in patients with renal cell carcinoma with either clear cell or non–clear cell histology. The investigators plan to expand the phase II study, depending on responses.
Nivolumab/Ipilimumab Combination in Advanced Renal Cell Carcinoma
Nivolumab plus low-dose ipilimumab continued to demonstrate strong responses as well as a survival benefit, with a median of 32.4 months of follow-up, in the front-line treatment of patients with intermediate- and poor-risk advanced renal cell carcinoma, according to an update of the phase III CheckMate 214 trial.1
The 30-month overall survival rate was 60% with the immunotherapy combination vs 47% with sunitinib in the intermediate- and poor-risk populations (P < .0001). The objective response rate by investigator assessment was 42% vs 29% (P = .0001), respectively, including a complete response rate of 11% vs 1%. Among responders, 52% of patients receiving nivolumab/ipilimumab had a duration of response of 18 months or longer vs 28% of patients on the sunitinib arm.
In an intent-to-treat analysis of all 1,096 patients, the 30-month overall survival rate was 64% with the immunotherapy combination vs 56% with sunitinib (P = .0003). The objective response rate in the intent-to-treat population was 41% vs 34% (P = .015), respectively, including a complete response rate of 11% vs 2%.
No new safety signals for the combination emerged with long-term follow-up. The adverse events were consistent with previous reports for these agents in patients with renal cell carcinoma.
“Regardless of the risk category, nivolumab/ipilimumab achieved impressive response rates and deeper, more durable responses than sunitinib.”— Nizar M. Tannir, MD
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“The results from this 30-month follow-up from the CheckMate 214 study are meaningful, as they continue to demonstrate that in patients with advanced renal cell carcinoma, a population with considerable unmet treatment needs, there is potential for long-term survival benefits with the combination of nivolumab and ipilimumab,” stated lead author Nizar M. Tannir, MD, of the Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston.
The open-label CheckMate 214 trial randomly assigned patients 1:1 to receive the combination of 3 mg/kg of nivolumab plus 1 mg/kg of ipilimumab every 3 weeks for 4 doses, followed by maintenance nivolumab at 3 mg/kg every 2 weeks (n = 425) or sunitinib at 50 mg daily on a 4-weeks-on/2-weeks-off schedule (n = 422). After completion of four doses with the combination, nivolumab was given until disease progression or unacceptable toxicity. Patients enrolled on the study had advanced or metastatic disease with no prior therapy. In the 1,096 patients in the intent-to-treat population, 78% had intermediate- or poor-risk disease.
The primary analysis found that the nivolumab/ipilimumab combination demonstrated a 37% reduction in the risk of death vs sunitinib in intermediate- and poor-risk patients with advanced renal cell carcinoma, regardless of programmed cell death ligand 1 (PD-L1) expression status (P < .0001). The median overall survival was not yet reached for the combination vs 25.9 months for sunitinib. In the favorable-risk group, although numerically overall response rate was higher with sunitinib (50% vs 39%) and median progression-free survival was longer (19.9 vs 13.9 months), these differences were not statistically significant, and there was no significant difference in overall survival between the two arms. It is noteworthy to mention that in the favorable-risk group, the complete response rate was 8% with nivolumab/ipilimumab vs 4% with sunitinib, with 9 of 10 patients still having an ongoing complete response with nivolumab/ipilimumab vs 2 of 5 patients having an ongoing complete response with sunitinib.
“Regardless of the risk category, nivolumab/ipilimumab achieved impressive response rates and deeper, more durable responses than sunitinib,” Dr. Tannir said.
The overall safety profile was consistent with previous data for nivolumab/ipilimumab. Adverse events leading to treatment discontinuation were reported in 22% of patients receiving nivolumab/ipilimumab compared with 12% in the sunitinib group.
Based on the primary CheckMate 214 data analysis, the U.S. Food and Drug Administration (FDA) approved the combination of nivolumab and ipilimumab in April 2018 as front-line treatment for intermediate- and poor-risk patients with advanced renal cell carcinoma. The updated analysis confirmed the primary analysis.
Savolitinib/Durvalumab in Metastatic Kidney Cancer
The combination of savolitinib, a small molecule inhibitor of c-Met, and durvalumab achieved responses in approximately one-fourth of patients with metastatic papillary renal cell carcinoma, in the phase II CALYPSO study.3 “The progression-free survival and overall survival are immature but encouraging,” said presenting author Cristina Suarez, MD, PhD, of Vall d’Hebron University Hospital and Vall d’Hebron Cancer Institute, Barcelona.
“The progression-free and overall survival are immature but encouraging [with the combination of savolitinib and durvalumab in metastatic papillary renal cell carcinoma].”— Cristina Suarez, MD, PhD
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In 41 evaluable patients, who were either naive or refractory to vascular endothelial growth factor treatment, 11 patients (27%) achieved a response (all partial responses) with savolitinib/durvalumab. Fifteen patients (39%) achieved stable disease. Responses were similar in previously untreated patients.
Of the 41 evaluable patients, 22 (54%) had a decrease in tumor burden. Of the 11 patients with an objective response, an interim analysis showed a duration of response approaching 6 months. Three patients were not evaluable for response.
Treatment options are limited for papillary renal cell carcinoma. Clinical guidelines recommend enrollment in a clinical trial—the preferred strategy—or sunitinib. With these options, overall survival is approximately 12 months, and new treatments represent an unmet need.
Based on preliminary data suggesting synergy, savolitinib was combined with durvalumab for the phase II CALYPSO trial, a multiarm study that includes patients with different renal cell carcinoma histologies: clear cell, sarcomatoid, and papillary.
The data Dr. Suarez presented at the 2019 Genitourinary Cancers Symposium was based on a cohort of 42 patients with measurable metastatic papillary renal cell carcinoma. One patient experienced disease progression prior to study therapy.
Savolitinib monotherapy at 600 mg/d was administered during a 4-week lead-in period; then durvalumab at 1,500 mg was added intravenously every 4 weeks. Treatment was continued until disease progression or unacceptable toxicity. The primary endpoint was objective response; secondary endpoints were progression-free survival, overall survival, duration of response, best response at 24 weeks, and safety.
The median age of patients was 62 years, and all patients had an Eastern Cooperative Oncology Group performance status of 0 or 1. A total of 29% were considered to be at “good risk,” according to International Metastatic Renal Cell Carcinoma Database Consortium criteria, 63% were intermediate-risk, and 7% were poor-risk.
At a median follow-up of 6.9 months, in an interim analysis, the investigator-assessed median progression-free survival was 5.3 months, and the median overall survival was not reached. There was no correlation between PD-L1 status and MET biomarker expression with outcome.
The combination was tolerable; the most prominent all-grade adverse events were mostly grade 1 and two nausea, edema, and fatigue. The most frequent grade 3 adverse event was edema, which occurred in 4 patients. One patient had a grade 4 toxicity (transaminitis); there were no grade 5 toxicities.
Tivozanib vs Sorafenib in Metastatic Kidney Cancer
Tivozanib, a VEGF tyrosine kinase inhibitor, achieved significantly improved progression-free survival compared with sorafenib in previously treated patients with metastatic renal cell carcinoma, in the randomized TIVO-3 trial, confirming the results of the previous TIVO-1 trial. However, no survival benefit was found for the investigational multitargeted tyrosine kinase inhibitor tivozanib.4 Brian Rini, MD, of the Cleveland Clinic Foundation, is the lead author of the TIVO-3 study.
Brian Rini, MD
The median progression-free survival was 5.6 months with tivozanib vs 3.9 months with sorafenib, representing a 27% reduction in the likelihood of disease progression or death (P = .0165). The 1-year and 2-year progression-free survival rates favored tivozanib: 28% vs 11% at 1 year and 18% vs 5% at 2 years.
Patients previously treated with checkpoint inhibitors had a greater benefit from tivozanib than sorafenib, including median progression-free survival (7.3 vs 5.1 months, P = .028), 1-year progression-free survival (35% vs 4%, respectively), and 2-year progression-free survival (25% vs 0%, respectively).
Despite these positive results for several endpoints, no significant benefit in overall survival was observed for tivozanib: median overall survival of 16.4 months vs 19.7 months with sorafenib.
Of the 351 patients enrolled in the trial, 60% received 2 prior lines of therapy and 40%, 3 prior lines. A total of 28% received prior checkpoint inhibitor therapy. Grade 3 treatment-related adverse events were reported in 44% of the tivozanib arm vs 55% of the sorafenib arm.
Thus far, both the TIVO-1 randomized trial, which included about 500 patients with advanced renal cell carcinoma, and the TIVO-3 randomized trial of 351 patients with previously treated metastatic renal cell carcinoma have failed to show a survival benefit for tivozanib. A planned survival analysis is scheduled for August 2019.
Layering Radium-223 With Abiraterone Acetate in Prostate Cancer
Layering radium-223 with abiraterone acetate reduced the incidence of symptomatic skeletal side effects compared with concurrent use of these agents in patients with metastatic castration-resistant prostate cancer, according to the results of a retrospective study based on the Flatiron Health prostate registry.5
The rate of skeletal side effects was reduced from 0.46 per person-year in men who started radium-223 or abiraterone acetate plus prednisone within 30 days of each other (concurrent use) compared with 0.28 per person-year in those who initiated either therapy at least 30 days apart (layered use). The rate of skeletal side effects among all 625 men who received radium-223 was 0.35 per person-year.
Layered therapy reduced the rate of pathologic fracture to 0.09 per person-year compared with 0.17 per person-year in the concurrent therapy group. The overall rate of pathologic fracture among all patients treated with radium-223 was 0.11 per person-year.
According to the lead author, Daniel J. George, MD, Co-Leader of the Duke Cancer Institute Center for Prostate and Urologic Cancers, these data are reassuring about the use of radium-223 alone or layered with a hormonal agent.
“These data are reassuring about the use of radium-223 alone or layered with a hormonal agent.”— Daniel J. George, MD
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“It’s only when they are used concomitantly that bone complications looked worse, and that’s true of both fractures and symptomatic skeletal events. These data give us peace of mind that we’re not making the clinical course worse by layering these agents,” Dr. George commented. He noted that radium-223 improves survival in patients with bone-dominant disease and said the best use of this agent is in patients with that clinical phenotype.
The study included 625 patients diagnosed with metastatic castration-resistant prostate cancer treated with radium-223 from January 1, 2013, to June 30, 2017, who were included in the Flatiron registry. Of them, 136 patients received combination therapy with radium-223 and abiraterone acetate: 97 (71%) received layered treatment (ie, initiating 1 of the treatments at least 30 days after the start of the first treatment), and 39 (29%) initiated radium-223 within 30 days of starting abiraterone acetate (ie, concurrent treatment).
Any symptomatic skeletal side effects occurred in 36% of patients receiving radium-223 and abiraterone acetate concurrently compared with 23% of the layered treatment arm and 27% of the overall 625-patient cohort treated with radium-223. The rates of pathologic fracture were 18%, 8%, and 10%, respectively, and the rates of spinal cord compression were 10%, 4%, and 5%, respectively.
Concomitant bone-directed therapy was given to about two-thirds of the group between the start or end of either radium-223 or abiraterone acetate/prednisone therapy. ■
DISCLOSURE: Dr. Tannir has received honoraria from Bristol-Myers Squibb, Calithera Biosciences, Exelixis, Nektar, Novartis, and Pfizer; is a consultant/advisor with Bristol-Myers Squibb, Exelixis, Nektar, Novartis, and Pfizer; has received research funding from Bristol-Myers Squibb, Exelixis, and Novartis; has received travel/accommodations/expenses from Bristol-Myers Squibb, Calithera Biosciences, Nektar, and Pfizer; and has other financial relationships with Eisai Medical Research, Epizyme, Mirati Therapeutics, Oncorena, and Ono Pharmaceutical. Dr. Keeler reported no conflicts of interest. Dr. Suarez is a consultant/advisor with Bristol-Myers Squibb, Ipsen, Pfizer, EUSA Pharma, Astellas Pharma, Novartis, and Sanofi; has received travel/accommodations/expenses from Bristol-Myers Squibb; and has received institutonal research funding from Astellas Pharma, Roche/Genentech, Exelixis, AstraZeneca, Bristol-Myers Squibb, Pfizer, Novartis, Janssen Oncology, Calithera Biosciences, AB Science, Arog, AVEO, Bayer, SFJ Pharmaceuticals Group, Blueprint Medicines, Clovis Oncology, Boehringer Ingelheim, Cougar Biotechnology, Deciphera, GlaxoSmithKline, Incyte, Karyopharm Threapeutics, MedImmune, Nanobiotix, Millennium, Puma Biotechnology, and Teva. Dr. Rini is a consultant/advisor with Pfizer, Merck, Genentech/Roche, and Novartis; has received institutional research funding from Pfizer, Roche/Genentech, and Bristol-Myers Squibb; has received honoraria from Bristol-Myers Squibb; travel/accommodations/expenses from Pfizer; and has other financial relationships with Peloton, Aveo Pharmaceuticals (supported TIVO-3 trial), AstraZeneca, Synthorx, Compugen, Corvus, Exelixis, and PTC Therapeutics. Dr. George is a consultant/advisor with Myovant Sciences, Astellas Pharma, Bayer, Bristol-Myers Squibb, Exelixis, Genentech, Innocrin Pharma, Janssen, Merck Sharp & Dohme, Pfizer, and Sanofi; is on the speakers bureau for Bayer, Exelixis, and Sanofi; has received institutional research funding from Acerta Pharma, Astellas Pharma, Bayer, Bristol-Myers Squibb, Dendreon, Exelixis, Genentech/Roche, Innocrin Pharma, Janssen, Novartis, and Pfizer; has received travel/accommodations/expenses from Bayer, Pfizer, Exelixis, Genentech/Roche, Merck, and Medivation; and has received honoraria from Sanofi, Bayer, and Exelixis.
1. Tannir NM, Arén Frontera O, Hammers HJ, et al: Thirty-month follow-up of the phase III CheckMate 214 trial of first-line nivolumab + ipilimumab or sunitinib in patients with advanced renal cell carcinoma. 2019 Genitourinary Cancers Symposium. Abstract 547. Presented February 16, 2019.
2. Keeler ME, Kessler ER, Bernard B, et al: Pembrolizumab and cabozantinib in patients with metastatic renal cell carcinoma: Phase I results. 2019 Genitourinary Cancers Symposium. Abstract 600. Presented February 16, 2019.
3. Powles T, Larkin JMG, Patel P, et al: A phase II study investigating the safety and efficacy of savolitinib and durvalumab in metastatic papillary renal cancer (CALYPSO). 2019 Genitourinary Cancers Symposium. Abstract 545. Presented February 16, 2019.
4. Rini BI, Pal S, Escudier B, et al: TIVO-3: A phase III, randomized, controlled, multicenter, open-label study to compare tivozanib to sorafenib in subjects with refractory advanced renal cell carcinoma. 2019 Genitourinary Cancers Symposium. Abstract 541. Presented February 16, 2019.
5. George DJ, Sternberg CN, Sartor AO, et al: Clinical outcome with concurrent or layered treatment with radium-223 and abiraterone: A retrospective study of real-world experience with patients with metastatic castration-resistant prostate cancer. 2019 Genitourinary Cancers Symposium. Abstract 253. Presented February 14, 2019.