Highlights in Renal Cell Carcinoma From the 2012 American Society of Clinical Oncology Annual Meeting

Volume 10, Issue 9, Supplement 15 September 2012

June 1–5, 2012 • Chicago, Illinois

Special Reporting on:

• Cardiac Safety Analysis for a Phase III Trial of Sunitinib (SU) or Sorafenib (SO) or Placebo (PLC) in Patients (pts) With Resected Renal Cell Carcinoma (RCC)

• Tivozanib Versus Sorafenib as Initial Targeted Therapy for Patients With Advanced Renal Cell Carcinoma: Results From a Phase III Randomized, Open-Label, Multicenter Trial

• Axitinib for First-Line Metastatic Renal Cell Carcinoma (mRCC): Overall Efficacy and Pharmacokinetic (PK) Analyses From a Randomized Phase II Study

• Patient Preference Between Pazopanib (Paz) and Sunitinib (Sun): Results of a Randomized Double-Blind, Placebo-Controlled, Cross-Over Study in Patients With Metastatic Renal Cell Carcinoma (mRCC)—PISCES Study, NCT 01064310

• Updated Results on Long Term Overall Survival (OS) of the French Randomized Phase II Trial TORAVA in Metastatic Renal Cell Carcinoma (mRCC) Patients

• Efficacy of Cabozantinib (XL184) in Patients (pts) With Metastatic, Refractory Renal Cell Carcinoma (RCC)

• Clinical Activity and Safety of Anti-PD-1 (BMS-936558, MDX-1106) in Patients With Previously Treated Metastatic Renal Cell Carcinoma (mRCC)

PLUS Meeting Abstract Summaries

With Expert Commentary by:

Brian I. Rini, MD

Associate Professor of Medicine

Cleveland Clinic Lerner College of Medicine

Case Western Reserve University

Cleveland, Ohio

Disclaimer

Every effort has been made to ensure that drug usage and other information are presented accurately; however, the ultimate responsibility rests with the prescribing physician. Millennium Medical Publishing, Inc, and the participants shall not be held responsible for errors or for any consequences arising from the use of information contained herein. Readers are strongly urged to consult any relevant primary literature. No claims or endorsements are made for any drug or compound at present under clinical investigation.

Cardiac Safety Analysis for a Phase III Trial of Sunitinib (SU) or Sorafenib (SO) or Placebo (PLC) in Patients (pts) With Resected Renal Cell Carcinoma (RCC)

Cardiac dysfunction is a well-known risk of tyrosine kinase inhibitor therapy. The mechanism of action is thought to be myocyte metabolic dysfunction. Sunitinib is the best-characterized tyrosine kinase inhibitor, and most analyses of cardiac dysfunction relating to its use are retrospective. Naomi B. Haas, MD, presented cardiac safety data¹ from the phase III Eastern Cooperative Oncology Group (ECOG) 2805/ASSURE (Adjuvant Sorafenib or Sunitinib for Unfavorable Renal Carcinoma) trial of adjuvant sorafenib versus sunitinib for patients with completely resected renal cell carcinoma (RCC).² Eligible patients were required to have a normal left ventricular ejection fraction (LVEF) by multigated acquisition (MUGA) scan, controlled blood pressure or hypertension, and no clinically significant recent cardiac arrhythmias or cardiovascular disease. Patients received either 1 year of sunitinib daily for 4 of every 6 weeks, 1 year of daily sorafenib, or 1 year of daily placebo. Accrual ended in September 2010, and the primary endpoint has not yet been met.

The primary endpoint of the cardiac substudy is to determine whether clinically significant decreases in LVEF—defined as an LVEF below the institutional lower limit of normal, where the drop was at least 16% from baseline—occurred within 6 months of treatment initiation. A planned interim analysis was undertaken when 200 patients had accrued in each arm, although data collection continued for the remainder of the study. Secondary cardiac objectives included determining the frequency of clinically significant congestive heart failure, exploring the association between congestive heart failure and LVEF changes, determining optimal timing of scans for assessing clinically significant changes of LVEF, describing relationships between blood pressure changes and changes in LVEF, and assessing reversibility of any changes in LVEF. Results of MUGA scans were obtained from institutional reporting; there was no central review. Due to a nationwide shortage of technetium 99 that occurred during the study, a small number of patients underwent monitoring by echocardiogram.

Asymptomatic left ventricular decline was managed by evaluating the absolute decline in LVEF and comparing it to the institutional lower limit of normal. For example, if a patient showed an LVEF decline of 16%, and the LVEF was at least 6% below the institutional lower limit of normal, then drugs were held and a repeat MUGA scan was repeated 2–4 weeks later. If the patient’s LVEF returned to the institutional lower limit of normal, then treatment with study agents was resumed. If the patient’s LVEF was within 1–5% of the institutional lower limit of normal, then study treatment was resumed with a dose reduction.

The trial randomized 1,943 patients, of whom 1,867 were assessed at baseline by MUGA scan and 59 were assessed by echocardiogram. From the patients with a baseline MUGA, 1,589 had at least 1 follow-up MUGA scan, and of these patients, 1,293 had a 6-month follow-up MUGA scan or experienced an event and thus could be assessed for the primary endpoint.

There were 9 (2.3%), 7 (1.8%), and 5 (1.0%) events in the sunitinib (n=397), sorafenib (n=384), and placebo (n=502) arms, respectively (Table 1). A similar proportion of patients in each arm experienced an LVEF decline of at least 16% shown cumulatively over 12 months. The group of patients who met the primary endpoint showed patient characteristics similar to those of the overall population. However, in comparison to the general study population, the 21 patients who had a primary cardiac event were more likely to have a very high risk of RCC recurrence, their performance status was worse, they were more likely to be male, they tended to be older, and they tended to have a history of cardiovascular events. Examination of individual changes in LVEF showed that in most patients, a decline in LVEF appeared to be reversible regardless of the treatment arm (Figure 1), and treatment was held and then resumed in most cases.

Other LVEF events were defined as LVEF declines of at least 16% below the institutional lower limit of normal occurring after 6 months, and grade 2 or 3 left ventricular systolic or diastolic dysfunction. Other events were reported by means of the Adverse Event Expedited Reporting System or case reports. These events occurred at a low rate and were evenly distributed among the 3 treatment arms, with 12 events recorded in the sunitinib arm and 11 events in each of the other 2 arms. Similarly, the combined cardiac events in each of the 3 arms show a low rate and even distribution across the arms, with combined rates of 4.3%, 5.3%, and 3.7% combined cardiac events in the sunitinib, sorafenib, and placebo arms, respectively. The analysis of hypertension was incomplete at the time of the presentation. Five events of cardiac ischemia occurred in each of the 3 arms, and these events were reported as possibly related or unrelated to study treatment. One event was reported as definitely related for a patient who was receiving placebo.

ECOG 2805 is the largest prospective study ever conducted to determine the cardiac effects of tyrosine kinase inhibitors. Its findings show that adjuvant sunitinib and sorafenib are not associated with significant cardiac dysfunction in the study population. Further prospective studies are needed to examine the effects of tyrosine kinase inhibitors on patients with pre-existing cardiac dysfunction. There are no significant cardiac contraindications against the use of sunitinib and sorafenib in the adjuvant setting.

References

1. Haas NB, Manola J, Ky B, et al. Cardiac safety analysis for a phase III trial of sunitinib (SU) or sorafenib (SO) or placebo (PLC) in patients (pts) with resected renal cell carcinoma (RCC). J Clin Oncol (ASCO Annual Meeting Proceedings). 2012;30(18 suppl): Abstract 4500.

2. ClinicalTrials.gov. Sunitinib or sorafenib in treating patients with kidney cancer that was removed by surgery. http://clinicaltrials.gov/ct2/show/NCT00326898. Identifier: NCT00326898.

ABSTRACT SUMMARY Phase III Randomized Sequential Open-Label Study to Evaluate Efficacy and Safety of Sorafenib (SO) Followed by Sunitinib (SU) Versus Sunitinib Followed by Sorafenib in Patients With Advanced/Metastatic Renal Cell Carcinoma Without Prior Systemic Therapy (SWITCH Study): Safety Interim Analysis Results

Sequencing of sorafenib and sunitinib in RCC patients has been examined retrospectively, but the preferred sequence has not been established. A phase III clinical trial is in progress comparing sorafenib followed by sunitinib versus sunitinib followed by sorafenib in patients with metastatic RCC unsuitable for cytokine treatment and no prior systemic therapy (Abstract 4539). Patients have ECOG performance status of 0 or 1, MSKCC score of low or intermediate, and at least 1 measurable lesion. The primary endpoint is PFS. Monitoring includes echocardiography and measurement of N-terminal pro-B-type natriuretic peptide. At the time of the presentation, 361 patients had been randomized to treatment, 116 patients had completed treatment, and safety data were available for 333 patients. In patients receiving sorafenib first versus sunitinib first, adverse events occurred in 93.4% and 92.8% of patients, grade 3/4 adverse events occurred in 59.9% and 50.0% of patients, and serious adverse events occurred in 46.7% and 42.2% of patients, respectively. For both arms, patients experienced a greater frequency of adverse events during the first treatment compared with the second treatment. Available data suggested that the frequency of LVEF was similar between the 2 treatment arms at screening and on the day of stopping first-line treatment, with an approximate range of 62–64%.

Tivozanib Versus Sorafenib as Initial Targeted Therapy for Patients With Advanced Renal Cell Carcinoma: Results From a Phase III Randomized, Open-Label, Multicenter Trial

Robert J. Motzer, MD, reported initial results from a randomized, multicenter, international, open-label, phase III trial comparing the anti-angiogenic agents tivozanib and sorafenib in patients with advanced RCC.¹ Tivozanib is a potent and selective inhibitor of vascular endothelial growth factor (VEGF) receptors 1, 2, and 3. The drug’s half-life of 3.7–4.7 days is designed to optimize blockade while minimizing off-target toxicity. Its pharmacokinetic profile allows once-daily dosing. A phase II trial conducted in 272 patients with advanced RCC yielded a median progression-free survival (PFS) of 11.7 months; hypertension was the predominant toxicity, and there was a low incidence of “off-target” adverse events.² The primary endpoint of the phase III trial was to demonstrate PFS superiority in patients with metastatic RCC receiving tivozanib versus sorafenib as first-line therapy. Objective response rate (ORR) and safety were secondary endpoints.

Key eligibility criteria included advanced RCC, clear cell histology, measurable disease, a prior nephrectomy, no more than 1 prior therapy for metastatic disease, no prior VEGF-directed or mammalian target of rapamycin (mTOR)-directed therapy, and ECOG performance status of 0 or 1. Patients were equally randomized to receive either tivozanib (1.5 mg/day) on a schedule of 3 weeks on and 1 week off or sorafenib (400 mg/day). Patients with progressive disease on the sorafenib arm were offered open-label tivozanib on a separate protocol.

Safety data were collected from the day of patient consent until 30 days after the patient’s final dose. Response assessment occurred every 8 weeks. Treatment continued until disease progression or intolerance. Blinded, real-time, third-party review was used to confirm investigator-determined disease progression, and radiographic progression was required for patients to cross over from sorafenib to tivozanib. In addition, independent, blinded review of all study scans was performed by a core imaging laboratory for primary endpoint assessment.

The statistical test for the primary endpoint of independently-assessed PFS was a stratified log-rank test with 2-sided significance and an alpha level of 5%. The planned trial size was 500 and required 310 events. The trial had 90% power to detect a 45% or greater improvement in median PFS from 6.7 months for sorafenib to 9.7 months for tivozanib.

The trial enrolled 517 patients between February and August of 2010 at 76 sites in 15 countries in North America, Europe, South America, and Asia. Approximately 90% of patients were enrolled in Europe. Patients were randomized to receive tivozanib (n=260) or sorafenib (n=257). The 2 arms were generally well balanced with respect to patient characteristics; however, the sorafenib arm had a slightly higher proportion of patients with ECOG performance status of 0 compared to the tivozanib arm (54% vs 45%, respectively). The majority of patients in both arms were of intermediate risk based on the Memorial Sloan-Kettering Cancer Center (MSKCC) prognostic criteria; however, 27% of patients in the tivozanib arm and 34% of patients in the sorafenib arm had favorable risk classification. In both arms, 70% of patients had received no prior therapy for their metastatic disease and were therefore considered treatment-naïve. Of the remaining 30% of patients, more than 95% had received interferon alpha as their prior therapy.

The median PFS was 11.9 months for patients who received tivozanib versus 9.1 months for those who received sorafenib (hazard ratio [HR], 0.797; P=.042; Figure 2), thus demonstrating superior efficacy for tivozanib over sorafenib and reaching the primary endpoint. The median PFS based on investigator assessment was 14.7 months for tivozanib versus 9.6 months for sorafenib (HR, 0.722; P=.003).

Prespecified subset analysis of the treatment-naïve patients yielded a PFS of 12.7 months with tivozanib treatment versus 9.1 months with sorafenib (HR, 0.756; P=.037). Other prespecified subset analyses, including those based on MSKCC prognostic group, geographic region, and prior systemic therapy, also favored tivozanib.

Based on independent review, complete and partial responses occurred in both arms and yielded an ORR of 33% for tivozanib versus 23% for sorafenib (P=.014). Dose adjustments due to adverse events were more frequent overall in the sorafenib arm. Dose interruptions occurred in 18% of patients receiving tivozanib versus 35% of patients receiving sorafenib. Dose reductions occurred in 12% of patients in the tivozanib arm and 43% of patients in the sorafenib arm. Treatment was discontinued in both arms at 4–5%.

Clinical laboratory abnormalities were generally similar between the 2 treatment arms, although liver function test abnormalities and hypophosphatemia occurred with a higher frequency in the sorafenib arm. Neutropenia of any grade was reported in 10% of the tivozanib arm and 9% of the sorafenib arm. Thrombocytopenia of any grade was reported in 17% and 11% of patients, respectively. Grade 3/4 myelosuppression was infrequent in both arms.

Treatment-emergent adverse events occurred in more than 90% of patients in both arms. The most common adverse event of any grade was hypertension, occurring in 44% of patients in the tivozanib arm and 34% of patients in the sorafenib arm. Grade 3/4 events of note included hypertension, occurring in 24% of patients treated with tivozanib and 17% of patients treated with sorafenib, and palmar-plantar erythrodysesthesia, occurring in 2% of patients receiving tivozanib and 17% of patients receiving sorafenib.

Important safety differences were observed for the 2 drugs. Patients on the tivozanib arm experienced higher rates of hypertension, dysphonia, and back pain, while patients on the sorafenib arm experienced higher rates of diarrhea, hand-foot skin reaction, and alopecia. Hypertension, which has been highlighted as an important adverse event associated with tivozanib, was controlled with medication in most patients receiving the drug, resulting in tivozanib dose reductions in 2% of patients and drug discontinuations in 1% of patients.

Based on this study and others, development of hypertension appears to be associated with tivozanib efficacy. In the current trial, patients with a diastolic blood pressure of greater than 90 mmHg had a median progression-free survival of 18.3 months compared to 9.1 months for patients without hypertension (Table 2). A similar relationship was found for systolic blood pressure and efficacy, and the findings are likely directly related to tivozanib’s mechanism of action. Dr. Motzer concluded that tivozanib achieved superior efficacy and decreased off-target toxicity in comparison to sorafenib in patients with metastatic RCC.

References

1. Motzer RJ, Nosov D, Eisen T, et al. Tivozanib versus sorafenib as initial targeted therapy for patients with advanced renal cell carcinoma: results from a phase III randomized, open-label, multicenter trial. J Clin Oncol (ASCO Annual Meeting Proceedings). 2012;30(18 suppl): Abstract 4501.

2. Nosov DA, Esteves B, Lipatov ON, et al. Antitumor activity and safety of tivozanib (V-951) in a phase II randomized discontinuation trial in patients with renal cell carcinoma. J Clin Oncol. 2012;30:1678-1685.

ABSTRACT SUMMARY Overall Survival (OS) in Metastatic Renal Cell Carcinoma (mRCC) Sequentially Treated With Different Targeted Therapies (TTs): Results From a Large Cohort of Patients

A retrospective study is examining the characteristics and outcomes of RCC patients who received targeted therapies (Abstract 4629). Data from 336 patients were available from the database of the Istituto Nazionale Tumori of Milan. Patient characteristics included ECOG performance status of 0 or 1 (94%), clear cell histology (87%), and prior nephrectomy (87%). Risk as assessed by MSKCC classification was low (32%), medium (48%), or poor (20%). Fifty percent of patients had received 2 or more targeted therapies. Prior targeted therapies included sorafenib (73% of patients), sunitinib (63%), a bevacizumab-containing regimen (10%), and other targeted therapies (22%), including everolimus, temsirolimus, and axitinib. After a median follow-up of 43 months, 199 patients (57%) had died. Median OS was 24 months (95% CI, 20.0–27.0 months). Five-year OS was 24.6% (95% CI, 18.7–30.8). Univariate analyses uncovered no differences in HR values for sorafenib followed by sunitinib compared with either sunitinib followed by sorafenib or with other therapies. Multivariate analysis failed to show a significant difference between the 2 sunitinib/sorafenib sequences or for bevacizumab-containing regimens compared with either sequence of sunitinib and sorafenib. In univariate and multivariate analyses, independent predictors of outcome included ECOG performance status, prior nephrectomy, Fuhrman grade, and number of disease sites (all P<.01). The authors concluded that targeted therapies improve OS in metastatic RCC patients without any statistically significant difference among different sequences.

Axitinib for First-Line Metastatic Renal Cell Carcinoma (mRCC): Overall Efficacy and Pharmacokinetic (PK) Analyses From a Randomized Phase II Study

Axitinib is a potent and selective, second-generation tyrosine kinase inhibitor of VEGF receptors 1, 2, and 3.¹ It has shown efficacy as second-line treatment for RCC.² Variable levels of drug exposure have been observed in patients receiving the starting dose of 5 mg twice daily.³ Based on population pharmacokinetic analyses from phase II trials of axitinib in RCC patients, higher drug exposure is associated with better clinical outcome.⁴ It was hypothesized that upward dose titration of axitinib in patients who tolerate the 5 mg twice daily regimen could optimize drug exposure and thus improve therapeutic efficiency.

Retrospective analyses of phase II studies of axitinib in metastatic RCC show variable levels of exposure to axitinib based on the area under the curve (AUC). Not only does the level of exposure vary among different patients, many patients’ exposure is below the proposed therapeutic threshold of AUC at 12 hours (AUC₁₂) of 150 ng·h/mL. Patients without drug titration are largely above the target threshold, with an average value of AUC₁₂ 231 ng·h/mL. For many patients who tolerate the initial dose of axitinib 5 mg twice daily, dose titration to either 7 mg or 10 mg twice daily can increase their drug exposure from below the therapeutic threshold to therapeutic drug levels.

Improved efficacy outcomes appear to correlate positively with therapeutic axitinib exposure defined as AUC 150 ng·h/mL, as evidenced by an approximate doubling of PFS in patients with at least a therapeutic level of axitinib versus patients who cannot achieve the therapeutic level either with or without dose titration (52 weeks vs 32 weeks, respectively; HR, 0.56; 95% confidence interval [CI], 0.359–0.874).

Based on these retrospective findings, a prospective trial was designed to determine whether axitinib drug titration could improve efficacy.⁵ Key eligibility requirements included metastatic RCC with clear cell histology, no prior systemic therapy for metastatic disease, measurable disease based on Response Evaluation Criteria In Solid Tumors (RECIST) criteria, ECOG performance status of 0 or 1, adequate organ function, and blood pressure controlled to less than or equal to 140/90 mmHg with the use of up to 2 antihypertensive medications.

All patients received axitinib at a starting dose of 5 mg twice daily during a lead-in period of 4 weeks. During cycle 1, a subset of approximately 60 patients underwent 24-hour ambulatory blood pressure monitoring on days 1 and 15. On day 15 of the same cycle, the same subset of patients underwent 6-hour pharmacokinetic sampling. At the end of the 4-week lead-in period, all patients were assessed for randomization criteria comprising blood pressure below 150/90 mmHg, no more than 2 concurrent antihypertensive medications, no grade 3 or greater axitinib-related toxicities, and no need for a dose reduction during the first cycle. Patients who met all 4 randomization criteria were then randomized 1:1 to receive either axitinib 5 mg twice daily with dose titration up to either 7 or 10 mg twice daily as tolerated (Arm A) or axitinib 5 mg twice daily plus placebo titration (Arm B). Patients who did not meet all 4 randomization criteria received axitinib 5 mg twice daily or a lower dosage as determined by tolerance (Arm C).

Brian I. Rini, MD, reported pooled efficacy data from all 3 trial arms and from arms A and B combined.⁵ Unblinding and comparison of arms A and B will occur after the specified number of events has occurred. The study’s primary objective was to compare the ORR of patients receiving axitinib plus dose titration versus axitinib plus placebo dose titration. The trial had an 80% power to detect an improvement of at least 25% in ORR. The presented findings pertain to the secondary objectives, including PFS, axitinib plasma pharmacokinetics, blood pressure measurements, and safety.

Tumor assessments were performed at screening and at 8, 16, and 24 weeks of therapy and every 12 weeks thereafter. Safety was assessed and adverse events graded based on the Common Terminology Criteria for Adverse Events version 3.0. In the subset of approximately 60 patients, serial 6-hour pharmacokinetic sampling was performed on day 15 of cycle 1, prior to making the decision for dose titration. In the same subset of patients, ambulatory blood pressure monitoring was performed at baseline and on days 4 and 15 of cycle 1, also prior to the decision for dose titration.

The trial enrolled 213 metastatic RCC patients with a median age of 61 years, of whom 82% had undergone prior nephrectomy and approximately 60% were diagnosed within 1 year of study registration. At the time of reporting, slightly more than half of the patients had progressed or died while on the study, and median follow-up was 644 days.

Analysis of the entire study population yielded a median PFS of 14.5 months and ORR of 48%. Arm C enrolled 91 patients and yielded a median PFS of 16.4 months and an ORR of 59%. Pooled data from the 112 patients in Arms A and B combined showed a PFS of 14.5 months and an ORR of 43%.

Comparison of pharmacokinetic parameters assessed on day 15 of cycle 1 showed that the patients in Arm C—many of whom were ineligible for dose titration due to blood pressure elevation—had a median AUC₁₂ of 234 ng·h/mL versus 99 ng·h/mL for patients in Arms A and B (P<.0001). Analysis of clinical outcome based on axitinib exposure on day 15 of cycle 1 showed a median PFS of 13.9 months in patients with AUC₁₂ of at least 150 ng·h/mL (n=27) versus 11.0 months for patients with AUC₁₂ less than AUC₁₂ 150 ng·h/mL (n=25; Table 3). Partial response rates were 59% versus 40%, respectively.

In the subset of patients who underwent ambulatory blood pressure monitoring, PFS and ORR were improved in patients who exhibited greater increases in diastolic blood pressure as measured on day 15 of cycle 1. For example, PFS was 16.7 months versus 8.3 months for patients with a change in diastolic blood pressure of at least 10 mmHg (n=39) versus less than 10 mmHg (n=22), respectively, with ORRs of 59% versus 45%, respectively, and median AUC₁₂ of 176 ng·h/mL versus 63 ng·h/mL, respectively. Improved outcomes were also observed for patients with changes in diastolic blood pressure of at least 15 mmHg versus those with a change of less than 15 mmHg. Finally, analysis of patients based on blood pressure of at least 90 mmHg versus less than 90 mmHg also showed improved outcomes and a higher plasma concentration of axitinib for the former group. Unblinding of Arms A and B and hence comparison of patients who received dose titration of axitinib versus those who remained at the starting dose will be forthcoming.

Consistent with previous reports, hypertension was the most common adverse event of any grade, reported in 63% of patients, and grade 3 hypertension was reported in 29% of patients. Other common adverse events of any grade occurring in at least 40% of the population included diarrhea (58%), fatigue (48%), and dysphonia (40%). Laboratory adverse events of any grade occurring in at least 5% of the study population included thrombocytopenia (9%) and anemia (7%). There were very few grade 3/4 laboratory adverse events.

References

1. Hu-Lowe DD, Zou HY, Grazzini ML, et al. Nonclinical antiangiogenesis and antitumor activities of axitinib (AG-013736), an oral, potent, and selective inhibitor of vascular endothelial growth factor receptor tyrosine kinases 1, 2, 3. Clin Cancer Res. 2008;14:7272-7283.

2. Rini BI, Escudier B, Tomczak P, et al. Comparative effectiveness of axitinib versus sorafenib in advanced renal cell carcinoma (AXIS): a randomised phase 3 trial. Lancet. 2011;378:1931-1939.

3. Rugo HS, Herbst RS, Liu G, et al. Phase I trial of the oral antiangiogenesis agent AG-013736 in patients with advanced solid tumors: pharmacokinetic and clinical results. J Clin Oncol. 2005;23:5474-5483.

4. Rixe O, Dutcher J, Motzer R, et al. Diastolic blood pressure (dBP) and pharmacokinetics (PK) as predictors of axitinib efficacy in metastatic renal cell cancer (mRCC). J Clin Oncol (ASCO Annual Meeting Proceedings). 2009;114(22 suppl): Abstract 5045.

5. Rini BI, Grünwald V, Fishman MN, et al. Axitinib for first-line metastatic renal cell carcinoma (mRCC): overall efficacy and pharmacokinetic (PK) analyses from a randomized phase II study. J Clin Oncol (ASCO Annual Meeting Proceedings). 2012;30(18 suppl): Abstract 4503.

ABSTRACT SUMMARY Sunitinib Objective Response (OR) in Metastatic Renal Cell Carcinoma (mRCC): Analysis of 1,059 Patients Treated on Clinical Trials

In light of the robust objective responses and improved PFS demonstrated by sunitinib in metastatic RCC patients, a retrospective analysis was performed to assess the ORR and survival rates with sunitinib treatment and to discern patient features associated with a response (Abstract 4542). Data from 6 phase II or III trials were pooled representing 1,059 patients who received sunitinib either on the approved schedule of 50 mg/day for 4 weeks on, 2 weeks off (n=689), or at 37.5 mg/day. The analysis included patients receiving sunitinib as first-line (n=783) or second-line (n=376) treatment. Median PFS and OS were estimated by the Brookmeyer and Crowley method. The log-rank test was used to compare results in responders versus nonresponders and in early responders (patients with a response at 12 weeks of treatment or earlier) versus late responders (those with a response after 12 weeks). Confirmed, investigator-assessed responses by RECIST occurred in 398 (38%) of patients. Median time to tumor response in all patients was 10.6 weeks (range, 2.7–94.4 weeks) and was similar in the first- and second-line settings. Characteristics of responders included better baseline ECOG performance status, more favorable MSKCC risk classification, longer interval since initial diagnosis, increased likelihood of prior nephrectomy, and reduced presence of baseline bone metastases (all P<.05). Early responders had more lung metastases than late responders (P<.01). Significant improvements were observed for responders versus nonresponders in PFS (16.3 months vs 5.3 months, respectively; P<.001) and OS (40.1 months vs 14.5 months, respectively; P<.001). Results were similar for first- and second-line treatment, and median OS was similar for early and late responders (P=.1438).

Patient Preference Between Pazopanib (Paz) and Sunitinib (Sun): Results of a Randomized Double-Blind, Placebo-Controlled, Cross-Over Study in Patients With Metastatic Renal Cell Carcinoma (mRCC)—PISCES Study, NCT 01064310

Bernard J. Escudier, MD, presented results from the PISCES (Patient Preference Study of Pazopanib Versus Sunitinib in Advanced or Metastatic Kidney Cancer) trial.¹ This randomized, double-blind, placebo-controlled, crossover study was designed to evaluate whether sunitinib and pazopanib result in clinically meaningful differences in tolerability for patients. Both pazopanib and sunitinib are approved for first-line treatment of metastatic RCC. Indirect comparison suggests that the 2 drugs have comparable efficacy and different safety profiles. Given the relationship between adverse events and quality of life, plus the increasing emphasis on health-related quality of life, patient preference was explored as an endpoint.

In the PISCES study, 169 patients were stratified based on ECOG performance status (0 vs 1) and number of metastatic sites (1 vs >1). They were then randomized 1:1 to receive 10 weeks of treatment with either pazopanib (800 mg daily) or sunitinib (50 mg daily). After a 2-week washout period, patients were crossed over to the other drug for another treatment period of 10 weeks. At the end of these 22 weeks, patient preference was assessed by means of a questionnaire.

Computed tomography (CT) scans were performed at baseline, after the 10-week treatment with the first drug, and at the study’s end. Questionnaires included EQ-5D, Functional Assessment of Chronic Illness Therapy-Fatigue, and Seville Quality of Life Questionnaire. The primary endpoint of the study was patient preference for sunitinib or pazopanib. The patients received the questionnaire at the end of the second 10-week treatment period, while they were still blinded regarding treatment and before the results of the final study imaging scan were available. The questionnaire was completed by patients who had received at least 1 dose in both treatment periods.

The primary question asked for the patient’s drug preference, and possible answers included the first treatment, the second treatment, or no preference. Patients were also asked to describe the reasons that influenced their drug choice and to select the most important reason. Endpoints in addition to drug preference included quality of life, safety, and dose modification. Further analyses assessed physician preference, pharmacokinetics, and biomarkers.

The trial design was based on the hypothesis that a difference of greater than 20% in patient preference would be clinically relevant. The design also assumed that 20% of patients would state no drug preference, resulting in a study requirement of 160 patients.

Eligible patients had previously untreated metastatic RCC, any renal cancer cell histology, measurable or non-measurable disease, ECOG performance status of 0 or 1, good or intermediate prognosis based on the MSKCC prognostic criteria, no brain metastases, and adequate cardiac and renal function. Baseline characteristics were well balanced between the 2 arms. Patients had a median age of 63 years, and 67% were male. Nephrectomy had been performed in 89% of patients. Twenty-six percent of patients had only 1 metastatic site; 92% had measurable disease; and 90% had clear cell carcinoma. The median time since diagnosis was 7.7 months.

The trial initially randomized 86 patients to receive pazopanib and 82 patients to receive sunitinib during the first treatment period. Because patients withdrew for various reasons (Table 4), 68 patients entered into the second treatment period in both arms.

At the end of treatment period 1, best responses included 1% complete response (CR), 20% partial response (PR), 53% stable disease, and 11% progressive disease for the 80 patients who had received sunitinib. Fifteen percent of patients were not evaluable. In the group of 85 patients who had received pazopanib, best responses included 1% CR, 18% PR, 42% stable disease, and 20% progressive disease. Twenty percent of patients were not evaluable.

Several patients withdrew from the study during treatment period 2. In addition, patients who experienced disease progression during the first treatment period were excluded from the primary analysis of health-related quality of life, resulting in completed questionnaires from 54 patients who received pazopanib followed by sunitinib and 60 patients who received sunitinib followed by pazopanib. These remaining 114 patients who had at least 1 drug dose from each treatment period, did not have progressive disease, and completed the questionnaire, thus constituted the primary analysis population.

The primary endpoint showed that 70% of patients preferred pazopanib, 22% preferred sunitinib, and 8% expressed no preference (Figure 3). The difference of pazopanib versus sunitinib preference was 49.3% (90% CI, 37.0–69.5; P<.001). Several preplanned analyses were undertaken to further explore the data. For the subset of 80 patients who completed full study treatment, preference for pazopanib over sunitinib was significant (P<.001). For all patients in the study, including patients with progressive disease in the first treatment period, the preference for pazopanib was again significant (P<.001). Physician drug preference was remarkably similar to that of the patients, with 61% of physicians preferring pazopanib, 22% preferring sunitinib, and 17% expressing no preference. After the investigators postulated a preference for sunitinib for all patients who withdrew from the study, the trend toward pazopanib persisted but was not significant (P<.065).

The reasons for drug preference included better quality of life, less fatigue, fewer changes in food tastes, less soreness in the mouth and throat, reduced nausea and vomiting, reduced soreness in hands and feet, and reduced loss of appetite. Most patients reported that their drug preference was not determined by a single reason, although many patients who preferred pazopanib cited less fatigue as the single reason.

A preliminary examination of health-related quality of life data based on 13 questions from the Functional Assessment of Chronic Illness Therapy-Fatigue questionnaire showed a strong preference for pazopanib (P=.002). In a supplementary questionnaire, patients also showed a preference for pazopanib based on soreness of the mouth, throat, hand, or foot, as well as limitations based on these conditions.

Dose reductions occurred in 20% of patients in the sunitinib arm and 13% of patients in the pazopanib arm. Treatment was prematurely discontinued in treatment period 1 due to adverse events in 18% versus 14% of patients, respectively. In period 2, treatment was prematurely discontinued due to an adverse event in 31% versus 15% of patients, respectively.

Adverse events reported for both pazopanib and sunitinib were consistent with reports from phase III trials, although diarrhea of any grade was slightly more common with pazopanib (42% vs 32%). Dysgeusia, mucositis, stomatitis, and hand and foot syndrome showed numerically greater frequency with sunitinib. Liver toxicity appeared more common with pazopanib treatment, as reflected in a slightly higher incidence of increased liver enzymes and total bilirubin. By contrast, sunitinib was associated with a higher incidence of myelosuppression, including thrombocytopenia (47% vs 15%) and neutropenia (45% vs 13%) of any grade.

The authors concluded that, despite the modest differences in reported adverse events, patients showed a clear preference for pazopanib over sunitinib. Efficacy of the 2 drugs is being examined in the COMPARZ (Pazopanib Versus Sunitinib in the Treatment of Locally Advanced and/or Metastatic Renal Cell Carcinoma) trial.²

References

1. Escudier BJ, Porta C, Bono P, et al. Patient preference between pazopanib (Paz) and sunitinib (Sun): results of a randomized double-blind, placebo-controlled, cross-over study in patients with metastatic renal cell carcinoma (mRCC)—PISCES study, NCT 01064310. J Clin Oncol (ASCO Annual Meeting Proceedings). 2012;30(18 suppl): Abstract CRA4502.

2. ClinicalTrials.gov. Pazopanib versus sunitinib in the treatment of locally advanced and/or metastatic renal cell carcinoma (COMPARZ). http://clinicaltrials.gov/ct2/show/NCT00720941?term=COMPARZ&rank=1. Identifier: NCT00720941.

ABSTRACT SUMMARY Safety and Efficacy of MET Inhibitor Tivantinib (ARQ 197) Combined With Sorafenib in Patients (pts) With Renal Cell Carcinoma (RCC) From a Phase I Study

This phase I study examined tivantinib plus sorafenib in patients with advanced solid tumors (Abstract 4545). Endpoints were safety, the recommended phase II dose of the combination, and antitumor activity. Dose escalation had previously established the recommended phase II dose as tivantinib 360 mg twice daily plus sorafenib 400 mg twice daily. Extension cohorts enrolled at least 20 patients each with RCC or other tumors. Twenty RCC patients received treatment at the recommended phase II dose (n=19) or a dose of tivantinib 360 mg twice daily plus sorafenib 200 mg twice daily (n=1). Four patients remain on study. Sixteen patients, including 13 with clear cell RCC, received 1 or more prior systemic therapies. The most common adverse events were rash (65%), diarrhea (45%), alopecia (40%), and hypophosphatemia (35%). Fatigue, stomatitis, palmar-plantar erythrodysesthesia syndrome, and pruritus each occurred in 25% of patients. Three patients with clear cell RCC exhibited a partial response, and 15 patients experienced stable disease, including 11 clear cell, 3 papillary, and 1 clear cell/chromophobe RCC patient. Seven patients with stable disease had a tumor size reduction of at least 10%. The ORR and disease control rate (PR plus stable disease) were 15% and 90%, respectively. Median PFS was 1.27 months (95% CI, 7.1–14.5 months). In the 14 patients treated previously with a VEGF inhibitor, the ORR and disease control rate were 14% and 86%, respectively, and median PFS was 12.7 months (95% CI, 5.3 months–not yet reached).

ABSTRACT SUMMARY An In-Depth Multicentered Population-Based Analysis of Outcomes of Patients With Metastatic Renal Cell Carcinoma (mRCC) That Do Not Meet Eligibility Criteria for Clinical Trials

Many patients with metastatic RCC are ineligible for enrollment in clinical trials due to factors such as Karnofsky Performance Status (KPS) less than 70%, brain metastases, non–clear cell histology, hemoglobin at or less than 9 g/dL, creatinine exceeding 2 times the upper limit of normal, platelet count less than 100 × 10³/uL, neutrophil count less than 1,500/mm³, and corrected calcium at or greater than 12 mg/dL. Although such patients are excluded from clinical trials, the data generated from these trials often play a role in their management. This study compared outcome in patients included (n=894) and excluded (n=2,076) from clinical trials (Abstract 4536). Response rate, median PFS, and median OS were all significantly lower in patients excluded from trials. Ineligible patients had a response rate of 21%, a median PFS of 5.2 months, and an OS of 14.5 months, whereas eligible patients had a response rate of 29%, a median PFS of 8.8 months, and an OS of 28.8 months (P<.001 for all differences). Second-line PFS was 3.2 months in excluded patients and 4.4 months in included patients (P=.0074). Among ineligible patients, the HR of death varied according to the exclusionary criteria, with an HR of 2.8 (95% CI, 2.4–3.4) for patients with KPS less than 70, HR of 1.8 (95% CI, 1.4–2.2) for patients with hemoglobin at or less than 9 g/dL, HR of 1.8 (95% CI, 1.2–2.7) for patients with calcium at or greater than 12 mg/dL, HR of 1.4 (95% CI, 1.1–1.8) for brain metastases, and HR of 1.4 (95% CI, 1.1–1.7) for non–clear cell histology (P<.01 for all differences). When adjusted by the Heng prognostic criteria, the HR for death between ineligible patients and eligible patients was 1.511 (95% CI, 1.335–1.710; P<.0001).

Updated Results on Long Term Overall Survival (OS) of the French Randomized Phase II Trial TORAVA in Metastatic Renal Cell Carcinoma (mRCC) Patients

The randomized, phase II TORAVA (Combination of Temsirolimus and Bevacizumab in Patient With Metastatic Renal Cell Carcinoma) trial investigated the safety and efficacy of combining temsirolimus and bevacizumab in previously untreated patients with metastatic RCC.¹ The study showed that the combination of temsirolimus plus bevacizumab failed to increase PFS over standard treatment. Moreover, adding temsirolimus to bevacizumab caused unexpectedly high toxicity. Extending these initial results, Jacques-Olivier Bay, MD, PhD, presented long-term results on OS and information on second-line therapy after failure from the TORAVA trial.²

Patients were randomly assigned in a 2:1:1 ratio to treatment with bevacizumab (10 mg/kg every 2 weeks) plus temsirolimus (25 mg weekly; Arm A [n=88]), or sunitinib (50 mg/day for 4 weeks followed by 2 weeks off; Arm B [n=42]), or interferon alfa (9 MIU 3 times per week) plus bevacizumab (10 mg/kg every 2 weeks; Arm C [n=41]). Patients were treated until disease progression or unacceptable toxicity. The primary endpoint was PFS at 48 weeks. Secondary endpoints included toxicity, ORR, and survival. Key eligibility requirements included metastatic RCC, ECOG performance status of 0 or 1, measurable disease by RECIST criteria, and no brain metastases.

PFS at 48 weeks was 29.5% in Arm A, 35.7% in Arm B, and 61.0% in Arm C. Median PFS was 8.2 months in Arm A, 8.2 months in Arm B, and 16.8 months in Arm C.¹ Fifty-one percent of patients in Arm A stopped treatment for reasons other than progression compared with 12% in Arm B and 38% in Arm C. Thus, the combination of temsirolimus plus bevacizumab showed low activity and unexpectedly high toxicity.

In the analysis presented by Dr. Bay, median follow-up was 35.1 months (range, 24.2–44.7 months).² Data were available in 65 patients from Arm A, 32 patients from Arm B, and 27 patients from Arm C. Patient characteristics were somewhat unevenly distributed across the 3 treatment groups (Table 5).

In the intent-to-treat population, 35-month OS rates were 37% (95% CI, 27–48%), 55% (95% CI, 40–69%), and 62% (95% CI, 47–76%) in Arms A, B, and C, respectively. OS was not significantly lower for Arm A relative to Arm B, but was significantly lower for Arm A relative to Arm C (HR, 0.48 [95% CI, 0.27–0.86]). In Arms A, B, and C, tyrosine kinase inhibitors were administered in 79.7%, 79.2%, and 63.9% of patients, respectively (P=.20). The authors concluded that the OS rates confirmed the absence of synergistic or additive effects of combined temsirolimus plus bevacizumab and that patients treated with bevacizumab plus interferon alfa showed a prolonged survival.

References

1. Négrier S, Gravis G, Pérol D, et al. Temsirolimus and bevacizumab, or sunitinib, or interferon alfa and bevacizumab for patients with advanced renal cell carcinoma (TORAVA): a randomised phase 2 trial. Lancet Oncol. 2011;12:673-680.

2. Bay J-O, Negrier S, Pérol D, et al. Updated results on long-term overall survival (OS) of the French randomized phase II trial TORAVA in metastatic renal cell carcinoma (mRCC) patients. J Clin Oncol (ASCO Annual Meeting Proceedings). 2012;30(18 suppl): Abstract 4625.

Efficacy of Cabozantinib (XL184) in Patients (pts) With Metastatic, Refractory Renal Cell Carcinoma (RCC)

Toni K. Choueiri, MD, presented data from a multi-institutional trial of patients with metastatic RCC who failed prior therapy.¹ Cabozantinib (XL184) is a potent dual inhibitor of the MET and VEGF receptor 2 pathways. Loss of the von Hippel–Lindau (VHL) tumor suppressor gene, a frequent occurrence in clear cell RCC, leads to upregulation of both VEGF and MET, which ultimately fuels metastasis.² Inhibition of MET can overcome acquired resistance to agents that target pathways regulated by VEGF.³ MET knockdown has been shown to reduce the viability of RCC VHL-negative cells, while cabozantinib has resulted in the resolution of metastatic bone lesions and the regression of soft tissue lesions in multiple tumor types.

Despite major advances with VEGF-targeted therapy in RCC, several unmet medical needs remain. Primary disease that is refractory to anti-VEGF therapy is evidenced by progressive disease as the best response to anti-VEGF therapy in 26% out of 1,056 consecutive patients with clear cell metastatic RCC in the International Metastatic RCC Database Consortium. In the same study, the median OS of patients with best response of progressive disease was 6.8 months versus 29 months for patients without progressive disease.⁴ Bone metastases, a negative prognostic factor, occur in up to 30% of RCC patients and are generally resistant to existing therapies.^5,6

The current study, designed to investigate drug-drug interaction, enrolled 25 patients with metastatic RCC who had failed prior therapy. Patients received cabozantinib at a dose of 140 mg/day, based on the maximum tolerated dose from a phase I trial, plus a single dose of rosiglitazone. Dose reductions were allowed to optimize tolerability. The study endpoints included safety and tolerability of cabozantinib and the drug’s antitumor activity.

Key eligibility criteria included Karnofsky performance status of at least 70 or ECOG performance status of 0 or 1; metastatic RCC with clear cell components; refractory disease or progression following standard therapies, with no limit on prior therapies; and measurable disease per RECIST 1.0. Patients were assessed for safety and activity per RECIST 1.0. Pharmacokinetic and pharmacogenetic sampling were performed but were not discussed in the current presentation.

The patients had a median age of 61 years, and 21 patients were male. Based on Heng prognostic criteria, 8% of patients were poor risk and 80% were intermediate risk. Patients had a median 2 prior systemic agents, and 32% of patients had received at least 4 prior systemic agents. Prior anticancer therapies included anti-VEGF therapy in 88% of patients, anti-mTOR therapy in 60% of patients, and both of these therapies in 52% of patients. Bone metastases were present in 16% of patients at baseline. At the time of the presentation, 7 patients remained on-study and 18 patients had discontinued, mainly as a result of progressive disease.

Median PFS was 14.7 months (Figure 4). After a median follow-up of 14.7 months, overall survival (OS) was not yet reached. Confirmed partial responses were observed in 28% of patients, stable disease in 52% of patients, and progressive disease in 4% of patients. The disease control rate at 16 weeks was 72%. The median duration of response could not yet be determined but ranged from approximately 1.9 months to 10.6 months.

Significant tumor reduction was observed in the majority of the 21 patients who underwent a post-baseline scan. In addition, some patients experienced a reduction in pain, as evidenced by reduced narcotic use in 1 patient and complete resolution of pain in another patient that occurred after 4 weeks and continued beyond 90 weeks.

The most common adverse events of any grade occurring in at least 50% of patients included fatigue (80%), diarrhea (64%), and hypophosphatemia (56%; Table 6). The most common grade 3/4 events occurring in at least 15% of patients were hypophosphatemia (36%), hyponatremia (20%), and fatigue (16%). Hypertension of any grade was reported in 16% of patients and grade 3/4 hypertension occurred in 8% of patients. No grade 5 events were reported.

The authors concluded that cabozantinib demonstrated encouraging activity in the heavily pretreated population of patients with metastatic RCC. The safety profile was similar to that of other tyrosine kinase inhibitors, and adverse events were manageable with an extended treatment period of more than 600 days.

References

1. Choueiri TK, Pal SK, McDermott DF, et al. Efficacy of cabozantinib (XL184) in patients (pts) with metastatic, refractory renal cell carcinoma (RCC). J Clin Oncol (ASCO Annual Meeting Proceedings). 2012;30(18 suppl): Abstract 4504.

2. Bergers G, Hanahan D. Modes of resistance to anti-angiogenic therapy. Nat Rev Cancer. 2008;8:592-603.

3. Aftab DT, McDonald DM. MET and VEGF: synergistic targets in castration-resistant prostate cancer. Clin Transl Oncol. 2011;13:703-709.

4. Heng DY, MacKenzie MJ, Vaishampayan UN, et al. Primary anti-vascular endothelial growth factor (VEGF)-refractory metastatic renal cell carcinoma: clinical characteristics, risk factors, and subsequent therapy. Ann Oncol. 2011;23:1549-1555.

5. Woodward E, Jagdev S, McParland L, et al. Skeletal complications and survival in renal cancer patients with bone metastases. Bone. 2011;48:160-166.

6. Beuselinck B, Oudard S, Rixe O, et al. Negative impact of bone metastasis on outcome in clear-cell renal cell carcinoma treated with sunitinib. Ann Oncol. 2011;22:794-800.

ABSTRACT SUMMARY The Use of Tumor Growth Rate (TGR) in Evaluating Sorafenib and Everolimus Treatment in mRCC patients: An Integrated Analysis of the TARGET and RECORD Phase III Trials Data

RECIST criteria have been used in clinical trials to evaluate targeted therapies in patients with metastatic RCC. Measurement of tumor growth rate (TGR) may provide additional important data. This study (Abstract 4540) prospectively examined patients at the Institut Gustave Roussy (IGR) treated with sorafenib, everolimus, or placebo in 2 phase III trials: TARGET (Treatment Approaches in Renal Cancer Global Evaluation Trial) and RECORD (Renal Cell Cancer Treatment With Oral RAD 001 Given Daily). TGR was assessed at several points: before treatment (wash-out), during treatment (in the first cycle), at progression (in patients still receiving the drug), and after treatment interruption (wash-out). Results were subsequently validated in the entire TARGET cohort (n=902). Compared with placebo, TGR was significantly decreased during the first cycles of sorafenib and everolimus. In most patients who received sorafenib or everolimus, TGR was decreased during treatment versus before treatment, regardless of the RECIST evaluation. TGR after sorafenib or everolimus interruption was significantly higher than TGR at progression. There was no significant difference in TGR after treatment interruption as compared with before treatment in both sorafenib and everolimus patients. High TGR during first-cycle treatment was associated with poor PFS and overall survival in sorafenib-treated patients and with poor OS in everolimus-treated patients. The authors concluded that the addition of TGR assessment may provide better evaluation of the tumor response, regardless of RECIST criteria. TGR may have independent prognosis value. This study also suggests that continuation of treatment with sorafenib or everolimus after disease progression might be beneficial.

ABSTRACT SUMMARY Incidence and Severity of Cardiotoxicity in Metastatic Renal Cell Carcinoma (RCC) Patients Treated With Targeted Therapies

Data were gathered regarding all RCC patients treated with therapies targeting the VEGF or mTOR axes at Stanford Medical Center (Abstract 4610). The incidence of hypertension, left ventricular dysfunction, changes in serum markers of cardiovascular toxicity, and heart failure were assessed and graded according to Common Terminology Criteria for Adverse Events 4.0. Out of 159 patients identified, cardiovascular toxicity developed in 116 (73%). Excluding hypertension, 52 (33%) patients developed cardiovascular toxicity, including asymptomatic reductions in LVEF, increased NT-proBNP, and heart failure. Asymptomatic cardiotoxicity, defined as a decrease in LVEF or increase in NT-proBNP, occurred in 43 (27%) patients. Symptomatic, grade 2/3 heart failure and grade 3/4 decrease in LVEF each occurred in 4% of patients. Of the 101 patients who had received sunitinib treatment, 66 (65%) developed some form of cardiovascular toxicity, including 32 (32%) with cardiotoxicity other than hypertension. In patients treated with bevacizumab, sorafenib, or pazopanib, cardiovascular toxicity was observed in 68%, 66%, and 51% of patients, respectively. The mTOR inhibitors showed significantly less cardiovascular toxicity, but sample sizes were small. The authors recommend close monitoring of cardiovascular toxicity in RCC patients receiving targeted therapies.

Clinical Activity and Safety of Anti-PD-1 (BMS-936558, MDX-1106) in Patients With Previously Treated Metastatic Renal Cell Carcinoma (mRCC)

An initial report on the clinical activity and safety of an antibody against the programmed death (PD) 1 receptor in patients with previously treated metastatic RCC was presented by David F. McDermott, MD.¹ The last 6 years have seen impressive advances in medical therapy for advanced kidney cancer. Many new therapies have proven superior to cytokine therapy, raising the question of whether immunotherapy may still have a role in the treatment of advanced kidney cancer. In the 20 years since interleukin-2 was introduced, groundbreaking research has provided a wealth of knowledge regarding how the immune response to cancer is regulated, thus leading to new opportunities to leverage the immune system.

T cells are regulated by both positive and negative signaling pathways, and one of the most important negative pathways involves the interaction between the PD1 receptor on T cells and its ligand, PD-L1, on antigen-presenting cells. PD-L1 is expressed on many tumors, either endogenously or induced by association with T cells, a process known as adaptive immune resistance. The interaction between T cells and tumor-expressed PD-L1 can act as an immune checkpoint that suppresses activated T cells. In RCC, investigators at the Mayo Clinic have shown that PD-L1 expression can be associated with more aggressive disease and shorter survival.² In preclinical models, monoclonal antibodies that bind the PD1 receptor have been shown to improve T-cell priming and prevent tumor-induced T-cell suppression.³

The clinical impact of an anti-PD1 antibody was therefore explored in a phase I clinical trial. BMS-936558 is a fully human IgG4 antibody that binds with high affinity to human PD1. It has no known Fc function, but it blocks binding of PD-L1 and PD-L2, the 2 known ligands for PD1. In a first-in-human, single-dose, dose escalation study, the antibody exhibited a manageable safety profile and yielded preliminary evidence of clinical activity in patients with solid tumors that were refractory to treatment.⁴

The phase I study presented by McDermott and colleagues enrolled patients with advanced melanoma, RCC, non–small cell lung cancer, colorectal cancer, or castration-resistant prostate cancer who had progressive disease after 1–5 systemic therapies.¹ Patients were given escalating doses of BMS-936558 every 2 weeks for up to 96 weeks or until they developed a confirmed CR, their progressive disease worsened, or toxicity was unacceptable.

The study’s primary objective was to assess the safety and tolerability of the antibody. Secondary objectives included assessment of antitumor activity and pharmacodynamic evaluation. Accrual was completed in December 2011, with 296 patients enrolled in the study; patient assessments are ongoing.

Analysis of the entire patient population revealed that, with doses of up to 10 mg/kg, the maximum tolerated dose had not been reached. No relationship between drug dose and adverse events emerged. Tumor activity was observed only in patients with non–small cell lung cancer, melanoma, and RCC. Upon completion of the dose escalation phase of the trial, more patients with specific tumor types were enrolled for dose expansion, including 17 RCC patients at 1 mg/kg and 16 RCC patients at 10 mg/kg. In the analysis presented by McDermott and colleagues of patients treated through February 2012, 34 patients were evaluable for safety and 33 were evaluable for clinical activity.¹

Median age for the RCC cohort was 58 years, and all had an ECOG performance status of 0 or 1. Forty-four percent of patients had received 3 or more prior therapies. For the entire cohort, prior therapies included immunotherapy (59%) and anti-angiogenic therapy (74%).

Toxicity findings from the current study have been reported (Table 7).⁵ Adverse events of any grade occurring with a frequency of at least 15% in the RCC cohort included fatigue (38%), rash (24%), pruritus (18%), and diarrhea (15%), all of which were consistent with the proposed mechanism of action of the anti-PD1 antibody. The most common grade 3/4 toxicities in the RCC patients included pulmonary disorders and hypophosphatemia, each of which occurred in 2 patients. In total, 18% of the RCC patients experienced a grade 3/4 toxicity.

In the total study population of 296 patients, grade 3/4 drug-related adverse events occurred in 14% of patients. Treatment was discontinued in 5 patients due to toxicity. Three drug-related deaths occurred in patients with pneumonitis, including 2 patients with non–small cell lung cancer and 1 patient with colorectal cancer.

Responses in the population of 33 patients evaluable for clinical efficacy included 1 CR and 8 PRs. Nine patients had stable disease lasting for at least 6 months (Table 8). Response duration has not yet reached a maximum and ranges from 5 months to longer than 22 months. The PFS rate at 24 weeks was 56%. Two patients showed a persistent reduction in baseline target lesions in the presence of new lesions. These patients were classified as having progressive disease based on RECIST criteria, and the ORR was 27%. No obvious difference in activity was apparent between the dose levels of 1 mg/kg versus 10 mg/kg.

Approximately 50% of the patients receiving the antibody at the 1 mg/kg dose had not progressed by 24 weeks on therapy. One patient developed numerous new liver lesions early during the treatment; however, because the patient felt better and his liver function tests improved, the patient qualified to continue treatment. Subsequently, this patient developed a PR in his target lesions, and his liver lesions resolved. Two patients in this group are now off study treatment and have yet to progress.

In the group of patients receiving treatment at 10 mg/kg, approximately 70% of patients were progression-free at 24 weeks. Four of these patients have ceased treatment after 96 weeks, according to the trial design, and these patients still show no signs of disease progression.

A 48-year-old patient in the trial had a low volume of disease, but his RCC was very poorly differentiated. He experienced disease progression after sunitinib, sorafenib, and thoracic surgery. He received the anti-PD1 antibody at 1 mg/kg during the study; however, his therapy was halted by the investigators after 3 cycles after a confirmed nearly complete response. His response has continued for 3 years after cessation of therapy.

The potential correlation between PD-L1 expression on tumor biopsies prior to treatment and clinical outcomes is also under investigation. Data from 5 patients with RCC for whom pretreatment biopsies were available suggested that only patients whose tumors expressed PD-L1 on the surface experienced a response to the study treatment, and patients whose tumors did not express PD-L1 did not respond. Despite the small sample size, the data support hypotheses regarding specific mechanisms that may be invoked by the anti-PD1 antibody and the potential for patient selection.

References

1. McDermott DF, Drake CG, Sznol M, et al. Clinical activity and safety of anti-PD-1 (BMS-936558, MDX-1106) in patients with previously treated metastatic renal cell carcinoma (mRCC). J Clin Oncol (ASCO Annual Meeting Proceedings). 2012;30(18 suppl): Abstract 4505.

2. Thompson RH, Gillett MD, Cheville JC, et al. Costimulatory B7-H1 in renal cell carcinoma patients: indicator of tumor aggressiveness and potential therapeutic target. Proc Natl Acad Sci. 2004;101:17174-17179.

3. Pardoll DM. The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer. 2012;12:252-264.

4. Brahmer JR, Drake CG, Wollner I, et al. Phase I study of single-agent anti-programmed death-1 (MDX-1106) in refractory solid tumors: safety, clinical activity, pharmacodynamics, and immunologic correlates. J Clin Oncol. 2010;28:3167-3175.

5. Topalian SF, Hodi FS, Brahmer JR, et al. Safety, activity, and immune correlates of anti–PD-1 antibody in cancer. N Engl J Med. 2012;366:2443-2454.

ABSTRACT SUMMARY PFS to Predict Long-Term OS After First-Line Treatment for Advanced Renal Cell Carcinoma (aRCC): Correlation and Power Analysis of Randomized Trials (RCT)

The correlation between PFS and OS is unknown. This study aimed to determine the relationship between PFS and OS in studies of patients receiving first-line therapy for advanced renal cell carcinoma (Abstract 4541). Six randomized controlled trials, which included a total of 4,096 patients, were analyzed to identify correlations between 6-, 9-, and 12-month PFS and OS rates according to parametric (Pearson’s r) and nonparametric (Spearman’s Rho and Kendall’s Tau) coefficients (with 95% CI). PFS at 3 and 6 months was significantly correlated with overall survival at 9 months. Pearson’s coefficients for the correlation between PFS at 3 months and overall survival at 6 and 12 months were 0.70 (P=.01) and 0.67 (P=.01). The correlation between PFS at 6 months and overall survival at 12 months was significant (Pearson 0.74, P=.005; Spearman 0.83, P=.005; Tau 0.71, P=.001). A significant correlation was also found between disease-control rates and OS.

ABSTRACT SUMMARY Association of Inherited Genetic Variation With Clinical Outcome in Patients With Advanced Renal Cell Carcinoma Treated With mTOR Inhibition

Predictive biomarkers for response are lacking in RCC. This study examined whether the presence of 2 critical genes in the mammalian target of rapamycin (mTOR) pathway—phosphoinositide-3-kinase catalytic alpha (PIK3CA) and mTOR—affect outcome in patients with advanced RCC treated with mTOR inhibition (Abstract 4543). Among the 76 patients in this study, 66% were at poor or intermediate risk and 89% had received prior systemic therapies. After a median follow-up of 23.7 months, median PFS was 4.3 months and median OS was 12.7 months. Two intronic PI3KCA single-nucleotide polymorphisms (SNPs) were significantly associated with PFS and OS. A SNP in the 5’ UTR of mTOR was associated with OS. These associations were maintained after adjustment for age, sex, and MSKCC RCC risk categories according to a Cox proportional hazard model.

Commentary

Brian I. Rini, MD

Associate Professor of Medicine
Cleveland Clinic Lerner College of Medicine
Case Western Reserve University
Cleveland, Ohio

Several interesting studies in renal cell carcinoma (RCC) were presented at the 2012 American Society of Clinical Oncology (ASCO) meeting. New data were presented regarding agents such as sorafenib, sunitinib, tivozanib, axitinib, and pazopanib.

In 2005, sorafenib became the first targeted therapy approved by the US Food and Drug Administration (FDA) for RCC. A randomized phase II trial compared sorafenib and tivozanib, a potent vascular endothelial growth factor (VEGF) receptor inhibitor.¹ Tivozanib showed an advantage in progression-free survival (PFS), demonstrating that biochemical potency may translate into clinical efficacy in this setting. In addition, this drug appeared very well tolerated, consistent with prior experience in RCC. Tivozanib will likely be approved by the FDA based on these data.

A cardiac safety analysis² of the ongoing ASSURE (Adjuvant Sorafenib or Sunitinib for Unfavorable Renal Carcinoma) trial³ was presented. The analysis showed a very low incidence of cardiac side effects in this population. There are 2 important caveats to consider when interpreting these data: patients received only a limited amount of treatment throughout 6–8 months, and many of the sunitinib and sorafenib patients dropped out before all cardiac safety analyses were performed. Despite these limitations, this analysis confirms the experience in the metastatic setting, which is that these drugs do have cardiac side effects, although their incidence in clinical practice is relatively low.

I presented preliminary results from a study of axitinib as initial systemic therapy for patients with metastatic RCC.⁴ This trial was primarily designed to examine dose escalation of this drug, which is required based on pharmacokinetic parameters. The final unblinded results are not yet available. Data were presented for overall efficacy, which showed a long median PFS of 14.5 months. This analysis has also confirmed that higher drug levels and axitinib-induced blood pressure elevations are associated with superior clinical outcomes. We await the full data from this trial as well as a separate randomized trial examining axitinib in the frontline setting⁵ for further understanding of the utility of this agent in previously untreated RCC.

In a retrospective analysis of renal cell carcinoma patients treated with sunitinib, patients who achieved an objective response had a long median survival of more than 40 months.⁶ Patients who did not achieve an objective response to sunitinib had a much shorter overall survival of approximately 1 year. This observation is useful in clinical practice, because patients who show a response at their first scan can be told with confidence that their prognosis is measured in years. In contrast, patients who do not have a response have a much shorter prognosis and require alternative treatments.

In the PISCES (Patient Preference Study of Pazopanib Versus Sunitinib in Advanced or Metastatic Kidney Cancer) trial, untreated RCC patients were randomized to receive either 1 cycle of pazopanib or 1 cycle of sunitinib.⁷ After a wash-out period of 2 weeks, the patients received the other agent for 1 cycle. The patients were then asked which agent they preferred. Approximately 70% preferred pazopanib. This finding is not surprising, based on tolerability outcomes in previous trials. One limitation of this study was that patient response—that is, tumor shrinkage in response to the drug—was not incorporated into patient preference. In my experience, patients are more willing to tolerate a drug if they know that they are responding to it. Further results from this trial are needed. In addition, a large, randomized trial comparing the efficacy of these drugs is ongoing.⁸

Data were reported on the clinical activity and safety of the novel agent BMS-936558, an antibody against the programmed death 1 receptor.⁹ This exciting, sophisticated immunotherapeutic agent belongs in a class called checkpoint inhibitors, which aim to release the natural break on an immune response. This subset analysis of a much larger phase I study¹⁰ showed that the drug is well tolerated and was associated with impressive tumor shrinkage in kidney cancer patients, many of whom maintained that disease control for long periods. BMS-936558 is being studied further in many different settings in RCC, and we look forward to more data.

Acknowledgment

Dr. Rini has received research funding from and performed consulting for Pfizer, GlaxoSmithKline, AVEO Oncology, and Bristol-Myers Squibb.

References

2. Haas NB, Manola J, Ky B, et al. Cardiac safety analysis for a phase III trial of sunitinib (SU) or sorafenib (SO) or placebo (PLC) in patients (pts) with resected renal cell carcinoma (RCC). J Clin Oncol (ASCO Annual Meeting Proceedings). 2012;30(18 suppl): Abstract 4500.

3. ClinicalTrials.gov. Sunitinib or sorafenib in treating patients with kidney cancer that was removed by surgery. http://clinicaltrials.gov/ct2/show/NCT00326898. Identifier: NCT00326898.

4. Rini BI, Grünwald V, Fishman MN, et al. Axitinib for first-line metastatic renal cell carcinoma (mRCC): overall efficacy and pharmacokinetic (PK) analyses from a randomized phase II study. J Clin Oncol (ASCO Annual Meeting Proceedings). 2012;30(18 suppl): Abstract 4503.

5. ClinicalTrials.gov. Axitinib (AG-013736) for the treatment of metastatic renal cell cancer. http://clinicaltrials.gov/ct2/show/NCT00920816?term=axitinib+AND+renal+cell+carcinoma&rank=7. Identifier: NCT00920816.

6. Molina AM, Zhang J, Lin X, et al. Sunitinib objective response (OR) in metastatic renal cell carcinoma (mRCC): analysis of 1,059 patients treated on clinical trials. J Clin Oncol (ASCO Annual Meeting Proceedings). 2012;30(18 suppl): Abstract 4542.

7. Escudier BJ, Porta C, Bono P, et al. Patient preference between pazopanib (Paz) and sunitinib (Sun): results of a randomized double-blind, placebo-controlled, cross-over study in patients with metastatic renal cell carcinoma (mRCC)—PISCES study, NCT 01064310. J Clin Oncol (ASCO Annual Meeting Proceedings). 2012;30(18 suppl): Abstract CRA4502.

8. ClinicalTrials.gov. Pazopanib versus sunitinib in the treatment of locally advanced and/or metastatic renal cell carcinoma (COMPARZ). http://clinicaltrials.gov/ct2/show/NCT00720941. Identifier: NCT00720941.

9. McDermott DF, Drake CG, Sznol M, et al. Clinical activity and safety of anti-PD-1 (BMS-936558, MDX-1106) in patients with previously treated metastatic renal cell carcinoma (mRCC). J Clin Oncol (ASCO Annual Meeting Proceedings). 2012;30(18 suppl): Abstract 4505.

10. ClinicalTrials.gov. BMS-936558 (MDX-1106) in subjects with advanced/metastatic clear-cell renal cell carcinoma (RCC). http://clinicaltrials.gov/ct2/show/NCT01354431?term=BMS-936558&rank=3. Identifier: NCT01354431.

ABSTRACT SUMMARY Phase II Trial of RAD001 in Renal Cell Carcinoma Patients With Non-Clear Cell Histology

A phase II trial evaluated the use of everolimus in patients with non–clear cell RCC (Abstract 4544). Patients (N=45) from 5 centers were enrolled. Exclusion criteria included previous therapy with a mammalian target of rapamycin (mTOR) inhibitor. Previous therapy with a VEGF tyrosine kinase inhibitor (TKI) was permitted, and 23 patients had received it. The patients ranged in age from 24–75 years (median, 57 years). There were more men than women in the study. RCC histology included papillary (n=29), chromophobe (n=8), collecting duct (n=2), sarcomatoid (n=4), and unclassifiable (n=6). All patients received everolimus at 10 mg/day until disease progression or unacceptable toxicity. The primary endpoint of the study was PFS. Forty-six patients underwent radiologic response assessment after they received everolimus. Five patients (10.2%) achieved a partial response, and 25 patients (51.0%) achieved stable disease. Disease progressed in 16 patients (32.7%). An objective response was observed in 5 patients; their RCC histology was chromophobe carcinoma (n=2), papillary carcinoma (n=2) and unclassifiable carcinoma (n=1). The median PFS was 5.2 months. The longest PFS was observed in patients with chromophobe histology (median PFS 18.8 months vs 3.5 months for other histologies; P=.027). There was no significant difference in estimated median PFS between patients who had or had not received previous VEGF-TKI treatment (median PFS of 7.1 months vs 3.7 months; P=.110). Toxicity profiles were similar to those reported in previous studies.

ABSTRACT SUMMARY Phase III AXIS Trial of Axitinib Versus Sorafenib in Metastatic Renal Cell Carcinoma: Updated Results Among Cytokine-Treated Patients

The phase III AXIS (Axitinib [AG 013736] as Second Line Therapy for Metastatic Renal Cell Cancer) trial (Rini BI, et al. Lancet. 2011;378:1931-1939) compared axitinib (5 mg twice daily [BID] starting dose) and sorafenib (400 mg BID) in patients with metastatic RCC. Axitinib was associated with a significantly increased PFS as compared with sorafenib (6.7 months vs 4.7 months; HR, 0.665; 95% CI, 0.544–0.812; 1-sided P<.0001). A study presented at the 2012 ASCO meeting reported updated PFS and OS data for the AXIS trial according to patients’ previous treatments (Abstract 4546). Among patients who had received previous treatment with cytokines, median PFS was 12.0 months with axitinib and 6.6 months with sorafenib (HR, 0.519; 95% CI, 0.375–0.720; P<.0001). Among patients who had previously received a regimen containing interleukin-2, median PFS was 15.7 months in the axitinib group and 8.3 months in the sorafenib group. Among patients who had received previous treatment with an interferon-alpha, median PFS was 12.0 months with axitinib and 6.5 months with sorafenib. In patients who had received previous cytokine therapy, median OS was 29.4 months with axitinib and 27.8 months with sorafenib (P=.144). Adverse events were similar in both arms.