Phase II trial of second-line everolimus in patients with metastatic renal cell carcinoma (RECORD-4)

BackgroundRECORD-1 demonstrated clinical benefit of everolimus in patients with metastatic renal cell carcinoma (mRCC) previously treated with sunitinib, sorafenib, or both; prior treatment with cytokines, bevacizumab, and chemotherapy was also permitted. RECORD-4 prospectively assessed everolimus in a purely second-line setting.MethodsPatients with clear-cell mRCC were enrolled into one of three cohorts based on first-line therapy with sunitinib, other anti-VEGF agents, or cytokines. Patients were treated with everolimus 10 mg/day until progression (RECIST, v1.0) or intolerance. The primary end point was progression-free survival (PFS) per investigator review. Data cutoff was 1 September 2014, for the primary analysis and 26 June 2015, for the final overall survival (OS) analysis.ResultsEnrolled patients (N = 134) previously received sunitinib (n = 58), other anti-VEGF therapy (n = 62; sorafenib, 23; bevacizumab, 16; pazopanib, 13; tivozanib, 5; and axitinib, 3), or cytokines (n = 14). Overall median age was 59 years, and most patients were men (68%) and of favorable/intermediate MSKCC risk (52/37%). Overall median PFS was 7.8 months [95% confidence interval (CI) 5.7–11.0]; in the cohorts, it was 5.7 months (95% CI 3.7–11.3) with previous sunitinib, 7.8 months (95% CI 5.7–11.0) with other previous anti-VEGF therapy, and 12.9 months [95% CI 2.6–not estimable (NE)] with previous cytokines. Overall, 67% of patients achieved stable disease as their best objective response. At final OS analysis, total median OS was 23.8 months (95% CI 17.0–NE) and, in the cohorts, it was 23.8 months (95% CI 13.7–NE) with previous sunitinib, 17.2 months (95% CI 11.9–NE) with other previous anti-VEGF therapy, and NE (95% CI 15.9–NE) with previous cytokine-based therapy. Overall, 56% of patients experienced grade 3 or 4 adverse events (regardless of relationship to study drug).ConclusionsThese results confirm the PFS benefit of second-line everolimus after first-line sunitinib or other anti-VEGF therapies. The safety profile of everolimus was consistent with previous experience.Clinical trial name and identifierEverolimus as Second-line Therapy in Metastatic Renal Cell Carcinoma (RECORD-4), ClinicalTrials.gov identifier, NCT01491672.     

Sunitinib-induced hypothyroidism predicts progression-free survival in metastatic renal cell carcinoma patients

Sunitinib is a tyrosine kinase inhibitor (TKI) used in treatment of metastatic renal cell carcinoma (mRCC), gastrointestinal stromal tumors and pancreatic neuroendocrine tumors. One of the most common side effects related to sunitinib is hypothyroidism. Recent trials suggest correlation between the incidence of hypothyroidism and treatment outcome in patients treated with TKI. This study evaluates whether development of hypothyroidism is a predictive marker of progression-free survival (PFS) in patients with mRCC treated with sunitinib. Twenty-seven patients diagnosed with clear cell mRCC, after nephrectomy and in ‘good’ or ‘intermediate’ MSKCC risk prognostic group, were included in the study. All patients received sunitinib as a first-line treatment on a standard schedule (initial dose 50 mg/day, 4 weeks on, 2 weeks off). The thyroid-stimulating hormone serum levels were obtained at the baseline and every 12 weeks of treatment. In statistic analyses, we used Kaplan–Meier method for assessment of progression-free survival; for comparison of survival, we used log-rank test. In our study, the incidence of hypothyroidism was 44%. The patients who had developed hypothyroidism had better median PFS to patients with normal thyroid function 28,3 months [95% (CI) 20.4–36.2 months] versus 9.8 months (6.4–13.1 months). In survival analysis, we perceive that thyroid dysfunction is a predictive factor of a progression-free survival (PFS). In the unified group of patients, the development of hypothyroidism during treatment with sunitinib is a positive marker for PFS. During that treatment, thyroid function should be evaluated regularly.     

Macrocytosis during sunitinib treatment predicts progression-free survival in patients with metastatic renal cell carcinoma

Sunitinib, a multi-targeted receptor tyrosine kinase inhibitor, is a first-line treatment for metastatic renal cell carcinoma (mRCC) in patients in ‘low’ and ‘intermediate’ Memorial Sloan Kettering Cancer Center and Heng risk groups. Disruptions of hematopoiesis, such as anemia, neutropenia, and thrombocytopenia, are typically observed during sunitinib treatment. When it comes to RBC parameters, an increase in mean cell volume (MCV) tends to occur, meeting the criteria for macrocytosis in some patients (MCV > 100 fL). We examined changes in RBC parameters of 27 mRCC patients treated with sunitinib (initial dose of 50 mg/day, 6-week treatment: 4 weeks on, 2 weeks off) and correlated them with progression-free survival time (PFS). Patients who had macrocytosis after 3 treatment cycles had significantly longer PFS than those whose MCV stayed less than 100 fL (not reached vs. 11.2 months, p < 0.001). We also found a correlation between MCV values after the first and third treatment cycles and the risk of progression: HR of 0.9 (0.81–0.99) and 0.76 (0.65–0.90) per 1 fL increase in MCV, respectively. The mechanism of MCV elevation during sunitinib treatment has not yet been fully explained. One of the probable causes is sunitinib’s inhibitory influence on c-Kit kinase, as is the case with imatinib. For mRCC patients, this phenomenon could help predict PFS, but since our sample was small, further studies are essential.     

Assessment of progression-free survival as a surrogate end-point for overall survival in patients with metastatic renal cell carcinoma

BackgroundTo determine suitability of progression-free survival (PFS) as a surrogate end-point for overall survival (OS), we evaluated the relationship between PFS and OS in 750 treatment-naïve metastatic renal cell carcinoma (mRCC) patients who received sunitinib or interferon-alpha (IFN-α) in a phase III study.MethodsThe relationship between PFS and post-progression survival (PPS; the difference between PFS and OS) was studied, which correctly removes inherent dependencies between PFS and OS, to properly estimate whether and to what extent PFS can serve as a surrogate for OS. A Weibull parametric model to failure time data was fit to determine whether longer PFS was significantly and meaningfully predictive of longer PPS. In a sensitivity analysis by Kaplan–Meier non-parametric method, PPS curves for three approximately equal numbered groups of patients categorised by PFS were compared by log-rank test.ResultsIn the Weibull parametric model, longer PFS was significantly predictive of longer PPS (P < 0.001). The model also allowed prediction of estimated median PPS duration from actual PFS times. In the Kaplan–Meier (non-parametric) analysis, incrementally longer PFS was also associated with longer PPS, and the PPS curves for the three PFS groups were significantly different (P < 0.0001).ConclusionsA positive relationship was found between PFS and PPS duration in individual mRCC patients randomised to first-line treatment with sunitinib or IFN-α. These results indicate that PFS can act as a surrogate end-point for OS in the first-line mRCC setting and provide clinical researchers with a potentially useful approach to estimate median PPS based on PFS.     

More than 4 years of progression-free survival in a patient with metastatic renal cell carcinoma treated sequentially with sunitinib, everolimus, sorafenib, and temsirolimus

Until recently, immunotherapy has been the standard of care for patients with nonresectable metastatic renal cell carcinoma (mRCC); however, immunotherapy is associated with a low response rate and significant toxicity. Because of their demonstrated ability to prolong progression-free survival, agents targeting vascular endothelial growth factor receptors or the mammalian target of rapamycin now have become standard therapies for patients with mRCC. Attaining lasting clinical benefits, however, requires multiple lines of therapy. This case study reports the case of a 52-year-old man with mRCC who remained free of disease progression for 48 months while receiving sequential therapy of sunitinib, everolimus, sorafenib, and temsirolimus.     

Long-term response with everolimus for metastatic renal cell carcinoma refractory to sunitinib

A 70-year-old man with metastatic renal cell carcinoma developed progressive liver metastases after 8 weeks of treatment with the multitargeted tyrosine kinase inhibitor (TKI) sunitinib. He then participated in the phase III placebo-controlled clinical trial of the oral mammalian target of rapamycin (mTOR) inhibitor everolimus, initially randomized to placebo (but had disease progression after 3 months) and crossed over to everolimus at time of unblinding. The patient had stable disease after 8 weeks (two cycles) of everolimus that was maintained until 28 months of therapy, at which time the patient had achieved a partial response. This case illustrates the potential for patients with metastatic renal cell carcinoma, a malignancy with historically poor prognosis, to derive long-term benefit from everolimus when used in a manner consistent with its approved indication (after TKI therapy with sunitinib or sorafenib).     

Everolimus in metastatic renal cell carcinoma patients intolerant to previous VEGFr-TKI therapy: a RECORD-1 subgroup analysis

Background:

A relevant percentage of patients with metastatic renal cell carcinoma develop intolerance to vascular endothelial growth factor receptor-tyrosine kinase inhibitors (VEGFr-TKIs) and require careful selection of subsequent treatment. This retrospective analysis evaluated the safety and efficacy of everolimus in patients enrolled in the phase-III RECORD-1 trial who discontinued previous VEGFr-TKI therapy because of toxicity.

Methods:

Patients with an adverse event (AE) as their primary reason for discontinuation of previous VEGFr-TKI therapy were included. Median progression-free survival (PFS) for VEGFr-TKI-intolerant patients in each arm was estimated using the Kaplan–Meier method, and effect on PFS (hazard ratio (HR)) was calculated using the Cox proportional hazard model.

Results:

In VEGFr-TKI-intolerant patients (n=58, 14%), median PFS was 5.4 months with everolimus and 1.9 months with placebo (HR: 0.32; P=0.004). In sunitinib-intolerant patients (n=26), median PFS was 5.1 months with everolimus and 2.8 months with placebo (HR: 0.28; P=0.033). Grade 3/4 AEs reported with everolimus in VEGFr-TKI-intolerant patients included infections (16%), fatigue (7%) and stomatitis (4%). The toxicity profile of everolimus was similar in the VEGFr-TKI-intolerant and overall study populations.

Conclusion:

Everolimus is well tolerated and efficacious with no increased toxicity in patients intolerant to VEGFr-TKI therapy.     

A phase 1 study of everolimus and sorafenib for metastatic clear cell renal cell carcinoma

BACKGROUND:

The current study was conducted to assess the maximum tolerated dose (MTD), safety, pharmacokinetics, and preliminary antitumor effect of everolimus, a mammalian target of rapamycin inhibitor, in combination with sorafenib, a tyrosine kinase inhibitor, in patients with metastatic clear cell renal cell carcinoma.

METHODS:

Sequential cohorts of patients received escalating doses of everolimus and sorafenib in 28‐day cycles in the absence of a dose‐limiting toxicity (DLT) or disease progression were examined.

RESULTS:

Twenty patients with a median age of 65 years received therapy in 3 cohorts. Dose level 1 was comprised of everolimus at a dose of 2.5 mg daily and sorafenib at a dose of 400 mg twice daily (6 patients), dose level 2 was comprised of everolimus at a dose of 5 mg daily and sorafenib at a dose of 400 mg twice daily (8 patients), and dose level 3 was comprised of everolimus at a dose of 10 mg daily and sorafenib at a dose of 200 mg twice daily (6 patients). DLTs included grade 4 (according to National Cancer Institute Common Terminology Criteria for Adverse Events [version 3.0]) hyperuricemia with grade 2 gout and grade 3 lipase associated with grade 2 pancreatitis at dose level 2, and grade 3 rash in 2 patients at dose level 3. Dose level 2 (everolimus at a dose of 5 mg daily and sorafenib at a dose of 400 mg twice daily) was established as the maximum tolerated dose. Treatment‐related adverse events occurring in >20% of patients included diarrhea, hand‐foot syndrome, hypertension, hypophosphatemia, hypothyroidism, and rash. Five of 20 patients achieved Response Evaluation Criteria In Solid Tumors (RECIST)‐defined partial responses, all of which occurred in patients without a history of prior systemic therapy. Seven of 8 patients treated at dose level 2 experienced a partial response or stable disease. Pharmacokinetic analysis revealed no interaction between everolimus and sorafenib.

CONCLUSIONS:

The combination of everolimus and sorafenib was associated with acceptable toxicity and evidence of antitumor activity in previously untreated patients with metastatic renal cell carcinoma. Cancer 2011;. © 2011 American Cancer Society.     

Phase 1 trial of everolimus plus sunitinib in patients with metastatic renal cell carcinoma

BACKGROUND:

Simultaneous inhibition of the vascular epithelial growth factor (VEGF) and the mammalian target of rapamycin (mTOR) pathway may improve treatment response in advanced renal cell carcinoma (RCC). Everolimus, an oral mTOR inhibitor, and sunitinib, an oral tyrosine kinase inhibitor targeting VEGF, are standard agents in the management of metastatic RCC.

METHODS:

Sequential cohorts of 3 to 6 patients with advanced RCC received dose‐escalated combinations of sunitinib (37.5 or 50 mg daily, 4 weeks on/2 weeks off) with everolimus (2.5‐5 mg daily or 20‐30 mg weekly). Dose‐limiting toxicities (DLTs) were assessed in the first 6‐week cycle to determine maximum tolerated dose (MTD). Pharmacokinetic profiles were obtained.

RESULTS:

Twenty patients (13 clear cell and 7 nonclear cell RCC) were enrolled in 5 cohorts. Daily everolimus was not tolerated when combined with sunitinib; the first 2 patients on the second cohort suffered DLTs. With weekly everolimus, the MTD was 30 mg everolimus on days 7, 14, 21, and 28, plus 37.5 mg sunitinib on days 1 to 28 of a 42‐day cycle; however, chronic treatment was associated with grade 3 and 4 toxicities. A schedule of 20 mg everolimus weekly/37.5 mg sunitinib was tolerated as chronic therapy. Five patients (25%) had confirmed partial responses, and 3 had nonclear cell RCC. No unexpected accumulation of everolimus, sunitinib, or N‐desethyl sunitinib was observed.

CONCLUSIONS:

The combination of everolimus and sunitinib is associated with significant acute and chronic toxicities and is only tolerated at attenuated doses. Responses were observed in nonclear cell and clear cell RCC. Cancer 2012. © 2011 American Cancer Society.     

Dynamic tumor modeling of the dose-response relationship for everolimus in metastatic renal cell carcinoma using data from the phase 3 RECORD-1 trial

ABSTRACT: BACKGROUND: The phase 3 RECORD-1 trial (NCT00410124) established the efficacy and safety of everolimus in patients with metastatic renal cell carcinoma (mRCC) who progress on sunitinib or sorafenib. In RECORD-1, patients received 10 mg everolimus daily, with dose reduction to 5 mg daily allowed for toxicity. We have developed a model of tumor growth dynamics utilizing serial measurements of the sum of the longest tumor diameters (SLD) from individual RECORD-1 patients to define the dose-response relationship of everolimus. Results: The model predicts that after 1 year of continuous dosing, the change in SLD of target lesions will be +142.1% +/- 98.3%, +22.4% +/- 17.2%, and -15.7% +/- 11.5% in the average patient treated with placebo, 5 mg everolimus, and 10 mg everolimus, respectively. This nonlinear, mixed-effects modeling approach can be used to describe the dynamics of each individual patient, as well as the overall population. This allows evaluation of how an actual dosing history and individual covariates impact on the observed drug effect, and offers the possibility of predicting clinical observations as a function of time. Conclusions: In this pharmacodynamic model of tumor response, everolimus more effectively shrinks target lesions in mRCC when dosed 10 mg daily versus 5 mg daily, although a 5-mg dose still shows an antitumor effect. These data support earlier studies that established 10 mg daily as the preferred clinical dose of everolimus, and improve our understanding of the everolimus dose-response relationship.     

Prognostic factors for survival in previously treated patients with metastatic renal cell carcinoma.

PURPOSE: To describe survival in previously treated patients with metastatic renal cell carcinoma (RCC) who are candidates for clinical trials of new agents as second-line therapy. PATIENTS AND METHODS: The relationship between pretreatment clinical features and survival was studied in 251 patients with advanced RCC treated during 29 consecutive clinical trials between 1975 and 2002. Clinical features were first examined in univariate analyses, and then a stepwise modeling approach based on Cox regression was used to form a multivariate model. RESULTS: Median survival for the 251 patients was 10.2 months and differed according to year of treatment, with patients treated after 1990 showing longer survival. In this group, the median overall survival time was 12.7 months. Because the purpose of this analysis was to establish prognostic factors for present-day clinical trial design, prognostic factor analysis was performed on these patients. Pretreatment features associated with a shorter survival in the multivariate analysis were low Karnofsky performance status, low hemoglobin level, and high corrected serum calcium. These were used as risk factors to categorize patients into three different groups. The median time to death in patients with zero risk factors was 22 months. The median survival in patients with one of these prognostic factors was 11.9 months. Patients with two or three risk factors had a median survival of 5.4 months. CONCLUSION: Treatment with novel agents during a clinical trial is indicated for patients with metastatic RCC after progression to cytokine treatment. Three prognostic factors for predicting survival were used to categorize patients into risk groups. These risk categories can be used in clinical trial design and interpretation.     

Pre-treatment neutrophil-to-lymphocyte ratio may be associated with the outcome in patients treated with everolimus for metastatic renal cell carcinoma

Background:

Everolimus is a mammalian target of rapamycin inhibitor approved for the treatment of metastatic renal cell carcinoma (mRCC). We aimed to assess the association between pre-treatment neutrophil-to-lymphocyte ratio (NLR) and the outcome of patients treated with everolimus for mRCC.

Methods:

Ninety-seven patients with mRCC were treated with everolimus till April 2013 in our institutions. Patients were stratified in two groups with NLR >3 (Group A) vs <3 (Group B). Progression-free survival (PFS) and overall survival (OS) were estimated using Kaplan–Meier method. Gender, age, Motzer prognostic group, PFS on first-line therapy, neutrophilia and NLR were included in the Cox analysis to investigate their prognostic relevance.

Results:

Median OS and PFS were 10.6 and 5.3 months, respectively. Median OS was 12.2 months in Group A and 24.4 months in Group B (P=0.001). Median PFS was 3.4 months in Group A and 9.9 months in Group B (P<0.001). At multivariate analysis, only Motzer prognostic group and NLR were independent prognostic factors for OS and PFS.

Conclusion:

Pre-treatment NLR is an independent prognostic factor for patients with mRCC treated with second- or third-line everolimus. This should be investigated and validated in prospective studies.     

Prognostic factors for survival in patients with metastatic renal cell carcinoma treated with targeted therapies

Background:

The most important prognostic factors for survival in patients with metastatic renal cell carcinoma (mRCC) were evaluated in the era of cytokine therapy, and only recently were revalidating in patients receiving targeted therapies (TTs).

Methods:

Clinical data for consecutive patients with mRCC who received TTs were retrieved from the database of Istituto Nazionale dei Tumori of Milan. Variables with a significant association with overall survival (OS) were estimated by proportional hazard regression, and a backward stepwise multivariate analysis identified the independent prognostic factors.

Results:

Data for 336 consecutive patients treated with TTs for RCC during the period 2004–2011 were evaluated. According to the Motzer classification, 32% patients were low risk, 48% were intermediate risk and 20% were poor risk. One hundred and sixty-seven (49.7%) patients received one TT, 116 (34.5%) received a second-line TT, 42 (12.5%) a third-line TT and 11 (3.3%) patients received a fourth-line TT. The median OS was 24 months (95% CI 20.0, 27.0) and the 5-year OS rate was 24.6% (95% CI 18.7, 30.8%). In the uni- and multivariate analysis Motzer risk classification, Fuhrman grade and previous cytokine therapy were identified as independent prognostic factors (P<0.01).

Conclusion:

The Motzer classification was confirmed as an independent prognostic factor for OS in patients with mRCC receiving TTs. Additionally, Fuhrman grade and previous cytokine therapy were independent prognostic factors for clinical outcome.     

Prognostic factors for survival in 1059 patients treated with sunitinib for metastatic renal cell carcinoma

Background:

Prognostic factors for progression-free survival (PFS), overall survival (OS), and long-term OS (⩾30 months) were investigated in sunitinib-treated patients with metastatic renal cell carcinoma (RCC).

Methods:

Data were pooled from 1059 patients in six trials. Baseline variables, including ethnicity, were analysed for prognostic significance by Cox proportional-hazards model.

Results:

Median PFS and OS were 9.7 and 23.4 months, respectively. Multivariate analysis of PFS and OS identified independent predictors, including ethnic origin, Eastern Cooperative Oncology Group performance status, time from diagnosis to treatment, prior cytokine use, haemoglobin, lactate dehydrogenase, corrected calcium, neutrophils, platelets, and bone metastases (OS only). Characteristics of long-term survivors (n=215, 20%) differed from those of non-long-term survivors; independent predictors of long-term OS included ethnic origin, bone metastases, and corrected calcium. There were no differences in PFS (10.5 vs 7.2 months; P=0.1006) or OS (23.8 vs 21.4 months; P=0.2135) in white vs Asian patients; however, there were significant differences in PFS (10.5 vs 5.7 months; P<0.001) and OS (23.8 vs 17.4 months; P=0.0319) in white vs non-white, non-Asian patients.

Conclusion:

These analyses identified risk factors to survival with sunitinib, including potential ethnic-based differences, and validated risk factors previously reported in advanced RCC.     

Efficacy and safety of everolimus in Korean patients with metastatic renal cell carcinoma

Purpose

Few studies have investigated the effects of everolimus therapy in Asian populations. This study evaluates the safety and efficacy of everolimus in Korean patients with metastatic renal cell carcinoma (mRCC).

Methods

We retrospectively reviewed records of Korean patients with mRCC (n = 22) who received everolimus between January 2009 and July 2010 and evaluated them for efficacy and safety.

Results

One patient achieved a partial response, and 16 patients had stable disease, corresponding to an overall response rate of 4.5 % and a disease control rate of 77.3 %. Median progression-free survival was 5.4 months (95 % CI 0.9–9.8). Median overall survival was not reached. Univariate analysis showed that Memorial Sloan-Kettering Cancer Center risk (P = .004), thrombocytopenia (P = .018), hyperglycemia (P = .007) and hypertriglyceridemia (P = .041) were associated with disease progression. The most common adverse events (AEs) were hypertriglyceridemia and anemia, similar to Western patients. Creatinine and aspartate aminotransferase levels were higher than those reported for Western patients. The most common grade ≥3 AEs in this study were hypertriglyceridemia and anemia, compared with lymphopenia (14 %) in Western patients.

Conclusions

Safety of everolimus in Korean mRCC patients differed from that reported in Western patients. Therefore, liver function enzymes, hemoglobin levels, lipid profile and chest CT scans should be monitored more closely in Asian mRCC patients receiving everolimus.     

Optimizing the size variation threshold for the CT evaluation of response in metastatic renal cell carcinoma treated with sunitinib

Background: In metastatic renal cell carcinoma (mRCC), antiangiogenic treatments rarely achieve a reduction of -30% in the sum of longest diameters (SLD) of target lesions required by RECIST for an ‘objective response’, although they objectively improve progression-free survival (PFS). We sought to determine a threshold for the computed tomography evaluation of these patients’ best reflecting patient outcome.Patients and methods: In 334 mRCC patients treated with sunitinib, we tested thresholds from -45% to +10%. We classified patients as ‘responders’ when the best relative variation of the sum of longest diameters (ΔSLD) reached the tested threshold and as ‘nonresponders’ otherwise. For each tested threshold, the median PFS of the two groups were compared. Receiver operating characteristic (ROC) analysis was also carried out among the 103 patients that progressed during follow-up. Finally, the ‘optimal’ threshold was retested on an independent cohort of 39 patients.Results: The ΔSLD threshold of -10% gave the most significant difference. It divided patients into 256 responders and 78 nonresponders (median PFS 11.1 and 5.6 months). The same -10% threshold was found using the ROC analysis. Results were confirmed on the external validation cohort.Conclusion: A variation of -10% in the SLD accurately and rapidly identifies mRCC patients benefiting from sunitinib.     

Sunitinib re-challenge in metastatic renal cell carcinoma treated sequentially with tyrosine kinase inhibitors and everolimus

Therapy of patients with metastatic renal cell carcinoma (mRCC) requires sequential use of several agents with different mechanisms and minimal cross-resistance between the different agents. Tyrosine kinase inhibitors (TKIs) and mammalian target of rapamycin (mTOR) inhibitors prolong progression-free survival (PFS) in patients with mRCC. Re-challenge with TKIs provides clinical benefit after everolimus in patients with mRCC. We report the case of an mRCC patient with lung and bone metastases, treated sequentially with sunitinib, sorafenib and everolimus. The patient had an objective response in reducing bone metastases, but adaptative and concomitant progression in lung metastases during sunitinib re-challenge. Previously, these lung metastases had responded to sunitinib. This intriguing paradox suggests that not only was sunitinib able to target a specific metastatic site during the re-challenge, as seen by the reduction of bone metastases, but it also elicited a more invasive adaptation and progression of lung tumor cells.     

Final overall survival analysis for the phase II RECORD-3 study of first-line everolimus followed by sunitinib versus first-line sunitinib followed by everolimus in metastatic RCC

BackgroundRECORD-3 compared everolimus and sunitinib as first-line therapy, and the sequence of everolimus followed by sunitinib at progression compared with the opposite (standard) sequence in patients with metastatic renal cell carcinoma (mRCC). This final overall survival (OS) analysis evaluated mature data for secondary end points.Patients and methodsPatients received either first-line everolimus followed by second-line sunitinib at progression (n = 238) or first-line sunitinib followed by second-line everolimus (n = 233). Secondary end points were combined first- and second-line progression-free survival (PFS), OS, and safety. The impacts of neutrophil lymphocyte ratio (NLR) and baseline levels of soluble biomarkers on OS were explored.ResultsAt final analysis, median duration of exposure was 5.6 months for everolimus and 8.3 months for sunitinib. Median combined PFS was 21.7 months [95% confidence interval (CI) 15.1–26.7] with everolimus-sunitinib and 22.2 months (95% CI 16.0–29.8) with sunitinib-everolimus [hazard ratio (HR)_{EVE-SUN/SUN-EVE}, 1.2; 95% CI 0.9–1.6]. Median OS was 22.4 months (95% CI 18.6–33.3) for everolimus-sunitinib and 29.5 months (95% CI 22.8–33.1) for sunitinib-everolimus (HR_{EVE-SUN/SUN-EVE}, 1.1; 95% CI 0.9–1.4). The rates of grade 3 and 4 adverse events suspected to be related to second-line therapy were 47% with everolimus and 57% with sunitinib. Higher NLR and 12 soluble biomarker levels were identified as prognostic markers for poor OS with the association being largely independent of treatment sequences.ConclusionsResults of this final OS analysis support the sequence of sunitinib followed by everolimus at progression in patients with mRCC. The safety profiles of everolimus and sunitinib were consistent with those previously reported, and there were no unexpected safety signals.Clinical Trials numberClinicalTrials.gov identifier, NCT00903175     

Phase 3 trial of everolimus for metastatic renal cell carcinoma

BACKGROUND:

A phase 3 trial demonstrated superiority at interim analysis for everolimus over placebo in patients with metastatic renal cell carcinoma (mRCC) progressing on vascular endothelial growth factor receptor–tyrosine kinase inhibitors. Final results and analysis of prognostic factors are reported.

METHODS:

Patients with mRCC (N = 416) were randomized (2:1) to everolimus 10 mg/d (n = 277) or placebo (n = 139) plus best supportive care. Progression‐free survival (PFS) and safety were assessed to the end of double‐blind treatment. Mature overall survival (OS) data were analyzed, and prognostic factors for survival were investigated by multivariate analyses. A rank‐preserving structural failure time model estimated the effect on OS, correcting for crossover from placebo to everolimus.

RESULTS:

The median PFS was 4.9 months (everolimus) versus 1.9 months (placebo) (hazard ratio [HR], 0.33; P < .001) by independent central review and 5.5 months (everolimus) versus 1.9 months (placebo) (HR, 0.32; P < .001) by investigators. Serious adverse events with everolimus, independent of causality, in ≥5% of patients included infections (all types, 10%), dyspnea (7%), and fatigue (5%). The median OS was 14.8 months (everolimus) versus 14.4 months (placebo) (HR, 0.87; P = .162), with 80% of patients in the placebo arm crossed over to everolimus. By the rank‐preserving structural failure time model, the survival corrected for crossover was 1.9‐fold longer (95% confidence interval, 0.5‐8.5) with everolimus compared with placebo only. Independent prognostic factors for shorter OS in the study included low performance status, high corrected calcium, low hemoglobin, and prior sunitinib (P < .01).

CONCLUSIONS:

These results established the efficacy and safety of everolimus in patients with mRCC after progression on sunitinib and/or sorafenib. Cancer 2010. © 2010 American Cancer Society.