Refractory Metastatic Renal Cell Carcinoma Research Articles

Treatment of Refractory Metastatic Renal Cell Carcinoma.

Simple SummaryThe treatment of metastatic renal cell carcinoma continues to rapidly evolve, with various combinations of immune checkpoint inhibitors and targeted tyrosine kinase inhibitors improving outcomes in the first-line setting. However, a significant subset of patients fail to respond to these therapies, and many patients eventually progress, necessitating effective therapeutic options in the treatment-refractory setting. Here, we review the treatment of refractory renal cell carcinoma, including the current standard of care, ongoing trials with the potential to alter current paradigms, and considerations for non-clear cell histologies.First-line treatment for metastatic renal cell carcinoma (mRCC) rapidly shifted in recent years with the advent of combination therapies, including immune checkpoint inhibitor (ICI) doublets and combinations of an ICI with a vascular endothelial growth factor receptor (VEGFR) targeted tyrosine kinase inhibitor (TKI). Despite improvements in overall survival and many durable responses, there exists a significant number of patients who fail to respond to these agents, and many patients eventually progress. Given the rapid changes in the front-line setting, it is essential to understand treatment options in refractory mRCC. Here, we review the evidence behind current options for later-line therapies, often involving additional VEGFR-TKIs alone or in combination with mammalian target of rapamycin (mTOR) targeted agents, as well as situations where consideration of immunotherapy rechallenge may be appropriate. Additionally, we describe ongoing clinical trials examining concurrent ICI and TKI in the refractory setting, as well as those studying novel agents, such as targeted drug–antibody conjugates and hypoxia inducible factor 2α (HIF-2α) inhibitors. Finally, we review considerations for non-clear cell histologies in the refractory setting and mechanisms of resistance in mRCC.

On-treatment C-reactive protein control could predict response to subsequent anti-PD-1 treatment in metastatic renal cell carcinoma.

The aim of this study was to evaluate the clinical significance of the on-treatment C-reactive protein (CRP) status during systemic treatment as the predictive marker for the response of subsequent nivolumab monotherapy in patients with refractory metastatic renal cell carcinoma (mRCC). A total of 73 mRCC patients treated with nivolumab were retrospectively reviewed. We evaluated the serum CRP levels before and after molecular-targeted treatments. Patients whose CRP did not exceed baseline value were defined as the CRP-control group and the others were defined as the CRP-progression group. The clinical impact of CRP-control on the efficacy of nivolumab was assessed. Twenty-four patients (33%) were categorized into the CRP-control group. The CRP-control group patients (median PFS not reached) had significantly longer PFS than the CRP-progression group (median PFS 11.9months, 95% confidence interval, CI 4.1-19.8, p = 0.038). The CRP-control group had a tendency of longer OS from nivolumab initiation than the CRP-progression group (p = 0.071). By multivariate analysis, the on-treatment CRP-control was the independent predictive factor for PFS (hazard ratio HR 0.37, 95% CI 0.14-0.99, p = 0.047). The on-treatment CRP-control could be the predictive factor for the efficacy of nivolumab in refractory mRCC patients.

Biomarker-based phase II study of sapanisertib (TAK-228), an mTORC1/2 inhibitor in patients with refractory metastatic renal cell carcinoma (mRCC).

306 Background: Approved rapalogs inhibit mTORC1 and have limited activity in mRCC, possibly due to compensatory feedback loops. Sapanisertib addresses the incomplete inhibition of the mTOR pathway through targeting of both mTORC1 and mTORC2 with antitumour activity demonstrated in patients with mRCC. In this multicenter, single arm phase II trial, we evaluated the efficacy of sapanisertib in patients with mRCC progressing on standard therapies (NCT03097328). Methods: Eligible mRCC patients had an ECOG performance status of 0-2 and had progressed on standard therapies. Prior therapy with rapalogs (everolimus, temsirolimus) and variant RCC histologies were permitted. Patients had a baseline biopsy and received treatment with sapanisertib 30 mg by mouth weekly until unacceptable toxicity or disease progression. The primary endpoint was overall response rate (ORR) by RECIST 1.1. Tissue biomarkers of mTOR pathway activation were explored. Results: We enrolled 38 mRCC patients (clear cell = 28; variant histology = 10) between August 2017 and November 2019. The majority had intermediate (76%) or poor risk (11%) by IMDC criteria. Twenty (53%) had received ≥ 3 lines of therapy; 13 (34%) patients received prior rapalogs. Median follow-up was 10.4 months (range 1-27.4) and median duration of therapy was 1.6 (range 0.3-13.8) months. ORR by central review was 2 of 38 (5.3% 90%CI: 1%-15.6%). 31.6% of all patients and 30.7% of those with prior rapalog exposure had some tumor shrinkage during course of treatment. Median progression free survival (PFS) was 2.5 months (95% CI 1.8,3.7). Twelve patients (32%) developed treatment-related grade 3 adverse events (AEs) with no grade 4 or 5 toxicity reported; 6 patients (16%) required dose reduction and 4 (11%) discontinued therapy for AEs. Oncopanel tumor sequencing identified alterations in the mTOR pathway in 6 of 29 patients ( MTOR n = 2, PTEN n = 3, TSC1 n = 1.) Reduced PTEN expression by immunohistochemistry was seen in 7 of 19 patients. There was no association between mTOR pathway mutations or PTEN loss and response to sapanisertib. Conclusions: In this study we demonstrate minimal activity of sapanisertib in patients with treatment refractory mRCC with no clear benefit among patients with mTOR/PTEN pathway alterations. Additional treatment strategies are needed for patients with refractory mRCC.

Efficacy of alpha-1,3-galactosyltransferase-expressing allogeneic renal cell carcinoma immunotherapy in patients (pts) with refractory metastatic renal cell carcinoma (mRCC).

590 Background: HyperAcute Renal (HAR) immunotherapy consists of two allogeneic renal cancer cell lines that have been genetically modified to express α(1,3)Gal, to which humans have an inherent pre-existing immunity. A previous report demonstrated that HAR is well tolerated in pts with mRCC (2017 GUASCO, abstract: 528). Herein, we report the efficacy of HAR immunotherapy in mRCC. Methods: Pts with refractory clear-cell mRCC were eligible for this phase 1 dose-escalation trial. Concomitant treatment (Rx) with other approved agents was permitted after initial 2 months (m) of HAR monotherapy. The trial followed a standard 3+3 design with cells injected intradermally weekly for 4 weeks then biweekly injections for 10 immunizations (150 x106cells then escalated to 300 x106cells). Co-primary objectives were safety and efficacy. Results: A total of 18 patients were enrolled (4 low dose, 14 high dose) between 06/2015 to 07/2016. Patients received a median of 1 systemic Rx prior to HAR immunotherapy, with 8 patients receiving 2 or more prior agents. IMDC risk categories at the time of initial metastatic disease were: favorable risk (33%), intermediate risk (66%), poor risk (0%). The ORR was 0% with a disease control rate of 50%. Median PFS for patients treated with HAR immunotherapy was 2.0 months (m) (range 1.7-30.3 m). For patients receiving the low dose HAR, median overall survival (OS) was 14.2 m (range 3.6-21.6 m), while median OS for high dose HAR was 25.3 m (5.8-29.3 m). At the time of data cutoff in 09/2018, 7 patients were still living. Detailed clinical data will be presented in the meeting. Conclusions: HAR immunotherapy in refractory mRCC was well tolerated and demonstrated potential efficacy for OS similar to currently approved salvage-line Rx. With a unique mechanism of action, HAR immunotherapy may be a candidate for inclusion in novel combinatorial regimens being developed in salvage therapy setting in pts with mRCC. Clinical trial information: NCT02035358.

Ipilimumab plus nivolumab (Ipi/Nivo) as salvage therapy in patients with immunotherapy (IO)-refractory metastatic renal cell carcinoma (mRCC).

669 Background: Ipi/Nivo is now FDA approved for the first line treatment of patients (pts) with intermediate and poor risk mRCC but activity in IO refractory mRCC patients is still not well reported. Here we seek to report activity of Ipi/Nivo in IO refractory mRCC pts. Methods: In this retrospective review, we identified a total of 30 pts with mRCC from 4 academic medical centers across the USA who received salvage Ipi/Nivo after disease progression on IO therapy. Pts with only predominant clear cell histology were captured. Ipi/Nivo was administered as per CHECKMATE 214. Investigator-assessed response rate were noted. Immune related adverse events (irAE) were captured in accordance with CTCAE v5.0. Results: The baseline demographics included median age of 60 years (21-82), ECOG PS 0-2, and 73% (22) male and 27% (8) female. IMDC risk categories at the time of salvage Ipi/Nivo initiation were 23% (7), 60% (18) and 3% (1) with favorable, intermediate and poor risk, respectively. The median number of prior systemic therapies was 3 (1-6). Prior IO therapies included nivolumab monotherapy (14), avelumab plus axitinib (3), high dose interleukin-2 (3), pembrolizumab monotherapy (2) and Ipi/Nivo, nivolumab plus hypoxia inducible factor (HIF) inhibitor, atezolizumab plus interferon, atezolizumab monotherapy, pembrolizumab plus bevacizumab, pembrolizumab plus axitinib, varlilumab plus atezolizumab and an oral adenosine inhibitor (1 each). The median time on prior IO therapy was 7 months (1-50), best response was 3% (1) CR, 40% (12) PR, 23% (7) SD and 33% (10) PD. 73% (22) had restaging scans to assess response to ipi/nivo of which 17% (5), 3% (3) and 47% (14) showed PR, SD and, PD respectively. 37% (11) developed any grade irAEs and 6% (2) had grade ≥3 irAE including one patient with splenic rupture and one with rash and pneumonitis. Conclusions: Ipi/Nivo is feasible and safe in IO-refractory mRCC population with preliminary evidence of anti-tumor activity. Updated response data will be presented.

Patterns, predictors and subsequent outcomes of disease progression in metastatic renal cell carcinoma patients treated with nivolumab

BackgroundNivolumab is approved for the treatment of refractory metastatic renal cell carcinoma. Patterns and predictors of progressive disease (PD) on nivolumab, and outcomes in such patients are lacking.MethodsA retrospective analysis of patients (pts) with metastatic clear cell renal cell carcinoma (ccRCC) who received nivolumab at Cleveland Clinic (2015–2017) was performed. PD was defined per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 or clinical progression as per treating physician. Univariate analyses (UVA) and multivariate analyses (MVA) were used to identify clinical and laboratory markers as potential predictors of progression-free survival (PFS).ResultsNinety patients with mean age of 65, 74% men, and 83% good or intermediate International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) risk group were included. Median number of prior systemic treatments was 2 (range, 1–6). Median overall survival (OS) and PFS were 15.8 and 4.4 months, respectively. Fifty-seven patients (63%) had PD and 44% of patients with radiographic PD had new organ sites of metastases with brain (8/23, 35%) being the most common. Twelve patients received treatment beyond progression (TBP), and among 6 patients with available data, 3 (50%) had any tumor shrinkage (2 pts. with 17% shrinkage, one pt. with 29% shrinkage). Of 57 patients with PD, 28 patients (49%) were able to initiate subsequent treatment, mainly with axitinib and cabozantinib, while 40% of patients were transitioned to hospice after PD. In MVA, a higher baseline Neutrophil-to-Lymphocyte ratio (NLR) (HR, 1.86; 95% CI, 1.05–3.29; p = 0.033) was associated with an increased risk of progression, whereas higher (> 0.1 k/uL) baseline eosinophil count was associated with a lower risk of progression (HR, 0.54; 95% CI, 0.30–0.98; p = 0.042).ConclusionBrain was the most common site of PD in patients treated with nivolumab, and only half of patients progressing on nivolumab were able to initiate subsequent treatment. The risk of PD increased with a higher baseline NLR and reduced with a higher baseline eosinophil count.

Nivolumab (nivo) for patients (pts) with metastatic non-clear cell renal cell carcinoma (nccRCC): A single-institution experience.

4585Background: Nivo is approved for refractory metastatic renal cell carcinoma (RCC). However, the clinical activity of nivo in nccRCC is unknown as these patients were excluded from the trial pop...

Outcomes and patterns of disease progression in metastatic renal cell carcinoma patients treated with nivolumab.

654 Background: Nivolumab (nivo) has been approved for the treatment of refractory metastatic renal cell carcinoma (mRCC). Data regarding the characteristics and outcomes of patients (pts) who progress on nivo are lacking. Methods: A retrospective analysis of pts with clear cell mRCC who received nivo at Cleveland Clinic (2015-2017) was performed. Pts were divided into two groups; 1) PD group; pts with progressive disease (PD) per RECIST v1.1 or clinical PD, and 2) NPD group; pts with non-progressive disease on nivo. Results: Ninety pts (PD group n = 55, NPD group n = 35) with median age of 67 (33-83), 74% men, and 79% ECOG 0-1 were included. Pts had received 1 (44%), 2 (29%), or ≥ 3 (27%) prior systemic treatments, most commonly with sunitinib (71%), axitinib (39%) and pazopanib (33%). Pts in the PD group had a greater incidence of baseline liver metastases (PD, 40% vs. NPD, 14%; p = 0.01), with other baseline characteristics not significantly different. Median follow up was similar in both groups (PD group, 8.0 months (95% CI, 5.5-10.5) and NPD group, 7.1 months (95% CI, 4.9-9.3); p = 0.87). Median duration of treatment for PD group was 8.7 months (95% CI, 7.3-10.1) compared to 16.1 months (95% CI, 8.6-23.6) for NPD group (p = 0.02). In the PD group, 50 (91%) pts developed PD per RECIST v1.1 whereas 5 (9%) pts had clinical PD. New organ sites of metastases were found in 20/55 (36%) pts; brain (8/20; 40%), liver (4/20; 20%), soft tissue (4/20; 20%), and locoregional (4/20; 20%) were the most common new organ sites, whereas lungs, lymph nodes and pancreas were never involved at PD as new organ sites. Twelve pts received treatment beyond progression (TBP) with a median duration of TBP of 2.8 months (95% CI, 0.6-5.0) and 50% of pts had stable disease as their best response. Median overall survival (OS) and progression free survival (PFS) on nivo were 10.1 months (95% CI, 6.6-13.6) and 5.5 months (95% CI, 2.9-8.1), respectively. Conclusions: Pts with PD on nivo have a higher incidence of hepatic metastases at baseline, and one third of these pts develop new sites of metastases at PD, most commonly brain.

A Randomised Phase 2 Study of AZD2014 Versus Everolimus in Patients with VEGF-Refractory Metastatic Clear Cell Renal Cancer

BackgroundEverolimus is a mammalian target of rapamycin (mTOR) inhibitor used in vascular endothelial growth factor (VEGF)–refractory metastatic renal cell carcinoma (mRCC). It acts on only part of the mTOR complex (TORC1 alone). In vitro data support the use of mTOR inhibitors with broader activity (TORC1 and TORC2). ObjectiveThe purpose of this study was to determine whether combined TORC1 and TORC2 inhibition with AZD2014 has superior activity to everolimus in VEGF-refractory clear cell mRCC. Design, setting, and participantsPatients with measurable mRCC and VEGF-refractory disease were eligible for this trial. InterventionStarting in February 2013, patients were randomised (1:1) to AZD2014 (50mg twice daily) or everolimus (10mg once daily) until progression of disease at 10 centres across the United Kingdom. Outcome measurements and statistical analysisProgression-free survival (PFS) was the primary end point and was compared using the stratified log-rank test. Secondary end points included tolerability, response rates, overall survival (OS), and pharmacokinetics (PK) analysis. The study was planned to recruit 120 patients. Results and limitationsRecruitment into the trial was stopped early (June 2014) due to lack of efficacy of AZD2014. At that point, 49 patients were randomised (26 to AZD2014 and 23 to everolimus). The PFS for AZD2014 and everolimus was 1.8 and 4.6 mo, respectively (hazard ratio: 2.8 [95% confidence interval (CI), 1.2–6.5]; p=0.01). Progression of disease as the best response to therapy was 69% for AZD2014 and 13% for everolimus (p<0.001). Grade 3–4 adverse events (AEs) occurred in 35% of AZD2014 and 48% of everolimus patients (p=0.3). Only 4% of patients stopped AZD2014 due to AEs. PK analysis suggested concentrations of AZD2014 were compatible with the therapeutic range. Final stratified OS hazard ratio at the time of trial closure (January 2015) was 3.1 (95% CI, 1.1–8.4; p<0.02). ConclusionsThe PFS and OS of AZD2014 were inferior to everolimus in this setting despite acceptable AE and PK profiles. Patient summaryThere is a strong rationale for testing mTOR inhibitors with a broader spectrum of activity than everolimus in metastatic clear cell renal cell carcinoma. AZD2014 is such an agent, but in this study, it was inferior to everolimus despite its attractive toxicity profile.

Abstract CT340: Phase 1b/2a study of the nanopharmaceutical CRLX101 with bevacizumab (bev) in the treatment of patients (pts) with refractory metastatic renal cell carcinoma (mRCC): results from the planned interim analysis

Abstract Introduction: The inactivation of VHL occurs in most clear cell RCC (ccRCC) tumors and gives rise to the HIF hypoxia response program and to tumor angiogenesis. While antiangiogenic therapies are active in ccRCC, resistance develops in all pts. We hypothesize that dual inhibition strategies will be useful in overcoming resistance. CRLX101 (Cerulean Pharma, Inc., Cambridge, MA, USA), a novel tumor-targeted nanopharmaceutical platform containing camptothecin as its payload, has been shown in pre-clinical models to target HIF and is synergistic with bevacizumab (bev). We combined CRLX101 with bev in refractory mRCC in order to determine the safety and the recommended phase 2 dose (RP2D) of the combination, and to determine its preliminary therapeutic activity in this setting. Experimental Procedures: Pts with mRCC of all histologic subtypes refractory to conventional antiangiogenic therapies were treated every 2 weeks with bev 10 mg/kg and escalating doses of CRLX101 (12 mg/m2, 15 mg/m2) in a standard 3+3 design with an expansion at the RP2D. Pts were treated until progression, death, or prohibitive toxicity. Adverse events were classified (CTCAE v 4.0), and radiographic results were assessed (RECIST v 1.1). Results Summary: 10 pts were enrolled on study with histologies of the following distribution - 6 clear cell, 2 papillary, 2 chromophobe. Pts had a median of 2 prior therapies. No dose limiting toxicities (DLTs) were observed. CRLX101 at its single-agent RP2D (15 mg/m2) was safely combined with standard bev. Two (2) episodes of grade 3 non-infectious cystitis and 1 episode of grade 3 hypertension were observed. All other toxicities were grade 1 or 2. The median progression free survival (PFS) was 7.6 months. One third of evaluable pts (33%) achieved a confirmed partial response (PR) including 1 patient with papillary mRCC; 4 pts (44%) had stable disease, and 2 had progressive disease as their best overall response. Prior therapies in the 3 PRs included sunitinib (all) and everolimus (all). PFS results from the stage 1 cohort exceeded the pre-specified threshold and have triggered 2nd stage accrual. Conclusions: CRLX101 can be safely combined with standard doses of bev in pts with refractory mRCC at a RP2D of 15 mg/m2 q2w of CRLX101. Preliminary outcomes to date are superior to historical controls in refractory ccRCC and suggest potential for clinical benefit across histologic subtypes of mRCC. Citation Format: Stephen M. Keefe, Meliessa Hennessy, Orvar Gunnarsson, Ronac Mamtani, David Vaughn, Jean Hoffman-Censits, Katherine Nathanson, Priti Lal, Priti Lal, Daniel Pryma, Scott Eliasof, Edward Garmey, Roger B. Cohen, Naomi B. Haas. Phase 1b/2a study of the nanopharmaceutical CRLX101 with bevacizumab (bev) in the treatment of patients (pts) with refractory metastatic renal cell carcinoma (mRCC): results from the planned interim analysis. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr CT340. doi:10.1158/1538-7445.AM2014-CT340

PD-1 as an emerging therapeutic target in renal cell carcinoma: current evidence.

Renal cell carcinoma (RCC) is the most common primary malignant tumor of the kidney in adults, representing approximately 4% of all adult cancers in the United States. Metastatic RCC is poorly responsive to conventional cytotoxic chemotherapies but can be sensitive to T-cell-directed immunotherapies such as interferon-α or interleukin-2. Despite recent progress in the application of antiangiogenic “targeted therapies” for metastatic RCC, high-dose interleukin-2 remains an appropriate first-line therapy for select patients and is associated with durable complete remissions in a small fraction of treated patients. Thus, advanced RCC provides a unique opportunity to investigate the requirements for effective antitumor immunotherapy. Accumulating evidence suggests that resistance mechanisms exploited by RCC and other tumor types may play a dominant role in limiting the effectiveness of tumor-reactive adaptive immune responses. Expression of the inhibitory coreceptor programmed cell death-1 (PD-1) on tumor-infiltrating lymphocytes within RCC tumors, as well as the expression of the PD-1 ligand (PD-L1) on RCC tumor cells, are strong negative prognostic markers for disease-specific death in RCC patients. Monoclonal antibodies targeting either PD-1 or PD-L1 have now entered clinic trials and have demonstrated promising antitumor effects for refractory metastatic RCC. This review summarizes the results of published and reported studies of PD-1- and PD-L1-targeted therapies enrolling patients with advanced RCC, focusing on key safety, toxicity, and efficacy end points. Prospects for advanced phase clinical testing and novel therapy combinations with PD-1- and PD-L1-targeted agents are discussed.

Interim results of a phase 1b/2a study evaluating the nano pharmaceutical CRLX101 with bevacizumab (bev) in the treatment of patients (pts) with refractory metastatic renal cell carcinoma (mRCC).

412 Background: VHL is inactivated in most clear cell RCC (ccRCC) tumors giving rise to the HIF hypoxia response program and tumor angiogenesis. Antiangiogenic therapies are active in ccRCC, but resistance develops in all pts. Dual inhibition strategies may be needed to overcome resistance. CRLX101, a novel nano pharmaceutical formulation of camptothecin, has been shown in pre-clinical models to target HIF. We combined CRLX101 with bev in the treatment of pts with refractory mRCC in order to determine the safety and the recommended phase 2 dose (RP2D) of the combination, and to determine the therapeutic activity of treatment. Methods: Pts with mRCC refractory to conventional antiangiogenic therapies (all subtypes) were treated every 2 weeks with bev 10 mg/kg and escalating doses of CRLX101 (12 mg/m2, 15 mg/m2) in a standard 3+3 design with an expansion at the RP2D. Pts were treated until progression, death, or prohibitive toxicity. Adverse events were classified using CTCAE v 4.0. Radiographic results were assessed by RECIST v1.1. Results: 10 pts were enrolled on study – 6 clear cell, 2 papillary, 2 chromophobe. Median prior number of therapies was 2. No dose limiting toxicities were observed. CRLX101 at its single-agent RP2D (15 mg/m2) was safely combined with standard bev. 2 episodes of grade 3 non-infectious cystitis and 1 episode of grade 3 hypertension were observed. All other toxicities were grade 1 or 2. The median progression free survival (PFS) was 7.6 months which exceeded our pre-specified threshold of 16 weeks and has triggered 2nd stage accrual. 3 of 9 evaluable pts (33%) achieved a confirmed partial response (PR) including 1 patient with papillary mRCC; 4 pts (44%) displayed stable disease, and 2 had progressive disease as their best overall response. Conclusions: Our results demonstrate that CRLX101 can be safely combined with bev in pts with refractory mRCC. The RP2D is 15 mg/m2 q2w of CRLX101 with standard bev. Preliminary outcomes to date suggest that clinical benefit, manifest as prolonged PFS, is conferred to pts with all histologic subtypes of mRCC. Clinical trial information: NCT01625936.

Temsirolimus controlled metastatic advanced renal cell carcinoma for over 4 years: a case study

We present a case report of long-term response with temsirolimus in cytokine refractory metastatic renal cell carcinoma (RCC). A 74-year-old Japanese man was diagnosed with advanced RCC in November 2007 and enrolled in a phase II study to examine the safety and efficacy of temsirolimus in East Asian patients with metastatic RCC. He achieved a partial response 12 months after starting treatment with temsirolimus followed by stable disease for 39 months. The most notable toxicity was grade 3 pericardial effusion, which gradually increased 2 years after treatment start until discontinuation of the trial resulting in pericardial tamponade, grade 3 hypoxia associated with chronic obstructive pulmonary disease (COPD), which he had before the trial, and latent interstitial pneumonia. The cease of temsirolimus led to improvement of interstitial pneumonia while the target lesion progressed. He died of progressive COPD and latent interstitial pneumonia 4 months after discontinuing temsirolimus. To our knowledge, he lived the longest in East Asian populations since starting temsirolimus.

A Phase II Study of Bevacizumab and Everolimus as Treatment for Refractory Metastatic Renal Cell Carcinoma

BackgroundAgents that inhibit the vascular endothelial growth factor (VEGF) and mammalian target of rapamycin (mTOR) pathways in metastatic renal cell carcinoma (mRCC) prolong progression-free survival (PFS), but durable complete responses are rare. Combinations of these cytostatic therapies have great potential to improve efficacy and to escape tumoral resistance mechanisms, but supra-additive toxicity is a valid concern. We investigated whether horizontal blockade with the combination of bevacizumab, a monoclonal antibody to VEGF-A, and of everolimus, an oral mTOR inhibitor, improved PFS in patients with clear cell mRCC who had received prior VEGF blockade. MethodsIn this phase II investigator-initiated study, 10 of 30 planned patients were enrolled. Bevacizumab 10 mg/kg was administered intravenously every 14 days. Everolimus was orally dosed at 10 mg daily. The patients were treated until disease progression or unacceptable toxicity. The primary endpoint was PFS. ResultsThe median age was 55 years. The majority of patients were white men with an Eastern Cooperative Oncology Group performance status of 1 (80%) and intermediate risk disease by Memorial Sloan-Kettering Cancer Center criteria (70%). All the patients had received 1 prior VEGF inhibitor. The median PFS in the 10 evaluable patients was 5.1 months, which was less than the expected historical control of bevacizumab monotherapy at 6 months. The median overall survival was 21 months. The best response was a partial response in 1 patient and stable disease in 9. Forty percent of the patients were discontinued from the study due to toxicity. ConclusionsIn our experience, the combination of bevacizumab and everolimus was toxic. The efficacy achieved did not support its combined use over sequential administration. Ongoing randomized studies will definitively evaluate the combination's efficacy and tolerability.

Primary anti-vascular endothelial growth factor (VEGF)-refractory metastatic renal cell carcinoma: clinical characteristics, risk factors, and subsequent therapy

A subset of patients treated with initial anti-vascular endothelial growth factor (VEGF) therapy exhibit progressive disease (PD) as the best response per RECIST criteria. Data from patients with metastatic renal cell carcinoma (mRCC) treated with anti-VEGF therapy were collected through the International mRCC Database Consortium from 12 centers. One thousand and fifty-six assessable patients received initial VEGF inhibitors and 272 (26%) of these patients had PD as best response. Initial treatment included sunitinib (n = 203), sorafenib (n = 51), or bevacizumab (n = 18). Six percent of patients were at favorable risk, 55% at intermediate risk, and 39% at poor risk. On multivariable analysis, predictors of PD were Karnofsky performance status < 80% [odds ratio (OR) = 2.3, P < 0.0001], diagnosis to treatment < 1 year (OR = 2.1, P < 0.0001), neutrophilia (OR = 1.9, P = 0.0021), thrombocytosis (OR = 1.7, P = 0.0068), and anemia (OR = 1.6, P = 0.0058). Median progression-free survival (PFS) in patients with PD versus without PD was 2.4 versus 11 months (P < 0.0001) and overall survival (OS) was 6.8 versus 29 months (P < 0.0001), respectively. One hundred and eight (40%) VEGF-refractory patients proceeded to receive further systemic therapies. Response rate, PFS, and OS for subsequent therapy were 9%, 2.5 months, and 7.4 months, respectively, with no statistical differences between patients who received VEGF versus mammalian target of rapamycin (mTOR) inhibitors. Primary anti-VEGF-refractory mRCC patients have a dismal prognosis. Second-line anti-mTOR and anti-VEGF agents produce similar outcomes.

Treatment of refractory metastatic renal cell carcinoma (RCC) with lenvatinib (E7080) and everolimus.

TPS4682 Background: Lenvatinib (E7080) is an oral tyrosine kinase inhibitor targeting vascular endothelial growth factor receptor (VEGFR) 1-3, fibroblast growth factor receptor 1-4, RET, KIT and platelet-derived growth factor receptor beta. Lenvatinib has demonstrated acceptable toxicity and antitumor activity in Phase I and II studies (Glen H et al. JCO 2008, 26;15S: 3526;Yamada K et. al. Clin Cancer Res 2011, 17:2528-2537; Sherman S I et al. JCO 2011, 29; 15S: 5503). Improved understanding of the molecular basis of renal cell carcinoma (RCC) has led to the development of targeted therapies (inhibitors of mTOR and of the VEGF pathway) that have shown clinical benefit in patients with metastatic RCC. However patients develop resistance and ultimately progress during treatment with available single agents. Combination therapy targeting different pathways have the potential to improve efficacy. Methods: This multicenter, randomized, open-label, phase Ib/II study is investigating everolimus (an oral mTOR inhibitor) in combination with lenvatinib in RCC patients with unresectable or metastatic disease (NCT01136733). The study is being conducted in two phases. The phase Ib dose-escalation component will determine the maximum tolerated dose (MTD) of the combination; starting doses are 12 mg/day lenvatinib and 5 mg/day everolimus. A cohort expansion will follow to confirm the MTD and establish a recommended phase II dose (RP2 dose). Approximately 150 patients will be enrolled in phase II and randomized 1:1:1 to receive: lenvatinib and everolimus at the RP2 dose (Arm A); lenvatinib 24 mg/day (Arm B); or everolimus 10 mg/day (Arm C). Patients with clear cell RCC, ECOG performance score &lt;2 and progression during or after one prior VEGF-targeted treatment are eligible for phase II. The primary endpoint for Phase II is to compare progression-free survival of the investigational arms (A and B) with single agent everolimus (Arm C). Three phase Ib dose escalation cohorts have completed enrollment, and enrollment of the expansion cohort commenced in November 2011. Participating phase II centers will be located in the US, UK, Spain, Poland and Czech Republic and are expected to enroll patients throughout 2012.

A phase II study of S-1 for the treatment of cytokine and/or tyrosine-kinase inhibitor (TKI) refractory metastatic renal cell carcinoma: Updated results.

393 Background: S-1 is an oral anticancer agent combining tegafur, a prodrug of 5-fluorouracil (5-FU), with 5-chloro-2,4-dihydroxypyridine and potassium oxonate. S-1 has shown efficacy for cytokine and/or tyrosine-kinase inhibitor (TKI) refractory metastatic renal-cell carcinoma (mRCC). We report the final results of a phase II study and evaluate 5-FU-related enzymes as a predictor of the response to S-1. Methods: 45 patients received S-1 at a dose of 40 mg/m2 twice daily for 28 days, followed by 14 days of rest. The primary endpoint was the objective response rate (ORR). The secondary endpoints of progression-free survival (PFS) and overall survival (OS) were estimated by the Kaplan-Meier method. Formalin-fixed, paraffin-embedded specimens obtained by radical nephrectomy were used for mRNA expression assay, performed by reverse-transcriptase polymerase chain reaction. Results: 45 patients including 6 were progressed after TKI were enrolled from April 2006. 24 patients received more than 5 cycles, and 2 continued to receive S-1 as of October 2011. Two (4.4%) of the 45 patients had complete responses to S-1, 9 (20.0%) had partial responses, and 28 (62.8%) had stable disease. The final PFS and OS were 9.2 and 42.8 months, respectively, and the PFS of TKI refractory patients was approximately two times of final PFS (18.0 months). The most common grade 3-4 adverse events according to CTCAE v.3.0 were similar to the previous report except for hemoglobin decreased and fatigue. On mRNA expression analysis, the expression level of thymidylate synthase correlated with ORR and PFS. On the other hand, OS did not differ significantly between patients with low expression and those with high expression of 5-FU-related enzymes. Conclusions: S-1 is effective and well tolerated in patients with cytokine and/or TKI refractory mRCC. Moreover, long-term treatment with S-1 is safe in mRCC patients enabling long-term disease control, especially in TKI refractory patients. Clinical trial with large number of TKI refractory patients is warranted to determine the efficacy of S-1.

Efficacy of Large Doses of IL-2-Activated Human Leukocyte Antigen Haploidentical Peripheral Blood Stem Cells on Refractory Metastatic Renal Cell Carcinoma

Traditional immunotherapy for patients with refractory metastatic renal cell carcinoma (RCC) is limited because the tumors themselves induce immunosuppression. The aim of this article was to evaluate the clinical efficacy of the infusion of a high dose of interleukin (IL)-2-activated allogeneic haploidentical peripheral blood stem cells (haplo-PBSCs) in patients with advanced intractable RCC. Ten advanced RCC patients and their haploidentical relatives, who were haplo-PBSC donors, were enrolled in this study. All patients accepted one cycle of activated haplo-PBSCs. The clinical and immunologic responses were evaluated. A range from 2.3 to 5.5×10(10) of activated haplo-PBSCs were harvested after exposure to recombinant human IL-2 (rhIL-2), along with a significant increase in the proportion of natural killer cells and activated lymphocytes (CD69+ and CD25+). Enhanced cytotoxicity of haplo-PBSCs for RCC was also observed. After treatment, 2 (2/10) cases of partial remission, 6 (6/10) cases of stable disease, and 2 (2/10) cases of progressive disease were identified in these 10 patients. The median progression-free survival of the 10 patients was 5.5 months (3-14 months). The adoptive transfusion of IL-2-activated haplo-PBSCs can induce sustained antitumor effects for advanced intractable RCC patients who have had no response to conventional immunotherapy.

A Phase II Trial of Panobinostat, a Histone Deacetylase Inhibitor, in the Treatment of Patients with Refractory Metastatic Renal Cell Carcinoma

Purpose: To evaluate the activity of panobinostat in refractory renal carcinoma. Patients and Methods: Patients with advanced clear cell renal carcinoma who had received previous therapy with at least one angiogenesis inhibitor and one mTOR inhibitor were treated with panobinostat 45 mg orally twice a week, and were reevaluated after 8 weeks.Results: Twenty patients were treated with no objective responses. All patients progressed or stopped treatment prior to the 16-week reevaluation. Panobinostat was generally well-tolerated.Conclusion: Panobinostat had no activity in this group of patients with refractory renal carcinoma. Further development of panobinostat in renal carcinoma is not recommended.

NCI 6896: A phase I trial of suberoylanilide hydroxamic acid (SAHA) and 13-cis retinoic acid in the treatment of patients with advanced renal cell carcinoma (RCC).

349 Background: Retinoid resistance in RCC inversely correlates with levels of intracellular retinol and retinyl esters suggesting that increasing intracellular levels of all-trans retinoic acid (RA) or enabling RA to become a more potent initiator of transcription will improve RA mediated anti-tumor effects. The combination of all-trans RA and a histone deacetylase (HDAC) inhibitor inhibited renal cancer cell proliferation and tumor growth in a xenograft model more than either drug alone. We performed a phase I clinical trial to evaluate the safety and preliminary efficacy of combining the oral HDAC inhibitor SAHA (vorinostat) plus oral 13-cis RA (isotretinoin) in patients with advanced RCC. Secondary endpoints include analysis of peripheral blood samples to study the effects on retinoid metabolites and retinoid related genes. Methods: Patients (pts) with metastatic RCC (any histology) who have failed at least two lines of prior therapy were eligible. Vorinostat (300 mg bid x 3 consecutive days per week + isotretinoin co-administered at 0.25 mg/kg, 0.375 mg/kg, or 0.5 mg/kg PO bid x 3 days per week in cohorts using standard 3+3 dose escalation. Dose limiting toxicity (DLT) was defined as any grade &gt; 3 toxicity during the first cycle. Results: 14 pts have enrolled on the trial of which 12 are evaluable for toxicity (6 cohort 1; 3 cohort 2; 3 cohort 3) and 11 for tumor response. Common grade 1-2 toxicities included fatigue and GI effects (nausea, diarrhea, anorexia). One pt on dose-level 1 experienced a DLT (grade 3 depression). One patient experienced a partial response and 10 patients had stable disease lasting a median of 4 months (range 2–10 mos). Three patients progressed with brain metastases in the setting of stable systemic disease for at least 6 months. Pharmacokinetic and correlative studies examining expression of retinoid related genes are ongoing. Conclusions: The recommended phase II dose is vorinostat (300 mg bid) + isoretinoin (0.5 mg/kg PO bid) 3 days per week. The combination of vorinostat and isotretinoin was well tolerated, and there was evidence of antitumor activity in this heavily pretreated population of patients with refractory metastatic RCC. [Table: see text]