Efficacy and Safety of Nivolumab Plus Ipilimumab versus Sunitinib in First-line Treatment of Patients with Advanced Sarcomatoid Renal Cell Carcinoma.

PURPOSE: Patients with advanced renal cell carcinoma with sarcomatoid features (sRCC) have poor prognoses and suboptimal outcomes with targeted therapy. This post hoc analysis of the phase III CheckMate 214 trial analyzed the efficacy of nivolumab plus ipilimumab (NIVO+IPI) versus sunitinib in patients with sRCC. PATIENTS AND METHODS: Patients with sRCC were identified via independent central pathology review of archival tumor tissue or histologic classification per local pathology report. Patients were randomized 1:1 to receive nivolumab (3 mg/kg) plus ipilimumab (1 mg/kg) every 3 weeks (four doses) then nivolumab 3 mg/kg every 2 weeks, or sunitinib 50 mg orally every day (4 weeks; 6-week cycles). Outcomes in patients with sRCC were not prespecified. Endpoints in patients with sRCC and International Metastatic Renal Cell Carcinoma Database Consortium intermediate/poor-risk disease included overall survival (OS), progression-free survival (PFS) per independent radiology review, and objective response rate (ORR) per RECIST v1.1. Safety outcomes used descriptive statistics. RESULTS: Of 1,096 randomized patients in CheckMate 214, 139 patients with sRCC and intermediate/poor-risk disease and six with favorable-risk disease were identified. With 42 months' minimum follow-up in patients with sRCC and intermediate/poor-risk disease, median OS [95% confidence interval (CI)] favored NIVO+IPI [not reached (NR) (25.2-not estimable [NE]); n = 74] versus sunitinib [14.2 months (9.3-22.9); n = 65; HR, 0.45 (95% CI, 0.3-0.7; P = 0.0004)]; PFS benefits with NIVO+IPI were similarly observed [median 26.5 vs. 5.1 months; HR, 0.54 (95% CI, 0.33-0.86; P = 0.0093)]. Confirmed ORR was 60.8% with NIVO+IPI versus 23.1% with sunitinib, with complete response rates of 18.9% versus 3.1%, respectively. No new safety signals emerged. CONCLUSIONS: NIVO+IPI showed unprecedented long-term survival, response, and complete response benefits versus sunitinib in previously untreated patients with sRCC and intermediate/poor-risk disease, supporting the use of first-line NIVO+IPI for this population.See related commentary by Hwang et al., p. 5.

Alternative Response Criteria and Clinical Risk Factors for Assessing Tumor Response in Patients With Metastatic Renal Cell Carcinoma Who Are Receiving Salvage Therapy.

OBJECTIVE: The purpose of this study is to compare the prognostic value of various solid tumor response criteria as well as the additive value of clinical risk factors in patients with advanced renal cell carcinoma (RCC). MATERIALS AND METHODS: Two sets of CT scans (pretreatment scans and scans obtained 1-3.5 months after treatment) were reviewed for 57 patients with metastatic RCC treated with pazopanib in the salvage setting. Tumor response on the posttherapy scan was evaluated using Response Evaluation Criteria in Solid Tumors (RECIST) and Choi, modified Choi (mChoi), MASS (Morphology, Attenuation, Size, and Structure), and 10% threshold criteria. In addition, combined Memorial Sloan-Kettering Cancer Center (MSKCC) risk factors plus imaging criteria were used to define response groups. Response evaluations using these criteria were correlated with overall survival (OS) and progression-free survival (PFS), with use of the log-rank test. RESULTS: Patients classified as having progressive disease (PD) on the basis of RECIST, mChoi, and MASS criteria had a significantly worse OS than patients with stable disease (SD) and partial response (PR). With the addition of MSKCC risk factors, all groups with PD defined by combined criteria had significantly worse OS. For 37 patients with no or one MSKCC risk factor, response groups defined by Choi, mChoi, MASS, and 10% threshold criteria did not differ in PFS or OS. However, among 20 patients with two to three MSKCC risk factors, those classified as having PR had longer PFS than did those with SD and had longer OS than did those with PD. CONCLUSION: For patients with advanced RCC for which prior therapies have failed, the prognostic value of various imaging-based tumor response criteria differs on the basis of the MSKCC clinical risk status.

A Double-Blind, Randomized, Placebo-Controlled Trial of Panax Ginseng for Cancer-Related Fatigue in Patients With Advanced Cancer.

Background: Despite the high frequency, severity, and effects of cancer-related fatigue (CRF) on the quality of life (QoL) of patients with cancer, limited treatment options are available. The primary objective of this study was to compare the effects of oral Panax ginseng extract (PG) and placebo on CRF. Secondary objectives were to determine the effects of PG on QoL, mood, and function. Methods: In this randomized, double-blind, placebo-controlled study, patients with CRF ≥4/10 on the Edmonton Symptom Assessment System (ESAS) were eligible. Based on a pilot study, we randomized patients to receive either 400 mg of standardized PG twice daily or a matching placebo for 28 days. The primary end point was change in the Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) subscale from baseline to day 29. Results: Of 127 patients, 112 (88.2%) were evaluable. The mean (SD) FACIT-F subscale scores at baseline, day 15, and day 29 were 22.4 (10.1), 29.9 (10.6), and 30.1 (11.6) for PG (P<.001), and 24.0 (9.4), 30.0 (10.1), and 30.4 (11.5) for placebo (P<.001). Mean (SD) improvement in the FACIT-F subscale at day 29 was not significantly different in the PG than in the placebo group (7.5 [12.7] vs 6.5 [9.9]; P=.67). QoL, anxiety, depression, symptoms, and functional scores were not significantly different between the PG and placebo groups. Improvement in the FACIT-F subscale correlated with baseline scores (P=.0005), Hospital Anxiety and Depression Scale results (P=.032), and sex (P=.023). There were fewer any-grade toxicities in the PG versus placebo group (28/63 vs 33/64; P=.024). Conclusions: Both PG and placebo result in significant improvement in CRF. PG was not significantly superior to placebo after 4 weeks of treatment. There is no justification to recommend the use of PG for CRF. Further studies are needed. Trial Registration: ClinicalTrials.gov identifier: NCT01375114.

High-Dose Asian Ginseng (Panax Ginseng) for Cancer-Related Fatigue: A Preliminary Report.

INTRODUCTION AND OBJECTIVE: Cancer-related fatigue (CRF) is the most common and severe symptom in patients with cancer. The number and efficacy of available treatments for CRF are limited. The objective of this preliminary study was to assess the safety of high-dose Panax ginseng (PG) for CRF. METHODS: In this prospective, open-label study, 30 patients with CRF (≥4/10) received high-dose PG at 800 mg orally daily for 29 days. Frequency and type of side effects were determined by the National Cancer Institute's Common Terminology Criteria for Adverse Events, version 4.0. Scores on the Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) scale, Edmonton Symptom Assessment System (ESAS), and Hospital Anxiety and Depression Scale (HADS) were assessed at baseline, day 15, and day 29. Global Symptom Evaluation (GSE) was assessed at day 29. RESULTS: Of the 30 patients enrolled, 24 (80%) were evaluable. The median age was 58 years; 50% were females, and 84% were white. No severe (≥grade 3) adverse events related to the study drug were reported. Of the 24 evaluable patients, 21 (87%) had an improved (by ≥3 points) FACIT-F score by day 15. The mean ESAS score (standard deviation) for well-being improved from 4.67 (2.04) to 3.50 (2.34) (P = .01374), and mean score for appetite improved from 4.29 (2.79) to 2.96 (2.46) (P = .0097). GSE score of PG for fatigue was ≥3 in 15/24 patients (63%) with median improvement of 5. CONCLUSION: PG is safe and improves CRF fatigue as well as overall quality of life, appetite, and sleep at night. Randomized controlled trials of PG for CRF are justified.

Outcomes of patients with metastatic renal cell carcinoma and end-stage renal disease receiving dialysis and targeted therapies: a single institution experience.

INTRODUCTION: Limited data are available regarding patients with renal cell carcinoma and ESRD treated with TTs. The objective of this study was to explore the tolerability and safety of TT in patients with mRCC and ESRD. PATIENTS AND METHODS: We retrospectively identified patients with mRCC and ESRD treated at the University of Texas M.D. Anderson Cancer Center from 2002 to 2012. Patient characteristics including demographic, histology, treatment, and adverse events are reported. Duration of treatment (TOT) was determined from date of drug initiation to discontinuation. Overall survival (OS) was determined from initiation of TT to death. Statistics are descriptive. RESULTS: Fourteen patients were identified. Ten patients had clear-cell histology and 4 had papillary histology. The median number of TTs per patient was 3 (range, 1-4) with median TOT of 28 months for all TTs. Eighty-eight percent of all toxicities were Grade 1 to 2; no Grade 4 toxicities were noted. Treatment discontinuations included 3 patients treated with sorafenib due to hand-foot syndrome, intolerable fatigue, and squamous cell skin cancer development; 2 patients treated with pazopanib due to intolerable fatigue and increased transaminase levels; and 1 patient treated with everolimus due to pneumonitis. Eight patients died from progressive disease. Median OS from initiation of TT was 28.5 months and 35 months from time of diagnosis. CONCLUSION: Toxicities were mild to moderate and consistent with those reported in previous studies. TTs appear to be safe, well tolerated and produce antitumor response in patients with mRCC and ESRD receiving dialysis.

Clinical outcomes for patients with metastatic renal cell carcinoma treated with alternative sunitinib schedules.

PURPOSE: We identified sunitinib alternative schedules that maintained dose intensity while decreasing adverse events in patients with metastatic renal cell cancer. We also determined the impact of alternative schedules on clinical outcomes. MATERIALS AND METHODS: We retrospectively reviewed the records of patients 18 years old or older with clear cell metastatic renal cell cancer who received first line sunitinib between January 26, 2006 and March 1, 2011 at our major comprehensive cancer center. A subset of patients was switched at the first intolerable adverse event from the traditional schedule of 28 days on and 14 days off to a schedule of 14 days on and 7 days off or other alternative schedules. A control group underwent standard dose reduction. We estimated progression-free and overall survival by the Kaplan-Meier method. Predictors of progression-free and overall survival were analyzed using Cox regression. RESULTS: A total of 187 patients were included in analysis, of whom 87% were on the traditional schedule at baseline. During treatment 53% of patients continued on the traditional schedule and 47% began or were transitioned to alternative schedules. Baseline characteristics were similar. Adverse events prompting schedule modification included fatigue in 64% of cases, hand-foot syndrome in 38% and diarrhea in 32%. Median time to alternative schedules was 5.6 months. Median overall survival was 17.7 months (95% CI 10.8-22.2) on the traditional schedule compared to 33.0 months (95% CI 29.3-not estimable) on alternative schedules (p <0.0001). On multivariable analysis poor Eastern Cooperative Oncology Group (ECOG) performance status, increased lactate dehydrogenase, decreased albumin, unfavorable Heng criteria and the traditional schedule were associated with decreased overall survival (p <0.05). CONCLUSIONS: Sunitinib administered on alternative schedules may mitigate adverse events while achieving outcomes comparable to those of the traditional schedule in patients with metastatic renal cell cancer. Prospective investigations of alternate dosing schemas are warranted.

AMG 386 in combination with sorafenib in patients with metastatic clear cell carcinoma of the kidney: a randomized, double-blind, placebo-controlled, phase 2 study.

BACKGROUND: This study evaluated the tolerability and antitumor activity of AMG 386, a peptibody (a peptide Fc fusion) that neutralizes the interaction of angiopoietin-1 and angiopoietin-2 with Tie2 (tyrosine kinase with immunoglobulin-like and EGF-like domains 2), plus sorafenib in patients with clear cell metastatic renal cell carcinoma (mRCC) in a randomized controlled study. METHODS: Previously untreated patients with mRCC were randomized 1:1:1 to receive sorafenib 400 mg orally twice daily plus intravenous AMG 386 at 10 mg/kg (arm A) or 3 mg/kg (arm B) or placebo (arm C) once weekly (qw). Patients in arm C could receive open-label AMG 386 at 10 mg/kg qw plus sorafenib following disease progression. The primary endpoint was progression-free survival (PFS). RESULTS: A total of 152 patients were randomized. Median PFS was 9.0, 8.5, and 9.0 months in arms A, B, and C, respectively (hazard ratio for arms A and B vs arm C, 0.88; 95% confidence interval [CI], 0.60-1.30; P = .523). The objective response rate (95% CI) for arms A, B, and C, respectively, was 38% (25%-53%), 37% (24%-52%), and 25% (14%-40%). Among 30 patients in arm C who had disease progression and subsequently received open-label AMG 386 at 10 mg/kg qw, the objective response rate was 3% (95% CI, 0%-17%). Frequently occurring adverse events (AEs) included diarrhea (arms A/B/C, 70%/67%/56%), palmar-plantar erythrodysesthesia syndrome (52%/47%/54%), alopecia (50%/45%/50%), and hypertension (42%/49%/46%). Fifteen patients had grade 4 AEs (arms A/B/C, n = 3/7/5); 4 had fatal AEs (n = 2/1/1), with 1 (abdominal pain, arm B) considered possibly related to AMG 386. CONCLUSIONS: In patients with mRCC, AMG 386 plus sorafenib was tolerable but did not significantly improve PFS compared with placebo plus sorafenib.

Systemic therapy for metastatic non-clear-cell renal cell carcinoma: recent progress and future directions.

Insights into the biology of clear-cell renal cell carcinoma (CCRCC) have identified multiple pathways associated with the pathogenesis and progression of this cancer. This progress has led to the development of multiple agents targeting these pathways, including the tyrosine kinase inhibitors sorafenib, sunitinib, and pazopanib, the monoclonal antibody bevacizumab, and the mTOR inhibitors temsirolimus and everolimus. With the exception of temsirolimus, phase 3 trials tested these agents in patients with clear-cell histology; therefore, their efficacy in non-CCRCC is unclear. To date, there is no established effective therapy for patients with advanced non-CCRCC. This article focuses on treatment options for metastatic non-CCRCC.

Upfront, randomized, phase 2 trial of sorafenib versus sorafenib and low-dose interferon alfa in patients with advanced renal cell carcinoma: clinical and biomarker analysis.

BACKGROUND: The objective of this study was to independently evaluate the objective response rate of sorafenib and sorafenib plus low-dose interferon-alfa 2b (IFN) as frontline therapy in patients with metastatic renal cell carcinoma (mRCC). METHODS: Untreated patients with clear cell mRCC were randomized to receive sorafenib 400 mg orally twice daily or sorafenib 400 mg orally twice daily plus subcutaneous IFN 0.5 million U (MU) twice daily. Primary endpoints included the objective response rate (ORR) and safety. Secondary endpoints included progression-free survival (PFS) and overall survival (OS). Exploratory endpoints included the predictive value of tumor tissue biomarkers. RESULTS: Eighty patients were enrolled. The median follow-up was 19.7 months (range, 0-34.2 months). The ORR was 30% (95% confidence interval [CI], 16.6%-46.5%) in the sorafenib arm and 25% (95% CI, 12.7%-41.2%) in the combination arm. The median PFS was 7.39 months in the sorafenib-alone arm (95% CI, 5.52-9.20 months) and 7.56 months in the sorafenib plus IFN arm (95% CI, 5.19-11.07 months). The median OS was 27.04 months in the combination arm (95% CI, from 22.31 to not attained) and was not reached in the sorafenib arm. Toxicities were comparable in both arms. In a multivariate model, increased phosphorylated protein kinase B (pAKT) levels were associated with poorer PFS (hazard ratio, 1.04; 95% CI, 1.00-1.08; P = .0411) and OS (hazard ratio, 1.15; 95% CI, 1.02-1.29; P = .0173). CONCLUSIONS: The addition of low-dose IFN to sorafenib resulted in efficacy outcomes that were comparable to those achieved with sorafenib monotherapy. The current results indicated that pAKT levels may predict for clinical outcome, but further mechanistic study is required.

Phase I trial of a combination of the multikinase inhibitor sorafenib and the farnesyltransferase inhibitor tipifarnib in advanced malignancies.

PURPOSE: We evaluated the safety, maximum tolerated dose, pharmacokinetics, and biological effects of the combination of the Raf-1, RET, KIT, platelet-derived growth factor receptor, and vascular endothelial growth factor receptor 2 kinase inhibitor sorafenib and the farnesyltransferase inhibitor tipifarnib. EXPERIMENTAL DESIGN: A standard 3 + 3 phase I dose-escalation design was used with a 28-day cycle (sorafenib daily and tipifarnib for 21 days, by mouth). RESULTS: Fifty patients were treated; 43 reached restaging evaluation after cycle 2. The most common side effects were grade 1 to 2 rash, hyperglycemia, and diarrhea. Dose-limiting toxicity was rash, and the recommended phase II dose is sorafenib 400 mg p.o. qam/200 mg p.o. qpm and tipifarnib p.o. 100 mg bd. Despite the low doses of tipifarnib, one quarter of patients had > or =50% reduction in farnesyltransferase levels. Interestingly, six of eight patients with medullary thyroid cancer had durable stable disease (n = 3) or partial remissions (n = 3), lasting 12 to 26+ months. Five of the six responders had available tissue, and RET gene mutations were identified in them. Prolonged (> or =6 months) stable disease was also seen in nine patients as follows: papillary thyroid cancer (n = 4; 18+ to 27+ months), adrenocortical cancer (n = 2; 7 and 11 months), and one each of melanoma (platelet-derived growth factor receptor mutation positive; 14 months), renal (6 months), and pancreatic cancer (6 months). CONCLUSIONS: Our study shows that the combination of tipifarnib and sorafenib is well tolerated. Activity was seen, especially in patients with medullary thyroid cancer, a tumor characterized by RET mutations.

Prospective assessment of systemic therapy followed by surgical removal of metastases in selected patients with renal cell carcinoma.

OBJECTIVE: To prospectively establish objective selection criteria for metastasectomy in patients with metastatic renal cell carcinoma (mRCC). PATIENTS AND METHODS: Between 1991 and 1999, 38 patients with mRCC with responsive or stable disease after initial systemic therapy, and with potentially resectable disease, were enrolled. Patients had a metastasectomy with curative intent and received consolidative adjuvant systemic therapy. RESULTS: Of the patients enrolled, 79% had stable disease after initial systemic therapy and 21% had a partial or complete response. Most (84%) had metastasectomy of one organ site. There was surgically no evidence of disease (sNED) in 76%. Operative morbidity and mortality were acceptable and 90% of the patients received adjuvant systemic therapy. The median (95% confidence interval) survival was 4.7 (3.0-7.8) years, and the median time to progression was 1.8 (0.8-3.1) years. Eight of 38 patients (21%) remained free of disease by the end of the study. Significant predictors of outcome were lack of sNED after metastasectomy, and the presence of pulmonary metastases. The median overall survival for those who had sNED was 5.6 years, vs 1.4 years for those who did not (P < 0.001). CONCLUSIONS: Metastasectomy in patients with mRCC not progressing after systemic therapy is feasible, with acceptable morbidity. Predictive factors for long-term outcome include pulmonary metastases and sNED. Future work evaluating treatments that can convert patients into surgical candidates will increase the cure rate of patients with mRCC.

Multiple squamous cell carcinomas of the skin after therapy with sorafenib combined with tipifarnib.

BACKGROUND: Keratoacanthomas, as well as an actinic keratosis progressing to squamous cell cancer, have been reported in patients who were treated with sorafenib, a multikinase inhibitor known to suppress the actions of Raf kinase and vascular endothelial growth factor receptor. OBSERVATIONS: We describe a 70-year-old white woman with metastatic renal cell carcinoma who was treated with a combination of sorafenib and tipifarnib (a farnesyltransferase inhibitor). She had no history of skin cancer. However, within 3 months after starting this therapy, she developed 3 erythematous nodules on her legs. Pathologic examination showed deeply invasive, well-differentiated squamous cell carcinomas. The tumors were excised, and sorafenib-tipifarnib treatment was discontinued. No new lesions have developed to date. CONCLUSIONS: Targeted agents, such as sorafenib and tipifarnib, are increasingly being used in the management of visceral malignant neoplasms. A temporal relationship was observed between the initiation of the targeted treatments and the emergence of these cutaneous cancers. Further study of the mechanisms responsible for the rapid appearance of squamous cell cancers in this setting may provide insights into the pathogenesis of skin tumors.