Improved Outcomes with Enzalutamide in Biochemically Recurrent Prostate Cancer.

BACKGROUND: Patients with prostate cancer who have high-risk biochemical recurrence have an increased risk of progression. The efficacy and safety of enzalutamide plus androgen-deprivation therapy and enzalutamide monotherapy, as compared with androgen-deprivation therapy alone, are unknown. METHODS: In this phase 3 trial, we enrolled patients with prostate cancer who had high-risk biochemical recurrence with a prostate-specific antigen doubling time of 9 months or less. Patients were randomly assigned, in a 1:1:1 ratio, to receive enzalutamide (160 mg) daily plus leuprolide every 12 weeks (combination group), placebo plus leuprolide (leuprolide-alone group), or enzalutamide monotherapy (monotherapy group). The primary end point was metastasis-free survival, as assessed by blinded independent central review, in the combination group as compared with the leuprolide-alone group. A key secondary end point was metastasis-free survival in the monotherapy group as compared with the leuprolide-alone group. Other secondary end points were patient-reported outcomes and safety. RESULTS: A total of 1068 patients underwent randomization: 355 were assigned to the combination group, 358 to the leuprolide-alone group, and 355 to the monotherapy group. The patients were followed for a median of 60.7 months. At 5 years, metastasis-free survival was 87.3% (95% confidence interval [CI], 83.0 to 90.6) in the combination group, 71.4% (95% CI, 65.7 to 76.3) in the leuprolide-alone group, and 80.0% (95% CI, 75.0 to 84.1) in the monotherapy group. With respect to metastasis-free survival, enzalutamide plus leuprolide was superior to leuprolide alone (hazard ratio for metastasis or death, 0.42; 95% CI, 0.30 to 0.61; P<0.001); enzalutamide monotherapy was also superior to leuprolide alone (hazard ratio for metastasis or death, 0.63; 95% CI, 0.46 to 0.87; P = 0.005). No new safety signals were observed, with no substantial between-group differences in quality-of-life measures. CONCLUSIONS: In patients with prostate cancer with high-risk biochemical recurrence, enzalutamide plus leuprolide was superior to leuprolide alone with respect to metastasis-free survival; enzalutamide monotherapy was also superior to leuprolide alone. The safety profile of enzalutamide was consistent with that shown in previous clinical studies, with no apparent detrimental effect on quality of life. (Funded by Pfizer and Astellas Pharma; EMBARK ClinicalTrials.gov number, NCT02319837.).

CREST: phase III study of sasanlimab and Bacillus Calmette-Guérin for patients with Bacillus Calmette-Guérin-naïve high-risk non-muscle-invasive bladder cancer.

Bacillus Calmette-Guérin (BCG) is the standard of care for patients with high-risk non-muscle-invasive bladder cancer (NMIBC) after transurethral resection of bladder tumor (TURBT). BCG in combination with programmed cell death-1 (PD-1) inhibitors may yield greater anti-tumor activity compared with either agent alone. CREST is a phase III study evaluating the efficacy and safety of the subcutaneous PD-1 inhibitor sasanlimab in combination with BCG for patients with BCG-naive high-risk NMIBC. Eligible participants are randomized to receive sasanlimab plus BCG (induction ± maintenance) or BCG alone for up to 25 cycles within 12 weeks of TURBT. The primary outcome is event-free survival. Secondary outcomes include additional efficacy end points and safety. The target sample size is around 1000 participants.

Non-muscle-invasive bladder cancer (NMIBC) is the most common type of bladder cancer. Most people have surgery to remove the cancer cells while leaving the rest of the bladder intact. This is called transurethral resection of a bladder tumor (TURBT). For people with high-risk NMIBC, a medicine called Bacillus Calmette-Guérin (BCG) is placed directly inside the bladder after TURBT. A 'high risk' classification means that the cancer is more likely to spread or come back after treatment. Some people's cancer does not respond to BCG or returns after BCG treatment. Researchers are currently looking at whether BCG combined with other immunotherapies may prevent cancer growth more than BCG on its own. Immunotherapy helps the immune system recognize and kill cancer cells. Sasanlimab is an immunotherapy medicine that is not yet approved to treat people with NMIBC. It is given as an injection under the skin. In this CREST study, researchers are looking at how safe and effective sasanlimab plus BCG is for people with high-risk NMIBC. Around 1000 people are taking part in CREST. They must have had TURBT 12 weeks or less before joining the study. Researchers want to know how long people live without certain events occurring, such as bladder cancer cells returning. A plain language summary of this article can be found as Supplementary Material. Clinical Trial Registration: NCT04165317; 2019-003375-19 (EudraCT) (ClinicalTrials.gov).

Phase Ib Study of Crizotinib plus Pembrolizumab in Patients with Previously Untreated Advanced Non-Small Cell Lung Cancer with ALK Translocation.

LESSONS LEARNED: This study evaluating first-line crizotinib plus pembrolizumab in patients with anaplastic lymphoma kinase (ALK)-positive advanced non-small cell lung cancer (NSCLC) was terminated early because increased availability of second-generation ALK inhibitors resulted in difficulty identifying and accruing eligible patients. In the small number of patients enrolled, elevated transaminases were the most common treatment-related toxicity. No other relevant toxicities were observed. Although no definitive conclusions could be drawn because of the small number of patients studied, the higher frequency of severe transaminase increases noted in this sample should be of concern if ALK inhibitor and PD-L1/PD-1 inhibitor combinations are tested in future studies. BACKGROUND: Previous research suggests single-agent crizotinib is efficacious for the treatment of anaplastic lymphoma kinase (ALK)-rearranged advanced non-small cell lung cancer (NSCLC). METHODS: This study evaluated the safety and preliminary antitumor activity of crizotinib plus pembrolizumab as first-line therapy in patients with ALK-rearranged NSCLC. Patients were initially treated at dose level 0 (DL0) with crizotinib 250 mg twice daily and pembrolizumab 200 mg every 3 weeks (cycle duration was 3 weeks). If a dose-limiting toxicity occurred, subsequent patients were enrolled at a lower dose level (dose level -1 [DL-1]: 3 weeks of crizotinib monotherapy 250 mg twice daily, followed by crizotinib 250 mg twice daily with the addition of pembrolizumab 200 mg every 3 weeks). The primary endpoint was dose-limiting toxicity. Antitumor activity was assessed. RESULTS: Nine patients were enrolled: two at DL0, then seven at DL-1. Dose-limiting toxicities occurred in four patients (grade 3 increases in alanine aminotransferase [ALT] and aspartate aminotransferase [AST] and grade 3 fatigue at DL0; grade 3 increase in ALT and grade 3 increases in both ALT and AST at DL-1). CONCLUSION: The maximum tolerated dose was not determined because slow accrual resulted in early study termination.

Angiogenic and immunomodulatory biomarkers in axitinib-treated patients with advanced renal cell carcinoma.

Aim: Immunomodulatory mechanisms contributing to angiogenic inhibition in renal tumors are not well characterized. We report associations between efficacy and tumor-associated immune cells and mRNA/miRNA expression in patients from AXIS. Materials & methods: Immunohistochemistry (n = 52) and mRNA/miRNA expression analyses (n = 72) were performed on tumor samples. Results: In axitinib-treated patients, higher CXCR4 and TLR3 expression, respectively, was associated with longer progression-free survival (hazard ratio; 95% CI: 0.3; 0.1-0.8 and 0.4; 0.2-0.9) and showed interaction with treatment (p = 0.029 and p < 0.001); lower CCR7 expression was associated with objective response (odds ratio: 0.1; 95% CI: 0.01-1.0) and longer overall survival (hazard ratio: 3.9; 95% CI: 1.4-10.3). Conclusion: CCR7, CXCR4 and TLR3 expression levels may be prognostic/predictive of clinical benefit with axitinib. Clinical trial identifier: ClinicalTrials.gov NCT00678392.

Axitinib in combination with pembrolizumab in patients with advanced renal cell cancer: a non-randomised, open-label, dose-finding, and dose-expansion phase 1b trial.

BACKGROUND: Previous studies combining PD-1 checkpoint inhibitors with tyrosine kinase inhibitors of the VEGF pathway have been characterised by excess toxicity, precluding further development. We hypothesised that axitinib, a more selective VEGF inhibitor than others previously tested, could be combined safely with pembrolizumab (anti-PD-1) and yield antitumour activity in patients with treatment-naive advanced renal cell carcinoma. METHODS: In this ongoing, open-label, phase 1b study, which was done at ten centres in the USA, we enrolled patients aged 18 years or older who had advanced renal cell carcinoma (predominantly clear cell subtype) with their primary tumour resected, and at least one measureable lesion, Eastern Cooperative Oncology Group performance status 0-1, controlled hypertension, and no previous systemic therapy for renal cell carcinoma. Eligible patients received axitinib plus pembrolizumab in a dose-finding phase to estimate the maximum tolerated dose, and additional patients were enrolled into a dose-expansion phase to further establish safety and determine preliminary efficacy. Axitinib 5 mg was administered orally twice per day with pembrolizumab 2 mg/kg given intravenously every 3 weeks. We assessed safety in all patients who received at least one dose of axitinib or pembrolizumab; antitumour activity was assessed in all patients who received study treatment and had an adequate baseline tumour assessment. The primary endpoint was investigator-assessed dose-limiting toxicity during the first two cycles (6 weeks) to estimate the maximum tolerated dose and recommended phase 2 dose. This study is registered with ClinicalTrials.gov, number NCT02133742. FINDINGS: Between Sept 23, 2014, and March 25, 2015, we enrolled 11 patients with previously untreated advanced renal cell carcinoma to the dose-finding phase and between June 3, 2015, and Oct 13, 2015, we enrolled 41 patients to the dose-expansion phase. All 52 patients were analysed together. No unexpected toxicities were observed. Three dose-limiting toxicities were reported in the 11 patients treated during the 6-week observation period (dose-finding phase): one patient had a transient ischaemic attack and two patients were only able to complete less than 75% of the planned axitinib dose because of treatment-related toxicity. At the data cutoff date (March 31, 2017), 25 (48%) patients were still receiving study treatment. Grade 3 or worse treatment-related adverse events occurred in 34 (65%) patients; the most common included hypertension (n=12 [23%]), diarrhoea (n=5 [10%]), fatigue (n=5 [10%]), and increased alanine aminotransferase concentration (n=4 [8%]). The most common potentially immune-related adverse events (probably related to pembrolizumab) included diarrhoea (n=15 [29%]), increased alanine aminotransferase concentration (n=9 [17%]) or aspartate aminotransferase concentration (n=7 [13%]), hypothyroidism (n=7 [13%]), and fatigue (n=6 [12%]). 28 (54%) patients had treatment-related serious adverse events. At data cutoff, 38 (73%; 95% CI 59·0-84·4) patients achieved an objective response (complete or partial response). INTERPRETATION: The treatment combination of axitinib plus pembrolizumab is tolerable and shows promising antitumour activity in patients with treatment-naive advanced renal cell carcinoma. Whether or not the combination works better than a sequence of VEGF pathway inhibition followed by an anti-PD-1 therapy awaits the completion of a phase 3 trial comparing axitinib plus pembrolizumab with sunitinib monotherapy (NCT02853331). FUNDING: Pfizer Inc.

Axitinib versus sorafenib as second-line treatment for advanced renal cell carcinoma: overall survival analysis and updated results from a randomised phase 3 trial.

BACKGROUND: In a phase 3 trial comparing the efficacy and safety of axitinib versus sorafenib as second-line treatment for metastatic renal cell carcinoma, patients given axitinib had a longer progression-free survival (PFS). Here, we report overall survival and updated efficacy, quality of life, and safety results. METHODS: Eligible patients had clear cell metastatic renal cell carcinoma, progressive disease after one approved systemic treatment, and an Eastern Cooperative Oncology Group performance status (ECOG PS) of 0-1. 723 patients were stratified by ECOG PS and previous treatment and randomly allocated (1:1) to receive axitinib (5 mg twice daily; n=361) or sorafenib (400 mg twice daily; n=362). The primary endpoint was PFS assessed by a masked, independent radiology review committee. We assessed patient-reported outcomes using validated questionnaires. Baseline characteristics and development of hypertension on treatment were studied as prognostic factors. Efficacy was assessed in the intention-to-treat population, and safety was assessed in patients who received at least one dose of the study drug. This ongoing trial is registered on ClinicalTrials.gov, number NCT00678392. FINDINGS: Median overall survival was 20.1 months (95% CI 16.7-23.4) with axitinib and 19.2 months (17.5-22.3) with sorafenib (hazard ratio [HR] 0.969, 95% CI 0.800-1.174; one-sided p=0.3744). Median investigator-assessed PFS was 8.3 months (95% CI 6.7-9.2) with axitinib and 5·7 months (4.7-6.5) with sorafenib (HR 0.656, 95% CI 0.552-0.779; one-sided p<0.0001). Patient-reported outcomes scores were similar in the treatment groups at baseline, were maintained during treatment, but decreased at end-of-treatment. Common grade 3 or higher treatment-related adverse events were hypertension (60 [17%]), diarrhoea (40 [11%]), and fatigue (37 [10%]) in 359 axitinib-treated patients and hand-foot syndrome (61 [17%]), hypertension (43 [12%]), and diarrhoea (27 [8%]) in 355 sorafenib-treated patients. In a post-hoc 12-week landmark analysis, median overall survival was longer in patients with a diastolic blood pressure of 90 mm Hg or greater than in those with a diastolic blood pressure of less than 90 mm Hg: 20.7 months (95% CI 18.4-24.6) versus 12.9 months (10.1-20.4) in the axitinib group (p=0.0116), and 20.2 months (17.1-32.0) versus 14.8 months (12.0-17.7) in the sorafenib group (one-sided p=0.0020). INTERPRETATION: Although overall survival, a secondary endpoint for the study, did not differ between the two groups, investigator-assessed PFS remained longer in the axitinib group compared with the sorafenib group. These results establish axitinib as a second-line treatment option for patients with metastatic renal cell carcinoma. FUNDING: Pfizer Inc.

Axitinib and/or bevacizumab with modified FOLFOX-6 as first-line therapy for metastatic colorectal cancer: a randomized phase 2 study.

BACKGROUND: In this multicenter, open-label, randomized phase 2 trial, the authors evaluated the vascular endothelial growth factor receptor inhibitor axitinib, bevacizumab, or both in combination with chemotherapy as first-line treatment of metastatic colorectal cancer (mCRC). METHODS: Patients with previously untreated mCRC were randomized 1:1:1 to receive continuous axitinib 5 mg twice daily, bevacizumab 5 mg/kg every 2 weeks, or axitinib 5 mg twice daily plus bevacizumab 2 mg/kg every 2 weeks, each in combination with modified 5-fluorouracil/leucovorin/oxaliplatin (FOLFOX-6). The primary endpoint was the objective response rate (ORR). RESULTS: In all, 126 patients were enrolled from August 2007 to September 2008. The ORR was numerically inferior in the axitinib arm (n = 42) versus the bevacizumab arm (n = 43; 28.6% vs 48.8%; 1-sided P = .97). Progression-free survival (PFS) (11.0 months vs 15.9 months; 1-sided P = .57) and overall survival (OS) (18.1 months vs 21.6 months; 1-sided P = .69) also were numerically inferior in the axitinib arm. Similarly, efficacy endpoints for the axitinib/bevacizumab arm (n = 41) were numerically inferior (ORR, 39%; PFS, 12.5 months; OS, 19.7 months). The patients who received axitinib had fewer treatment cycles compared with other arms. Common all-grade adverse events across all 3 treatment arms were fatigue, diarrhea, and nausea (all ≥49%). Hypertension and headache were more frequent in the patients who received axitinib. Patients in the bevacizumab arm had the longest treatment exposures and the highest rates of peripheral neuropathy. CONCLUSIONS: Neither the addition of continuous axitinib nor the axitinib/bevacizumab combination to FOLFOX-6 improved ORR, PFS, or OS compared with bevacizumab as first-line treatment of mCRC.

Efficacy and safety of axitinib versus sorafenib in metastatic renal cell carcinoma: subgroup analysis of Japanese patients from the global randomized Phase 3 AXIS trial.

OBJECTIVE: Axitinib is a potent and selective second-generation inhibitor of vascular endothelial growth factor receptors 1, 2 and 3. The efficacy and safety of axitinib in Japanese patients with metastatic renal cell carcinoma were evaluated. METHODS: A subgroup analysis was conducted in Japanese patients enrolled in the randomized Phase III trial of axitinib versus sorafenib after failure of one prior systemic therapy for metastatic renal cell carcinoma. RESULTS: Twenty-five (of 361) and 29 (of 362) patients randomized to the axitinib and sorafenib arms, respectively, were Japanese and included in this analysis. Median progression-free survival in Japanese patients was 12.1 months (95% confidence interval 8.6 to not estimable) for axitinib and 4.9 months (95% confidence interval 2.8-6.6) for sorafenib (hazard ratio 0.390; 95% confidence interval 0.130-1.173; stratified one-sided P = 0.0401). The objective response rate was 52.0% for axitinib and 3.4% for sorafenib (P = 0.0001). The common all-causality adverse events (all grades) in Japanese patients were dysphonia (68%), hypertension (64%), hand-foot syndrome (64%) and diarrhea (56%) for axitinib, and hand-foot syndrome (86%), hypertension (62%) and diarrhea (52%) for sorafenib. The safety profiles of axitinib and sorafenib in Japanese patients were generally similar to those observed in the overall population, with the exceptions of higher incidences of hypertension, dysphonia, hand-foot syndrome, hypothyroidism and stomatitis. CONCLUSIONS: Axitinib is efficacious and well tolerated in Japanese patients with previously treated metastatic renal cell carcinoma, consistent with the results in the overall population, providing a new targeted therapy for these Japanese patients.

Comparative effectiveness of axitinib versus sorafenib in advanced renal cell carcinoma (AXIS): a randomised phase 3 trial.

BACKGROUND: The treatment of advanced renal cell carcinoma has been revolutionised by targeted therapy with drugs that block angiogenesis. So far, no phase 3 randomised trials comparing the effectiveness of one targeted agent against another have been reported. We did a randomised phase 3 study comparing axitinib, a potent and selective second-generation inhibitor of vascular endothelial growth factor (VEGF) receptors, with sorafenib, an approved VEGF receptor inhibitor, as second-line therapy in patients with metastatic renal cell cancer. METHODS: We included patients coming from 175 sites (hospitals and outpatient clinics) in 22 countries aged 18 years or older with confirmed renal clear-cell carcinoma who progressed despite first-line therapy containing sunitinib, bevacizumab plus interferon-alfa, temsirolimus, or cytokines. Patients were stratified according to Eastern Cooperative Oncology Group performance status and type of previous treatment and then randomly assigned (1:1) to either axitinib (5 mg twice daily) or sorafenib (400 mg twice daily). Axitinib dose increases to 7 mg and then to 10 mg, twice daily, were allowed for those patients without hypertension or adverse reactions above grade 2. Participants were not masked to study treatment. The primary endpoint was progression-free survival (PFS) and was assessed by a masked, independent radiology review and analysed by intention to treat. This trial was registered on ClinicalTrials.gov, number NCT00678392. FINDINGS: A total of 723 patients were enrolled and randomly assigned to receive axitinib (n=361) or sorafenib (n=362). The median PFS was 6·7 months with axitinib compared to 4·7 months with sorafenib (hazard ratio 0·665; 95% CI 0·544-0·812; one-sided p<0·0001). Treatment was discontinued because of toxic effects in 14 (4%) of 359 patients treated with axitinib and 29 (8%) of 355 patients treated with sorafenib. The most common adverse events were diarrhoea, hypertension, and fatigue in the axitinib arm, and diarrhoea, palmar-plantar erythrodysaesthesia, and alopecia in the sorafenib arm. INTERPRETATION: Axitinib resulted in significantly longer PFS compared with sorafenib. Axitinib is a treatment option for second-line therapy of advanced renal cell carcinoma. FUNDING: Pfizer Inc.

Axitinib plus pembrolizumab in patients with advanced renal-cell carcinoma: Long-term efficacy and safety from a phase Ib trial.

BACKGROUND: Axitinib plus pembrolizumab showed superior overall survival (OS), progression-free survival (PFS) and objective response rate (ORR) versus sunitinib in a randomised phase III trial in patients with advanced renal-cell carcinoma (RCC). We report long-term efficacy and safety of the axitinib/pembrolizumab from the phase I trial (NCT02133742), after 46-55 months from study initiation (data cut-off date, 23rd July 2019). METHODS: Fifty-two treatment-naïve patients with advanced RCC were treated with oral axitinib 5 mg twice daily and intravenous pembrolizumab 2 mg/kg every 3 weeks. PFS, duration of response (DoR) and OS were summarised using the Kaplan-Meier method. RESULTS: At a median follow-up of 42.7 months (95% confidence interval [CI]: 41.1-44.1), median OS was not reached; 38 (73.1%) patients were alive. The probability of being alive at 4 years was 66.8% (95% CI: 49.1-79.5). Median PFS in the overall population was 23.5 months (95% CI: 15.4-30.4). ORR was 73.1%; five patients had complete response. Median DoR was 22.1 months (95% CI: 15.1-34.5). Grade III/IV adverse events (AEs) were reported in 38 (73.1%) patients and 20 (38.5%) discontinued treatment because of AEs: 17 (32.7%) discontinued axitinib, 13 (25.0%) discontinued pembrolizumab, and 10 (19.2%) discontinued both drugs. Common AEs included diarrhoea (84.6%), fatigue (80.8%), hypertension (53.8%), cough (48.1%) and dysphonia (48.1%). There were no new AE terms reported and no treatment-related deaths. CONCLUSIONS: In patients with advanced RCC with ~4 years of follow-up, combination axitinib/pembrolizumab continued to demonstrate clinical benefit, with no new safety signals.

Angiogenic and Immune-Related Biomarkers and Outcomes Following Axitinib/Pembrolizumab Treatment in Patients with Advanced Renal Cell Carcinoma.

PURPOSE: Combined axitinib/pembrolizumab is approved for advanced renal cell carcinoma (aRCC). This exploratory analysis examined associations between angiogenic and immune-related biomarkers and outcomes following axitinib/pembrolizumab treatment. PATIENTS AND METHODS: Prospectively defined retrospective correlative exploratory analyses tested biospecimens from 52 treatment-naïve patients receiving axitinib and pembrolizumab (starting doses 5 mg twice daily and 2 mg/kg respectively, every 3 weeks). Tumor tissue, serum, and whole blood samples were collected at baseline, at cycle 2 day 1 (C2D1), and end of treatment (EOT) for blood-based samples. Clinical outcomes were objective response rate (ORR) and progression-free survival (PFS). RESULTS: Higher baseline tumor levels of CD8 showed a trend toward longer PFS (HR 0.4; P = 0.091). Higher baseline serum levels of CXCL10 (P = 0.0197) and CEACAM1 (P = 0.085) showed a trend toward better ORR and longer PFS, respectively. Patients for whom IL6 was not detected at baseline had longer PFS versus patients for whom it was detected (HR 0.4; P = 0.028). At C2D1 and/or EOT, mainly immune-related biomarkers showed any association with better outcomes. The genes CA9 (P = 0.084), HIF1A (P = 0.064), and IFNG (P = 0.073) showed trending associations with ORR, and AKT3 (P = 0.0145), DDX58 (P = 0.0726), GZMA (P = 0.0666), LCN2 (NGAL; P = 0.0267), and PTPN11 (P = 0.0287) with PFS. CONCLUSIONS: With combined axitinib/pembrolizumab treatment in patients with aRCC, mostly immune-related biomarkers are associated with better treatment outcomes. This exploratory analysis has identified some candidate biomarkers to consider in future prospective testing.

A Randomized Placebo Controlled Phase II Trial Evaluating Exemestane with or without Enzalutamide in Patients with Hormone Receptor-Positive Breast Cancer.

PURPOSE: To determine whether the androgen receptor (AR) inhibitor, enzalutamide, improves effectiveness of endocrine therapy (ET) in hormone receptor-positive (HR+) breast cancer. PATIENTS AND METHODS: In this phase II trial, patients with HR+/HER2 normal advanced/metastatic breast cancer were randomized 1:1 to exemestane 25 mg with placebo or exemestane 50 mg with enzalutamide 160 mg daily (NCT02007512). Two parallel cohorts enrolled patients with 0 (cohort 1) or 1 (cohort 2) prior ET for advanced disease. Progression-free survival (PFS) was the primary endpoint in the intent-to-treat (ITT) population of each cohort. Biomarkers were evaluated in an exploratory analysis. RESULTS: Overall, 247 patients were randomized (cohort 1, n = 127 and cohort 2, n = 120). PFS was not improved in either cohort of the ITT population [HR, 0.82 (95% confidence interval (CI), 0.54-1.26); P = 0.3631 for cohort 1 and HR, 1.02 (95% CI, 0.66-1.59); P = 0.9212 for cohort 2]. In cohort 1, high levels of AR mRNA were associated with greater benefit of enzalutamide (P interaction = 0.0048). This effect was particularly apparent in patients with both high levels of AR mRNA and low levels of ESR1 mRNA [HR, 0.24 (95% CI, 0.10-0.60); P = 0.0011]. The most common any grade adverse events in the enzalutamide arms were nausea (39%) in cohort 1 and fatigue (37%) in cohort 2. CONCLUSIONS: Enzalutamide with exemestane was well tolerated. While PFS was not improved by the addition of enzalutamide to exemestane in an unselected population, ET-naïve patients with high AR mRNA levels, particularly in combination with low ESR1 mRNA levels, may benefit from enzalutamide with exemestane.

Is Axitinib Still a Valid Option for mRCC in the Second-Line Setting? Prognostic Factor Analyses From the AXIS Trial.

BACKGROUND: Axitinib resulted in significantly longer progression-free survival (PFS) versus sorafenib in patients with metastatic renal-cell carcinoma (mRCC) previously treated with sunitinib in the AXIS trial. We report post hoc analyses evaluating patient subgroups that may benefit more from axitinib in this setting. PATIENTS AND METHODS: AXIS was an open-label randomized phase 3 trial (NCT00678392) in mRCC patients with disease that failed to respond to one prior systemic therapy. Univariate and multivariate analyses evaluated potential prognostic factors for improved PFS and overall survival (OS) after sunitinib. PFS and OS of axitinib versus sorafenib were assessed within subgroups identified according to these factors. RESULTS: Of 723 patients, 389 received first-line sunitinib; 194 and 195 were randomized to second-line axitinib and sorafenib, respectively. Identified prognostic factors were: nonbulky disease (sum of the longest diameter < 98 mm), favorable/intermediate risk disease (Memorial Sloan Kettering Cancer Center or International Metastatic Renal Cell Carcinoma Database Consortium criteria), and no bone or liver metastases. In patients with all of these prognostic factors (n = 86), significantly longer PFS was observed for axitinib versus sorafenib (hazard ratio = 0.476; 95% confidence interval, 0.263-0.863; 2-sided P = .0126). OS (hazard ratio = 0.902; 95% confidence interval, 0.457-1.780; 2-sided P = .7661) was similar between treatments. Across subgroups, PFS was generally longer in patients treated with axitinib versus sorafenib, and OS was generally similar between the two treatments. CONCLUSION: In patients with mRCC, axitinib remains a suitable second-line treatment option across multiple subgroups. A relevant reduction in the risk of a PFS event was observed for axitinib compared to sorafenib in selected subgroups of patients.

Long-term Duration of First-Line Axitinib Treatment in Advanced Renal Cell Carcinoma.

OBJECTIVE: We conducted a retrospective analysis of two clinical trials in treatment-naïve patients (n = 402) with advanced renal cell carcinoma (RCC) treated with axitinib. Our objective was to compare duration of treatment (DT) and clinical outcome in patients who achieved DT >18 months (longer DT) versus ≤18 months (shorter DT). PATIENTS AND METHODS: DT, objective response rate (ORR), tumor shrinkage, and overall survival (OS) were summarized for patients with longer and shorter DT. RESULTS: Overall, 152 patients (37.8%) had longer DT and 250 (62.2%) had shorter DT (median, 34.7 vs. 6.5 months, respectively). ORR in all 402 patients with advanced RCC was 43.5%. ORR was 75% for longer DT versus 24.4% for shorter DT (p < 0.0001). More patients with longer DT versus shorter DT had ≥10% tumor shrinkage at first scan (74.8% vs. 55.3%; p = 0.0001) and maximum on-study tumor shrinkage was greater in longer-DT versus shorter-DT group (-51.8% vs. -22.1%; p < 0.0001). Median OS was 32.6 months in the overall population while in the patients with longer DT the median was not reached. Treatment-related adverse events (AEs) grade ≥3 were more frequent in longer-DT versus shorter-DT and included hypertension (25.7% vs. 18.8%), diarrhea (15.1% vs. 4.4%), and weight decrease (11.2% vs. 3.2%); however, these AEs decreased over time in both groups. Eastern Cooperative Oncology Group performance status 0, favorable hematology values, no bone or liver metastases, and baseline tumor burden below the overall median were associated with longer DT. CONCLUSIONS: Longer duration (>18 months) of axitinib treatment was associated with increased frequency of early tumor shrinkage, greater magnitude of tumor shrinkage, and a favorable OS.

Evaluation of response from axitinib per Response Evaluation Criteria in Solid Tumors versus Choi criteria in previously treated patients with metastatic renal cell carcinoma.

BACKGROUND: Axitinib, a selective and potent tyrosine kinase inhibitor of vascular endothelial growth factor receptors, was available to patients from Canada and Australia, prior to regulatory approval of axitinib in these countries, for treatment of clear-cell metastatic renal cell carcinoma (mRCC) after failure of one prior systemic regimen. METHODS: This single-arm, open-label study of axitinib evaluated the efficacy, safety, and quality of life (QoL) in patients with mRCC whose disease progressed after one prior systemic first-line regimen. Primary objective was objective response rate evaluated per Response Evaluation Criteria in Solid Tumors (RECIST) and Choi criteria. Progression-free survival, overall survival, safety, and QoL were secondary end points. Due to the small study size, analyses comprised of descriptive statistics. RESULTS: Fifteen patients were recruited, five from Canada and ten from Australia, over a limited recruitment period. Thirteen patients received sunitinib as prior therapy. All patients had clear-cell carcinoma, eleven had prior nephrectomy. Liver, lung, and lymph nodes were the most frequent sites of metastases; one patient had brain metastasis. Median time on axitinib was 118.0 days (range: 3.5-645.0 days); estimated survival probability at 12 months was 57.8%. Two (13.3%) patients had objective responses per RECIST versus nine (60.0%) per Choi criteria. Six patients had progressive disease based on RECIST versus three per Choi criteria. Nine (60.0%) events of progression or death occurred by the end of study, and three patients continued to receive the study drug. Fatigue (33%) and diarrhea (20%) were the most common grade ≥3 all-causality, treatment-emergent adverse events. The mean change in European Quality of Life - 5 Dimensions score from baseline to end of treatment was -0.0837. CONCLUSION: The small number of patients and lack of a comparator arm limit the ability to draw definitive conclusions; however, safety and efficacy profiles of axitinib were consistent with reports from previous studies in patients with mRCC, and patients generally maintained QoL. The sizeable difference observed in objective response rate by RECIST versus Choi criteria merits further research.

Effect of Renal Impairment on the Pharmacokinetics and Safety of Axitinib.

BACKGROUND: Axitinib, an inhibitor of vascular endothelial growth factor (VEGF) receptors, is approved as second-line treatment for advanced renal cell carcinoma (RCC). Agents targeting the VEGF pathway may induce renal toxicities, which may be influenced by pre-existing renal dysfunction. OBJECTIVE: The objective was to characterize axitinib pharmacokinetics and safety in patients with renal impairment. PATIENTS AND METHODS: Effect of renal function (baseline creatinine clearance [CrCL]) on axitinib clearance was evaluated in a population pharmacokinetic model in 207 patients with advanced solid tumors who received a standard axitinib starting dose, and in 383 healthy volunteers. Axitinib safety according to baseline CrCL was assessed in previously treated patients with RCC (n = 350) who received axitinib in the phase 3 AXIS study. RESULTS: Median axitinib clearance was 14.0, 10.7, 12.3, 7.81, and 12.6 L/h, respectively, in individuals with normal renal function (≥90 ml/min; n = 381), mild renal impairment (60-89 ml/min; n = 139), moderate renal impairment (30-59 ml/min; n = 64), severe renal impairment (15-29 ml/min; n = 5), and end-stage renal disease (<15 ml/min; n = 1). The population pharmacokinetic model adequately predicted axitinib clearance in individuals with severe renal impairment or end-stage renal disease. Grade ≥3 adverse events (AEs) were reported in 63 % of patients with normal renal function or mild impairment, 77 % with moderate impairment, and 50 % with severe impairment; study discontinuations due to AEs were 10 %, 11 %, and 0 %, respectively. CONCLUSIONS: Axitinib pharmacokinetics and safety were similar regardless of baseline renal function; no starting-dose adjustment is needed for patients with pre-existing mild to severe renal impairment.

Long-Term Safety With Axitinib in Previously Treated Patients With Metastatic Renal Cell Carcinoma.

BACKGROUND: Axitinib is an approved treatment for advanced renal cell carcinoma (RCC) after failure of 1 systemic therapy. PATIENTS AND METHODS: Long-term safety with single-agent axitinib was analyzed using pooled data from clinical trials in 672 previously treated patients with metastatic RCC (mRCC) and in 1304 patients with different advanced solid tumors. In all studies, except the phase I first-in-human, dose-finding study, the starting dose of oral axitinib was 5 mg twice daily continuously. Common long-term treatment-emergent adverse events (AEs) were identified in patients who received axitinib for ≥ 2 years, then evaluated in all patients, and assessed using interval, cumulative, and latency analyses. RESULTS: In all, 108 (16%) previously treated patients with mRCC received axitinib for ≥ 2 years. In interval analysis, most AEs occurred during the first 6 months of treatment, with rates stable or decreased over time; rates increased for proteinuria, peripheral edema, and increased blood creatinine. Common Grade ≥ 3 AE rates declined or plateaued over time, except for increased amylase and myocardial infarction. Results were similar in cumulative analysis in this population, and in interval and cumulative analyses in all patients with mRCC and those with advanced solid tumors. CONCLUSION: Declining or stable rates of most AEs support an acceptable long-term safety profile for axitinib in patients with mRCC. However, increases in the rates of some AEs warrant monitoring. This analysis is limited in that it was retrospective and included a relatively small patient population.

Genotype Correlations With Blood Pressure and Efficacy From a Randomized Phase III Trial of Second-Line Axitinib Versus Sorafenib in Metastatic Renal Cell Carcinoma.

BACKGROUND: In the phase III axitinib second-line (AXIS) trial, axitinib significantly prolonged progression-free survival (PFS) versus sorafenib in patients with previously treated metastatic renal cell carcinoma (mRCC). Analyses of associations between germline single-nucleotide polymorphisms (SNPs) and outcomes are reported. PATIENTS AND METHODS: DNA samples from blood were genotyped using TaqMan allelic discrimination. Logistic/Cox regression analyses were used to evaluate association of 15 SNPs in vascular endothelial growth factor (VEGF)-A, VEGF receptor (VEGFR)1, VEGFR2, or hypoxia-inducible factor (HIF)-1α with outcomes for blood pressure (BP; Grade ≥ 3 hypertension, diastolic BP > 90 mm Hg, and increase ≥ 15 mm Hg from baseline) and efficacy (independent review committee-assessed objective response rate and PFS, and overall survival [OS]). Multivariate analyses assessed SNPs and baseline characteristics as potential predictors of PFS and OS. RESULTS: Genotype data were available for 305 (42.7%) of 714 patients; 159 received axitinib and 146 sorafenib. After Bonferroni adjustment, no SNP was associated with BP outcomes. In axitinib-treated patients, VEGF-A rs699947 (A/A vs. C/C) and rs833061 (C/C vs. T/T) were associated with longer OS (27.0 vs. 13.4 months; hazard ratio [HR], 0.39; Padjusted = .015). In sorafenib-treated patients, VEGFR2 rs2071559 (G/G vs. A/A) was associated with longer OS (26.8 vs. 13.8 months; HR, 0.41; Padjusted = .030). In multivariate analyses, no SNP predicted axitinib efficacy; VEGFR2 rs2071559 predicted PFS (P = .0053) and OS (P = .0027) for sorafenib. Sensitivity/specificity of VEGFR2 rs2071559 for OS was < 80%. CONCLUSION: No SNP predicted axitinib outcomes. Although VEGFR2 rs2071559 predicted sorafenib efficacy in patients with mRCC, sensitivity/specificity limitations preclude its use for selecting individual patients for sorafenib treatment.

Axitinib versus sorafenib as a second-line therapy in Asian patients with metastatic renal cell carcinoma: results from a randomized registrational study.

BACKGROUND: This registrational trial evaluated the efficacy, safety, and patient-reported outcomes of axitinib versus sorafenib as a second-line treatment in Asian patients with clear-cell metastatic renal cell carcinoma (mRCC). METHODS: In this open-label, multicenter study, previously treated Asian patients with clear-cell mRCC were stratified by Eastern Cooperative Oncology Group performance status and prior therapy and randomized in a 2:1 ratio to receive axitinib (5 mg twice daily) or sorafenib (400 mg twice daily). The primary end point was progression-free survival (PFS) assessed by a masked independent review committee. RESULTS: A total of 204 Asian patients received axitinib (n=135) or sorafenib (n=69). Median PFS (95% confidence interval [CI]) was 6.5 (4.7-9.1) months with axitinib versus 4.8 (3.0-6.5) months with sorafenib (hazard ratio, 0.731; 95% CI, 0.506-1.058; one-sided P=0.0531). The objective response rate (95% CI) was 23.7% (16.8%-31.8%) with axitinib versus 10.1% (4.2%-19.8%) with sorafenib. Common, grade ≥3, all-causality adverse events were hypertension (19.3%), weight decrease (5.2%), and proteinuria (5.2%) with axitinib and hypertension (8.7%) and palmar-plantar erythrodysesthesia (7.2%) with sorafenib. In a time-to-deterioration composite end point of death, progression, and worsening of Functional Assessment of Cancer Therapy Kidney Symptom Index score, patients treated with axitinib demonstrated a 17%-24% risk reduction compared with sorafenib-treated patients. CONCLUSION: Axitinib is clinically active and well tolerated in previously treated Asian patients with mRCC, consistent with the results from the global Phase III trial. These results establish axitinib as a second-line treatment option for Asian patients with mRCC.