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Purpose: This study investigates the biologic activity of radium-223 with VEGF-targeted therapy in patients with advanced renal cell carcinoma (aRCC) and bone metastases.Patients and Methods: Fifteen treatment-naïve patients (n = 15) received pazopanib 800 mg orally once daily, and 15 previously treated patients received sorafenib 400 mg orally twice daily. Radium-223 55 kilobecquerel/kg was administered concurrently every 4 weeks for up to six infusions in both cohorts. The primary endpoint was decline in bone turnover markers (Procollagen I Intact N-Terminal, N-telopeptide, C-telopeptide, osteocalcin, and bone-specific alkaline phosphatase) compared with baseline. Secondary endpoints included safety, rate of symptomatic skeletal event (SSE) and time to first SSE, objective response rate, change in analgesic use, and quality of life. Exploratory analysis of tumor genomic alterations was performed.Results: Of the 30 patients enrolled, 83% had IMDC intermediate- or poor-risk disease, 33% had liver metastases, and 83% had a history of SSE prior to enrollment. No dose-limiting toxicity was observed. All bone turnover markers significantly declined from baseline at week 8 and 16. Forty percent of patients experienced treatment-related grade ≥3 adverse events. Response rates were 15% and 18% per RECIST v1.1 and bone response was 50% and 30% per MD Anderson criteria, in the pazopanib and sorafenib cohort, respectively. Median SSE-free interval was 5.8 months and not reached, respectively. Analgesic use remained stable over the study time.Conclusions: Radium-223 combined with VEGF-targeted therapy is biologically active and safe. Randomized-controlled trials are needed to define the role of radium-223 in aRCC with skeletal metastases. Clin Cancer Res; 24(17); 4081–8. ©2018 AACR.

List of all patients with complete information on mutations found and allele frequency

supplemental table and legend for suppl figures

Supplementary Table S1- Number of patients with 1-4 and {greater than or equal to}5 CTCs per 7.5mL of whole blood at baseline, and at 3, 6 and 12 months. Supplementary Table S2- Biochemical markers of bone turnover and bone mineral density (BMD).

Purpose: We examined the hypothesis that mutations in mTOR pathway genes are associated with response to rapalogs in metastatic renal cell carcinoma (mRCC).Experimental Design: We studied a cohort of mRCC patients who were treated with mTOR inhibitors with distinct clinical outcomes. Tumor DNA from 79 subjects was successfully analyzed for mutations using targeted next-generation sequencing of 560 cancer genes. Responders were defined as those with partial response (PR) by RECIST v1.0 or stable disease with any tumor shrinkage for 6 months or longer. Nonresponders were defined as those with disease progression during the first 3 months of therapy. Fisher exact test assessed the association between mutation status in mTOR pathway genes and treatment response.Results: Mutations in MTOR, TSC1, or TSC2 were more common in responders, 12 (28%) of 43, than nonresponders, 4 (11%) of 36 (P = 0.06). Mutations in TSC1 or TSC2 alone were also more common in responders, 9 (21%), than nonresponders, 2(6%), (P = 0.05). Furthermore, 5 (42%) of 12 subjects with PR had mutations in MTOR, TSC1, or TSC2 compared with 4 (11%) of 36 nonresponders (P = 0.03). Eight additional non-mTOR pathway genes were found to be mutated in at least 4 of 79 tumors (5%); none were associated positively with response.Conclusions: In this cohort of mRCC patients, mutations in MTOR, TSC1, or TSC2 were more common in patients who experienced clinical benefit from rapalogs than in those who progressed. However, a substantial fraction of responders (24 of 43, 56%) had no mTOR pathway mutation identified. Clin Cancer Res; 22(10); 2445–52. ©2016 AACR.See related commentary by Voss and Hsieh, p. 2320

Purpose: Orteronel (TAK-700) is an investigational, nonsteroidal, oral, inhibitor of androgen synthesis with greater specificity for 17,20-lyase than for 17α-hydroxylase. We investigated orteronel without steroids in patients with nonmetastatic castration-resistant prostate cancer (nmCRPC; M0). Experimental Design: Patients with nmCRPC and rising prostate-specific antigen (PSA) received orteronel 300 mg twice daily until PSA progression, metastases, or unacceptable toxicity. The primary endpoint was percentage of patients achieving PSA ≤0.2 ng/mL (undetectable levels) at 3 months. Secondary endpoints included safety, PSA response, time to metastases, and correlated endpoints. Results: Thirty-nine patients with a median baseline PSA doubling time of 2.4 months (range, 0.9–9.2) received a median of fourteen 28-day treatment cycles. PSA decreased >30% in 35 patients and 6 (16%) achieved PSA ≤ 0.2 ng/mL at 3 months. Median times to PSA progression and metastasis were 13.8 and 25.4 months, respectively. Kaplan–Meier estimates of freedom from PSA progression were 57% and 42% at 12 and 24 months, and of freedom from metastasis were 94% and 62% at 12 and 24 months, respectively. At 3 months, median testosterone declined by 89% from baseline. Adverse events led to therapy discontinuation in 12 patients and grade ≥3/4 adverse events occurred in 22 patients. Most frequent all-cause adverse events included fatigue (64%), hypertension (44%), diarrhea (38%), and nausea (33%), which were primarily grade 1/2. Conclusions: Single-agent orteronel produced marked and durable declines in PSA in patients with nmCRPC. Orteronel has moderate but manageable toxicities and its chronic administration without steroids appears feasible. Clin Cancer Res; 20(16); 4218–27. ©2014 AACR.

Background: Cabozantinib is an oral MET/VEGFR2 inhibitor. A recent phase II study of cabozantinib (100 mg daily) showed improved bone scans in subjects with metastatic castration-resistant prostate cancer (mCRPC), but adverse events (AE) caused frequent dose reductions. This study was designed to determine the efficacy and tolerability of cabozantinib at lower starting doses. Experimental Design: An adaptive design was used to determine the lowest active daily dose among 60, 40, and 20 mg. The primary endpoint was week 6 bone scan response, defined as ≥30% decrease in bone scan lesion area. The secondary endpoint was change in circulating tumor cells (CTC). Results: Among 11 evaluable subjects enrolled at 40 mg, there were 9 partial responses (PR), 1 complete response, and 1 stable disease (SD). Of 10 subjects subsequently enrolled at 20 mg, there were 1 PR, 5 SDs, and 4 with progressive disease. Among 13 subjects enrolled on the 40 mg expansion cohort, there were 6 PRs and 7 SDs. No subjects required dose reduction or treatment interruption at 6 or 12 weeks; 3 subjects at dose level 0 discontinued due to AEs by 12 weeks. At 40 mg, median treatment duration was 27 weeks. 58% of subjects with ≥5 CTCs/7.5mL at baseline converted to Conclusions: Cabozantinib 40 mg daily was associated with a high rate of bone scan response. Cabozantinib 40 mg daily was associated with better tolerability than previously reported for cabozantinib 100 mg daily. These observations informed the design of phase III studies of cabozantinib in mCRPC. Clin Cancer Res; 19(11); 3088–94. ©2013 AACR.

Purpose: Biochemical markers of both osteoblast and osteoclast activity are elevated in men with osteoblastic metastases from prostate cancer. Androgen deprivation therapy (ADT), the mainstay of therapy for advanced prostate cancer, increases markers of osteoblast and osteoclast activity, even in the absence of bone metastases. Little is known about the relative contributions of ADT and skeletal metastases to elevated bone turnover in men with prostate cancer. Experimental Design: To evaluate the relative contributions of ADT and skeletal metastases to osteoblast and osteoclast activity, we performed a cross-sectional study in three groups of men with advanced prostate cancer: (a) hormone-naïve men without bone metastases; (b) castrate men without bone metastases; and (c) castrate men with bone metastases. The primary study end points were serum levels of bone-specific alkaline phosphatase (BSAP), a marker of osteoblast activity, and N-telopeptide (NTX), a marker of osteoclast activity. Results: Serum levels of both BSAP and NTX were significantly higher in groups of castrate men (groups 2 and 3) than in hormone-naïve men (group 1; P < 0.01 for all comparisons). Among castrate men, serum BSAP was significantly higher in men with bone metastases than in men without bone metastases (P = 0.01). In contrast, serum levels of NTX were similar in groups 2 and 3 (P = 0.33). Conclusions: The unintended effects of ADT on the skeleton are sufficient to explain increased osteoclast activity in castrate men with bone metastases. These results may have important implications for the optimal timing and schedule of osteoclast-targeted therapy in men with advanced prostate cancer.

IntroductionWe sought to test the safety and efficacy of cabozantinib in patients with advanced solid (non-breast, non-prostate) malignancies and bony metastasis (ClinicalTrials.gov Identifier: NCT01588821). Patients with bone metastasis were enrolled in this study. Primary endpoint of the study was change in bone biomarkers in serum and urine. Tumor responses were an additional endpoint and measured by RECIST v1.1. Methods:Participants with progressive metastatic solid tumors other than breast and prostate cancer, age >/= 18 yrs, and with bone metastasis were consented and enrolled onto open label phase II study at Massachusetts General Hospital. The starting dose was 60 mg/d cabozantinib. CT of the tumor, chest, abdomen, and pelvis were performed every 2 cycles (each cycle = 28 days). Serial PET and Tc99m bone scans were performed in a subset of participants. Radiologic tumor responses were evaluated by RECIST. Bone biomarkers were measured at baseline and week 8, with a bony response to treatment defined as ≥ 40% decrease in urinary Ntx, serum Ntx, or serum Ctx at week 8. Results:37 patients enrolled onto this study. 14 had sarcoma, 7 renal cell carcinoma, 5 non-small cell lung cancer, 4 head and neck carcinoma, 2 thyroid cancer, 2 melanoma, 1 adenoid cystic carcinoma, 1 metastatic chondroblastoma, and 1 chordoma. Patient age at enrollment ranged from 18 to 83 years, with an average age of 54.4 years old. 37 % of patients were female. 19 patients were evaluable for determination of response by bone biomarkers. 13 had ≥ 40% decrease in serum Ctx, 9 had ≥ 40% decrease in serum Ntx, and 8 had ≥ 40% decrease in urinary Ntx. These measurements, however, had low correlation with RECIST measurements (r^2 of .05, .00, and .15, respectively).The average time to disease progression was 6.6 months. 3 patients had a partial response by RECIST (with chondroblastoma, head and neck cancer, and thyroid cancer), 16 of 20 radiologically measureable patients had some decrease in tumor size as best response, and 9 of those 16 had decrease in tumor size by 10% or greater by RECIST, and 6 of those 9 had sarcoma or chondroblastoma. The other 17 of 37 enrolled patients had bone only disease or were otherwise not measureable by RECIST. 55% of patients required dose reduction. Most common all grade adverse events were fatigue (59%), nausea (46%), anorexia (32%), and plantar-palmar erythrodysesthesia (27%). Conclusion:Cabozantinib is an active drug for patients with bone metastasis as measured by changes in serum/urine Ntx and Ctx. Plantar-palmar erythrodysesthesias, fatigue, nausea, and anorexia were common adverse events. Adverse events were manageable by dose reduction to 40 mg QD. This is the first study showing that cabozantinib has significant anti-tumor activity in patients with metastatic sarcoma with bone metastasis. Citation Format: Edwin Choy, Gregory M. Cote, M. Dror Michaelson, Lori Wirth, Justin F. Gainor, Lecia V. Sequist, Ryan J. Sullivan, Panagiotis M. Fidias, Alice Shaw, Rebecca S. Heist. Phase 2 study of cabozantinib in patients with non-breast, non-prostate cancer with bone metastasis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr CT129. doi:10.1158/1538-7445.AM2017-CT129

Background: Cabozantinib is an orally available inhibitor of MET and VEGFR2. In a randomized discontinuation trial of cabozantinib (100 mg daily), 86% of men with mCRPC and bone metastases had partial or complete resolution of lesions on bone scan as early as week 6; dose reductions for AEs occurred in 51% of pts, and discontinuations in 10%.[1] The current study is designed to determine the efficacy and safety of cabozantinib at lower doses. Methods: The study uses an adaptive response scheme based on Sargent one-stage design [2] to determine the lowest effective cabozantinib dose among three dose levels: dose level +1 (60 mg daily), dose level 0 (40 mg daily), and dose level −1 (20 mg daily). Bone scan responses were assessed by comparison of baseline and week 6 bone scans using an automated FDA 510(k) approved computer-aided detection (CAD) system.[3] A decrease in total bone scan lesion area of ≥ 30% was defined as a response The first cohort was treated at dose level 0 (40 mg po QD). Using the adaptive design, the number of bone scan responses at dose level 0 (≥8 responses versus Results: The study has enrolled a total of 23 subjects. Twelve subjects were enrolled in the first study cohort and treated with cabozantinib 40 mg daily. Median followup is 14 weeks. One subject discontinued the study at week 2 because of anorexia and fatigue. Another subject discontinued at week 6 after experiencing a hip fracture. The remaining 10 subjects remain on treatment without dose reduction. Baseline and week 6 bone scans have been centrally reviewed for the first 10 evaluable subjects. There were 9 confirmed bone scan responses at week 6 including complete response. Median decrease in bone lesion area at week 6 was 69%. Eleven subjects were accrued to the second cohort and treated with cabozantinib 20 mg daily; all subjects remain on study. Conclusions: Cabozantinib 40 mg daily results in high rates of bone scan response in men with CRPC and bone metastases. Cabozantinib 40 mg daily is associated with improved tolerability compared to cabozantinib 100 mg daily. Evaluation of the efficacy and tolerability of cabozantinib 20 mg daily is ongoing. References: 1. Hussain, M., Smith M.R., Sweeney C., et al. Cabozantinib (XL184) in metastatic castration-resistant prostate cancer (mCRPC): Results from a phase II randomized discontinuation trial. Proc ASCO 2011 (Abstract 4516) 2. Sargent DJ, Chan V, Goldberg RM. A three-outcome design for phase II clinical trials. Control Clin Trials 2001;22:117–25. 3. Chu G. H., Brown M.S., Kim H.J., et al. Initial analytic validation of automated bone scan measures for treatment response assessment in patients with metastatic castration-resistant prostate cancer (CRPC). J Clin Oncol 29: 2011 (suppl; abstr e15174). Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr A90.