Paul G. Corn

Cabozantinib in Patients With Advanced Prostate Cancer: Results of a Phase II Randomized Discontinuation Trial

PURPOSE Cabozantinib (XL184) is an orally bioavailable tyrosine kinase inhibitor with activity against MET and vascular endothelial growth factor receptor 2. We evaluated the activity of cabozantinib in patients with castration-resistant prostate cancer (CRPC) in a phase II randomized discontinuation trial with an expansion cohort. PATIENTS AND METHODS Patients received 100 mg of cabozantinib daily. Those with stable disease per RECIST at 12 weeks were randomly assigned to cabozantinib or placebo. Primary end points were objective response rate at 12 weeks and progression-free survival (PFS) after random assignment. RESULTS One hundred seventy-one men with CRPC were enrolled. Random assignment was halted early based on the observed activity of cabozantinib. Seventy-two percent of patients had regression in soft tissue lesions, whereas 68% of evaluable patients had improvement on bone scan, including complete resolution in 12%. The objective response rate at 12 weeks was 5%, with stable disease in 75% of patients. Thirty-one patients with stable disease at week 12 were randomly assigned. Median PFS was 23.9 weeks (95% CI, 10.7 to 62.4 weeks) with cabozantinib and 5.9 weeks (95% CI, 5.4 to 6.6 weeks) with placebo (hazard ratio, 0.12; P < .001). Serum total alkaline phosphatase and plasma cross-linked C-terminal telopeptide of type I collagen were reduced by ≥ 50% in 57% of evaluable patients. On retrospective review, bone pain improved in 67% of evaluable patients, with a decrease in narcotic use in 56%. The most common grade 3 adverse events were fatigue (16%), hypertension (12%), and hand-foot syndrome (8%). CONCLUSION Cabozantinib has clinical activity in men with CRPC, including reduction of soft tissue lesions, improvement in PFS, resolution of bone scans, and reductions in bone turnover markers, pain, and narcotic use.

Prostate cancer progression after androgen deprivation therapy: mechanisms of castrate resistance and novel therapeutic approaches.

Prostate cancer is the second-leading cause of cancer-related mortality in men in Western societies. Androgen receptor (AR) signaling is a critical survival pathway for prostate cancer cells, and androgen-deprivation therapy (ADT) remains the principal treatment for patients with locally advanced and metastatic disease. Although a majority of patients initially respond to ADT, most will eventually develop castrate resistance, defined as disease progression despite serum testosterone levels of <20 ng/dl. The recent discovery that AR signaling persists during systemic castration via intratumoral production of androgens led to the development of novel anti-androgen therapies including abiraterone acetate and enzalutamide. Although these agents effectively palliate symptoms and prolong life, metastatic castration-resistant prostate cancer remains incurable. An increased understanding of the mechanisms that underlie the pathogenesis of castrate resistance is therefore needed to develop novel therapeutic approaches for this disease. The aim of this review is to summarize the current literature on the biology and treatment of castrate-resistant prostate cancer.

Trial Design and Objectives for Castration-Resistant Prostate Cancer: Updated Recommendations From the Prostate Cancer Clinical Trials Working Group 3

PURPOSE Evolving treatments, disease phenotypes, and biology, together with a changing drug development environment, have created the need to revise castration-resistant prostate cancer (CRPC) clinical trial recommendations to succeed those from prior Prostate Cancer Clinical Trials Working Groups. METHODS An international expert committee of prostate cancer clinical investigators (the Prostate Cancer Clinical Trials Working Group 3 [PCWG3]) was reconvened and expanded and met in 2012-2015 to formulate updated criteria on the basis of emerging trial data and validation studies of the Prostate Cancer Clinical Trials Working Group 2 recommendations. RESULTS PCWG3 recommends that baseline patient assessment include tumor histology, detailed records of prior systemic treatments and responses, and a detailed reporting of disease subtypes based on an anatomic pattern of metastatic spread. New recommendations for trial outcome measures include the time to event end point of symptomatic skeletal events, as well as time to first metastasis and time to progression for trials in the nonmetastatic CRPC state. PCWG3 introduces the concept of no longer clinically benefiting to underscore the distinction between first evidence of progression and the clinical need to terminate or change treatment, and the importance of documenting progression in existing lesions as distinct from the development of new lesions. Serial biologic profiling using tumor samples from biopsies, blood-based diagnostics, and/or imaging is also recommended to gain insight into mechanisms of resistance and to identify predictive biomarkers of sensitivity for use in prospective trials. CONCLUSION PCWG3 moves drug development closer to unmet needs in clinical practice by focusing on disease manifestations most likely to affect prognosis adversely for therapeutics tested in both nonmetastatic and metastatic CRPC populations. Consultation with regulatory authorities is recommended if a trial is intended to seek support for drug approval.

Epigenetic inactivation of LKB1 in primary tumors associated with the Peutz-Jeghers syndrome

Germ-line mutations of the LKB1 gene cause Peutz-Jeghers syndrome (PJS) characterized by mucocutaneous pigmentation, predisposition to benign hamartomas of the gastrointestinal tract and also to several types of tumors. However, somatic mutations of this gene are very rare. To examine inactivation of LKB1 by epigenetic mechanisms, we investigated a series of primary tumors and cancer cell lines, for hypermethylation affecting the CpG island located in the 5′ region of the LKB1 gene using Methylation-specific PCR (MSP). First, we screened 51 cancer cell lines. Only three colorectal and one cervical carcinoma cell lines were methylated at LKB1, and loss of the LKB1 transcript was demonstrated. Treatment with the demethylating agent 5-aza-2′-deoxycytidine restored LKB1 expression. To address the incidence of LKB1 epigenetic inactivation in primary tumors, we analysed colorectal, breast, gastric, pancreatic, thyroid, bladder and testicular carcinomas (n=195). Normal tissues from the mentioned organs were unmethylated in this region. Among the described tumors, only one colorectal carcinoma and three testicular tumors displayed LKB1 promoter hypermethylation. Further study of those histological types more commonly associated with PJS, demonstrated that LKB1 promoter hypermethylation was present in five of 11 (45%) papillary breast carcinomas. Finally, in three patients with a strong family story suggestive of PJS disease, abnormal LKB1 methylation was found in four of 22 (18%) hamartomatous polyps lesions. Our findings provide an alternative pathway for inactivation of the LKB1 tumor suppressor gene involving promoter hypermethylation.

Platinum-Based Chemotherapy for Variant Castrate-Resistant Prostate Cancer

Purpose: Clinical features characteristic of small-cell prostate carcinoma (SCPC), “anaplastic,” often emerge during the progression of prostate cancer. We sought to determine the efficacy of platinum-based chemotherapy in patients meeting at least one of seven prospectively defined “anaplastic” clinical criteria, including exclusive visceral or predominantly lytic bone metastases, bulky tumor masses, low prostate-specific antigen levels relative to tumor burden, or short response to androgen deprivation therapy. Experimental Design: A 120-patient phase II trial of first-line carboplatin and docetaxel (CD) and second-line etoposide and cisplatin (EP) was designed to provide reliable clinical response estimates under a Bayesian probability model with early stopping rules in place for futility and toxicity. Results: Seventy-four of 113 (65.4%) and 24 of 71 (33.8%) were progression free after four cycles of CD and EP, respectively. Median overall survival (OS) was 16 months [95% confidence interval (CI), 13.6–19.0 months]. Of the seven “anaplastic” criteria, bulky tumor mass was significantly associated with poor outcome. Lactic acid dehydrogenase strongly predicted for OS and rapid progression. Serum carcinoembryonic antigen (CEA) concentration strongly predicted OS but not rapid progression. Neuroendocrine markers did not predict outcome or response to therapy. Conclusion: Our findings support the hypothesis that patients with “anaplastic” prostate cancer are a recognizable subset characterized by a high response rate of short duration to platinum-containing chemotherapies, similar to SCPC. Our results suggest that CEA is useful for selecting therapy in men with castration-resistant prostate cancer and consolidative therapies to bulky high-grade tumor masses should be considered in this patient population. Clin Cancer Res; 19(13); 3621–30. ©2013 AACR.

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

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).

Mxi1 is induced by hypoxia in a HIF-1-dependent manner and protects cells from c-Myc-induced apoptosis.

HIF-1, a hypoxia inducible transcription factor, plays a pivotal role in the cellular response to hypoxia by activating genes involved in glucose metabolism, vascular remodeling, and erythropoiesis. We identified Mxi1, a c-Myc antagonist, as a novel target gene induced in hypoxia. Mxi1 was not induced in cells deficient in ARNT (HIF-1?), suggesting that Mxi1 is a transcriptional target of the HIF-1 complex. Notably, c-Myc protein levels decreased during hypoxia but were stabilized by a proteasome inhibitor. Analysis of downstream transcriptional targets of c-Myc during hypoxia revealed that genes regulated by c-Myc, such as ornithine decarboxylase (ODC), were downregulated during hypoxia. In contrast, genes that are regulated by c-Myc and HIF-1, such as LDH-A, were upregulated. Mxi1 protects against c-Myc-dependent sensitization to hypoxia-induced apoptosis. The results suggest a coordinated mechanism for opposing c-Myc signaling during hypoxia that is mediated by a reduction in c-Myc levels, the induction of Mxi1, and a dominant effect of HIF-1 transcriptional activity.

Cabozantinib in Chemotherapy-Pretreated Metastatic Castration-Resistant Prostate Cancer: Results of a Phase II Nonrandomized Expansion Study

PURPOSE Cabozantinib (XL184), an oral inhibitor of multiple receptor tyrosine kinases such as MET and VEGFR2, was evaluated in a phase II nonrandomized expansion study in castration-resistant prostate cancer (CRPC). PATIENTS AND METHODS Patients received open-label cabozantinib at daily starting doses of 100 mg or 40 mg until disease progression or unacceptable toxicity. The primary end point was bone scan response, defined as ≥ 30% reduction in bone scan lesion area. Other efficacy end points included overall survival, pain, analgesic use, and biomarkers. RESULTS One hundred forty-four patients sequentially enrolled in either a 100-mg (n = 93) or 40-mg (n = 51) study cohort. Ninety-one patients (63%) had a bone scan response, often by week 6. Treatment resulted in clinically meaningful pain relief (57% of patients) and reduction or discontinuation of narcotic analgesics (55% of patients), as well as improvements in measurable soft tissue disease, circulating tumor cells, and bone biomarkers. Improvements in each of these outcomes were observed in both cohorts: bone scan response in 73% and 45%, respectively; reductions in measurable soft tissue disease in 80% and 79%, respectively. Median overall survival was 10.8 months for the entire population. Most common grade 3 or 4 adverse events were fatigue (22%) and hypertension (14%). Fewer dose reductions because of toxicity were required in the 40-mg group. CONCLUSION The evidence suggests that cabozantinib has clinically meaningful activity in CRPC. Cabozantinib resulted in improvements in bone scans, pain, analgesic use, measurable soft tissue disease, circulating tumor cells, and bone biomarkers. Taken together, these phase II observations warrant further development of cabozantinib in prostate cancer.

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.

Vascular endothelial growth factor-targeted therapy for the treatment of adult metastatic Xp11.2 translocation renal cell carcinoma.

Adult “translocation” renal cell carcinoma (RCC), bearing transcription factor E3 (TFE3) gene fusions at Xp11.2, is a recently recognized, unique entity for which prognosis and therapy remain poorly understood. In the current study, the authors investigated the effect of vascular endothelial growth factor (VEGF)‐targeted therapy in this distinct subtype of RCC.