Pedro C. Barata

RNA-targeted therapeutics in cancer clinical trials: Current status and future directions

Recent advances in RNA delivery and target selection provide unprecedented opportunities for cancer treatment, especially for cancers that are particularly hard to treat with existing drugs. Small interfering RNAs, microRNAs, and antisense oligonucleotides are the most widely used strategies for silencing gene expression. In this review, we summarize how these approaches were used to develop drugs targeting RNA in human cells. Then, we review the current state of clinical trials of these agents for different types of cancer and outcomes from published data. Finally, we discuss lessons learned from completed studies and future directions for this class of drugs.

Treatment of renal cell carcinoma: Current status and future directions

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Next-generation sequencing (NGS) of cell-free circulating tumor DNA and tumor tissue in patients with advanced urothelial cancer: a pilot assessment of concordance

Background Advances in cancer genome sequencing have led to the development of various next-generation sequencing (NGS) platforms. There is paucity of data regarding concordance of different NGS tests carried out in the same patient. Methods Here, we report a pilot analysis of 22 patients with metastatic urinary tract cancer and available NGS data from paired tumor tissue [FoundationOne (F1)] and cell-free circulating tumor DNA (ctDNA) [Guardant360 (G360)]. Results The median time between the diagnosis of stage IV disease and the first genomic test was 23.5 days (0-767), after a median number of 0 (0-3) prior systemic lines of treatment of advanced disease. Most frequent genomic alterations (GA) were found in the genes TP53 (50.0%), TERT promoter (36.3%); ARID1 (29.5%); FGFR2/3 (20.5%), PIK3CA (20.5%) and ERBB2 (18.2%). While we identified GA in both tests, the overall concordance between the two platforms was only 16.4% (0%-50%), and 17.1% (0%-50%) for those patients (n = 6) with both tests conducted around the same time (median difference = 36 days). On the contrary, in the subgroup of patients (n = 5) with repeated NGS in ctDNA after a median of 1 systemic therapy between the two tests, average concordance was 55.5% (12.1%-100.0%). Tumor tissue mutational burden was significantly associated with number of GA in G360 report (P < 0.001), number of known GA (P = 0.009) and number of variants of unknown significance (VUS) in F1 report (P < 0.001), and with total number of GA (non-VUS and VUS) in F1 report (P < 0.001). Conclusions This study suggests a significant discordance between clinically available NGS panels in advanced urothelial cancer, even when collected around the same time. There is a need for better understanding of these two possibly complementary NGS platforms for better integration into clinical practice.

Characterization of metastatic urothelial carcinoma via comprehensive genomic profiling of circulating tumor DNA

Biomarker‐guided clinical trials are increasingly common in metastatic urothelial carcinoma (mUC), yet patients for whom contemporary tumor tissue is not available are not eligible. Technological advancements in sequencing have made cell‐free circulating DNA (cfDNA) next‐generation sequencing (NGS) readily available in the clinic. The objective of the current study was to determine whether the genomic profile of mUC detected by NGS of cfDNA is similar to historical tumor tissue NGS studies. A secondary objective was to determine whether the frequency of genomic alterations (GAs) differed between lower tract mUC (mLTUC) and upper tract mUC (mUTUC).

Feasibility of Cisplatin-Based Neoadjuvant Chemotherapy in Muscle-Invasive Bladder Cancer Patients With Diminished Renal Function

Micro‐Abstract A retrospective analysis assessed chemotherapy tolerability and outcomes of patients with glomerular filtration rate (GFR) < 60 mL/min who received cisplatin‐based neoadjuvant chemotherapy for muscle‐invasive bladder cancer. Patients with impaired GFR had more treatment discontinuations and modifications relative to normal GFR patients, but most completed intended treatment cycles. For carefully selected patients with impaired GFR, cisplatin‐based chemotherapy remains a treatment option. Background: Cisplatin‐based neoadjuvant chemotherapy (NAC) before radical cystectomy is the standard of care in muscle‐invasive bladder cancer. There are limited data regarding chemotherapy tolerability and outcomes for patients with low glomerular filtration rate (GFR) who receive cisplatin‐based NAC. Patients and Methods: A retrospective analysis of patients who received cisplatin‐based NAC at Cleveland Clinic (2005‐2016) was undertaken. Patients with pre‐NAC GFR < 60 mL/min by either Cockcroft‐Gault (CG) or Modification of Diet in Renal Disease (MDRD) formula were compared to patients with GFR ≥ 60 mL/min for NAC tolerability, pathologic complete and partial response (pPR), and the ability to undergo radical cystectomy. Results: Thirty patients with low GFR (34‐59 mL/min) and 94 patients with normal GFR (≥ 60 mL/min) were identified. Low GFR patients were older (median, 71 vs. 65 years), but other demographic and transurethral resection of bladder tumor characteristics were comparable. Low GFR patients more frequently had early NAC discontinuation (30% vs. 13%), NAC modifications (delays, dose reduction, or discontinuation, 66% vs. 40%), and cisplatin‐based NAC administered in split doses (37% vs. 16%). No differences in NAC tolerability or outcomes were noted among low GFR patients receiving split‐dose versus standard regimens. No differences were noted between low and normal GFR patients in NAC cycles (median, 3 for each), cystectomy rates (93% for each), time to cystectomy, and GFR change from baseline to after NAC. Pathologic complete response was higher among normal GFR patients (24% vs. 14%). Conclusion: Patients with low GFR had more NAC discontinuations and modifications, but most completed planned NAC cycles. For carefully selected patients with GFR < 60 mL/min, cisplatin‐based NAC remains a treatment option.

The Evolving Treatment Landscape of Advanced Renal Cell Carcinoma in Patients Progressing after VEGF Inhibition

Despite significant changes in the therapeutic landscape of renal cell carcinoma, the majority of patients with metastatic disease eventually progress after first-line treatment with vascular endothelial growth factor receptors (VEGFR) tyrosine kinase inhibitor (TKI) therapy. Understanding existing data on subsequent therapies is crucial to define an optimal treatment sequence following first-line failure. This review examines the data supporting currently approved agents in this setting and provides a framework for decision-making regarding treatment sequencing beyond first-line therapy with VEGFR TKIs.

Treatment selection for men with metastatic prostate cancer who progress on upfront chemo-hormonal therapy

Androgen deprivation therapy plus docetaxel (D‐ADT) increases overall survival (OS) in men with high‐volume, metastatic hormone‐sensitive prostate cancer (mHSPC). Although the vast majority of men initially respond to D‐ADT, most will progress and develop castration‐resistant prostate cancer (CRPC). Little is known about the optimal treatment sequence for men with progressive disease on D‐ADT.

Prevalence of MDM2 amplification and coalterations in 523 advanced cancer patients in the MD Anderson phase 1 clinic

Background TP53 is the most commonly mutated gene in cancer and codes for the best studied tumor suppressor, p53. MDM2 is involved in the negative regulation of p53 and itself serves as an oncogene, reported to be overexpressed in several cancer tumor types. In this retrospective study, we assessed the occurrence of MDM2 amplification among patients with various types of cancers and its association with clinical factors, other genetic aberrations, and response to targeted therapy in a phase I clinical trial setting. Methods Samples from patients with advanced solid tumors who had been referred to the MD Anderson phase I clinical trials program between January 2011 and January 2016 were collected and analyzed for MDM2 amplification using FoundationOne’s genomic profiling assay. Patients whose tumors expressed MDM2 amplification were compared to those with tumors of the same histologic types without MDM2 amplification. Results We tested tumors from 523 patients, of which 23 (4.4%) had MDM2 amplification. The highest prevalence of MDM2 amplification was in sarcoma (57%), breast cancer (13%) and bladder cancer (9%). Six patients with liposarcoma were treated on phase I protocol with an MDM2 inhibitor. The most common molecular aberrations co-occurring with MDM2 amplification was CDK4 amplification (70%). TP53 mutation was also detected in 7 patients (30%). Conclusion MDM2 amplification was most commonly associated with liposarcoma. Concomitant alterations in additional genes such as CDK4 amplification and TP53 mutations, along with variable responses to targeted therapies including MDM2 inhibitors, suggest that further combinational studies are needed to target this population.

The Challenges of Implementing Multiarmed Early Phase Oncology Clinical Trials

Abstract In the recent years, drug development in oncology has shifted from classical cytotoxic chemotherapy to the novel molecularly targeted agents (MTAs). With the emergence of MTAs, early phase trials have evolved into complex studies, and trial designs have changed with it. Herein, we address how early phase studies have evolved in the last few years to optimize the process of drug development. We also discuss the challenges that both investigators and institutions have to face as a result of this evolution. Finally, we summarize a number of actions both researchers and research centers may adopt to improve efficiency and rate of late stage trials evolving Phase 1 methodologies.

Evaluation of Response to Enzalutamide Consecutively After Abiraterone Acetate/Prednisone Failure in Patients With Metastatic Castration-resistant Prostate Cancer

Introduction: Treatment of metastatic castration‐resistant prostate cancer (mCRPC) has evolved significantly during the past decade, and the preferred combination and/or sequence of these treatments remains controversial. In this retrospective study, we explored clinical and pathologic factors that could predict response to consecutive treatment with enzalutamide (ENZA) after disease progression (PD) on abiraterone acetate and prednisone (AA/P). Patients and Methods: Data were collected from 40 consecutive patients with mCRPC who were treated with ENZA without other interim therapy after progression on AA/P. Results: The median time from prostate cancer initial diagnosis to AA/P treatment was 6.2 (range, 0.9‐16.3) years. The median prostate‐specific antigen (PSA) progression‐free survival (PSA‐PFS) from treatment initiation was 8.5 months (95% confidence interval [CI], 7.1‐10.1 months) and 2.3 months (95% CI, 1.8‐3.4 months) on AA/P and ENZA, respectively. The median time to PD from treatment initiation was 9.7 months (95% CI, 7.1‐12.4 months) and 3 months (95% CI, 2.3‐4.1 months) on AA/P and ENZA, respectively. The correlations were weak between the best percent change in PSA on ENZA and time from diagnosis to AA/P initiation, best absolute or percentage change in PSA on AA/P, time to PSA progression or PD on AA/P. Patients with longer than the median duration of treatment with AA/P (11.73 months) had longer PSA‐PFS on ENZA (median 2.8 vs. 1.9 months; P = .035). Conclusions: In this retrospective analysis, we did not find any clinical or pathologic factors associated with response to ENZA administered consecutively after AA/P. Patients with longer than median AA/P treatment duration had longer PSA‐PFS on ENZA. Further evaluations and validation are greatly needed.