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Supplementary Table S1: Complex Signature Oncology In Vitro Diagnostic Devices

As technologies evolve, and diagnostics move from detection of single biomarkers toward complex signatures, an increase in the clinical use and regulatory submission of complex signatures is anticipated. However, to date, no complex signatures have been approved as companion diagnostics. In this article, we will describe the potential benefit of complex signatures and their unique regulatory challenges, including analytic performance validation, complex signature simulation, and clinical performance evaluation. We also will review the potential regulatory pathways for clearance, approval, or acceptance of complex signatures by the FDA. These regulatory pathways include regulations applicable to in vitro diagnostic devices, including companion diagnostic devices, the potential for labeling as a complementary diagnostic, and the biomarker qualification program. Clin Cancer Res; 23(6); 1368–72. ©2016 AACR.

Small molecule kinase inhibitors (SMKIs) are being approved at a fast pace under expedited programs for anticancer treatment. In this study, we construct a multi-domain dataset from a total of 4638 patients in the registrational trials of 16 FDA-approved SMKIs and employ a machine-learning model to examine the relationships between kinase targets and adverse events (AEs). Internal and external (datasets from two independent SMKIs) validations have been conducted to verify the usefulness of the established model. We systematically evaluate the potential associations between 442 kinases with 2145 AEs and made publicly accessible an interactive web application “Identification of Kinase-Specific Signal” (https://gongj.shinyapps.io/ml4ki). The developed model (1) provides a platform for experimentalists to identify and verify undiscovered KI-AE pairs, (2) serves as a precision-medicine tool to mitigate individual patient safety risks by forecasting clinical safety signals and (3) can function as a modern drug development tool to screen and compare SMKI target therapies from the safety perspective.

Programmed cell death-1 (PD-1) and/or cytotoxic T lymphocyte–associated antigen 4 (CTLA-4) immune checkpoint inhibitor (ICI) treatments are associated with adverse events (AEs), which may be dependent on ICI dose. Applying a model-based meta-analysis to evaluate safety data from published clinical trials from 2005 to 2018, we analyzed the dose/exposure dependence of ICI treatment-related AE (trAE) and immune-mediated AE (imAE) rates. Unlike with PD-1 inhibitor monotherapy, CTLA-4 inhibitor monotherapy exhibited a dose/exposure dependence on most AE types evaluated. Furthermore, combination therapy with PD-1 inhibitor significantly strengthened the dependence of trAE and imAE rates on CTLA-4 inhibitor dose/exposure.

Purpose The outcome and proportion of patients with bone-only (BO) metastatic breast cancer (MBC) has not been well described. We sought to describe the differential outcomes of patients with BO MBC in clinical trials and explore whether there was a discrepancy in radiographic reads between investigator and blinded independent central review. Methods We pooled and analyzed data on 10,521 patients from 13 prospective trials submitted for MBC treatment in initial or supplemental New Drug or Biologics License Applications from 2005. Three subsets were evaluated: BO, bone with other metastases (BWO), and no bone metastases (NBM). Early discordance rate and late discordance rate were calculated from 3,733 and 2,813 patients subject to a blinded independent central review, respectively. Results Bone metastases were identified in 49% (range: 42% to 73%) of patients across trials. BO disease was present in 12.5% (range: 4% to 26%), dependent on subtype. Investigator-assessed progression-free survival (PFS) and overall survival (OS) for the pooled trials demonstrated improved outcomes for the BO subgroup compared with other subgroups (BO v BWO PFS hazard ratio [HR], 0.64; 95% CI, 0.591 to 0.696; BO v NBM PFS HR, 0.70; 95% CI, 0.65 to 0.76; BO v BWO OS HR, 0.56; 95% CI, 0.50 to 0.61; BO v NBM OS HR, 0.68; 95% CI, 0.61 to 0.76). The BO subgroup has a higher early discordance rate and lower late discordance rate than the BWO and NBM subgroups. Conclusion To our knowledge, this review is the largest analysis to date of the BO subgroup of MBC and suggests this subgroup may have a distinct natural history. There also seems to be a difference in how the local investigators assessed progression events in the BO subgroup when compared with the other two groups.

Today’s cancer therapy has made substantial progresses. Recent success in immuno-oncology (IO) has generated enormous excitement and expectation. With the existing and novel therapies, combination therapies provide opportunities to coordinate actions on multiple targets, and could enhance activity in broader population with less drug resistance. However, these advances also raised tremendous challenges to balance efficacy and safety in oncology drug development. Hence, dose finding has become more urgent than ever in cancer therapy. This review summarizes the challenges and opportunities in dose selection in oncology and IO. The opportunities of utilizing modeling and simulation (M&S) during both early and late phase oncology drug development were highlighted. The need of multi-disciplinary collaboration across functions and affiliations was emphasized.

On December 19, 2016, the FDA granted accelerated approval to rucaparib (RUBRACA; Clovis Oncology, Inc.) for the treatment of patients with deleterious BRCA mutation (germline and/or somatic)–associated advanced ovarian cancer who have been treated with two or more chemotherapies. The FDA also approved the FoundationFocus CDxBRCA test (Foundation Medicine, Inc.), the first next-generation sequencing-based companion diagnostic, for identifying patients with advanced ovarian cancer eligible for treatment with rucaparib based on detection of deleterious BRCA1 and/or BRCA2 mutations in tumor tissue. Rucaparib's approval was based primarily on efficacy data from 106 patients with BRCA mutation–associated ovarian cancer who had prior treatment with two or more chemotherapies and safety data from 377 patients with ovarian cancer treated with rucaparib 600 mg orally twice daily on two open-label, single-arm trials. Investigator-assessed objective response rate was 54% [57/106; 95% confidence interval (CI), 44–64], and median duration of response was 9.2 months (95% CI, 6.6–11.7). The approved companion diagnostic verified tumor BRCA mutation status retrospectively in 96% (64/67) of patients. Common adverse reactions (≥20%) to rucaparib were nausea, fatigue, vomiting, anemia, abdominal pain, dysgeusia, constipation, decreased appetite, diarrhea, thrombocytopenia, and dyspnea. This article summarizes the FDA review and data supporting rucaparib's accelerated approval. Clin Cancer Res; 23(23); 7165–70. ©2017 AACR. See related commentary by Kohn et al., p. 7155

On May 18, 2016, the U.S. Food and Drug Administration approved atezolizumab for the treatment of patients with locally advanced or metastatic urothelial carcinoma whose disease progressed during or following platinum‐containing chemotherapy or within 12 months of neoadjuvant or adjuvant treatment with platinum‐containing chemotherapy. This article summarizes key review findings that supported this approval., Until recently in the United States, no products were approved for second‐line treatment of advanced urothelial carcinoma. On May 18, 2016, the U.S. Food and Drug Administration approved atezolizumab for the treatment of patients with locally advanced or metastatic urothelial carcinoma whose disease progressed during or following platinum‐containing chemotherapy or within 12 months of neoadjuvant or adjuvant treatment with platinum‐containing chemotherapy. Atezolizumab is a programmed death‐ligand 1 (PD‐L1) blocking antibody and represents the first approved product directed against PD‐L1. This accelerated approval was based on results of a single‐arm trial in 310 patients with locally advanced or metastatic urothelial carcinoma who had disease progression after prior platinum‐containing chemotherapy. Patients received atezolizumab 1,200 mg intravenously every 3 weeks until disease progression or unacceptable toxicity. Key efficacy measures were objective response rate (ORR), as assessed by Independent Review per RECIST 1.1, and duration of response (DoR). With a median follow‐up of 14.4 months, confirmed ORR was 14.8% (95% CI: 11.1, 19.3) in all treated patients. Median DoR was not reached and response durations ranged from 2.1+ to 13.8+ months. Of the 46 responders, 37 patients had an ongoing response for ≥ 6 months. The most common adverse reactions (≥20%) were fatigue, decreased appetite, nausea, urinary tract infection, pyrexia, and constipation. Infection and immune‐related adverse events also occurred, including pneumonitis, hepatitis, colitis, endocrine disorders, and rashes. Overall, the benefit‐risk assessment was favorable to support accelerated approval. The observed clinical benefits need to be verified in confirmatory trial(s). Implications for Practice. This accelerated approval of atezolizumab for second‐line use in advanced urothelial carcinoma provides patients with an effective, novel treatment option for the management of their disease. This represents the first immunotherapy approved in this disease setting.

On November 23, 2015, the U.S. Food and Drug Administration approved nivolumab for patients with advanced renal cell carcinoma who have received prior anti‐angiogenic therapy. The overall benefit/risk profile demonstrated in trial CA209025 supported this approval, and the trial design and results are presented here. Patients' prognostic risk category may serve as a putative predictive biomarker for treatment selection., On November 23, 2015, the U.S. Food and Drug Administration approved nivolumab (OPDIVO, Bristol‐Myers Squibb Company) for patients with advanced renal cell carcinoma (RCC) who have received prior anti‐angiogenic therapy. The approval was based on efficacy and safety data demonstrated in an open‐label, randomized study of 821 patients with advanced RCC who progressed after at least one anti‐angiogenic therapy. Patients were randomized to nivolumab or everolimus and followed for disease progression. The primary end point was overall survival. Subsequent therapies, including everolimus for patients who developed progressive disease on the nivolumab arm, were allowed, but no cross‐over was permitted. The median overall survival was 25.0 months on the nivolumab arm and 19.6 months on everolimus arm (hazard ratio: 0.73; 95% confidence interval: 0.60–0.89). The confirmed response rates were 21.5% versus 3.9%; median durations of response were 23.0 versus 13.7 months, and median times to response were 3.0 versus 3.7 months in the nivolumab and everolimus arms, respectively. A statistically significant improvement in progression‐free survival was not observed in this trial. The safety profile of nivolumab in renal cell cancer was similar to that in other disease settings. However, the incidence of immune‐mediated nephritis appeared to be higher in patients with RCC. Implications for Practice. The overall benefit/risk profile demonstrated in trial CA209025 supported the approval of nivolumab as an additional treatment option for patients with advanced renal cell carcinoma after anti‐angiogenic therapy. The use of nivolumab in patients who had received vascular endothelial growth factor‐targeted therapy resulted in a 5.4 month improvement in median overall survival compared with the everolimus arm. This difference is statistically significant and clinically meaningful.

On February 19, 2016, the FDA approved palbociclib (Ibrance, Pfizer) for use in combination with fulvestrant (Faslodex, AstraZeneca) for the treatment of women with hormone receptor (HR)-positive, HER2-negative advanced or metastatic breast cancer (MBC) with disease progression following endocrine therapy. The approval was based on the results of a randomized, double-blind, placebo-controlled trial conducted in 521 pre- and postmenopausal women with HR-positive, HER2-negative advanced or MBC. Patients were randomized (2:1) to receive palbociclib plus fulvestrant (n = 347) or placebo plus fulvestrant (n = 174). The primary endpoint was investigator-assessed progression-free survival (PFS). A statistically significant and clinically meaningful improvement in PFS (9.5 months vs. 4.6 months) was observed in patients receiving palbociclib plus fulvestrant [HR 0.46; 95% confidence interval (CI), 0.36–0.59; P < 0.0001]. Safety data confirmed the known adverse reaction profile of palbociclib. The most common adverse reactions (>20%) in patients treated with palbociclib were neutropenia, leukopenia, infections, fatigue, nausea, anemia, stomatitis, headache, diarrhea, and thrombocytopenia. This approval was granted in the context of a prior accelerated approval for palbociclib in combination with letrozole in patients with HR-positive, HER2-negative advanced breast cancer as initial endocrine-based therapy. Clin Cancer Res; 22(20); 4968–72. ©2016 AACR.

In the current era of rapid marketing approval for promising new products in oncology, dose finding and optimization for small-molecule oncology drugs occurs throughout the development cycle and into the postmarketing setting. Many trials that support a regulatory application have high rates of dose reductions and discontinuations, which may result in postmarketing requirements (PMR) to study alternate doses or dosing schedules. Kinase inhibitors particularly have been susceptible to this problem, and among the 31 approved drugs of this class, the approvals of eight have included such PMRs and/or commitments. Thus, the current paradigm for dose finding and optimization could be improved. Newer strategies for dose finding rather than traditional 3 + 3 designs should be considered where feasible, and dose optimization should be continued after phase I and throughout development. Such strategies will increase the likelihood of a right dose for the right drug at the time of regulatory approval. Clin Cancer Res; 22(11); 2613–7. ©2016 AACR. See all articles in this CCR Focus section, “New Approaches for Optimizing Dosing of Anticancer Agents.”

Cancer clinical trials have relied on overall survival and measures of tumor growth or reduction to assess the efficacy of a drug. However, benefits are often accompanied by significant symptomatic toxicities. The degree to which a therapy improves disease symptoms and introduces symptomatic toxicity affects how patients function in their daily lives. These concepts are important contributors to health-related quality of life (HRQOL). In this article, we discuss patient-reported outcome (PRO) assessment in cancer trials and challenges relying solely on static multi-item HRQOL instruments. We propose focusing on three separate measures of well-defined concepts: symptomatic adverse events, physical function, and disease-related symptoms, which are key contributors to the effect of a therapy on HRQOL. Separate measures of these three concepts may facilitate the incorporation of emerging contemporary instruments that can tailor the PRO assessment strategy to different trial contexts. Irrespective of the PRO measures used, continued improvement in trial design and conduct is crucial to decrease missing data and optimize the quality of PRO information. International stakeholder collaboration and continued research into optimal practices for PRO and other clinical outcome assessments are necessary to advance a common framework for generating and reporting rigorous patient-centered data from cancer clinical trials. Clin Cancer Res; 22(7); 1553–8. ©2016 AACR.

In 1962, the passage of the Kefauver–Harris Amendment to the 1938 Food, Drug, and Cosmetic Act required that sponsors seeking approval of new drugs demonstrate the drug's efficacy, in addition to its safety, through a formal process that includes “adequate and well-controlled” clinical trials as the basis to support claims of effectiveness. As a result of this amendment, FDA formalized in regulation the definitions of various phases of clinical investigations (i.e., phase I, phase II, and phase III). The clinical drug development paradigm for anticancer drugs intended to support marketing approval has historically followed this “phased” approach with sequential, stand-alone trials, with an increasing number of patients exposed to an investigational drug with each trial in order to fulfill the objectives of that particular stage in development. Increasingly, it is the Office of Hematology and Oncology Products' experience that commercial sponsors of solid tumor oncology drug development programs are amending ongoing phase I trials to add expansion cohorts designed to evaluate study objectives typical of later-phase trials. For investigational anticancer drugs that demonstrate preliminary clinical evidence of substantial antitumor activity early in clinical testing, use of expansion cohorts as a component of the solid tumor oncology drug development pathway, with appropriate measures to mitigate the risks of this approach, may fit in well with the goals and concepts described by FDA's expedited programs for serious conditions.Clin Cancer Res; 21(20); 4545–51. ©2015 AACR. See all articles in this CCR Focus section, “Innovations to Speed Drug Development.”

There are few approved drugs available for the treatment of patients with non-muscle invasive bladder cancer (NMIBC) and none have been approved in the twenty-first century. Four drugs; thiotepa in 1959, BCG Tice in 1989, BCG Connaught in 1990, and valrubicin in 1998, have been approved for the treatment of NMIBC. In addition to these four agents, mitomycin is commonly used off-label as an intravesical treatment for NMIBC. New drugs are needed for the management of NMIBC. This article outlines important aspects of the design and conduct of clinical trials to develop new therapies for these patients and to obtain marketing approval. It includes a discussion of the patient population, BCG-unresponsive disease, and the appropriate endpoints for drug approval. It is hoped that this article will spur drug development in NMIBC within the Center for Drug Evaluation and Research at the Food and Drug Administration.

The U.S. Food and Drug Administration approved enzalutamide for the treatment of patients with chemotherapy-naïve metastatic castration-resistant prostate cancer (mCRPC). At the prespecified interim analysis, a statistically significant improvement in overall survival was demonstrated for patients in the enzalutamide arm compared with patients in the placebo arm. The overall benefit-risk profile supports the expanded indication for enzalutamide. On September 10, 2014, the U.S. Food and Drug Administration approved enzalutamide for the treatment of patients with chemotherapy-naïve metastatic castration-resistant prostate cancer (mCRPC). Enzalutamide was initially approved in 2012 for use in patients with mCRPC who had previously received docetaxel. The current approval was based on the results of a randomized, placebo-controlled, double-blind trial conducted in 1,717 asymptomatic or minimally symptomatic patients with chemotherapy-naïve mCRPC. Patients were assigned to receive either enzalutamide 160 mg or placebo orally once daily. The coprimary endpoints were overall survival (OS) and radiographic progression-free survival (rPFS), which was assessed by independent central radiology review. At the prespecified interim analysis, a statistically significant improvement in OS was demonstrated for patients in the enzalutamide arm compared with patients in the placebo arm (hazard ratio [HR], 0.71; 95% confidence interval [CI], 0.60–0.84). The median OS was 32.4 and 30.2 months in the enzalutamide and placebo arms, respectively. A statistically significant prolongation of rPFS was observed in patients in the enzalutamide arm (HR, 0.17; 95% CI, 0.14–0.21). In addition, the time to initiation of cytotoxic chemotherapy was prolonged in the enzalutamide arm (HR, 0.35; 95% CI, 0.30–0.40), with median times of 28.0 and 10.8 months in the enzalutamide and placebo arms, respectively. The safety profile was similar to that previously reported for enzalutamide. Adverse reactions of interest included seizure, hypertension, and falls. Enzalutamide should be discontinued if a seizure occurs during treatment. The overall benefit-risk profile supports the expanded indication for enzalutamide. Implications for Practice: This new approval expands the enzalutamide indication, allowing health care providers and patients to use enzalutamide for the treatment of metastatic castration-resistant prostate cancer either before or after cytotoxic chemotherapy.

On October 18, 2016, the FDA approved atezolizumab (TECENTRIQ; Genentech, Inc.) for treatment of patients with metastatic non–small cell lung cancer (mNSCLC) whose disease progressed during or following platinum-containing chemotherapy. Approval was based on demonstration of clinically meaningful improvements in overall survival (OS) and an acceptable safety profile in two randomized clinical trials (OAK and POPLAR). Median OS in OAK, a phase III trial, was 13.8 months [95% confidence interval (CI), 11.8–15.7] in the atezolizumab arm compared with 9.6 months (95% CI, 8.6–11.2) in the docetaxel arm [hazard ratio (HR) = 0.74; 95% CI, 0.63–0.87; P = 0.0004]. Median OS in POPLAR, a phase II trial, was 12.6 months (95% CI, 9.7–16.0) and 9.7 months (95% CI, 8.6–12.0; HR = 0.69; 95% CI, 0.52–0.92) for the atezolizumab and docetaxel arms, respectively. In patients treated with atezolizumab, the most common (≥20%) adverse reactions were fatigue, decreased appetite, dyspnea, cough, nausea, musculoskeletal pain, and constipation; the most common (≥2%) grade 3 to 4 adverse events were dyspnea, pneumonia, hypoxia, hyponatremia, fatigue, anemia, musculoskeletal pain, aspartate aminotransferase increase, alanine aminotransferase increase, dysphagia, and arthralgia. Clinically significant immune-related adverse events for patients receiving atezolizumab included 1.4% incidence each of grade 3 to 4 pneumonitis, hepatitis, colitis, and thyroid disease. Clin Cancer Res; 23(16); 4534–9. ©2017 AACR.

Nivolumab is a human monoclonal antibody that blocks the interaction between PD-1 programmed death-1 (PD-1) and its ligands, PD-L1 and PD-L2. Nivolumab demonstrated efficacy in clinical trials for various types of cancer. A time-varying clearance was identified for nivolumab. We show that the change of clearance over time is associated with the post-treatment effects: clearance decreases when disease status improves. This interaction between posttreatment effects and drug exposure may lead to a biased steep estimate of the exposure-response (E-R) relationship for efficacy. Under this scenario, simulations were performed to develop a proposed methodology to assess the causal effect of drug exposure upon clinical response. Data from nivolumab trials were subsequently used to verify the proposed methodology for E-R analysis. The results showed that E-R analysis results based on pharmacokinetic (PK) metrics derived from the first dose are more consistent with the true E-R or dose-response relationship than the steady-state PK metrics.

There has been increased interest in optimizing dosing regimens for oncology products over the past decade. Investigations to refine dosing regimens often occur after new drug approval. There is growing focus on the use of exposure-response (ER) approaches to identify optimal dosing regimens for therapeutic biologics. Herein, we describe several recent observations that have informed our thinking on the use of ER analyses in the dose regimen optimization of therapeutic biologics developed to treat cancer.

We thank Gronvold and colleagues for comments on our publication presenting a U.S. regulatory perspective on patient-reported outcome (PRO) data in cancer clinical trials ([1][1]). In this article, we propose to focus our analysis of submitted PRO data on symptomatic adverse events, symptoms of

As technologies evolve, and diagnostics move from detection of single biomarkers toward complex signatures, an increase in the clinical use and regulatory submission of complex signatures is anticipated. However, to date, no complex signatures have been approved as companion diagnostics. In this article, we will describe the potential benefit of complex signatures and their unique regulatory challenges, including analytic performance validation, complex signature simulation, and clinical performance evaluation. We also will review the potential regulatory pathways for clearance, approval, or acceptance of complex signatures by the FDA. These regulatory pathways include regulations applicable to in vitro diagnostic devices, including companion diagnostic devices, the potential for labeling as a complementary diagnostic, and the biomarker qualification program. Clin Cancer Res; 23(6); 1368–72. ©2016 AACR.

On April 25, 2016, the FDA approved cabozantinib (Cabometyx; Exelixis, Inc.) for the treatment of advanced renal cell carcinoma (RCC) in patients who have received prior antiangiogenic therapy. The approval was based on data from one randomized, open-label, multicenter study in which patients with RCC who had received prior antiangiogenic therapy were treated with either cabozantinib 60 mg orally once daily (n = 330) or everolimus 10 mg orally once daily (n = 328). The major efficacy outcome measure was progression-free survival (PFS) as assessed by a blinded independent radiology review committee in the first 375 randomized patients. A statistically significant improvement in PFS was seen, with a median PFS of 7.4 and 3.8 months in the cabozantinib and everolimus arms, respectively [hazard ratio (HR), 0.58; 95% confidence interval (CI), 0.45–0.74; P < 0.0001]. At a second interim analysis, a statistically significant improvement in overall survival (OS) in the intent-to-treat population was also demonstrated, with a median OS of 21.4 and 16.5 months in the cabozantinib and everolimus arms, respectively (HR, 0.66; 95% CI, 0.53–0.83; P = 0.0003). The most common (greater than or equal to 25%) adverse reactions included diarrhea, fatigue, nausea, decreased appetite, palmar–plantar erythrodysesthesia syndrome, hypertension, vomiting, weight loss, and constipation. Clin Cancer Res; 23(2); 330–5. ©2016 AACR.

On December 11, 2015, the FDA approved uridine triacetate (VISTOGARD; Wellstat Therapeutics Corporation) for the emergency treatment of adult and pediatric patients following a fluorouracil or capecitabine overdose regardless of the presence of symptoms, and of those who exhibit early-onset, severe, or life-threatening toxicity affecting the cardiac or central nervous system, and/or early onset, unusually severe adverse reactions (e.g., gastrointestinal toxicity and/or neutropenia) within 96 hours following the end of fluorouracil or capecitabine administration. Uridine triacetate is not recommended for the nonemergent treatment of adverse reactions associated with fluorouracil or capecitabine because it may diminish the efficacy of these drugs, and the safety and efficacy of uridine triacetate initiated more than 96 hours following the end of administration of these drugs has not been established. The approval is based on data from two single-arm, open-label, expanded-access trials in 135 patients receiving uridine triacetate (10 g or 6.2 g/m2 orally every 6 hours for 20 doses) for fluorouracil or capecitabine overdose, or who exhibited severe or life-threatening toxicities within 96 hours following the end of fluorouracil or capecitabine administration. Ninety-six percent of patients met the major efficacy outcome measure, which was survival at 30 days or survival until the resumption of chemotherapy, if prior to 30 days. The most common adverse reactions were vomiting, nausea, and diarrhea. This article summarizes the FDA review of this New Drug Application, the data supporting approval of uridine triacetate, and the unique regulatory situations encountered by this approval. Clin Cancer Res; 22(18); 4545–49. ©2016 AACR.

On April 6, 2011, the U.S. Food and Drug Administration approved vandetanib (Caprelsa tablets; AstraZeneca Pharmaceuticals LP) for the treatment of symptomatic or progressive medullary thyroid cancer in patients with unresectable, locally advanced, or metastatic disease. Vandetanib is the first drug approved for this indication, and this article focuses on the basis of approval. Approval was based on the results of a double-blind trial conducted in patients with medullary thyroid carcinoma. Patients were randomized 2:1 to vandetanib, 300 mg/d orally (n = 231), or to placebo (n = 100). The primary objective was demonstration of improvement in progression-free survival (PFS) with vandetanib compared with placebo. Other endpoints included evaluation of overall survival and objective response rate. The PFS analysis showed a marked improvement for patients randomized to vandetanib (hazard ratio = 0.35; 95% confidence interval, 0.24–0.53; P < 0.0001). The objective response rate for the vandetanib arm was 44% compared with 1% for the placebo arm. The most common grade 3 and 4 toxicities (>5%) were diarrhea and/or colitis, hypertension and hypertensive crisis, fatigue, hypocalcemia, rash, and corrected QT interval (QTc) prolongation. This approval was based on a statistically significant and clinically meaningful improvement in PFS. Given the toxicity profile, which includes prolongation of the QT interval and sudden death, only prescribers and pharmacies certified through the vandetanib Risk Evaluation Mitigation Strategy Program are able to prescribe and dispense vandetanib. Treatment-related risks should be taken into account when considering the use of vandetanib in patients with indolent, asymptomatic, or slowly progressing disease. Clin Cancer Res; 18(14); 3722–30. ©2012 AACR.

Objective:To describe the role of proteomic profiling in the diagnosis and treatment of ovarian cancer.Methods:We report a thorough review of the literature, ongoing trials, and our group's experience with proteomic profiling for early detection, recurrence, and treatment of ovarian cancer.Results/Conclusions:Ovarian cancer remains the deadliest gynecologic malignancy in the western world and is most often diagnosed at a rarely curable late stage. Novel applications of proteomic techniques, such as mass spectrometry, show promise in the quest for reliable multimodality screening programs for the early detection of ovarian cancer. Proteomic analysis of tissue samples has underscored the heterogeneity of this disease process. Development of validated assays that survey the genetic and/or proteomic makeup of an individual tumor will add greatly to the histological classification of the tumor and may lead to different treatment approaches tailored to the unique expression pattern of each individual patient. As novel agents that disrupt signal propagation develop, proteomic profiling by reverse-phase protein arrays can characterize the in-tumor efficacy of the agent by quantification of the changes in expression levels of activated proteins. Together, better understanding of the potential diagnostic and therapeutic targets followed with proof-of-target effect will lead to rational combinations of novel therapy and improve individual ovarian cancer patient outcome.

Poly (ADP-ribose) polymerases (PARPs) are a family of enzymes involved in cellular homeostasis, including DNA transcription, cell-cycle regulation, and DNA repair (1, 2). PARPs can detect DNA damage and bind to DNA single strand breaks (SSBs) through their N-terminal zinc finger domains. DNA binding activates the C-terminal catalytic domain, which hydrolyzes NAD+ to attach poly ADP-ribose (PAR) polymers covalently to nuclear proteins, including PARP itself. Negatively charged PAR polymers promote recruitment of DNA repair proteins, and auto-PARylation causes dissociation of PARPs from DNA, allowing completion of DNA repair. In the absence of PARP activity, unrepaired SSBs can lead to more deleterious double strand breaks (DSBs), which require high fidelity, homologous recombination (HR) or low fidelity, non-homologous end joining (NHEJ) for repair. In vitro and in vivo studies have demonstrated that tumor cells harboring defects in DNA repair are highly sensitive to PARP inhibitors, leading to genomic instability and cell death. Two publications demonstrated the concept of synthetic lethality in BRCA-deficient cells treated with PARP inhibitors (3, 4). Cells lacking functional alleles of BRCA are defective in HR repair and have an increased susceptibility to cause tumor development. Loss of BRCA or inhibition of PARP alone has little effect on in vitro and in vivo tumor growth; however, loss of function of both proteins enhances anti-tumor activity. Restoring BRCA expression blocks the cytotoxic effects of PARP inhibitor treatment. Several clinical PARP inhibitors are under investigation in Phase 2 and Phase 3 clinical trials as monotherapy in cancers with DNA repair defects or in combination with radiation, chemotherapy, or other targeted agents (Table ​(Table1).1). Progress in PARP inhibitor development has led to the recent accelerated approval of Lynparza (olaparib) by the U.S. Food and Drug Administration (5). Lynparza is currently indicated as monotherapy for patients with advanced germline BRCA-mutated ovarian cancer who have received three or more prior lines of chemotherapy. Lynparza was approved with a companion diagnostic test to select patients with deleterious or suspected deleterious BRCA mutations. PARP inhibitors are anticipated to have a much broader clinical application in additional tumor types, particularly those with DNA repair defects and in combination with chemotherapy and other targeted agents. In light of renewed interest in PARP inhibitors and the recent approval of Lynparza, this review will highlight data of PARP inhibitors in in vitro and in vivo cancer models and explore some of the clinical applications and challenges of PARP inhibitor therapy. Table 1 PARP inhibitors in Phase 2 and Phase 3 clinical developmenta. Mechanisms of Anti-Tumor Effect of Parp Inhibitors Poly (ADP-ribose) polymerase inhibitors are structurally similar in that they contain a nicotinamide moiety and mimic the NAD+ substrate. PARP inhibitors competitively bind to the catalytic domain of PARPs and inhibit PAR synthesis with half-maximal inhibitory concentration (IC50) values in the low nanomolar range (6–8). PARP inhibitors were developed to block the enzymatic activity of PARPs and prevent SSB repair by inhibiting the base excision repair (BER) pathway, and initial clinical development focused on potentiating the effects of chemotherapy and radiation (6, 9, 10). Subsequent studies demonstrated that PARP inhibitors alone were cytotoxic in HR-deficient cells (3, 4, 11). Based on these findings, a model was proposed in which PARP inhibition causes unrepaired SSBs, which are subsequently converted to DSBs, leading to synthetic lethality in HR-deficient cells (4). However, knockdown of XRCC1, the protein immediately downstream of PARP in the BER pathway did not lead to synthetic lethality (12), suggesting that loss of PARP activity is critical for synthetic lethality, but the loss of BER is not. Poly (ADP-ribose) polymerases function in other aspects of DNA repair, and emerging data suggest other mechanisms of action for the anti-tumor activity of PARP inhibitors in HR-deficient cells (13, 14). One potential mechanism proposes that PARP inhibition activates NHEJ in HR-deficient cells, leading to genomic instability and cell death (12). In vitro studies have demonstrated that PARPs can regulate components of the NHEJ machinery, including DNA-dependent protein kinase (DNA-PK), Ku70, and Ku80 (15–18). In HR-deficient cells, PARP inhibitor treatment induced the activation of DNA-PK and phosphorylation of downstream substrates and increased NHEJ of a reporter plasmid containing a DSB (12). Pharmacological blockade or loss of NHEJ proteins reduced chromosomal aberrations and the cytotoxic effects of PARP inhibition, indicating a role for NHEJ in PARP inhibitor activity. In vitro studies have demonstrated that the activity of PARP inhibitors may also involve formation of deleterious PARP–DNA complexes, which hinder DNA replication and repair (19–21). Avian cells lacking PARP1 and PARP2 were resistant to olaparib treatment and remained viable at concentrations greater than 10 μM (19). In contrast, olaparib caused significant cytotoxicity in wild type cells and increased levels of γ-H2AX, a marker of DNA damage. PAR polymers were undetectable by ELISA in both olaparib-treated wild type cells and PARP-deficient cells, suggesting that PARP inhibition is distinct from genetic deletion of PARP. A comparison of PARP inhibitors demonstrated comparable inhibition of PAR synthesis by Western blot and ELISA (19, 20). In contrast, each PARP inhibitor showed varying ability to induce PARP–DNA complexes in the presence of alkylating agent. In the absence of PARP inhibitor, PARP1 was detected in the nuclear soluble fraction by Western blot and accumulated in the chromatin-bound fraction following PARP inhibitor treatment. In tumor cells, BMN 673 (talazoparib) induced greater accumulation of PARP1 and PARP2 in the chromatin-bound fraction compared to olaparib and rucaparib. Niraparib induced greater PARP–DNA binding than olaparib, and veliparib was the least effective enhancer of PARP–DNA binding at concentrations that maximally inhibited PARP enzymatic activity. PARP–DNA binding was detected at pharmacologically relevant concentrations and correlated with the cytotoxicity of each agent in vitro. In vivo, enhanced PARP–DNA binding did not correlate with better anti-tumor activity but resulted in increased toxicity (22). The significance of differential PARP–DNA binding on efficacy and tolerability requires further investigation in the context of different tumor types and different PARP inhibitor and chemotherapy regimens. The complex role of PARPs in cellular homeostasis, including DNA repair, highlights the need to evaluate PARP inhibitors for modulating other biological functions of PARPs.

On February 3, 2015, the FDA granted accelerated approval to palbociclib (IBRANCE, Pfizer Inc.), an inhibitor of cyclin-dependent kinases 4 and 6 (CDK4 and CDK6), for use in combination with letrozole for the treatment of postmenopausal women with estrogen receptor (ER)–positive, HER2-negative advanced breast cancer as initial endocrine-based therapy for their metastatic disease. The approval is based on a randomized, multicenter, open-label phase I/II trial (PALOMA-1) in 165 patients randomized to palbociclib (125 mg orally daily for 21 consecutive days, followed by 7 days off treatment) plus letrozole (2.5 mg orally daily) or letrozole alone. The phase II portion of the trial was divided into two cohorts: cohort 1 enrolled 66 biomarker-unselected patients and cohort 2 enrolled 99 biomarker-positive patients. The major efficacy outcome measure was investigator-assessed progression-free survival (PFS). A large magnitude of improvement in PFS was observed in patients receiving palbociclib plus letrozole compared with patients receiving letrozole alone (HR, 0.488; 95% confidence interval, 0.319–0.748). Multiple sensitivity analyses were supportive of clinical benefit. The most common adverse reaction in patients receiving palbociclib plus letrozole was neutropenia. This article summarizes the FDA thought process and data supporting accelerated approval based on PALOMA-1 that may be contingent upon verification and description of clinical benefit in the ongoing and fully accrued confirmatory trial PALOMA-2. Clin Cancer Res; 21(21); 4760–6. ©2015 AACR.

On December 19, 2014, the FDA approved olaparib capsules (Lynparza; AstraZeneca) for the treatment of patients with deleterious or suspected deleterious germline BRCA-mutated (gBRCAm) advanced ovarian cancer who have been treated with three or more prior lines of chemotherapy. The BRACAnalysis CDx (Myriad Genetic Laboratories, Inc.) was approved concurrently. An international multicenter, single-arm trial enrolled 137 patients with measurable gBRCAm-associated ovarian cancer treated with three or more prior lines of chemotherapy. Patients received olaparib at a dose of 400 mg by mouth twice daily until disease progression or unacceptable toxicity. The objective response rate (ORR) was 34% with median response duration of 7.9 months in this cohort. The most common adverse reactions (≥20%) in patients treated with olaparib were anemia, nausea, fatigue (including asthenia), vomiting, diarrhea, dysgeusia, dyspepsia, headache, decreased appetite, nasopharyngitis/pharyngitis/upper respiratory infection, cough, arthralgia/musculoskeletal pain, myalgia, back pain, dermatitis/rash, and abdominal pain/discomfort. Myelodysplatic syndrome and/or acute myeloid leukemia occurred in 2% of the patients enrolled on this trial. Clin Cancer Res; 21(19); 4257–61. ©2015 AACR.

Regulatory watch: Evaluating the potential for digital submission of expedited premarket safety reports to the FDA

10009 Background: Older adults are a growing segment of our oncology population, with an expected increase in cancer incidence of 67% from 2010 to 2030 in people age 65 and older. However, older adults have been proportionally underrepresented in clinical trials. We sought to analyze the age-related enrollment of cancer patients onto trials supporting registration of new drugs or new indications approved by the US Food and Drug Administration from 2005 to 2015. Methods: This study involved retrospective analyses of demographic data of cancer patients enrolled onto trials supporting registration from 2005-2015. The data on 224,766 cancer patients supporting 105 drug applications were analyzed according to age distributions of

3018 Background: With FDA approval of three novel agents targeting the PD-L1/PD-1 checkpoint pathway in multiple tumor types, use of these agents in the clinical setting is becoming increasingly common. However, little is published on their use in patients with a history of autoimmune diseases. We therefore aimed to collect safety data on patients with a history of autoimmune diseases treated with PD-1/PD-L1 immunotherapy agents in a clinical trial setting. Methods: Data on patients with a history of autoimmune disease were collected for four different PD-1/PD-L1 immunotherapy agents. Information collected included name of autoimmune disease, corticosteroid dependency at baseline, duration of dosing, immune-related adverse events (iRAEs) and worsening of underlying autoimmune disease. Results: In total, 552 patients enrolled in 22 clinical trials of PD-1/PD-L1 immunotherapy agents were identified with a history of autoimmune disease. None were known to be dependent on systemic corticosteroids at baseline. The most common autoimmune diseases identified were thyroid disorder (n = 188), psoriasis (n = 70), and vitiligo (n = 44). For the four agents identified, mean duration of dosing was 183, 187, 196, and 145 days. Worsening of underlying autoimmune disease occurred in 16%, 6%, 13% and 6%. There were two grade 4 cases of hyperglycemia in patients with diabetes, three cases each of grade 3 AEs related to the underlying disorder in patients with psoriasis, interstitial lung disease, and hypothyroidism, and one grade 3 AE in a patient related to ankylosing spondylitis.For two of these agents, data were available on the development of grade 1-4 irAEs (per investigator) that required treatment with systemic steroids, which occurred in 8% and 9% of patients. Conclusions: Clinical trial data demonstrates relative safety of the use of PD-1/PD-L1 immunotherapy agents in patients with a history of autoimmune disease compared to their use in patients without such history. No consistent pattern of worsening of baseline autoimmune disease was identified. These results should be interpreted with caution, as diagnostic method and clinical manifestations of reported baseline autoimmune conditions are not known.

2539 Background: Clinical trials are increasingly conducted on a global scale in an effort to accelerate accrual. This analysis attempts to quantify and characterize participants in trials submitted to support approval of drugs for oncology indications by the region of enrollment. Methods: Demographic information was extracted for patients enrolled in clinical trials submitted to the FDA from 2005-2015. Only trials submitted to support approval for malignant solid tumor or hematology indications were included. Countries were grouped into regions for further analysis. A total of 178,024 patients with information regarding age and country were included in this analysis. Results: Forty five percent (80,460) of clinical trial participants were enrolled from Europe, 36% (63,958) from North America (includes U.S.A and Canada) and 8.4% (14,975) from Asia. Countries in Latin America, Middle East/Africa and the Baltic States/Russia enrolled the remainder 10.5% of the patients. Among 99,556 participants < 65 years of age; 38.7% (38,538) were enrolled from North America, 40.5% (40,362) from Europe, 9.7 % (9674) from Asia and 11% from the rest of the regions. Europe enrolled the highest number of cancer patients aged 65 years or older; 51.1% (40,098) compared to 32.4% (25,420) from North America and 6.8 % (5301) from Asia. Conclusions: Majority of patients enrolled into clinical trials submitted for oncology drug approvals were from regions other than North America, with highest number enrolled from Europe particularly in the older age group. While it is interesting to speculate, the reasons for differential enrollment of patients between Europe and North America and the impact of these findings on interpretation of clinical trial results need additional exploration. Analysis of trends over time may be useful to address this issue. [Table: see text]

On August 17, 2011, the U.S. Food and Drug Administration (FDA) approved vemurafenib tablets (Zelboraf, Hoffmann-LaRoche Inc.) for the treatment of patients with unresectable or metastatic melanoma with the BRAFV600E mutation as detected by an FDA-approved test. The cobas 4800 BRAF V600 Mutation Test (Roche Molecular Systems, Inc.) was approved concurrently. An international, multicenter, randomized, open-label trial in 675 previously untreated patients with BRAFV600E mutation–positive unresectable or metastatic melanoma allocated 337 patients to receive vemurafenib, 960 mg orally twice daily, and 338 patients to receive dacarbazine, 1,000 mg/m2 intravenously every 3 weeks. Overall survival was significantly improved in patients receiving vemurafenib [HR, 0.44; 95% confidence interval (CI), 0.33–0.59; P < 0.0001]. Progression-free survival was also significantly improved in patients receiving vemurafenib (HR, 0.26; 95% CI, 0.20–0.33; P < 0.0001). Overall response rates were 48.4% and 5.5% in the vemurafenib and dacarbazine arms, respectively. The most common adverse reactions (≥30%) in patients treated with vemurafenib were arthralgia, rash, alopecia, fatigue, photosensitivity reaction, and nausea. Cutaneous squamous cell carcinomas or keratoacanthomas were detected in approximately 24% of patients treated with vemurafenib. Other adverse reactions included hypersensitivity, Stevens–Johnson syndrome, toxic epidermal necrolysis, uveitis, QT prolongation, and liver enzyme laboratory abnormalities. Clin Cancer Res; 20(19); 4994–5000. ©2014 AACR.

e18091Background: CBR is commonly used as one the secondary endpoints in many cancer clinical trials. There are no comprehensive analyses to demonstrate that CBR adds to the value of the conventional time-to-event efficacy endpoints of progression-free and overall survival (PFS and OS) in clinical trials, and to date, CBR data are not reported in the clinical studies section of the U.S. package inserts for products approved for the treatment of MBC. We conducted a pooled analysis of data from MBC trials submitted to the FDA to understand the association of CBR with PFS and OS. In this analysis, CBR is defined as the percentage of patients with MBC who have achieved complete response, partial response or stable disease ≥ 6 months. Methods: We identified 13 trials of experimental agents with 10,263 patients submitted for treatment of MBC in initial or supplemental New Drug or Biologics License Applications since 2005. Criteria for inclusion of the trials in this analysis were: randomized, active-controlled,...

4508Background: Traditional measurement of disease progression by RECIST v1.1 criteria may not fully capture patient benefit from PD-1 and PD-L1 inhibitors. Contemporary immunotherapy protocols gen...

10010Background: With recent FDA approvals of immune checkpoint inhibitors for the treatment of advanced cancer, an increasing number of elderly patients will be treated with immunotherapy. Nivolumab is an immune checkpoint inhibitor, currently approved for the treatment of advanced renal cell cancer, melanoma, and non-small cell lung cancer based on significant responses including benefit in overall survival. However, little is known about the safety of nivolumab in an elderly patient population. Methods: Eligible patients recieved at least one dose of nivolumab as a single agent while enrolled in a phase 3 registration trial for the treatment of advanced renal cell cancer (CA209025), melanoma (CA209066), or non-small lung cancer (CA209057 and CA209017). Adverse events which occurred up to 100 days after last dose of nivolumab based on standardized adverse event datasets submitted by the sponsor were included. Results: See table. Conclusions: Immune therapies can benefit patients across a wide range of t...

Recent work identified L-asparaginase (L-ASP) as a putative therapeutic target for ovarian cancer. We suggest that L-ASP, a dysregulator of glycosylation, would interrupt the local microenvironment, affecting the ovarian cancer cell-endothelial cell interaction and thus angiogenesis without cytotoxic effects. Ovarian cancer cell lines and human microvascular endothelial cells (HMVEC) were exposed to L-ASP at physiologically attainable concentrations and subjected to analyses of endothelial tube formation, invasion, adhesion and the assessment of sialylated proteins involved in matrix-associated and heterotypic cell adhesion. Marked reduction in HMVEC tube formation in vitro, HMVEC and ovarian cancer cell invasion, and heterotypic cell-cell and cell-matrix adhesion was observed (P < 0.05-0.0001). These effects were associated with reduced binding to s1integrin, activation of FAK, and cell surface sialyl Lewis(X) (sLe(x)) expression. No reduction in HMVEC E-selectin expression was seen consistent with the unidirectional inhibitory actions observed. L-ASP concentrations were non-toxic to either ovarian cancer or HMVEC lines in the time frame of the assays. However, early changes of autophagy were observed in both cell types with induction of ATG12, beclin-1, and cleavage of LC-3, indicating cell injury did occur. These data and the known mechanism of action of L-ASP on glycosylation of nascent proteins suggest that L-ASP reduces of ovarian cancer dissemination and progression through modification of its microenvironment. The reduction of ovarian cancer cell surface sLe(x) inhibits interaction with HMVEC and thus HMVEC differentiation into tubes, inhibits interaction with the local matrix reducing invasive behaviour, and causes cell injury initiating autophagy in tumour and vascular cells.

BACKGROUND: Ovarian cancer cells in malignant effusions lack attachment to solid-phase matrix substrata and receive survival stimuli through cell–cell and cell–soluble matrix molecule interactions. We hypothesized that adhesion-related survival and proliferation pathway signals can inform clinical outcomes and guide targeted therapeutics. METHODS: Lysed cell pellets from a blinded set of benign (n = 20) and malignant (n = 51) peritoneal and pleural ovarian cancer patient effusions were applied to reverse-phase protein arrays and examined using validated antibodies to adhesion-associated protein endpoints. Results were subjected to hierarchical clustering for signature development. Association between specimen type, protein expression, and clinicopathologic associations were analyzed using the Mann-Whitney U test. Survival outcomes were estimated using the Kaplan-Meier method with log-rank comparison. RESULTS: A cell adhesion protein signature obtained from unsupervised clustering distinguished malignant from benign effusions (P = 6.18E-06). Protein subset analyses from malignant cases defined 3 cell adhesion protein clusters driven by E-cadherin, epithelial cell adhesion molecule, and N-cadherin, respectively. The components of the E- and N-cadherin clusters correlated with clinical outcome by Kaplan-Meier statistics. Univariate analysis indicated that FAK and phosphorylated AKT were associated with higher overall and progression-free survival (PFS) (P = .03), and Akt, phosphorylated paxillin, and E- and N-cadherin were associated with improved PFS (P ≤ .05). If 4 or 5 of the index adhesion proteins were high, PFS was improved by multivariate analysis (P ≤ .01). CONCLUSIONS: This hypothesis-testing examination of tumor cell adhesion molecules and pathways yielded potential predictive biomarkers with which to triage patients to selected molecular therapeutics and may serve as a platform for biomarker-based stratification for clinical application. Cancer 2011;. Published 2011 by the American Cancer Society.

5025 Background: We have found clinical activity of carboplatin (C) with the PARP inhibitor olaparib (O) in BRCA1/2mut or BRCA-like breast and ovarian cancers. Current clinical trials are testing the hypothesis that PARP inhibition will sensitize tumors to platinum agents. We have examined sequence specificity of C and O combinations in cell lines, including two BRCA1mut (HCC1937, UWB1.289) and two BRCA-WT lines (OVCAR8, HeyA8), on the development of DNA damage and cell injury. Methods: Cell injury was measured with XTT assays. DNA damage was examined using Comet assay with tail quantification and γH2AX foci by immunofluorescence. Platinum DNA-adduct formation was measured using atomic absorption spectrometry and normalized to DNA input. Results: Exposure to O prior to C for 24 hours (O>C) reduced the efficiency of double stranded DNA damage compared to C alone or O+C (p C vs. C or O+C) measured by γH2AX foci/nucleus in BRCA1mut cell lines, UWB1.289: 11.0 (O>C), 40.9 (C), 46.4 (O+C); HCC1937: 1...

TPS163 Background: Despite the tremendous promise of new signal transduction and angiogenesis inhibitors, these targeted drugs have met with mixed results so far in the clinic. In solid tumors, inhibition of multiple targets may be necessary for significant clinical effects. Dasatinib is an inhibitor of all SRC-family kinases, as well as BCR-ABL, c-KIT, multiple EPH-family kinases, PDGFβ receptor and other tyrosine kinases. Bevacizumab is a humanized IgG1 monoclonal antibody that binds all biologically active isoforms of human vascular endothelial growth factor (VEGF) with high affinity. Attenuation of both c-Src and VEGF pathways simultaneously provides the potential for synergistic antitumor activity, as there is a extensive interaction between these pathways. VEGFR transmits its downstream signal through multiple pathways involving c-Src (including activation of the prosurvival FAK pathway). Alternatively, VEGF production is known to be Src-mediated (including via STAT5 signaling). Thus, inhibition of ...

TPS258 Background: Although the bacterial enzyme L-asparaginase (L-ASP) has been used in combination with traditional cytotoxic therapy for decades, its use has been limited mainly to its FDA-approved treatment of acute lymphoblastic leukemia. By catalyzing the hydrolysis of asparagine to aspartate, L-ASP depletes serum levels of asparagine resulting in direct cytotoxicity of sensitive cells. The noncytotoxic effects of L-ASP, such as the inhibition of glycoprotein synthesis, have been known for decades. Our ongoing preclinical work has demonstrated that L-ASP reduces the ability of endothelial cells to form capillary-like tubes, reduces the invasive potential of endothelial cells and cancer cells, and prevents heterotypic interaction between ovarian cancer and endothelial cells. These results suggest that L-ASP may provide therapeutic benefit by inhibiting angiogenesis, invasion and metastasis. Our finding that L-ASP is capable of modifying the tumor microenvironment led us to hypothesize that pegasparga...