Amy E. McKee

On Trk—The TrkB Signal Transduction Pathway Is an Increasingly Important Target in Cancer Biology

In the beginning, Trk was an oncogene. Yet Neurotrophin-Trk signaling came to preeminence in the field of neurobiology. Now it is appreciated that Trks regulate important processes in nonneuronal cells and, in addition to their impact on tumors of neural origin, may contribute to the pathogenesis of carcinomas, myelomas, and prostate and lymphoid tumors. Although mutations and rearrangements of Trk are seen only sporadically in human cancers, such as medullary thyroid carcinoma, a number of recent studies indicate that expression of TrkB contributes to tumor pathology. In neuroblastoma, TrkA expression marks good prognosis which TrkB and Brain-derived neurotrophic factor (BDNF) expression marks poor prognosis. Activation of the BDNF/TrkB signal transduction pathway also stimulates tumor cell survival and angiogenesis and contributes to resistance to cytotoxic drugs and anoikis, enabling cells to acquire many of the characteristic features required for tumorigenesis. Small molecule inhibitors, such as Cephalons CEP-701, are in phase 1 and 2 clinical trials, and a series of AstraZeneca Trk inhibitors are poised to enter the clinic. As monotherapy, inhibitors may be effective only in tumors with activating Trk mutations. Important clinical follow-up will be the assessment of Trk inhibitors in combination with standard chemo- or radiotherapy or other signal transduction pathway inhibitors. (Clin Cancer Res 2009;15(19):5962–7)

FDA Approval Summary: Vemurafenib for Treatment of Unresectable or Metastatic Melanoma with the BRAFV600E Mutation

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.

FDA Approval of Palbociclib in Combination with Fulvestrant for the Treatment of Hormone Receptor–Positive, HER2-Negative Metastatic Breast Cancer

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.

Successes and Challenges of PARP Inhibitors in Cancer Therapy

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. n nIn 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. n nSeveral 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 u200b(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. n n n nTable 1 n nPARP inhibitors in Phase 2 and Phase 3 clinical developmenta. n n n n nMechanisms of Anti-Tumor Effect of Parp Inhibitors nPoly (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. n nPoly (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. n nIn 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 10u2009μM (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. n nA 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.

FDA Approval: Uridine Triacetate for the Treatment of Patients Following Fluorouracil or Capecitabine Overdose or Exhibiting Early-Onset Severe Toxicities Following Administration of These Drugs

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.

FDA Approval Summary: Pembrolizumab for the Treatment of Recurrent or Metastatic Head and Neck Squamous Cell Carcinoma with Disease Progression on or After Platinum‐Containing Chemotherapy

This article summarizes the evidence for the impact of BRAF mutations on treatment outcome of anti‐EGFR monoclonal antibodies. Based on a review of literature, eight meta‐analyses were included in this study, which consistently show that patients with BRAF mutations have a lack of treatment benefit of anti‐EGFR monoclonal antibodies. Considering the quality and quantity of available evidence, current guidelines may be revised.

FDA Approval of Nivolumab for the First-Line Treatment of Patients with BRAFV600 Wild-Type Unresectable or Metastatic Melanoma

On November 23, 2015, the FDA approved nivolumab (OPDIVO; Bristol-Myers Squibb) as a single agent for the first-line treatment of patients with BRAFV600 wild-type, unresectable or metastatic melanoma. An international, double-blind, randomized (1:1) trial conducted outside of the United States allocated 418 patients to receive nivolumab 3 mg/kg intravenously every 2 weeks (n = 210) or dacarbazine 1,000 mg/m2 intravenously every 3 weeks (n = 208). Patients with disease progression who met protocol-specified criteria (∼25% of each trial arm) were permitted to continue with the assigned treatment in a blinded fashion until further disease progression is documented. Overall survival was statistically significantly improved in the nivolumab arm compared with the dacarbazine arm [hazard ratio (HR), 0.42; 95% confidence interval (CI), 0.30–0.60; P < 0.0001]. Progression-free survival was also statistically significantly improved in the nivolumab arm (HR, 0.43; 95% CI, 0.34–0.56; P < 0.0001). The most common adverse reactions (≥20%) of nivolumab were fatigue, diarrhea, constipation, nausea, musculoskeletal pain, rash, and pruritus. Nivolumab demonstrated a favorable benefit–risk profile compared with dacarbazine, supporting regular approval; however, it remains unclear whether treatment beyond disease progression contributes to the overall clinical benefit of nivolumab. Clin Cancer Res; 23(14); 3479–83. ©2017 AACR.

Oncology Drug Approvals: Evaluating Endpoints and Evidence in an Era of Breakthrough Therapies

With the Breakthrough Therapy Designation program adding to the tools that the U.S. Food and Drug Administration (FDA) has for expediting drug development, the FDA reassessed the endpoints needed for approval of transformative therapies. Although the demonstration of an improvement in overall survival remains the gold standard for drug approval, innovation in cancer research has led to use of other endpoints in regulatory decision‐making. These endpoints include substantially delaying tumor progression or extending progression‐free survival, substantially reducing tumor size for a prolonged time, improving objective response rate and duration of response, or improving cancer‐related symptoms and patient function.

FDA's approach to regulating biosimilars

The Biologics Price Competition and Innovation (BPCI) Act, enacted as part of the Affordable Care Act, created a new licensure pathway for biological products demonstrated to be biosimilar with or interchangeable with an FDA-licensed biological product (the “reference product”). The FDAs approach to the regulation of biosimilars is based on the requirements set forth in the BPCI Act. A biosimilar product is highly similar to the reference product, notwithstanding minor differences in clinically inactive components, and there are no clinically meaningful differences between products in terms of safety, purity, and potency. The foundation of a biosimilar development program is an analytic similarity assessment that directly compares the structural/physiochemical and functional properties of the proposed biosimilar with the reference product. Data from clinical studies, which include an assessment of immunogenicity and pharmacokinetics/pharmacodynamics, are used to assess for clinically meaningful differences and not to independently establish the safety and effectiveness of the biosimilar. Like all products that the FDA regulates, the FDA requires that biosimilar products meet the agencys rigorous standards of safety and efficacy for approval. That means patients and health care professionals are able to rely upon the safety and effectiveness of biosimilar products in the same manner as for the reference product. Clin Cancer Res; 23(8); 1882–5. ©2016 AACR.

How Often Are Drugs Made Available Under the Food and Drug Administration's Expanded Access Process Approved?

In this review of individual patient expanded‐access requests to the Center for Drug Evaluation and Research for the period Fiscal Year 2010 to Fiscal Year 2014, we evaluated the number of applications received and the number allowed to proceed. We also evaluated whether drugs and certain biologics obtained under expanded access went on to be approved by the Food and Drug Administration. Finally, we considered concerns that adverse events occurring during expanded access might place sponsors at risk for legal liability. Overall, 98% of individual patient expanded‐access requests were allowed to proceed. During the study period, among drugs without a previous approval for any indication or dosage form, 24% of unique drugs (ie, multiple applications for access to the same drug were considered to relate to 1 unique drug), and 20% of expanded‐access applications received marketing approval by 1 year after initial submission; 43% and 33%, respectively, were approved by 5 years after initial submission. A search of 3 legal databases and a database of news articles did not appear to identify any product liability cases arising from the use of a product in expanded access. Our analyses seek to give physicians and patients a realistic perspective on the likelihood of a drugs approval as well as certain information regarding the product liability risks for commercial sponsors when providing expanded access to investigational drugs. The US Food and Drug Administration (FDA)’s expanded‐access program maintains a careful balance between authorizing patient access to potentially beneficial drugs and protecting them from drugs that may have unknown risks. At the same time, the agency wishes to maintain the integrity of the clinical trials process, ultimately the best way to get safe and effective drugs to patients.