Cancer Treatment Reviews

Prognostic value of receptor tyrosine kinase-like orphan receptor (ROR) family in cancer: A meta-analysis Publication date: July 2019 Source: Cancer Treatment Reviews, Volume 77 Author(s): Ramy R. Saleh, Jesús Fuentes Antrás, Paloma Peinado, Pedro Pérez-Segura, Atanasio Pandiella, Eitan Amir, Alberto Ocaña Abstract Introduction Identification of membrane proteins expressed exclusively on tumor cells is a goal for cancer drug development. The receptor tyrosine kinase-like orphan receptor type 1 and 2 (ROR1/2), are type-I transmembrane proteins expressed in cancer but not in adult normal tissue. Here, we explore the prognostic role ROR1/2 expression on patient outcome. Methods A systematic search of electronic databases identified publications exploring the effect of ROR1/2 on overall survival (OS). Hazard ratios (HR) from collected data were pooled in a meta-analysis using generic inverse-variance and random effects modeling. Subgroup analyses were conducted based on disease site or tumor type. Results Twenty five studies met the inclusion criteria. ROR1 was associated with worse overall survival (HR 2.13, 95% confidence interval (CI) 1.62–2.80; P < 0.001) with subgroup analysis showing the strongest association between ROR1 and OS was in lung cancer. There was no significant difference between solid tumors and hematological malignancies (HR 2.15, 95% CI 1.52–3.06 vs. HR 2.02, 95% CI 1.46–2.84; subgroup difference P = 0.80). ROR2 was also associated with worse OS (HR 1.84, 95% CI 1.43–2.38; P < 0.001). There was no significant difference between disease sites although the highest association seen was in head and neck cancers (HR 3.19, 95% CI 1.13–8.97) and the lowest in gynecological cancers (HR 1.19, 95% CI 0.71–2.00; subgroup difference P = 0.10). Conclusions ROR1 and ROR2 expression is associated with adverse outcome in several tumors. ROR1/2 warrants study as a target for developmental therapeutics.

Optimizing the management of locally advanced pancreatic cancer with a focus on induction chemotherapy: Expert opinion based on a review of current evidence Publication date: July 2019 Source: Cancer Treatment Reviews, Volume 77 Author(s): Thomas Seufferlein, Pascal Hammel, Jean Robert Delpero, Teresa Macarulla, Per Pfeiffer, Gerald W. Prager, Michele Reni, Massimo Falconi, Philip A. Philip, Eric Van Cutsem Abstract Surgical resection of pancreatic cancer offers a chance of cure, but currently only 15–20% of patients are diagnosed with resectable disease, while 30–40% are diagnosed with non-metastatic, unresectable locally advanced pancreatic cancer (LAPC). Treatment for LAPC usually involves systemic chemotherapy, with the aim of controlling disease progression, reducing symptoms and maintaining quality of life. In a small proportion of patients with LAPC, primary chemotherapy may successfully convert unresectable tumours to resectable tumours. In this setting, primary chemotherapy is termed ‘induction therapy’ rather than ‘neoadjuvant’. There is currently a lack of data from randomized studies to thoroughly evaluate the benefits of induction chemotherapy in LAPC, but Phase II and retrospective data have shown improved survival and high R0 resection rates. New chemotherapy regimens such as nab–paclitaxel + gemcitabine and FOLFIRINOX have demonstrated improvement in overall survival for metastatic disease and shown promise as neoadjuvant treatment in patients with resectable and borderline resectable disease. Prospective trials are underway to evaluate these regimens further as induction therapy in LAPC and preliminary data indicate a beneficial effect of FOLFIRINOX in this setting. Further research into optimal induction schedules is needed, as well as guidance on the patients who are most suitable for induction therapy. In this expert opinion article, a panel of surgeons, medical oncologists and gastrointestinal oncologists review the available evidence on management strategies for LAPC and provide their recommendations for patient care, with a particular focus on the use of induction chemotherapy.

PD-L1 expression and clinical outcomes in patients with advanced urothelial carcinoma treated with checkpoint inhibitors: A meta-analysis Publication date: June 2019 Source: Cancer Treatment Reviews, Volume 76 Author(s): Ketan Ghate, Eitan Amir, Markus Kuksis, David Hernandez-Barajas, Laura Rodriguez-Romo, Christopher M. Booth, Francisco E. Vera-Badillo Abstract Context Five checkpoint inhibitors have been approved as 1st line (cisplatin-ineligible) or 2nd line therapies for patients with metastatic urothelial carcinoma of the bladder. As only about 30% of patients respond, the need for a biomarker for patient selection exists. Objective To determine if PD-L1 expression is a prognostic factor of objective response rate (ORR) and overall survival (OS) in patients with urothelial carcinoma being treated with checkpoint inhibitors. Evidence acquisition A search of PubMed and major conference proceedings identified trials of PD-L1 inhibitors as first- or second-line therapies for metastatic bladder cancer. Odds ratios (OR) for ORR and OS compared PD-L1 positive and PD-L1 negative patients. Data were weighted and pooled in a meta-analysis, and subgroup analyses compared PD-L1 status cut-offs. Evidence synthesis Ten studies comprising 2755 patients were identified, of which 2030 patients (74%) received immune checkpoint inhibitors. Eight studies were eligible for ORR analysis (1530 patients) and five studies for OS (829 patients). PD-L1 patients had a significantly higher ORR than PD-L1 negative patients (1.82, 95%CI 1.18–2.77; p = 0.007). Weighted mean OS was 11.5 months (range 8.7–15.9 months). PD-L1 status was not prognostic for 12 month OS (OR = 0.81, 95%CI 0.47–1.40; p = 0.45). Conclusion In patients treated with PD-L1 inhibitors for metastatic urothelial carcinoma, PD-L1 status is prognostic for ORR but not OS. Our findings warrant additional investigation. Patient summary Five immunotherapy drugs are approved for bladder cancer therapy. PD-L1 expression predicts higher ORR but not OS. More data is needed to identify the patient population most benefitted by immunotherapy.

Management of bone health in solid tumours: From bisphosphonates to a monoclonal antibody Publication date: June 2019 Source: Cancer Treatment Reviews, Volume 76 Author(s): Roger von Moos, Luis Costa, Eva Gonzalez-Suarez, Evangelos Terpos, Daniela Niepel, Jean–Jacques Body Abstract Patients with solid tumours are at risk of impaired bone health from metastases and cancer therapy-induced bone loss (CTIBL). We review medical management of bone health in patients with solid tumours over the past 30 years, from first-generation bisphosphonates to the receptor activator of nuclear factor κB ligand (RANKL)-targeted monoclonal antibody, denosumab. In the 1980s, first-generation bisphosphonates were shown to reduce the incidence of skeletal-related events (SREs) in patients with breast cancer. Subsequently, more potent second- and third-generation bisphosphonates were developed, particularly zoledronic acid (ZA). Head-to-head studies showed that ZA was significantly more effective than pamidronate for reducing SREs in patients with breast and castrate-resistant prostate cancer (CRPC), becoming the standard of care for more than a decade. The RANKL inhibitor denosumab was licensed in 2010, and head-to-head studies and integrated analyses confirmed its superiority to ZA for preventing SREs, particularly in breast cancer and CRPC. Bisphosphonates and denosumab have also been investigated for prevention of CTIBL in patients receiving hormonal therapy for breast and prostate cancer, and denosumab is licensed in this indication. Despite advances in management of bone health, several issues remain, notably the optimal time to initiate therapy, duration of therapy, and dosing frequency, and how to avoid toxicity, particularly with long-term treatment. In summary, introduction of ZA and denosumab has protected patients with bone metastasis from serious bone complications and improved their quality of life. Ongoing research will hopefully guide the optimal use of these agents to help maintain bone health in patients with solid tumours.

Hedgehog signaling inhibitors in solid and hematological cancers Publication date: June 2019 Source: Cancer Treatment Reviews, Volume 76 Author(s): Jorge E. Cortes, Ralf Gutzmer, Mark W. Kieran, James A. Solomon Abstract Background The hedgehog signaling pathway is normally tightly regulated. Mutations in hedgehog pathway components may lead to abnormal activation. Aberrantly activated hedgehog signaling plays a major role in the development of solid and hematological cancer. In recent years, inhibitors have been developed that attenuate hedgehog signaling; 2 have been approved for use in basal cell carcinoma (BCC), while others are under development or in clinical trials. The aim of this review is to provide an overview of known hedgehog inhibitors (HHIs) and their potential for the treatment of hematological cancers and solid tumors beyond BCC. Design Published literature was searched to identify articles relating to HHIs in noncutaneous cancer. Both preclinical and clinical research articles were included. In addition, relevant clinical trial results were identified from www.clinicaltrials.gov. Information on the pharmacology of HHIs is also included. Results HHIs show activity in a variety of solid and hematological cancers. In preclinical studies, HHIs demonstrated efficacy in pancreatic cancer, rhabdomyosarcoma, breast cancer, and acute myeloid leukemia (AML). In clinical studies, HHIs showed activity in medulloblastoma, as well as prostate, pancreatic, and hematological cancers. Current clinical trials testing the efficacy of HHIs are underway for prostate, pancreatic, and breast cancers, as well as multiple myeloma and AML. Conclusions As clinical trial results become available, it will be possible to discern which additional tumor types are suited to HHI mono- or combination therapy with other anticancer agents. The latter strategy may be useful for delaying or overcoming drug resistance.

Emerging therapeutic targets for patients with advanced prostate cancer Publication date: June 2019 Source: Cancer Treatment Reviews, Volume 76 Author(s): Fred Saad, Neal Shore, Tian Zhang, Shikhar Sharma, Helen K. Cho, Ira A. Jacobs Abstract Although recent advances in the treatment of castration-resistant prostate cancer (CRPC) have significantly improved patient outcomes, advanced prostate cancer is still associated with substantial morbidity and mortality, particularly in patients who develop resistance after multiple lines of therapy. Various cell signaling, DNA repair, and epigenetic enzymatic pathways are being targeted with small-molecule inhibitors in order to identify treatment strategies for patients with CRPC. In this review, we discuss novel targets and agents, studied preclinically and now being validated in clinical trials, including poly ADP-ribose polymerase (PARP), enhancer of zeste homologue 2 (EZH2), hedgehog pathway, MDM2/p53, and tyrosine kinase inhibitors. Further, we outline current approaches for novel prostate cancer vaccines such as DCVAC/PCa, PROSTVAC-V/F, MVI-816, CV9104, and PF-06753512. This wide spectrum of potential treatment strategies holds promise for additional improvements in the treatment of patients with CRPC, as these novel agents are aimed at targets known to be associated with growth and malignant progression of prostate cancer. If primary study endpoints are met, findings from ongoing phase III trials of well-tolerated and active combinations may provide new effective treatment options for advanced prostate cancer and thereby contribute to enhanced disease control in CRPC patients.

Immunotherapy of colorectal cancer: Challenges for therapeutic efficacy Publication date: June 2019 Source: Cancer Treatment Reviews, Volume 76 Author(s): Davide Ciardiello, Pietro Paolo Vitiello, Claudia Cardone, Giulia Martini, Teresa Troiani, Erika Martinelli, Fortunato Ciardiello Abstract A better knowledge of the complex interactions between cancer cells and the immune system has led to novel immunotherapy approaches. Treatment with selective anti-PD1, anti-PD-L1 and/or anti-CTLA-4 monoclonal antibodies (mAbs) has been a revolution in the therapeutic scenario of several cancer types, with the highest clinical efficacy in melanoma and in lung cancer. Colorectal cancer is one of the tumours in which immunotherapy has been shown less effective. Whereas in deficient mismatch repair (MMR) or in highly microsatellite instable (MSI-H) metastatic colorectal cancer there is clear clinical evidence for a therapeutic role of immune checkpoint inhibitors, the vast majority of patients with proficient MMR or with microsatellite stable (MSS) tumours do not benefit from immunotherapy. Defining the molecular mechanisms for immunogenicity in metastatic colorectal cancer is needed in order to develop predictive biomarkers and effective therapeutic combination strategies. A major challenge will be to identify, among the heterogeneous spectrum of this disease, those patients with specific tumour and tumour infiltrating stroma molecular and functional characteristics, that could be effectively treated with immunotherapy. In this review, we discuss the role of immune response in the context of metastatic colorectal cancer. We summarize the available clinical data with the use of anti PD-1/PD-L1 mAbs as single agents or in combination with anti CTLA-4 mAbs in MSI-H patients. Finally, we address the challenges and the potential strategies for rendering the more frequent microsatellite stable (MSS) tumours “immune-competent” and, therefore, amenable for effective immunotherapy interventions.

Management of metastatic bladder cancer Publication date: June 2019 Source: Cancer Treatment Reviews, Volume 76 Author(s): Rosa Nadal, Joaquim Bellmunt Abstract Important advances in the understanding of the biology and mechanisms of tumor progression of urothelial carcinoma (UC) have been achieved over the past decade. The treatment landscape for advanced-stage, unresectable or metastatic UC has shifted dramatically over a short period of time, with 6 new therapeutic agents available for clinical use. The use of traditional chemotherapy and new immune checkpoints inhibitors (ICIs) directed at programmed cell-death protein 1 (PD-1) or its ligand has led to unprecedented survival benefits in selected patients with metastatic UC. Data show that anti-PD-1 ICIs are not only improving long-term clinical benefit, but also quality of life for patients in the second-line setting. In the front-line setting, regulatory agencies have restricted the indications of atezolizumab and pembrolizumab (both ICIs) to patients with PD-L1positivity with advanced UC and who are platinum-ineligible. Very recently, erdafitinib, a pan-FGFR inhibitor, has been granted accelerated approval by FDA for platinum-pretreated advanced metastatic UC with susceptible FGFR3 or FGFR2 genetic alterations. Enfortumab vedotin, an antibody-drug conjugate, have been granted breakthrough designation by the FDA for the treatment of metastatic UC. Here we review the clinical trial data that have established standard-of-care treatment for advanced-stage UC. In addition, mechanisms of resistance and biomarkers of response to platinum-based chemotherapies and immunotherapies are also discussed, along with the clinical benefits and limitations of these therapies.

Improving attribution of adverse events in oncology clinical trials Publication date: June 2019 Source: Cancer Treatment Reviews, Volume 76 Author(s): Goldy C. George, Pedro C. Barata, Alicyn Campbell, Alice Chen, Jorge E. Cortes, David M. Hyman, Lee Jones, Thomas Karagiannis, Sigrid Klaar, Jennifer G. Le-Rademacher, Patricia LoRusso, Sumithra J. Mandrekar, Diana M. Merino, Lori M. Minasian, Sandra A. Mitchell, Sandra Montez, Daniel J. O'Connor, Syril Pettit, Elaine Silk, Jeff A. Sloan Abstract Attribution of adverse events (AEs) is critical to oncology drug development and the regulatory process. However, processes for determining the causality of AEs are often sub-optimal, unreliable, and inefficient. Thus, we conducted a toxicity-attribution workshop in Silver Springs MD to develop guidance for improving attribution of AEs in oncology clinical trials. Attribution stakeholder experts from regulatory agencies, sponsors and contract research organizations, clinical trial principal investigators, pre-clinical translational scientists, and research staff involved in capturing attribution information participated. We also included patients treated in oncology clinical trials and academic researchers with expertise in attribution. We identified numerous challenges with AE attribution, including the non-informative nature of and burdens associated with the 5-tier system of attribution, increased complexity of trial logistics, costs and time associated with AE attribution data collection, lack of training in attribution for early-career investigators, insufficient baseline assessments, and lack of consistency in the reporting of treatment-related and treatment-emergent AEs in publications and clinical scientific reports. We developed recommendations to improve attribution: we propose transitioning from the present 5-tier system to a 2–3 tier system for attribution, more complete baseline information on patients’ clinical status at trial entry, and mechanisms for more rapid sharing of AE information during trials. Oncology societies should develop recommendations and training in attribution of toxicities. We call for further harmonization and synchronization of recommendations regarding causality safety reporting between FDA, EMA and other regulatory agencies. Finally, we suggest that journals maintain or develop standardized requirements for reporting attribution in oncology clinical trials.

Comparison and Applicability of Molecular Classifications for Gastric Cancer Publication date: Available online 28 May 2019 Source: Cancer Treatment Reviews Author(s): O. Serra, M. Galán, M.M. Ginesta, M. Calvo, N. Sala, R. Salazar Abstract Gastric Cancer (GC) is a complex and heterogeneous disease, which represents a global health concern. Despite advances in prevention, diagnosis, and therapy, GC is still a leading cause of cancer-related death. Over the last decade, several clinical trials have tested novel agents for advanced GC with mostly disappointing results. Heterogeneity, the absence of molecular selection in clinical trials and powerless predictive biomarkers may be potential explanations. Different molecular classification proposals for GC based on the genetic, epigenetic, and molecular signatures have been published. Molecular characterization of GC may offer new tools for more effective therapeutic strategies, such as the development of therapies for specifically well-defined sets of patients as well as the use of new clinical trial designs, which will ultimately lead to an improvement of medical management of this disease. However, the possibilities of implementation of GC molecular classifications on daily practice and their therapeutic implications remain challenging to date. In this review, we will describe and compare these GC molecular classifications, focusing on their main characteristics as the basis for their potential therapeutic implications and strategies for their clinical application. Key Message: A better understanding of gastric cancer molecular characteristics may lead to further improvements in treatment and outcomes for patients with the disease.