Expert Review of Anticancer Therapy

Rijkers, Ger T.; Andriessen, S. Quirine; van Overveld, Frans J.

doi: 10.1080/14737140.2019.1677158pmid: 31592683

Marandino, Laura; Raggi, Daniele; Giannatempo, Patrizia; Farè, Elena; Necchi, Andrea

doi: 10.1080/14737140.2019.1671190pmid: 31544541

Introduction: Fibroblast growth-factor receptor (FGFR) inhibition is a promising strategy of treatment in urothelial cancer (UC). FGFR3 mutations or fusions (mut/fus) are common in luminal-1 UC subtype, which exhibits poor responses to immunotherapy. Erdafitinib is a potent and selective pan-FGFR tyrosine kinase inhibitor. Based on the results of the phase 2 BLC2001 trial (NCT02365597), in which erdafitinib showed an overall response rate of 40% in metastatic UC with FGFR3 mut/fus, it is the first approved targeted therapy in metastatic UC. Areas covered: This review covers the preclinical and clinical evidence for erdafitinib, summarizes the results of other FGFR inhibitors tested in UC and explores future perspectives of FGFR inhibition in UC. Expert opinion: In the era of precision medicine, erdafitinib approval marks a step forward in UC. Erdafitinib qualifies as a compelling comparator in the salvage therapy setting. Special attention must be paid to typical adverse class-effects of FGFR inhibitors. In the near future, in order to achieve an optimal selection of molecularly-altered tumors, it will be important to assess the performance of different diagnostic tools and to investigate the role of liquid biopsy. Combinations with immunotherapy represent a novel therapeutic opportunity being tested in ongoing trials.

Personeni, Nicola; Rimassa, Lorenza; Pressiani, Tiziana; Smiroldo, Valeria; Santoro, Armando

doi: 10.1080/14737140.2019.1674141pmid: 31603008

Introduction: The randomized, placebo-controlled, phase III CELESTIAL trial demonstrated statistically and clinically significant improvement in overall survival with cabozantinib in patients with advanced hepatocellular carcinoma (HCC) previously treated with sorafenib. Most frequently reported adverse events included palmar-plantar erythrodysesthesia, hypertension, increased aspartate aminotransferase, fatigue, and diarrhea. Areas covered: In this review we analyze and discuss preclinical and clinical data of cabozantinib. We summarize efficacy and safety results of phase II and III trials of cabozantinib in the treatment of patients with advanced HCC and we present ongoing trials of cabozantinib in combination with checkpoint inhibitors. Expert opinion: Cabozantinib is a new second-line and the only third-line treatment for patients with advanced HCC, nevertheless some data are still missing to better inform clinical decisions on how to treat specific patient populations. Next trials designs will have to incorporate heavy efforts in terms of translational research to maximize the benefits of such treatments.

Turnquist, Casmir; Watson, Robert A; Protheroe, Andrew; Verrill, Clare; Sivakumar, Shivan

doi: 10.1080/14737140.2019.1667236pmid: 31510810

Introduction: It has long been recognized that tumors are composed of a mosaic of cells and numerous methods have been developed to detect tumor heterogeneity, including in situ hybridization, multi-regional sampling, cytological assays, and whole genome and single cell sequencing. Using these methods, heterogeneity has been observed at the genetic, epigenetic, and phenotypic level in numerous cancers. With the advent of deep sequencing technology, we now appreciate a greater complexity of distinct genotypes and phenotypes that drive the biological behavior of cancer. Despite decades of progress in detecting tumor heterogeneity, the question remains: to what extent does it matter? Areas covered: This review explores the evidence for and against the importance of tumor heterogeneity in three main areas: prognostication, development of targeted therapeutics and tumor resistance; summarizing current understanding before evaluating ongoing experimental and clinical developments. Expert opinion: Theoretical understanding and in vitro detection of intratumour heterogeneity promises much but is yet to translate into meaningful clinical benefit. However, the recent emergence of a host of technological innovations and upcoming clinical trials may soon change the landscape of this field.

Kamyabi, Nabiollah; Bernard, Vincent; Maitra, Anirban

doi: 10.1080/14737140.2019.1670063pmid: 31533487

Introduction: Pancreatic ductal adenocarcinoma (PDAC) is a disease of high lethality. Invasive tissue biopsies of primary or metastatic lesions remain the gold standard for diagnosis, but repeated sampling is infeasible. Noninvasive liquid biopsies offer new opportunities for early diagnosis for high-risk cohorts, and for the longitudinal analysis of tumor evolution and progression in patients on therapy. Liquid biopsies can capture tumor-associated components, such as circulating tumor DNA (ctDNA), extracellular vesicles (EVs), and circulating tumor cells (CTCs), each of which provides genomic and molecular information about the underlying PDAC that can potentially inform clinical decisions. Areas covered: Here, we reviewed current knowledge and recent technological advances regarding liquid biopsy in PDAC and mention the pitfalls and benefits in each methodology. We also discuss clinical correlative studies for diagnosis and prognosis in PDAC. Expert opinion:In pancreatic cancer where tissue samples are limited and repeated tissue biopsies are mostly invasive and infeasible, liquid biopsies opened a new window for tumor diagnosis, molecular stratification, and treatment monitoring. While none of the isolation and analysis methods have gained widespread clinical acceptance, it is imperative that the advantages and limitations of each platform for isolation and analysis of tumor associated components are taken into consideration.

Macrì, Antonio; Morabito, Federico

doi: 10.1080/14737140.2019.1671189pmid: 31544548

Introduction: Gastric cancer is the fourth/fifth most common malignancy worldwide, with only a quarter of patients achieving a 5-year survival rate. It has been estimated that 15–50% or more of patients have peritoneal disease upon surgical exploration. Until the early 1990s, peritoneal metastasis was considered as terminal stage of the disease; in the late 1990s, selected patients with peritoneal metastasis were recategorized as local disease. Over the past two decades, the treatment of peritoneal involvement has transformed, and cytoreductive surgery plus intraperitoneal therapy have drastically altered the natural course of several malignancies. Areas covered: We performed a review of studies available on PubMed from 1 January 2014 to 31 July 2019 and the analysis of their reference citations. We describe the most current intraperitoneal chemotherapy opportunities in the treatment of gastric cancer: hyperthermic intraoperative intraperitoneal chemotherapy (HIPEC), laparoscopic hyperthermic intraperitoneal chemotherapy (LHIPEC), neoadjuvant intraperitoneal and systemic chemotherapy (NIPS), LHIPEC + NIPS, extensive intraoperative peritoneal lavage (EIPL), early postoperative intraperitoneal chemotherapy (EPIC), and pressurized intraperitoneal aerosol chemotherapy (PIPAC). Expert opinion: Comprehensive treatment consisting of CRS combined with perioperative intraperitoneal/systemic chemotherapy can, today, be considered an effective strategy to improve the long-term survival of gastric cancer patients with peritoneal metastasis.

Merz, Almuth Maria Anni; Merz, Maximilian; Hillengass, Jens; Holstein, Sarah A.; McCarthy, Philip

doi: 10.1080/14737140.2019.1674142pmid: 31595807

Introduction: Maintenance therapy after autologous transplantation is a standard of care in newly diagnosed myeloma. However, there is no universal answer to the question of which maintenance strategy should be pursued after ASCT? Areas covered: We conducted a MEDLINE search using the medical subject headings ‘multiple myeloma’, ‘autologous transplantation’ and ‘maintenance’ to identify available data from clinical trials on the role of different maintenance strategies after autologous transplantation for the newly diagnosed disease. Expert opinion: A large meta-analysis demonstrated that lenalidomide prolongs progression-free and overall survival after autologous transplantation compared to observation/placebo. Further trials confirmed that lenalidomide maintenance increases rates of high-quality responses and one study demonstrated that lenalidomide maintenance improves outcomes regardless of cytogenetic risk. Although lenalidomide can cause side effects and is associated with an increased risk of second primary malignancies, its benefits outweigh the mentioned risks. The proteasome inhibitors ixazomib and bortezomib may partially overcome the negative effects of high-risk cytogenetics. Future trials will combine different agents and monoclonal antibodies during maintenance and will investigate whether minimal residual disease status can guide maintenance duration.

Vartanian, Jose Guilherme; Gonçalves Filho, Joao; Kowalski, Luiz Paulo; Shah, Jatin P.; Suárez, Carlos; Rinaldo, Alessandra; De Bree, Remco; Rodrigo, Juan P; Hamoir, Marc; Takes, Robert P.; Mäkitie, Antti A.; Zbären, Peter; Andreasen, Simon; Poorten, Vincent Vander;

Seidel, Sabine; Schlegel, Uwe

doi: 10.1080/14737140.2019.1677157pmid: 31594423

Introduction: Primary CNS lymphomas (PCNSL) are highly aggressive tumors and optimal treatment is not yet defined. For the last two decades, clinical trials have focused on developing efficient chemotherapy protocols with or without dose-reduced radiation to avoid late cognitive decline after whole brain radiotherapy (WBRT). Areas covered: This review addresses the question if these substantial developments have led to clinically relevant therapeutic improvement for PCNSL within the last decade. Expert opinion: The high risk of neurotoxic side effects of WBRT was further substantiated, and in most centers WBRT is omitted from first-line treatment in patients eligible for high-dose systemic methotrexate (HDMTX)-based chemotherapy. Intensified polychemotherapy regimens, particularly high-dose chemotherapy regimens with autologous stem cell transplantation (HD-ASCT), were investigated within prospective multicenter randomized trials and have achieved long-term disease control in a fraction of patients, but no significant progress was made for elderly patients, who are not able to tolerate intensified chemotherapy. Results on the efficacy of rituximab in PCNSL are conflicting; it did not show clinical benefit in a recent large prospective multicenter randomized trial. New substances such as immune-checkpoint inhibitors and targeted molecules are subject to investigation, but have not yet been implemented in clinical routine.