Adjuvant therapy for advanced renal cell carcinoma

Introduction: Locally advanced, non-metastatic renal cell carcinoma (RCC) is conventionally managed with surgery. However, patients are at a high risk of RCC recurrence and have poor survival outcomes. An effective adjuvant systemic treatment is needed to improve on these outcomes. Targeted molecular and immune-based therapies have been investigated, or are under investigation, but their role in this setting remains unclear.

Areas covered: A comprehensive search of PubMed and ClinicalTrials.gov was performed for relevant literature. The following topics pertinent to adjuvant therapy in RCC were evaluated: strategies for patient selection, cytokine-based immunotherapy, vaccine therapy, VEGF and non-VEGF targeted molecular agents, and immune checkpoint inhibitors.

Expert commentary: Strong evidence for the incorporation of adjuvant therapy in high-risk RCC is lacking. Multiple targeted molecular therapies have been examined with only one approved for use. Genetic and molecular-based prognostic models are needed to determine who may benefit from adjuvant therapy. Developing adjuvant therapy strategies in the future depends on the results of important ongoing trials with immunotherapy and targeted agents.     

Improving patient outcomes to targeted therapies in melanoma

Introduction: The arrival of targeted therapies has led to significant improvements in clinical outcomes for patients with BRAFV600 mutated advanced melanoma over the past five years.

Areas Covered: In several clinical trials, BRAF and MEK inhibitors have shown improvement in progression free and overall survival, along with much higher tumor response rates in comparison to chemotherapy, with the combination of these drugs superior to monotherapy. These agents are also being tested in earlier-stage patients, in addition to alternative dosing regimens and in combinations with other therapeutics. Efforts are also ongoing to expand the success found with targeted therapies to other subtypes of melanoma, including NRAS and c-kit mutated melanomas, uveal melanomas, and BRAF/NRAS wild type melanomas.

Expert Commentary: We aim to provide an overview of clinical outcomes with targeted therapies in melanoma patients.     

Prospects of targeted and immune therapies in SCLC

Introduction: Small cell lung cancer (SCLC) is a tumor with a poor prognosis, often diagnosed in an advanced stage. Despite aggressive treatment of early and locally advanced disease, SCLC often relapses. First line chemotherapy provides good response rates in advanced disease, but progression free and overall survival are limited. New drugs such as some targeted therapies and immune therapies are promising in SCLC.

Areas covered: In this review, we discuss the preclinical rationale and trial data for targeted therapies and immune therapies in SCLC, with a specific focus on clinical trials.

Expert commentary: Lack of identification of clear prognostic and predictive biomarkers has limited the advances in treatment efficacy. This has most likely been the main cause of failure for compounds tested so far. Due to the highly mutational profile and the rapid growth pattern of SCLC, immunotherapy combined with chemotherapy seems the most promising treatment option. Concerning targeted agents, achievements made so far are small, but DLL3-antibodies or combinations of PARPi and immunotherapy could be very promising. These promising strategies also need testing in limited disease.     

Update on medical treatment of small intestinal neuroendocrine tumors

Introduction: Small intestinal (SI) neuroendocrine tumors (NETs) are relatively rare tumors. Due to the lack of symptom or specific symptoms, SI-NETs are often diagnosed at an advanced stage, making therapy challenging. The management of patients with advanced stage SI-NETS requires a multidisciplinary approach that combines surgical and medical treatment including novel targeted molecular therapies.

Areas covered: This article summarizes current strategies for the medical treatment of SI-NETS.

Expert commentary: The treatment plan of advanced-stage SI-NETs should be tailored in a case-by-case manner with the adoption of a multidisciplinary approach that combines different treatment options, including biological targeted therapies. In particular, we believe that the identification of the optimal treatment sequence(s), correct treatment timing and the selection of patients eligible to different treatments need specific investigation in controlled clinical trials.     

Current and future therapeutic approaches for the treatment of small cell lung cancer

Introduction: Small-cell lung cancer (SCLC) is a very aggressive disease characterized by a high response rate to first-line chemotherapy, but most patients relapse within 1 year with disappointing results to second-line treatments. Chemotherapy has reached a plateau of effectiveness and new therapeutic strategies are needed to change the natural history of SCLC.

Areas covered: This review will focus on the current results and the future development of the therapeutic approaches for the treatment of SCLC.

Expert commentary: Immunotherapy is becoming a new frontier for the management of SCLC with preliminary interesting results. To date, no targeted drugs have been approved for clinical practice but several novel agents are in an advanced stage of clinical development in SCLC.     

Therapeutic approaches for refractory germ cell cancer

Introduction: Most germ cell cancer patients with metastatic disease are cured by cisplatin-based combination chemotherapy. 30% of metastatic patients will develop relapse or progress despite adequate first-line treatment and will require salvage therapy, with about 10% of metastasized patients ultimately developing platinum-resistant and fatal disease.

Areas covered: Based on a comprehensive literature search of MEDLINE, EMBASE and conference proceedings of ESMO, ASCO and EAU meetings, this review provides an overview on current and potential future treatment options for platinum-refractory germ cell cancer patients including cytostatics and molecularly targeted therapies.

Expert commentary: Treatment of platinum-refractory disease remains challenging and long-term survival is rarely achieved despite multimodal treatment approaches. Targeted treatment approaches do not yet play a role in the treatment of platinum-refractory disease due to lacking efficacy in small, unselected clinical trials. Inclusion of patients into clinical trials is strongly recommended.     

Emerging data on improving response to hormone therapy: the role of novel targeted agents

Introduction: Hormone receptor positive (HR+) breast cancer represents the most common subtype of breast cancer. Metastatic HR+ breast cancer may develop resistance to standard hormone therapies, arising from genomic alterations in the estrogen receptor and/or upregulation of other signal transduction pathways.

Areas covered: In this review, we discuss hormone resistance and strategies to overcome it, from the pre-clinical and clinical perspectives. This review includes a discussion of inhibition of the PI3K/AKT/mTOR, CDK 4/6, histone deacetylation, fibroblast growth factor receptor, and immune pathways, based on review of relevant literature.

Expert commentary: Several emerging novel therapies to improve the response to hormone therapy are approved or are in development. The most promising agents at present are inhibitors of CDK 4/6 and mTOR, which have already been incorporated into treatment in the advanced stage setting and are under study for early stage disease.     

Opportunities and challenges of long term anti-estrogenic adjuvant therapy: treatment forever or intermittently?

Introduction: Extended adjuvant (5–10 years) therapy targeted to the estrogen receptor (ER) has

significantly decreased mortality from breast cancer (BC).

Areas covered: Translational research advanced clinical testing of extended adjuvant therapy with tamoxifen or aromatase inhibitors (AIs). Short term therapy or non-compliance increase

recurrence, but surprisingly recurrence and death does not increase dramatically after 5 years of adjuvant therapy stops.

Expert commentary: Compliance ensures optimal benefit from extended antihormone adjuvant therapy.Retarding acquired resistance using CDK4/6 or mTOR inhibitors is discussed. Preventing acquired resistance from mutations of ER could be achieved with Selective ER Downregulators (SERDs), eg fulvestrant. Fulvestrant is a depot injectable so oral SERDs are sought for extended use. In reality, a ‘super SERD’ which destroys ER but improves women’s health like a Selective ER Modulator (SERM), would aid compliance to prevent recurrence and death. Estrogen-induced apoptosis occurs in 30% of BC with antihormone resistance. The ‘one in three’ rule that dictates that one in three unselected patients respond to either hormonal or antihormonal therapy in BC occurs with estrogen or antiestrogen therapy and must be improved. The goal is to maintain patients for their natural lives by blocking cancer cell survival through precision medicine using short cycles of estrogen apoptotic salvage therapy, and further extended antihormone maintenance.     

Future applications of FGF/FGFR inhibitors in cancer

Introduction: Deregulation of the fibroblast growth factor (FGF)/FGF receptor (FGFR) network occurs frequently in tumors due to gene amplification, activating mutations, and oncogenic fusions. Thus, the development of FGF/FGFR-targeting therapies is the focus of several basic, preclinical, and clinical studies.

Areas covered: This review will recapitulate the status of current FGF/FGFR-targeted drugs.

Expert commentary: Non-selective FGF/FGFR inhibitors have been approved for cancer treatment but evidence highlights various complications affecting their use in the clinical practice. It appears mandatory to identify FGF/FGFR alterations and appropriate biomarkers that may predict and monitor response to treatment, to establish the contribution of the FGF/FGFR system to the onset of mechanisms of drug resistance, and to develop effective combinations of FGF/FGFR inhibitors with other targeted therapies.     

Targeting pathways mediating resistance to anti-EGFR therapy in squamous cell carcinoma of the head and neck

Introduction: As epidermal growth factor receptor (EGFR) is overexpressed in approximately 90% of squamous cell carcinomas of the head and neck (SCCHN), several therapeutic agents that target EGFR have been evaluated for the treatment of SCCHN. Although patients with SCCHN derive clinical benefit from anti-EGFR agents, most notably the EGFR monoclonal antibody cetuximab, these patients eventually become resistant to EGFR-based therapies; preclinical studies have shown activation of secondary signaling pathways that lead to resistance to EGFR inhibition and, as such, serve as potential therapeutic targets to overcome resistance to EGFR inhibitors.

Areas covered: This review summarizes the results of recently completed trials of anti-EGFR agents in SCCHN, highlights the various mechanisms that drive resistance to EGFR inhibitors in SCCHN, and focuses on several novel targeted agents that could potentially help overcome resistance to EGFR-based therapies in SCCHN.

Expert commentary: Due to the development of resistance to EGFR-targeted therapies, novel treatment approaches to overcome resistance are a key unmet need for SCCHN.     

Radiosurgery/stereotactic radiotherapy in combination with immunotherapy and targeted agents for melanoma brain metastases

Introduction: The clinical landscape of advanced melanoma drastically changed after the introduction of both targeted therapies and immunotherapy. This rapid development in systemic therapies led to a change in the management of patients with brain metastases, with the subsequent need to re-assess the role of local therapies, in particular stereotactic radiosurgery (SRS).

Areas covered: In this non-systematic review, we report on the current knowledge on the use of SRS in combination with immunotherapy and BRAF/MEK inhibitors for patients with melanoma brain metastases, as well as ongoing trials in this field.

Expert commentary: It is now more common to observe patients with melanoma brain metastases with better performance status and prolonged life expectancy. A combination of targeted therapy and immunotherapy, in different sequences, has been shown to be feasible and well tolerable, on the basis of retrospective reports. Additional data from ongoing prospective trials are however needed to confirm or not these findings and better explore the efficacy of the combination.     

Therapeutic approaches for T790M mutation positive non-small-cell lung cancer

Introduction: Epidermal growth factor receptor (EGFR) mutation positive non-small cell lung cancer (NSCLC) is a subset of lung cancer with demonstrated response to targeted therapies. However, resistance to the first targeted approach usually occurs within the first year, and it is associated in 50–60% of cases to the T790M resistance mutation.

Areas covered: The review provides an overview on the significance of the presence of the T790M mutation, its detection, treatment options and subsequent mechanisms of resistance.

Expert commentary: Osimertinib is the current treatment option for T790M mutation positive NSCLC after progression to first or second-generation EGFR TKIs, with activity also on brain metastasis. However, the scenario is in continuous evolution and results from clinical trials are awaited in first-line setting and in combination strategies.     

The safety and efficacy of sonidegib for the treatment of locally advanced basal cell carcinoma

Introduction: Basal cell carcinomas (BCCs) are the commonest malignancy in the Western world. Locally advanced BCCs (laBCCs) represent tumours that have developed in difficult-to-treat facial sites, aggressively recurrent tumours, large neglected tumours and those in which current treatment options are excluded by clinical or patient-driven criteria. It is estimated laBCCs represent 1% of BCCs.

Areas covered: Sonidegib is an oral hedgehog pathway inhibitor with a novel structure. It has recently been licensed for the treatment of laBCC.

This article provides a comprehensive review of the literature regarding sonidegib, detailing the pharmacology of the compound, clinical trial data, competitor compounds and a future perspective.

Expert commentary: Sonidegib is a novel smoothened (SMO) inhibitor with comparable efficacy to vismodegib, with patient response rates of 44% (sonidegib) and 43% (vismodegib). The adverse effect profile of these two treatments is similar with the main effects being considered to be class effects of SMO inhibitors.     

Recent advances in the management of pancreatic adenocarcinoma

Introduction: Pancreatic cancer (PC) demonstrates very poor prognosis and its incidence continues to increase, despite developments in chemotherapy, radiotherapy, and targeted therapies. Surgical resection is currently the only curative approach for PC. The role of radiotherapy in adjuvant and locally advanced PC continues to be increasingly controversial. This review article aims to explore the current knowledge of pancreatic adenocarcinoma, focusing on diagnosis, treatment strategies, and the best supportive care.

Areas covered: The current literature on pancreatic adenocarcinoma treatment modalities has been summarized, with a focus on clinical trials and reviews. New treatment strategies and their impact on clinical practice have also been discussed.

Expert commentary: Despite many therapeutic developments, only modest improvements in survival rates have been achieved. There is an essential need to increase survival by developing more innovative treatment approaches for patients with PC.     

Preventing central nervous system metastases in non-small cell lung cancer

Introduction: There are no effective central nervous system (CNS) metastases prevention methods in lung cancer patients. Prophylactic cranial irradiation has a limited effectiveness and relatively high toxicity. Systemic chemotherapy is not relevant in reducing the risk of CNS in lung cancer patients. The understanding of molecular background of brain metastases in non-small cell lung cancer (NSCLC) patients could contribute to the development of personalized treatments for such patients.

Areas covered: This article summarizes the latest clinical trials concerning the use of radiotherapy, chemotherapy, molecularly targeted therapies, and immunotherapy in lung cancer patients, with particular consideration of brain lung cancer metastasis prevention. The literature search was undertaken via PubMed and EMBASE searches and relevant articles are included in this review.

Expert commentary: The recent data supports that EGFR-TKIs and ALK inhibitors are clinically relevant for first-line treatment to prevent and treat CNS metastases in molecularly selected NSCLC patients. In the future, high hopes for the prevention of CNS metastases in NSCLC patients are associated with immunotherapy concerning immune check-points inhibitors.     

A look at treatment strategies for relapsed multiple myeloma

Introduction: Multiple myeloma treatment considerably improved during the past decade, thanks to novel effective drugs, a better understanding of myeloma biology and clonal heterogeneity, and an improved management of toxicities. The choice of regimen at relapse is usually based on prior response, toxicities, age and comorbidities of relapsed patients.

Areas covered: A review was performed of the most recent and effective therapeutic strategies for the relapsed myeloma setting, by documenting the latest clinical evidence from phase II and III clinical trials. Of note, new drugs, such as carfilzomib, ixazomib, pomalidomide, daratumumab and elotuzumab, alone or in combinations in doublet or triplet regimens, have greatly increased the treatment armamentarium against myeloma.

Expert commentary: Impressive results have been obtained with new drugs in relapsed patients. Besides number of prior therapies and previous response, other factors play a crucial role in the selection of therapy. Re-challenge with previous drugs can be adopted if previous responses lasted at least 6 months and therapy had induced low toxicity. Patients’ risk status can further help to appropriately select therapy at relapse, and clinical trials will allow physicians to use newer targeted therapies and immune-therapies, thus delaying palliative approaches to later relapse stages.     

Fulvestrant for the treatment of advanced breast cancer

Introduction: The current issues with endocrine therapy for treatment of advanced breast cancer include balance of efficacy of therapy versus tolerability as well as hormone resistance. The efficacy of fulvestrant, a selective oestrogen receptor degrader (SERD), has been demonstrated in hormone receptor positive patients previously untreated or treated with hormonal therapy.

Areas covered: This article discusses the journey of fulvestrant licensing, its efficacy in combination with other endocrine therapies and the future role it may have within breast cancer treatment.

Expert commentary: Within phase III trials, fulvestrant has demonstrated equivalent or improved clinical efficacy when compared with established endocrine agents. In the recent decade, fulvestrant has achieved licensing as a second line agent in non-operative advanced breast cancer at initially 250mg, increasing to 500mg. Presently, fulvestrant is licensed globally as first line endocrine management for advanced breast cancer in post-menopausal women. Early combination trials of fulvestrant and cyclin dependent kinase 4/6 inhibitors have demonstrated good clinical efficacy with improved progression free survival when compared to fulvestrant alone.     

Optimizing treatments for recurrent or metastatic head and neck squamous cell carcinoma

Introduction: The majority of patients with locally advanced head and neck squamous cell carcinoma (HNSCC) will recur. The treatment of patients with recurrent/metastatic (R/M HNSCC) is rapidly evolving.

Areas covered: This article will comprehensively review the current systemic treatment of R/M HNSCC.

Expert commentary: For the time being, the EXTREME regimen (cetuximab in combination with platinum and 5-fluorouracil) still remains standard of care in previously untreated R/M HNSCC patients who are candidates for combination chemotherapy. Single agents with well documented activity in HNSCC include methotrexate, cisplatin, 5-FU, docetaxel, and paclitaxel. The anti-PD-1 monoclonal antibody nivolumab can be considered the current standard of care in patients with R/M HNSCC progressing after platinum-based therapy based on the results of CheckMate 141 showing a survival benefit over standard of care drugs, such as single agent weekly cetuximab, methotrexate, or docetaxel.

Multiple randomized phase III trials comparing anti-PD(L)-antibodies either as single agent or in combination with chemotherapy or an anti-CTLA-4 with the EXTREME as fist line treatment are ongoing or planned. The outcome of these trials might change the current treatment paradigm in previously untreated R/M HNSCC. Immunotherapeutic agents under active investigation include Toll-like receptor 8 agonists and inhibitors of IDO1.     

Capture-based ultra-deep sequencing in plasma ctDNA reveals the resistance mechanism of ALK inhibitors in a patient with advanced ALK-positive NSCLC

Background: Anaplastic lymphoma kinase (ALK) is a validated molecular target in non–small-cell lung cancer (NSCLC). However, the clinical benefits of ALK inhibitors are almost universally limited by the emergence of drug resistance.

Methods: We monitored the plasma circulating tumor DNA (ctDNA) using captured-based ultra-deep sequencing analysis of one patient with metastatic ALK-positive NSCLC who had received therapies including first-, second- and third-generation ALK inhibitors. Functional in vitro studies were further undertaken to elucidate the mechanism of resistance.

Results: ALK T1151Sins mutation was detected when the patient developed resistance to ceritinib, and undetectable when she responded to lorlatinib. MET amplification was present when the tumor developed resistance to lorlatinib, and reduced when the patient received combination therapy of lorlatinib with crizotinib, which corresponded to clinical radiologic responses. In addition, further functional in vitro studies demonstrated that ALK harboring the T1151Sins mutation, while conferring resistance to ceritinib, was inhibited by lorlatinib.

Conclusions: Clinical evidence and in vitro validation revealed the clinical usefulness of captured-base ultra-deep sequencing on longitudinal plasma ctDNA in revealing the underlying resistance mechanism and guiding the precise administration of ALK inhibitors in patients with advanced ALK-positive NSCLC.     

Predictive biomarkers along gastric cancer pathogenetic pathways

Introduction: Gastric cancer is the second leading cause of cancer all over the world. Unfortunately, several gastric cancers are diagnosed in an advanced stage and chemotherapy and/or target therapies remain the only options to treat patients.

Areas covered: Herein we evaluate the new molecular proposal of gastric cancer classification, offering the possibility to recognize different pathogenetic mechanisms and molecular biomarkers potentially useful for target therapies.

Expert commentary: The possibility of introducing new specific tests for identification of molecular biomarkers critical for targeted therapies response represents the new frontier in the selection of gastric cancer patients to improve their survival. Besides HER2, already used in clinical settings as a target biomarker for biological therapy in gastric cancer patients with tissue cancer cells overexpressing HER2, other promising target biomarkers which are deregulated in gastric cancer, such as MET and FGFR, could be identified in tissue and then used for therapeutic purposes. In addition immunotherapy represents the most promising possibility of advanced gastric cancer treatment. In particular, as in other solid tumors, PD-1/PDL1 pathway has emerged in several clinical trials as an interesting therapeutic target.