Treatment beyond progression with immunotherapy may be appropriate in selected patients based on the potential for late responses. The aim of this systematic review was to explore the impact of ...treatment beyond progression in patients receiving an anti-PD-1/PD-L1 based regimen for an advanced solid tumor.
A systematic literature search was performed to identify prospective clinical trials reporting data on overall response rate by immune-related criteria and/or the number of patients treated beyond conventional criteria-defined PD and/or the number of patients achieving a clinical benefit after an initial PD with regimens including an anti-PD-1/PD-L1 agent which received the FDA approval for the treatment of an advanced solid tumor.
254 (4.6%) responses after an initial RECIST-defined progressive disease were observed among 5588 patients, based on 35 trials included in our analysis reporting this information. The overall rate of patients receiving treatment beyond progressive disease was 30.2%, based on data on 5334 patients enrolled in 36 trials, and the rate of patients who achieved an unconventional response among those treated beyond progressive disease was 19.7% (based on 25 trials for a total of 853 patients).
The results of our systematic review support the clinical relevance of unconventional responses to anti-PD-1/PD-L1-based regimens; however, most publications provided only partial information regarding immune-related clinical activity, or did not provide any information at all, highlighting the need of a more comprehensive report of such data in trials investigating immunotherapy for the treatment of patients with advanced tumors.
Incidence of melanoma has been constantly growing during the last decades. Although most of the new diagnoses are represented by thin melanomas, the number of melanoma-related deaths in 2018 was ...60,712 worldwide (Global Cancer Observatory, 2019). Until 2011, no systemic therapy showed to improve survival in patients with advanced or metastatic melanoma. At that time, standard of care was chemotherapy, with very limited results. The identification of BRAF V600 mutation, and the subsequent introduction of BRAF targeting drugs, radically changed the clinical practice and dramatically improved outcomes. In this review, we will retrace the development of molecular-target drugs and the current therapeutic scenario for patients with BRAF mutated melanoma, from the introduction of BRAF inhibitors as single agents to modern clinical practice. We will also discuss the resistance mechanisms identified so far, and the future therapeutic perspectives in BRAF mutated melanoma.
The first-line therapy in advanced kidney cancer has changed in recent years due to the introduction of combinations of tyrosine kinase inhibitors (TKIs) of vascular endothelial growth factor ...receptors (VEGFR) and immune checkpoint inhibitors (ICIs). Although immune-related adverse events are well-known, in the case of combination treatments, the determination of which drug is related to an adverse event may be challenging. We reported two cases of patients who developed muscle enzyme elevation in association with hypothyroidism during therapy with pembrolizumab plus axitinib for metastatic kidney cancer. The myopathy rapidly resolved after hormone replacement therapy with levothyroxine. Hypothyroid myopathy is a scarcely known and underreported adverse event. This adverse event may be relevant in the differential diagnosis with immune-related myositis, which has an autoimmune pathogenesis and a potentially fatal course.
Cutaneous squamous cell carcinoma (CSCC) accounts for approximately 20% of all keratinocytic tumors. In most cases, the diagnosis and treatments are made on small, low-risk lesions. However, in about ...5% of cases, CSCC may present as either locally advanced or metastatic (i.e. with locoregional lymph nodes metastases or distant localizations). Prior to the introduction of immunotherapy in clinical practice, the standard treatment of advanced CSCC was not clearly defined, and up to 60% of patients received no systemic therapy. Thanks to a strong pre-clinical rationale, clinical trials led to the FDA (Food and Drug Administration) and EMA (European Medicines Agency) registration of cemiplimab, a PD-1 inhibitor that achieved encouraging results in terms of objective response, overall survival, and quality of life. Subsequently, the anti-PD-1 pembrolizumab received the approval for the treatment of advanced CSCC by the FDA only. In this review, we will focus on the definition of advanced CSCC and on the current and future therapeutic options, with a particular regard for immunotherapy.
Major advances have been made in CRC treatment in recent years, especially in molecularly driven therapies and immunotherapy. Despite this, a large number of advanced colorectal cancer patients do ...not benefit from these treatments and their prognosis remains poor. The landscape of DNA damage response (DDR) alterations is emerging as a novel target for treatment in different cancer types. PARP inhibitors have been approved for the treatment of ovarian, breast, pancreatic, and prostate cancers carrying deleterious
pathogenic variants or homologous recombination repair (HRR) deficiency (HRD). Recent research reported on the emerging role of HRD in CRC and showed that alterations in these genes, either germline or somatic, are carried by up to 15-20% of CRCs. However, the role of HRD is still widely unknown, and few data about their clinical impact are available, especially in CRC patients. In this review, we report preclinical and clinical data currently available on DDR inhibitors in CRC. We also emphasize the predictive role of DDR mutations in response to platinum-based chemotherapy and the potential clinical role of DDR inhibitors. More preclinical and clinical trials are required to better understand the impact of DDR alterations in CRC patients and the therapeutic opportunities with novel DDR inhibitors.
While cutaneous melanomas are well-documented, primary melanoma of the lung (PMML), particularly with endobronchial origin, remains rare and poorly characterized. This case report addresses gaps in ...understanding by presenting a comprehensive case of a 71-year-old male with primary endobronchial melanoma and conducting a systematic review of PMML cases.
The patient, a former smoker, presented with dyspnea, cough, and hemoptysis. Imaging revealed left lung atelectasis and a suspicious nodule. Bronchoscopy identified an endobronchial mass, subsequently treated with argon plasma coagulation and resection. Biopsy confirmed melanoma. Extensive examinations ruled out a primary skin lesion. Despite initial treatment, recurrence led to pneumonectomy. Histopathology confirmed melanoma. The patient received treatment with pembrolizumab and ipilimumab, but with poor clinical benefit.
Primary endobronchial melanoma is a rare entity, comprising 0.01% of lung tumors. This case underscores diagnostic challenges and emphasizes histological criteria to distinguish primary from metastatic lesions. The pathogenesis remains unclear, with theories proposing foetal melanocyte migration or squamous metaplasia. Prognosis varies, necessitating radical surgical extirpation. A systematic review revealed diverse outcomes, supporting the need for further research. In conclusion, endobronchial melanoma involves an endoscopic and surgical management, but evolving therapies, such as immunotherapy, may reshape treatment paradigms. This case contributes to our understanding of PMML, guiding future research and clinical management. As therapeutic options evolve, continued research is crucial to refine our understanding and improve outcomes for this rare malignancy.
Merkel cell carcinoma (MCC) is a rare, highly aggressive, neuroendocrine cutaneous tumor. The incidence of MCC is growing worldwide, and the disease-related mortality is about three-fold higher than ...melanoma. Since a few years ago, very little has been known about this disease, and chemotherapy has been the standard of care. Nowadays, new discoveries about the pathophysiology of this neoplasm and the introduction of immunotherapy allowed to completely rewrite the history of these patients. In this review, we provide a summary of the most important changes in the management of Merkel cell carcinoma, with a focus on immunotherapy and a landscape of future treatment strategies.
Adjuvant treatment of operated melanoma has deeply changed in the last few years with the introduction of immune-checkpoint inhibitors and BRAF/MEK inhibitors. Sarcoidosis is a systemic inflammatory ...disease causing non-caseous granulomatous reactions. Sarcoid-like granulomatous reactions have been reported in patients with advanced melanoma, mostly related to immunotherapy with immune-checkpoint inhibitors. We report a case of a 38-year-old woman with stage III operated melanoma treated with adjuvant BRAF plus MEK inhibitors, who developed sarcoidosis-like syndrome with systemic involvement, resolved after discontinuation of treatment. The occurrence of immune-related toxicity with the use of MAPK inhibitors supports the hypothesis that this class of drugs may also have an immunological effect, and that the long-term efficacy of adjuvant MAPK inhibitors may be due to their immunological function.
Melanoma is one of the most aggressive tumors of the skin, and its incidence is growing worldwide. Historically considered a drug resistant disease, since 2011 the therapeutic landscape of melanoma ...has radically changed. Indeed, the improved knowledge of the immune system and its interactions with the tumor, and the ever more thorough molecular characterization of the disease, has allowed the development of immunotherapy on the one hand, and molecular target therapies on the other. The increased availability of more performing technologies like Next-Generation Sequencing (NGS), and the availability of increasingly large genetic panels, allows the identification of several potential therapeutic targets. In light of this, numerous clinical and preclinical trials are ongoing, to identify new molecular targets. Here, we review the landscape of mutated non-
BRAF
skin melanoma, in light of recent data deriving from Whole-Exome Sequencing (WES) or Whole-Genome Sequencing (WGS) studies on melanoma cohorts for which information on the mutation rate of each gene was available, for a total of 10 NGS studies and 992 samples, focusing on available, or in experimentation, targeted therapies beyond those targeting mutated BRAF. Namely, we describe 33 established and candidate driver genes altered with frequency greater than 1.5%, and the current status of targeted therapy for each gene. Only 1.1% of the samples showed no coding mutations, whereas 30% showed at least one mutation in the
RAS
genes (mostly
NRAS
) and 70% showed mutations outside of the
RAS
genes, suggesting potential new roads for targeted therapy. Ongoing clinical trials are available for 33.3% of the most frequently altered genes.
A significant number of women receive a cancer diagnosis before their age of natural menopause. Among these patients, the most frequent neoplasms are breast cancer, gynecological, and hematological ...malignancies. Premature ovarian insufficiency and infertility are among the most feared short- to long-term consequences of anticancer treatments in premenopausal patients. Both patient- and treatment-related characteristics are key factors in influencing the risk of gonadotoxicity with the use of chemotherapy. The cryopreservation of oocytes/embryos is a standard strategy for fertility preservations offered to young women interested in future family planning, but it does not allow gonadal function protection during chemotherapy. Ovarian suppression with gonadotropin-releasing hormone agonist (GnRHa) during chemotherapy is now recommended as an option to reduce the risk of gonadotoxicity in order to avoid the negative consequences of premature ovarian insufficiency in premenopausal women receiving cytotoxic therapy, including those not interested in fertility preservation. This review summarizes the risk of treatment-induced gonadotoxicity in premenopausal patients and the evidence available on the protective role of administering GnRHa during chemotherapy to preserve ovarian function.
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