Advanced Pancreatic Neuroendocrine Neoplasms: Which Systemic Treatment Should I Start With?

PURPOSE OF REVIEW: Pancreatic neuroendocrine neoplasms (panNENs) often present as advanced disease and there is little data to guide treatment sequencing in the advance disease setting. Therefore, we aim to provide a comprehensive summary of the current evidence supporting the use of systemic treatment for patients with diagnosis of advanced and metastatic panNENs, as well as to provide strategies for treatment selection and address challenges for treatment selection and sequencing of therapy. RECENT FINDINGS: Substantial advances have been made and many clinical trials have been performed over the past two decades expanding therapeutic options available for patients with advanced panNETs. Available systemic treatments for patients with well-differentiated pancreatic neuroendocrine tumors include somatostatin receptors ligands (SRLs), traditional cytotoxic chemotherapy regimens, peptide receptor radiotherapy (PRRT), and biologically targeted therapies, whereas patients with poorly differentiated neurodocrine carcinomas have more limited treatment options. Despite these advances, no clear guidelines exist to support the best sequence of treatments, not only the first-line, but also subsequent lines of therapy in patients with panNENs. Advances in molecular research and discovery of biomarkers for response allowing a more personalized approach to the multimodality therapy of panNENs are still limited. Understanding the impact of previous therapies on subsequent treatment efficacy and toxicity is also an ongoing research question. In the absence of definite predictive markers and paucity of comparative randomized trials, along with the heterogeneity of this patient population, systemic therapy selection in advanced non-resectable disease should be patient centered and often require evaluation within a multidisciplinary setting. The specific clinical context of the patient, with assessment of individual patient clinical and pathological features, somatostatin receptors imaging, and goals of treatment must all be considered when deciding on systemic therapy in the patient. Additional research is needed to address the gap in knowledge regarding optimal sequencing and timing of therapies and to provide individual care.

Therapeutic potential of the new TRIB3-mediated cell autophagy anticancer drug ABTL0812 in endometrial cancer.

OBJECTIVES: The PI3K/AKT/mTOR pathway is frequently overactivated in endometrial cancer (EC). We assessed the efficacy of ABTL0812, a novel first-in-class molecule presenting a unique mechanism of action inhibiting this pathway. METHODS: We investigated the effects of ABTL0812 on proliferation, cell death and modulation of intracellular signaling pathways in a wide panel of endometrioid and non-endometrioid cell lines, an inducible PTEN knock-out murine model, and two patient-derived xenograft murine models of EC. Then, TRIB3 expression was evaluated as potential ABTL0812 pharmacodynamic biomarker in a Phase 1b/2a clinical trial. RESULTS: ABTL0812 induced an upregulation of TRIB3 expression, resulting in the PI3K/AKT/mTOR axis inhibition and autophagy cell death induction on EC cells but not in healthy endometrial cells. ABTL0812 treatment also impaired PTEN knock-out cells to progress from hyperplasia to cancer. The therapeutic effects of ABTL0812 were demonstrated in vivo. ABTL0812 increased TRIB3 mRNA levels in whole blood samples of eight EC patients, demonstrating that TRIB3 mRNA could be used as a pharmacodynamic biomarker to monitor the ABTL0812 treatment. CONCLUSIONS: ABTL0812 may represent a novel and highly effective therapeutic agent by inducing TRIB3 expression and autophagy in EC patients, including those with poorer prognosis.

New Targeted Agents in Endometrial Cancer: Are We Really Making Progress?

Endometrial cancer is the most common gynecological malignancy in Europe and North America. Metastatic and recurrent disease is generally incurable with poor prognosis. Recent advances in molecular profiling of endometrial cancer have elucidated four distinct molecular subtypes with different biology and prognosis which should facilitate the development of treatments tailored to disease-specific subgroups. To date, some molecular-targeted agents have shown interesting clinical activity in the recurrent setting, but no targeted therapies are approved for endometrial cancer. Novel pan-PI3K, AKT, and dual PI3K-mTOR inhibitors are being investigated with early signs of activity, but there are concerns about tolerability and toxicity in this often elderly patient population with comorbidities. The development of anti-angiogenic therapies, PARP inhibitors, and immunotherapies, alone or in combinations, appear to be promising strategies. This paper will describe the current evidence supporting the efficacy of molecular-targeted agents already tested in the treatment of metastatic and recurrent EC, and provide some insights on emerging data related to novel-targeted therapies.

Dynamic Contrast-enhanced CT to Evaluate Early Response in Neuroendocrine Liver Metastases Treated With Everolimus and Radiation.

BACKGROUND/AIM: The optimal method to evaluate response of neuroendocrine liver metastases (NELM) to radiation treatment (RT) is unknown; tumor perfusion parameters were evaluated by using dynamic contrast-enhanced computed tomography (DCE-CT) to correlate with efficacy in a prospective pilot study utilizing everolimus with radiotherapy for NELM. PATIENTS AND METHODS: Fourteen patients with progressive NELM received everolimus for 28 days prior to, concurrent with, and 14 days following radiation. Patients had a DCE-CT at baseline (t0), prior to radiation (t1) and 7 days after radiation (t2). Per lesion response was evaluated per standard response evaluation criteria (RECIST v1.1). Median statistics of the perfusion parameters were tabulated and included: blood flow (BF), blood volume (BV), and permeability (PS). Correlations between the parameters and the maximum percent change in size of the NELM at 12-months were explored. NELM not treated with radiation served as an internal control. RESULTS: Twenty-one treated NELM in 10 patients were evaluable. Compared to t0, BV increased at t1 (median 11%, range -15 to +37%, p=0.59), and then decreased significantly at t2 (median -8.4%, range -29 to +5.4%, p<0.03). A trend of increased BV in internal controls at each time point supports that the observed effect is due to radiation. Conventional objective response rate was 33%; no progression was seen within 12-months. CONCLUSION: Changes in DCE-CT were observed in patients receiving everolimus and radiation for NELM, with BV decreasing significantly following radiotherapy. Given the challenges in assessing response in NELM using traditional response evaluation criteria in any context, DCE-CT appears to be a promising modality.

Phase 2 Trial (POLA Study) of Lurbinectedin plus Olaparib in Patients with Advanced Solid Tumors: Results of Efficacy, Tolerability, and the Translational Study.

We hypothesized that the combination of olaparib and lurbinectedin maximizes DNA damage, thus increasing its efficacy. The POLA phase 1 trial established the recommended phase 2 dose of lurbinectedin as being 1.5 mg (day 1) and that of olaparib as being 250 mg/12 h (days 1-5) for a 21-day cycle. In phase 2, we explore the efficacy of the combination in terms of clinical response and its correlation with mutations in the HRR genes and the genomic instability (GI) parameters. Results: A total of 73 patients with high-grade ovarian (n = 46), endometrial (n = 26), and triple-negative breast cancer (n = 1) were treated with lurbinectedin and olaparib. Most patients (62%) received ≥3 lines of prior therapy. The overall response rate (ORR) and disease control rate (DCR) were 9.6% and 72.6%, respectively. The median progression-free survival (PFS) was 4.54 months (95% CI 3.0-5.2). Twelve (16.4%) patients were considered long-term responders (LTR), with a median PFS of 13.3 months. No clinical benefit was observed for cases with HRR gene mutation. In ovarian LTRs, although a direct association with GI and a total loss of heterozygosity (LOH) events was observed, the association did not reach statistical significance (p = 0.055). Globally, the total number of LOHs might be associated with the ORR (p =0.074). The most common grade 3-4 toxicities were anemia and thrombocytopenia, in 6 (8.2%) and 3 (4.1%) patients, respectively. Conclusion: The POLA study provides evidence that the administration of lurbinectedin and olaparib is feasible and tolerable, with a DCR of 72.6%. Different GI parameters showed associations with better responses.

A phase I dose-finding, pharmacokinetics and genotyping study of olaparib and lurbinectedin in patients with advanced solid tumors.

The poly (ADP-Ribose) polymerase (PARP) inhibitor olaparib has shown antitumor activity in patients with ovarian or breast cancer with or without BRCA1/2 mutations. Lurbinectedin is an ecteinascidin that generates DNA double-strand breaks. We hypothesized that the combination of olaparib and lurbinectedin maximizes the DNA damage increasing the efficacy. A 3 + 3 dose-escalation study examined olaparib tablets with lurbinectedin every 21 days. The purpose of this phase I study is to determine the dose-limiting toxicities (DLTs) of the combination, to investigate the maximum tolerated dose (MTD), the recommended phase II dose (RP2D), efficacy, pharmacokinetics, in addition to genotyping and translational studies. In total, 20 patients with ovarian and endometrial cancers were included. The most common adverse events were asthenia, nausea, vomiting, constipation, abdominal pain, neutropenia, anemia. DLT grade 4 neutropenia was observed in two patients in dose level (DL) 5, DL4 was defined as the MTD, and the RP2D was lurbinectedin 1.5 mg/m2 + olaparib 250 mg twice a day (BID). Mutational analysis revealed a median of 2 mutations/case, 53% of patients with mutations in the homologous recombination (HR) pathway. None of the patients reached a complete or partial response; however, 60% of stable disease was achieved. In conclusion, olaparib in combination with lurbinectedin was well tolerated with a disease control rate of 60%. These results deserve further evaluation of the combination in a phase II trial.

A pilot study of everolimus and radiation for neuroendocrine liver metastases.

Liver metastases are common in patients with neuroendocrine tumours. For patients, management must balance disease control with consideration of toxicity, given limited treatment options. Everolimus has demonstrated effectiveness in neuroendocrine neoplasms. Given emerging data of a synergistic effect with radiation therapy, we evaluated combined everolimus and radiation for neuroendocrine liver metastases. This single-arm, single-centre prospective pilot study evaluated the safety and efficacy of combined everolimus and radiotherapy for well-differentiated neuroendocrine liver metastases. Patients with unresectable liver metastases received everolimus for 30 days, followed by concurrent everolimus and liver radiotherapy, then a further 14 days of everolimus. Tolerability was evaluated using the CTCAE v.4.03. Individual metastasis response rate and local control were measured by RECIST v1.1. Overall survival, progression-free survival and freedom from a change in systemic therapy were estimated by the Kaplan-Meier method. Forty metastases were treated in 14 patients. No grade 3 or higher toxicities were identified in the concurrent treatment phase; one patient developed grade 3 toxicity in the post-radiation phase. Overall response rate was 38%. One- and 2-year local control were 97% and 71%. Median progression-free survival was 12 months. One- and 2-year overall survival were 100% and 92%. In conclusion, combined everolimus and radiation are well-tolerated for neuroendocrine liver metastases and are associated with excellent local control. The approach of selective local ablation of oligometastatic or oligoprogressive disease warrants further evaluation in this patient population.

Practical recommendations for the management of patients with gastroenteropancreatic and thoracic (carcinoid) neuroendocrine neoplasms in the COVID-19 era.

Neuroendocrine neoplasms (NENs) are a heterogeneous family of uncommon tumours with challenging diagnosis, clinical management and unique needs that almost always requires a multidisciplinary approach. In the absence of guidance from the scientific literature, along with the rapidly changing data available on the effect of COVID-19, we report how 12 high-volume NEN centres of expertise in 10 countries at different stages of the evolving COVID-19 global pandemic along with members of international neuroendocrine cancer patient societies have suggested to preserve high standards of care for patients with NENs. We review the multidisciplinary management of neuroendocrine neoplasms during the COVID-19 pandemic, and we suggest potential strategies to reduce risk and aid multidisciplinary treatment decision-making. By sharing our joint experiences, we aim to generate recommendations for proceeding to other institutions facing the same challenges.

Genomic heterogeneity and efficacy of PI3K pathway inhibitors in patients with gynaecological cancer.

OBJECTIVES: Aberrant PI3K/AKT/mTOR activation is common in gynaecological malignancies. However, predictive biomarkers of response to PI3K pathway inhibitors (PAMi) have yet to be identified. METHODS: We analysed the outcomes of patients with advanced gynaecological cancer with available genomic data, treated with PAMi as single agents or in combination in phase I clinical trials. Clinical relevance of the PIK3CA mutant allele fraction (MAF) was investigated. MAF of each variant was normalised for tumour purity in the sample (adjMAFs) to infer clonality of PIK3CA mutations, defined as clonal (≥0.4) or subclonal (<0.4). RESULTS: A total of 50 patients with gynaecological cancer (24 ovarian; 15 endometrial; 11 cervical) with available targeted mutation profiling were selected. PAMi therapy was matched to PIK3CA/PTEN mutation in 30 patients (60%). The overall response rate, median time to progression (mTTP) and clinical benefit rate (CBR) of the entire population were 10% (N=5), 3.57 months (2.57-4.4) and 40% (N=18), respectively. Genotype-matched therapy did not lead to a favourable CBR (OR 0.91, p=1 (0.2-3.7)) or mTTP (3.57 months (2.6-4.4) vs 3.73 months (1.9-13.2); HR 1.41; p=0.29). We did not detect differences in mTTP according to therapy or PIK3CA codon mutation (HR 1.71, p=0.24). Overall, 41% of patients had a TTP ratio (TTP PAMi/TTP on immediately prior or subsequent palliative chemotherapy) ≥1.3, without statistically significant differences according to tumour type (p=0.39), molecular alteration status (p=0.13) or therapy (p=0.54). In univariate analysis, genotype-matched therapy in patients with PIK3CA clonal events was associated with improved mTTP (HR 3.6; p=0.03). CONCLUSIONS: Our study demonstrates that patients with advanced gynaecological cancer, refractory to standard therapies, achieved meaningful clinical benefit from PAMi. The impact of PI3KCA clonality on response to selected PAMi in patients with gynaecological cancer deserves further investigation.

Current and emerging treatment options in the management of advanced ovarian cancer.

INTRODUCTION: Epithelial ovarian cancer is the most lethal gynecologic malignancy. Recent advances in understanding the biology and its molecular and histological diversity have led to mechanism based therapeutic strategies such as poly-ADP-ribose polymerase inhibitors (PARP) targeting homologous recombination deficient tumor cells and anti-angiogenic therapies. Clinical trial designs in ovarian cancer have to evolve to incorporate assessment of the genomic complexity and identify predictive biomarkers to improve precision of treatment and outcome. AREAS COVERED: This review summarizes present-day strategies used in the management of ovarian cancer and novel promising therapeutic approaches in development. The article is based on English peer-reviewed articles located on MEDLINE and related abstracts presented at major international meetings. EXPERT OPINION: Two types of molecular targeted therapies, anti-angiogenics and PARP inhibitors, have been shown to be active in randomized clinical trials and approved by regulatory agencies. Management of ovarian cancer is poised to change with the continued advancement of precision medicine that is founded upon improved understanding of disease biology; separation into histologically and molecularly defined subgroups; and the incorporation of this new knowledge into early phase drug development and novel clinical trial design.

Breaking down the evidence for bevacizumab in advanced cervical cancer: past, present and future.

Despite the introduction of screening and, latterly, vaccination programs in the developed world, globally cervical cancer remains a significant health problem. For those diagnosed with advanced or recurrent disease even within resource rich communities, prognosis remains poor with an overall survival (OS) of just over 12 months. New therapeutic interventions are urgently required. Advances in our understanding of the mechanisms underlying tumor growth and the downstream effects of human papilloma virus (HPV) infection identified angiogenesis as a rational target for therapeutic intervention in cervical cancer. Anti-angiogenic agents showed promising activity in early phase clinical trials culminating in a randomized phase III study of the humanized monoclonal antibody to vascular endothelial growth factor (VEGF), bevacizumab, in combination with chemotherapy. This pivotal study, the Gynecologic Oncology Group protocol 240, met its primary endpoint demonstrating a significant improvement in OS. Bevacizumab became the first targeted agent to be granted regulatory approval by the United States Food and Drug Administration for use alongside chemotherapy in adults with persistent, recurrent or metastatic carcinoma of the cervix. This review outlines the rationale for targeting angiogenesis in cervical cancer focusing on the current indications for the use of bevacizumab in this disease and future directions.

Fluorescence in situ hybridization and immunohistochemistry as diagnostic methods for ALK positive non-small cell lung cancer patients.

BACKGROUND: Anaplastic Lymphoma Kinase (ALK) positivity represents a novel molecular target in a subset of Non-Small Cell Lung Cancers (NSCLC). We explore Fluorescence in situ Hybridization (FISH) and Immunohistochemistry (IHC) as diagnostic methods for ALK positive patients and to describe its prevalence and outcomes in a population of NSCLC patients. METHODS: NSCLC patients previously screened for Epidermal Growth Factor Receptor (EGFR) at our institution were selected. ALK positive patients were identified by FISH and the value of IHC (D5F3) was explored. RESULTS: ninety-nine patients were identified. Median age was 61.5 years (range 35-83), all were caucasians, eighty percent were adenocarcinomas, fifty-one percent were male and thirty-eight percent were current smokers. Seven (7.1%) patients were ALK positive by FISH, thirteen (13.1%) were EGFR mutant, and 65 (65.6%) were negative/Wild Type (WT) for both ALK and EGFR. ALK positivity and EGFR mutations were mutually exclusive. ALK positive patients tend to be younger than EGFR mutated or wt patients. ALK positive patients were predominantly never smokers (71.4%) and adenocarcinoma (71.4%). ALK positive and EGFR mutant patients have a better outcome than negative/WT. All patients with ALK FISH negative tumours were negative for ALK IHC. Out of 6 patients positive for ALK FISH with more tissue available, 5 were positive for ALK IHC and 1 negative. CONCLUSIONS: ALK positive patients represent 7.1% of a population of selected NSCLC. ALK positive patients have different clinical features and a better outcome than EGFR WT and ALK negative patients. IHC is a promising method for detecting ALK positive NSCLC patients.

SEOM guidelines for endometrial cancer.

Endometrial cancer (EC) is the most common gynaecological tumour in developing countries. Most patients with EC are diagnosed at an early stage with a low risk of relapse and overall survival at 5 years greater than 85%. Nevertheless, there is a subgroup of patients with a very poor prognosis due to the pathological features and molecular characteristics. Until now there has been no consensus regarding adjuvant treatment in EC patients, with many open questions: In which patients is it indicated? Which is the best approach: chemotherapy, radiotherapy or both? What is the right timing? Relevant clinical trials are in progress in order to answer these questions. Unfortunately, the survival of patients with metastatic or recurrent EC is quite short due to the poor responses to standard first-line chemotherapy and the lack of second lines of treatment.

SEOM guidelines for cervical cancer.

Cervical cancer (CC) is the second most common cancer worldwide, with a well known origin, infection by high-risk human papilloma virus. Although screening programmes have led to a relevant reduction in the incidence and mortality due to CC in developed countries, it is still an important cause of mortality in young women in undeveloped countries. Clinical stage is the most relevant prognostic factor in CC and the standard of care is still based on it. In early stages, the primary treatment is surgery or radiotherapy, whereas concomitant chemo-radiotherapy is the conventional approach in locally advanced stage. In the setting of recurrent or metastatic CC the treatment is largely palliative, so it is important to develop new therapeutic strategies.