Promising targetable biomarkers in pancreatic neuroendocrine tumours.

INTRODUCTION: In the treatment scenario of PanNETs-targeted therapies are desired but limited, as rarity and heterogeneity on PanNETs pose limitations to their development. AREAS COVERED: We performed a literature review searching for promising druggable biomarkers and potential treatments to be implemented in the next future. We focused on treatments which have already reached clinical experimentation, although in early phases. Six targets were identified, namely Hsp90, HIFa, HDACs, CDKs, uPAR, and DDR. Even though biological rational is strong, so far reported efficacy outcomes are quite disappointing. The reason of that should be searched in the patients' heterogeneity, lack of biomarker selection, poor knowledge of interfering mechanisms as well as difficulties in patients accrual. Moreover, different ways to assess treatment efficacy should be considered, other than response rate, in light of the more indolent nature of NETs. EXPERT OPINION: Development of targeted treatments in PanNETs is still an uncovered area, far behind other more frequent cancers. Rarity of NETs led to accrual of unselected populations, possibly jeopardizing the drug efficacy. Better patients' selection, both in terms of topography, grading and biomarkers is crucial and will help understanding which role targeted therapies can really play in these tumors.

Ten years-experience of sunitinib in the treatment of advanced pan-NETs: an update on safety profile.

INTRODUCTION: Sunitinib still represents a milestone in the treatment for progressive, well-differentiated, advanced panNETs. AREAS COVERED: We performed an evidence reappraisal to critically discuss its safety profile. We included nine studies, five clinical trials and four real-world (RW) studies. Within non-real-world (NRW) studies, diarrhea was the most frequent clinical AE. With regard to G3-4 AEs, fatigue and hypertension were the two most frequent, while neutropenia was the most recurrent hematological one. Considering four real-world trials, hand-foot-syndrome (HFS) was the most frequent clinical any-grade AE of any grade and neutropenia was the most common G3-4. Alongside to the AEs rate, the discontinuation rate of sunitinib due to TRAEs was variable among all the nine selected studies, ranging from 10% to 35% in the NRW setting and from 7% to 31% in the RW setting. Conversely, temporary interruption is an accepted strategy to reduce toxicity, even though not specifically tested in pan-NET. EXPERT OPINION: Till now, sunitinib continues to be one of the main therapeutic options for patients with well differentiated advanced panNETs, potentially covering any line of treatment. Therefore, tolerability plays a crucial role to increase adherence to therapy and maximize QoL.

Clinical efficacy of sequential treatments in KRASG12C-mutant metastatic colorectal cancer: findings from a real-life multicenter Italian study (CRC-KR GOIM).

BACKGROUND: The presence of KRASG12C mutation in metastatic colorectal cancer (mCRC) correlates with poor outcome. Although different selective inhibitors are under clinical development, the optimal treatment remains uncertain. Thus, we conducted a retrospective analysis in a large cohort of patients with KRASG12C mCRC treated in 12 Italian oncology units. PATIENTS AND METHODS: Patients with unresectable mCRC harboring KRASG12C mutation receiving a first-line chemotherapy doublet or triplet between 2011 and 2021 were included in the study. Evaluation of overall response rate (ORR), progression-free survival (PFS) and overall survival (OS) analysis was carried out. RESULTS: A total of 256/6952 (3.7%) patients with mCRC displayed KRASG12C mutation; of these, 111 met the inclusion criteria. The ORR of first-line therapy was 38.7% (43/111). Median PFS (mPFS) was 9 months [95% confidence interval (CI) 7.5-10.5 months]. After progression, only 62% and 36% of the patients are fit to receive second or third lines of treatment, with limited clinical benefit. Median OS (mOS) was 21 months (95% CI 17.4-24.6 months). In patients receiving first-line triplet chemotherapy, ORR was 56.3% (9/16), mPFS was 13 months (95% CI 10.3-15.7 months) and mOS was 32 months (95% CI 7.7-56.3 months). For irinotecan-based doublets, ORR was 34.5 (10/29), mPFS was 9 months (95% CI 6.4-11.6 months) and mOS was 22 months (95% CI 16.0-28.0 months). With oxaliplatin-based doublets ORR was 36.4% (24/62), mPFS was 7 months (95% CI 4.6-9.4 months) and mOS was 18 months (95% CI, 13.6-22.4 months). CONCLUSION: Patients with KRASG12C-mutant mCRC had a disappointing response to standard treatments. Within the limitations of a retrospective study, these results suggest that first-line chemotherapy intensification with FOLFOXIRI is a valid option in fit patients.

Should temozolomide be used on the basis of O6-methylguanine DNA methyltransferase status in patients with advanced neuroendocrine tumors? A systematic review and meta-analysis.

BACKGROUND: Temozolomide (TEM) is an active treatment in metastatic neuroendocrine tumors (NETs). Patients affected by glioblastoma multiforme or advanced melanoma treated with TEM who have deficiency of O6-methylguanine DNA methyltransferase (MGMT) have a better responses and survival. However, the predictive role of MGMT in patients with NETs treated with TEM is still debated. METHODS: We conducted a systematic review of the literature and meta-analysis, based on PRISMA methodology, searching in the main databases (PubMed, Embase, Scopus, Web of Science, Cochrane Library and clinical trial.gov) and the proceedings of the main international congresses, until April 26, 2021. RESULTS: Twelve out of 616 articles were selected for our analysis, regarding a total of 858 NET patients treated with TEM-based chemotherapy. The status of MGMT had been tested in 513 (60%) patients, using various methods. The pooled overall response rate (ORR) was higher in MGMT-deficient compared with MGMT-proficient NETs, with a risk difference of 0.31 (95% confidence interval, CI: 0.13-0.50; p < 0.001; I2: 73%) and risk ratio of 2.29 (95% CI: 1.34-3.91; p < 0.001; I2: 55%). The pooled progression free survival (PFS) (hazard ratio, HR = 0.56; 95% CI: 0.43-0.74; p < 0.001) and overall survival (OS) (HR = 0.41; 95% CI: 0.20-0.62; p = 0.011) were longer in MGMT-deficient versus MGMT-proficient NETs. CONCLUSIONS: Our meta-analysis suggested that MGMT status may be predictive of TEM efficacy. However, due to the high heterogeneity of the evaluated studies the risk of biases should be considered. On this hypothesis future homogeneous prospective studies are warranted.

SARS-CoV-2-related pneumonia can be successfully managed in patients with metastatic neuroendocrine tumors: a critical point of view.

Primary neuroendocrine tumors of the thymus are extremely rare. In patients with advanced disease, tumor growth control, and sometimes also syndrome control are the main goals of systemic therapy. Unfortunately, no standard therapies are available in clinical practice; therefore, clinical studies are strongly recommended. Axitinib (AXI) is a tyrosine kinase inhibitor, currently under investigation in an international phase II/III trial including thymic neuroendocrine tumors. Over the past 5 months, the entire world has been facing a devastating medical emergency brought about by a pandemic due to a novel coronavirus known as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which emerged in Wuhan, China, in late 2019. Since then, health professionals have been expending all their efforts on trying to provide the best available treatments for patients involved. Patients with cancer, especially those with thoracic involvement, are at higher risk of coronavirus disease 19 (COVID-19) and its complications because of their immunosuppressive status caused by the cancer and the anticancer therapies. As it remains unclear how to optimally manage such patients, we wished to report our experience with a patient with a metastatic neuroendocrine tumor of the thymus infected with SARS-CoV-2 in the hope that it may provide some insights and reflections on the management of cancer patients during this challenging time in our history.