Immunotherapy has recently emerged as a novel strategy for treating different types of solid tumors, with promising results. However, still a large fraction of patients do not primarily respond to such approaches, and even responders sooner or later develop resistance. Moreover, immunotherapy is a promising strategy for certain malignancies but not for others, with this discrepancy having been attributed to a more immunogenic microenvironment of some tumors. As abnormal and augmented tumor vessels often occur in cancerogenesis, anti-angiogenic drugs have already demonstrated their effectiveness both in preclinical and in clinical settings. By targeting abnormal formation of tumor vessels, anti-angiogenetic agents potentially result in an enhanced infiltration of immune effector cells. Moreover, crosstalks downstream of the immune checkpoint axis and vascular endothelial growth factor receptor (VEGFR) signaling may result in synergistic effects of combined treatment in tumor cells. In this review, we will describe and discuss the biological rationale of a combined therapy, underlying the modification in tumor microenvironment as well as in tumor cells after exposure to checkpoint inhibitors and anti-angiogenic drugs. Moreover, we will highlight this strategy as a possible way for overcoming drug resistance. By first discussing potential prognostic and predictive factors for combined treatment, we will then turn to clinical settings, focusing on clinical trials where this strategy is currently being investigated.

RET rearrangements are observed in 1–2% of non-small-cell lung cancer (NSCLC) patients and result in the constitutive activation of downstream pathways normally implied in cell proliferation, growth, differentiation and survival. In NSCLC patients, RET rearrangements have been associated with a history of non-smoking, a higher rate of brain metastasis at initial diagnosis and a low immune infiltrate. Traditionally, RET fusions are considered mutually exclusive with other oncogenic drivers, even though a co-occurrence with EGFR mutations and MET amplifications has been observed. Cabozantinib, vandetanib and lenvatinib are the first multi-kinase inhibitors tested in RET-rearranged NSCLC patients with contrasting results. More recently, two selective RET inhibitors, selpercatinib and pralsetinib, demonstrated higher efficacy rates and good tolerability and they were approved for the treatment of patients with metastatic RET fusion-positive NSCLC on the bases of the results of phase II studies. Two ongoing phase III clinical trials are currently comparing selpercatinib or pralsetinib to standard first line treatments and will definitively establish their efficacy in RET-positive NSCLC patients.

Inhibition of angiogenesis has been demonstrated to be an efficacious strategy in treating several tumors. Vascular endothelial growth factor (VEGF) is the most important protein with proangiogenic functions and it is overexpressed in small cell lung cancer (SCLC). Bevacizumab, a monoclonal antibody directed against VEGF, showed a promising activity in combination with etoposide and cisplatin as first-line treatment of patients with extended stage (ES)-SCLC and two randomized studies confirmed that bevacizumab improved PFS, but failed to prolong OS. Instead, disappointing results have been observed with endostar, sunitinib, sorafenib, vandetanib, and thalidomide in combination with chemotherapy in the first-line setting, with sunitinib in the maintenance setting, with sunitinib, cediranib and nintedanib as single agents or ziv-aflibercept in combination with topotecan in second-line setting. Only anlotinib improved OS and PFS as third-line therapy in Chinese patients with SCLC, and it was approved with this indication in China. Future challenges are the evaluation of the role of angiogenesis inhibitors in combination with immune- checkpoint inhibitors and chemotherapy in SCLC patients and the identification of predictive biomarkers of response to both agents.

Cancer and obesity are the two major epidemics of the 21st century. Pancreatic ductal adenocarcinoma (PDAC) is one of the leading causes of death, with a five-year overall survival rate of only 8%. Its incidence and mortality have increased in recent years, and this cancer type is expected to be among the top five leading causes of cancer-related death by 2030 in the United States (US). In the last three decades, the prevalence of overweight people has boosted with a consequent increase in obesity-related diseases. Considerable epidemiologic evidence correlates overweight and obese conditions to an increased risk of several types of cancer, including PDAC. Besides being a risk factor for multiple metabolic disorders, the tumor-promoting effects of obesity occur at the local level via inflammatory mediators that are associated with adipose inflammation and metabolic or hormones mediators and microbiota dysbiosis. Although an excess of body mass index (BMI) represents the second most modifiable risk factor for PDAC with an increased cancer related-death of more than 20–40%, still little is known about the molecular mechanisms that underlie this strong association. In this review, we focused on the role of obesity as a preventable risk factor of PDAC, discussing the molecular mechanisms linking obesity to cancer initiation and progression. Moreover, we highlighted the role of obesity in defining chemoresistance, showing how a high BMI can actually reduce response to chemotherapy.

The optimal therapeutic strategy for locally advanced pancreatic cancer patients (LAPC) has not yet been established. Our aim is to evaluate how surgery after neoadjuvant treatment with either FOLFIRINOX (FFN) or Gemcitabine-NabPaclitaxel (GemNab) affects the clinical outcome in these patients. LAPC patients treated at our institution were retrospectively analysed to reach this goal. The group characteristics were similar: 35 patients were treated with the FOLFIRINOX regimen and 21 patients with Gemcitabine Nab-Paclitaxel. The number of patients undergoing surgery was 14 in the FFN group (40%) and six in the GemNab group (28.6%). The median Disease-Free Survival (DFS) was 77.10 weeks in the FFN group and 58.65 weeks in the Gem Nab group (p = 0.625), while the median PFS in the unresected group was 49.4 weeks in the FFN group and 30.9 in the GemNab group (p = 0.0029, 95% CI 0.138–0.862, HR 0.345). The overall survival (OS) in the resected population needs a longer follow up to be completely assessed, while the median overall survival (mOS) in the FFN group was 72.10 weeks and 53.30 weeks for the GemNab group (p = 0.06) in the unresected population. Surgery is a valuable option for LAPC patients and it is able to induce a relevant survival advantage. FOLFIRINOX and Gem-NabPaclitaxel should be offered as first options to pancreatic cancer patients in the locally advanced setting.