Evaluation of Fruquintinib in the Continuum of Care of Patients with Colorectal Cancer.

The management of patients with metastatic colorectal cancer (mCRC) has the continuum of care as the treatment paradigm. To date, trifluridine/tipiracil, a biochemically modulated fluoropyrimidine, and regorafenib, a multi-kinase inhibitor, remain the main options for the majority of patients who progressed to standard doublet- or triplet-based chemotherapies, although a tailored approach could be indicated in certain circumstances. Being highly selective for vascular endothelial growth factor receptor (VEGFR)-1, -2 and -3, fruquintinib demonstrated a strong anti-tumor activity in preclinical models and received approval from China's National Medical Products Administration (NMPA) in 2018 for the treatment of patients with chemo-refractory mCRC. The approval was based on the results of the phase III FRESCO trial. Then, in order to overcome geographic differences in clinical practice, the FRESCO-2 trial was conducted in the US, Europe, Japan, and Australia. In a heavily pretreated patient population, the study met its primary endpoint, demonstrating an advantage of fruquintinib over a placebo in overall survival (OS). Here, we review the clinical development of fruquintinib and its perspectives in gastrointestinal cancers. Then, we discuss the introduction of fruquintinib in the continuum of care of CRC paying special attention to unmet needs, including the identification of cross-resistant and potentially susceptible populations, evaluation of radiological response, and identification of novel biomarkers of clinical benefit.

Lung Cancer Immunotherapy: Beyond Common Immune Checkpoints Inhibitors.

Immunotherapy is an ever-expanding field in lung cancer treatment research. Over the past two decades, there has been significant progress in identifying immunotherapy targets and creating specific therapeutic agents, leading to a major paradigm shift in lung cancer treatment. However, despite the great success achieved with programmed death protein 1/ligand 1 (PD-1/PD-L1) monoclonal antibodies and with anti-PD-1/PD-L1 plus anti-cytotoxic T-lymphocyte antigen 4 (CTLA-4), only a minority of lung cancer patients respond to treatment, and of these many subsequently experience disease progression. In addition, immune-related adverse events sometimes can be life-threatening, especially when anti-CTLA-4 and anti-PD-1 are used in combination. All of this prompted researchers to identify novel immune checkpoints targets to overcome these limitations. Lymphocyte activation gene-3 (LAG-3), T cell immunoglobulin (Ig) and Immunoreceptor Tyrosine-Based Inhibitory Motif (ITIM) domain (TIGIT), T cell immunoglobulin and mucin-domain containing-3 (TIM-3) are promising molecules now under investigation. This review aims to outline the current role of immunotherapy in lung cancer and to examine efficacy and future applications of the new immune regulating molecules.

Mutations matter: An observational study of the prognostic and predictive value of KRAS mutations in metastatic colorectal cancer.

Background: About half of metastatic colorectal cancers (CRCs) harbor Rat Sarcoma (RAS) activating mutations as oncogenic driver, but the prognostic role of RAS mutations is not fully elucidated. Interestingly, specific hotspot mutations have been identified as potential candidates for novel targeted therapies in several malignancies as per G12C. This study aims at evaluating the association between KRAS hotspot mutations and patient characteristics, prognosis and response to antiangiogenic drugs. Methods: Data from RAS-mutated CRC patients referred to Careggi University Hospital, between January 2017 and April 2022 were retrospectively and prospectively collected. Tumor samples were assessed for RAS mutation status using MALDI-TOF Mass Spectrometry, Myriapod NGS-56G Onco Panel, or Myriapod NGS Cancer Panel DNA. Results: Among 1047 patients with available RAS mutational status, 183 KRAS-mutated patients with advanced CRC had adequate data for clinicopathological and survival analysis. KRAS mutations occurred at codon 12 in 67.2% of cases, codon 13 in 23.5%, codon 61 in 2.2%, and other codons in 8.2%. G12C mutation was identified in 7.1% of patients and exon 4 mutations in 7.1%. KRAS G12D mutation, as compared to other mutations, was significantly associated with liver metastases (1-sided p=0.005) and male sex (1-sided p=0.039), KRAS G12C mutation with peritoneal metastases (1-sided p=0.035), KRAS G12V mutation with female sex (1-sided p=0.025) and no surgery for primary tumor (1-sided p=0.005). No associations were observed between specific KRAS variants and age, ECOG PS, site of primary tumor, pattern of recurrence for resected patients, and lung, distant lymph node, bone, or brain metastases.Overall survival (OS) was significantly longer in patients with KRAS exon 4 mutations than in those with other KRAS mutations (mOS 43.6 months vs 20.6 months; HR 0.45 [0.21-0.99], p=0.04). No difference in survival was observed for mutations at codon 12/13/61 (p=0.1). Treatment with bevacizumab (BV) increased significatively mPFS (p=0.036) and mOS (p=0.019) of the entire population with a substantial benefit in mOS for G12V mutation (p=0.031). Conclusions: Patterns of presentation and prognosis among patients with specific RAS hotspot mutations deserve to be extensively studied in large datasets, with a specific attention to the uncommon isoforms and the role of anti-angiogenic drugs.