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Several uncommon genomic alterations beyondA prospective data set at three Italian Academic Hospitals included 650 patients with mCRC with comprehensive genomic profiling by FoundationOne CDx and treated with anti-EGFRs. PRESSING2 panel alterations were selected on the basis of previous clinico-biologic studies and includedAmong 162 hyperselected patients, 24 (15%) had PRESSING2 alterations, which were mutually exclusive except in two samples and were numerically higher in right-sided versus left-sided cancers (28%Negative ultraselection warrants further investigation with the aim of maximizing the benefit of EGFR blockade strategies in patients with

PURPOSE Several uncommon genomic alterations beyond RAS and BRAFV600E mutations drive primary resistance to anti–epidermal growth factor receptor (EGFR) monoclonal antibodies in metastatic colorectal cancer (mCRC). Our PRESSING panel (including PIK3CA exon 20/ AKT1/ PTEN mutations, ERBB2/ MET amplifications, gene fusions, and microsatellite instability-high status) represented a paradigm of negative hyperselection with more precise tailoring of EGFR blockade. However, a modest proportion of hyperselected mCRC has intrinsic resistance potentially driven by even rarer genomic alterations. MATERIALS AND METHODS A prospective data set at three Italian Academic Hospitals included 650 patients with mCRC with comprehensive genomic profiling by FoundationOne CDx and treated with anti-EGFRs. PRESSING2 panel alterations were selected on the basis of previous clinico-biologic studies and included NTRKs, ERBB3, NF1, MAP2K1/ 2/ 4, AKT2 pathogenic mutations; PTEN/ NF1 loss; ERBB3, FGFR2, IGF1R, KRAS, ARAF, and AKT1-2 amplification; and EGFR rearrangements. These were collectively associated with outcomes in patients with hyperselected disease, ie, RAS/ BRAF wild-type, PRESSING-negative, and microsatellite stable. RESULTS Among 162 hyperselected patients, 24 (15%) had PRESSING2 alterations, which were mutually exclusive except in two samples and were numerically higher in right-sided versus left-sided cancers (28% v 13%; P = .149). Independently of sidedness and other factors, patients with PRESSING2-positive status had significantly worse progression-free survival and overall survival compared with PRESSING2-negative ones (median progression-free survival: 6.4 v 12.8 months, adjusted hazard ratio 4.19 [95% CI, 2.58 to 6.79]; median overall survival: 22.6 v 49.9 months, adjusted hazard ratio 2.98 [95% CI, 1.49 to 5.96]). The combined analysis of primary tumor sidedness and PRESSING2 status allowed us to better stratify outcomes. CONCLUSION Negative ultraselection warrants further investigation with the aim of maximizing the benefit of EGFR blockade strategies in patients with RAS and BRAF wild-type, microsatellite stable mCRC.

Immunotherapy with antibodies against PD-1 or PD-L1, either alone or in combination with chemotherapy, has revolutionized treatment paradigms of non-small cell lung cancer (NSCLC) patients without oncogenic driver alterations. These agents, namely immune checkpoint inhibitors (ICIs), have also widely demonstrated a remarkable efficacy in locally advanced as well as in early-stage NSCLC. Assessment of tumor PD-L1 expression by immunohistochemistry has entered into routine clinical practice to select patients for immunotherapy, even though its predictive role has long been debated. Despite improved survival outcomes over standard chemotherapy, treatment with ICIs is associated with initial low response rate, with a significant proportion of patients not responding to these agents. Hence, novel appealing predictive biomarkers, such as those related to tumor cell signaling pathways, metabolism or the tumor microenvironment, have emerged as potentially useful to select those patients most likely to benefit from immunotherapy. Moreover, most patients ultimately develop acquired resistance to ICI treatment over time and novel therapeutic strategies are urgently needed to overcome or delay resistance. Herein, we provide an overview on recent advances in immunotherapy in NSCLC, focusing on updated results from studies on ICIs in different disease settings and at different lines of treatment. We further describe currently emerging predictive biomarkers, beyond PD-L1, to optimize patient selection and novel strategies to improve clinical outcomes.

Treatment of advanced non-small cell lung cancer (NSCLC) has radically improved in the last years due to development and clinical approval of highly effective agents including immune checkpoint inhibitors (ICIs) and oncogene-directed therapies. Molecular profiling of lung cancer samples for activated oncogenes, including epidermal growth factor receptor (EGFR), anaplastic lymphoma kinase (ALK), c-ros oncogene 1 (ROS1) and BRAF, is routinely performed to select the most appropriate up-front treatment. However, the identification of new therapeutic targets remains a high priority. Recently, MET exon 14 skipping mutations have emerged as novel actionable oncogenic alterations in NSCLC, sensitive to MET inhibition. In this review we discuss: (I) MET gene and MET receptor structure and signaling pathway; (II) MET exon 14 alterations; (III) current data on MET inhibitors, mainly focusing on selective MET tyrosine kinase inhibitors (TKIs), in the treatment of NSCLC with MET exon 14 skipping mutations. We identified the references for this review through a literature search of papers about MET, MET exon 14 skipping mutations, and MET inhibitors, published up to September 2020, by using PubMed, Scopus and Web of Science databases. We also searched on websites of main international cancer congresses (ASCO, ESMO, IASLC) for ongoing studies presented as abstracts. MET exon 14 skipping mutations have been associated with clinical activity of selective MET inhibitors, including capmatinib, that has recently received approval by FDA for clinical use in this subgroup of NSCLC patients. A large number of trials are testing MET inhibitors, also in combinatorial therapeutic strategies, in MET exon 14-altered NSCLC. Results from these trials are eagerly awaited to definitively establish the role and setting for use of these agents in NSCLC patients.