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Background: The role of MET alterations in non-small cell lung cancer (NSCLC) is increasing and several targeted agents are under evaluation. MET exon 14 skipping mutations and MET amplifications are associated with potential sensitivity to MET inhibition, though resistance mechanisms are emerging. In MET addicted cells, MET inhibition leads to activation of proviral integration site for Moloney murine leukemia virus-1 (PIM1). PIM1 and proto-oncogene tyrosine-protein kinase Src (SRC) can regulate the expression of receptor tyrosine kinases (RTKs), potentially inducing resistance to MET inhibition through cross-activation. Methods: We evaluated the activity of class I-II MET inhibitors, the SRC inhibitor dasatinib, and panPIM inhibitors in four MET addicted cell lines. We assessed the effect of the dual MET/PIM and MET/ SRC inhibition on cell viability and at the protein level. We evaluated RNA expression profiles of the cell lines. Advanced NSCLCs were also screened for MET alterations. Results: All cell lines were sensitive to class I-II MET inhibitors. All cell lines were resistant to single PIM and SRC inhibition. Dual MET/PIM inhibition was synergistic or additive in MET amplified cell lines and dual MET/SRC inhibition was highly synergistic in all MET addicted cell lines. The addition of an SRC inhibitor partially prevents the RTKs cross-activation. MET alterations were found in 9 out of 97 evaluable samples (9.3%); median overall survival in MET altered patients was 5 months (95% CI, 3 m-NA). Conclusions: We identified a potential role of PIM inhibition in MET amplified tumors and of SRC inhibition in MET addicted tumors. Potential applications of this new treatment strategy warrant further evaluation.

During the last decades, genetic characterization of tumors has gained an increasing role in the development of new systemic treatments and one of the most commonly recognized needs in modern oncology is to use molecular characterization to tailor therapy. In many malignancies, but especially in non-small cell lung cancer (NSCLC), therapeutic algorithms are shaped based on genetic characterization and identification of driver alterations, which can be targeted with highly specific drugs (1). The current paradigm in precision oncology is that the more accurate we are in defining the disease, the best treatment we can administer to the patient in terms of efficacy, duration of clinical benefit and survival. This common ground is slowly but firmly pushing techniques for broad genetic characterization into daily practice of NSCLC. Next generation sequencing (NGS) allows screening of a large number of genetic alterations simultaneously and advanced stage disease is the first setting in which such analyses are currently applied.

IMPORTANCE: Bevacizumab treatment beyond progression has been investigated in breast and metastatic colorectal cancers. Avastin in All Lines Lung (AvaALL) is the first randomized phase 3 study of bevacizumab across multiple lines of treatment beyond progression in non–small cell lung cancer (NSCLC). OBJECTIVE: To assess the efficacy and safety of continuous bevacizumab treatment beyond first progression in NSCLC. DESIGN, SETTING, AND PARTICIPANTS: AvaALL was a randomized, open-label, phase 3b trial, conducted from 2011 to 2015 in 123 centers worldwide. Patients with nonsquamous NSCLC previously treated with first-line bevacizumab plus platinum-doublet chemotherapy and at least 2 cycles of bevacizumab maintenance were randomized (1:1) at first progression to receive bevacizumab plus standard of care (SOC) or SOC alone. INTERVENTIONS: Patients received bevacizumab (7.5 or 15 mg/kg intravenously every 21 days) and/or investigator’s choice of SOC. For subsequent lines, patients treated with bevacizumab received SOC with or without bevacizumab; the SOC arm received SOC only. MAIN OUTCOMES AND MEASURES: The primary outcome was overall survival (OS). Secondary outcomes included progression-free survival from first to second (PFS2) and third progression (PFS3), time to second (TTP2) and third progression (TTP3), and safety. RESULTS: Between June 2011 and January 2015, 485 patients (median age, 63.0 years [range, 26-84 years]; 293 [60.4%] male) were randomized. Median OS was not significantly longer with bevacizumab plus SOC vs SOC alone: 11.9 (90% CI, 10.2-13.7) vs 10.2 (90% CI, 8.6-11.9) months (hazard ratio [HR], 0.84; 90% CI, 0.71-1.00; P = .104). Median PFS2 was numerically longer with bevacizumab plus SOC vs SOC alone: 5.5 (90% CI, 4.2-5.7) vs 4.0 (90% CI, 3.4-4.3) months (HR, 0.83; 90% CI, 0.70-0.98; P = .06). Median PFS3 appeared longer with bevacizumab plus SOC vs SOC alone: 4.0 (90% CI, 2.9-4.5) vs 2.6 (90% CI, 2.3-2.9) months (HR, 0.63; 90% CI, 0.49-0.83), as did TTP2 and TTP3. Grade 3/4 adverse events were more frequent with bevacizumab plus SOC (186 [76.5%]) vs SOC alone (140 [60.3%]). No new safety signals were observed. CONCLUSIONS AND RELEVANCE: The primary end point was not met; however, OS was underpowered according to initial statistical assumptions. Continued therapy beyond first progression led to improved PFS3 (but not PFS2), TTP2, and TTP3. Although a result with P = .06 for PFS2 would conventionally be considered significant at a specified 2-sided α of .10, in the absence of adjustments for multiplicity, this result could be a chance finding. No new safety signals were identified with bevacizumab treatment beyond progression. TRIAL REGISTRATION: clinicaltrialsregister.eu Identifier: 2010-022645-14; ClinicalTrials.gov identifier: NCT01351415