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Exploiting MET Dysregulation in EGFR-Addicted Non-Small-Cell Lung Carcinoma: a Further Step Toward Personalized Medicine

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Exploiting MET Dysregulation in EGFR-Addicted Non-Small-Cell Lung Carcinoma: a Further Step Toward Personalized Medicine 317 Editorial Exploiting MET dysregulation in EGFR-addicted non-small-cell lung carcinoma: a further step toward personalized medicine Vincenzo Di Noia1, Ettore D’Argento1, Sara Pilotto2, Miriam Grazia Ferrara1, Michele Milella2, Giampaolo Tortora1, Emilio Bria1 1U.O.C. Medical Oncology, Fondazione Policlinico Universitario Agostino Gemelli, IRCCS, Università Cattolica del Sacro Cuore, Rome, Italy; 2U.O.C. Oncology, Azienda Ospedaliera Universitaria Integrata, University and Hospital Trust of Verona, Verona, Italy Correspondence to: Prof. Emilio Bria. U.O.C. Medical Oncology, Fondazione Policlinico Universitario Agostino Gemelli, IRCCS, Università Cattolica del Sacro Cuore, Rome, Italy. Email: [email protected]. Comment on: Wu YL, Zhang L, Kim DW, et al. Phase Ib/II Study of Capmatinib (INC280) Plus Gefitinib After Failure of Epidermal Growth Factor Receptor (EGFR) Inhibitor Therapy in Patients With EGFR-Mutated, MET Factor-Dysregulated Non-Small-Cell Lung Cancer. J Clin Oncol 2018. [Epub ahead of print]. Submitted Dec 07, 2018. Accepted for publication Dec 14, 2018. doi: 10.21037/tlcr.2018.12.08 View this article at: http://dx.doi.org/10.21037/tlcr.2018.12.08 Patients affected by non-small-cell lung cancer (NSCLC) based chemotherapy remains the only available worldwide harboring epidermal growth factor receptor (EGFR) approved treatment option. For these reasons, such clinical activating mutations derive a dramatic and essential clinical scenario represents a challenging issue for physicians in benefit from EGFR tyrosine kinase inhibitors (TKIs) clinical practice. therapy in terms of activity, efficacy and quality of life (1,2). MET gene amplification is the second most important Nevertheless, besides the important therapeutic impact of mechanism (5–20% of patients) of acquired resistance to these targeted agents, EGFR-addicted diseases typically EGFR TKIs and in a half of cases concurrently occurs with develop resistance under the selective pressure of TKIs, T790M EGFR mutation (6). MET-dependent resistance usually within 1 year of treatment. In 50–60% of patients, is triggered by the activation of common downstream such acquired resistance to first- and second-generation pathways to EGFR receptor, directly by the homodimer EGFR TKIs is related to the acquisition of EGFR T790M formation or indirectly by trans-activating other tyrosine mutation, a second-site ‘on-target’ point mutation which kinase receptors. This way EGFR signaling becomes affects the adenosine triphosphate (ATP) binding pocket of redundant and, as preclinical studies suggest, targeting both EGFR tyrosine-kinase domain. In this regard, osimertinib, receptors by adding an anti-MET agent to EGFR TKIs a third-generation EGFR inhibitor with prominent activity is required to obtain an effective antitumor activity (7). A against both T790M resistance mutation and the standard series of anti-MET-agents, including TKIs or monoclonal activating EGFR mutations, represents a very active antibodies (MoAbs), have been developed and tested treatment for patients with EGFR T790M-dependent in NSCLC patients. The outcomes of EGFR mutated NSCLC who experienced disease progression after first- population included in anti-MET trials are reported in line EGFR TKIs therapy, as demonstrated in AURA1-2-3 Table 1 (8-12). studies (3-5). While the EGFR T790M-driven disease still Wu et al. recently published a phase 1b/2 study (13), in mirrors the typical oncogene-addicted NSCLC, with the which the combination of the MET inhibitor capmatinib majority of tumors dramatically responding to osimertinib and the EGFR inhibitor gefitinib appears safe and active and deriving a significant delay in tumor progression, in patients with T790M-negative acquired resistance to T790M negative patients represent a heterogeneous prior EGFR TKI therapy carrying MET-dysregulation population whereas tumors with extremely different clinical (amplification or overexpression). Different doses of and biological findings co-exist and where platinum- capmatinib plus gefitinib (250 mg) were examined in © Translational lung cancer research. All rights reserved. tlcr.amegroups.com Transl Lung Cancer Res 2018;7(Suppl 4):S312-S317 Translational LungCancerResearch,Vol7,Suppl4December2018 Table 1 Other phase II and III trials evaluating anti-MET in EGFR-mutated non-small cell lung cancer EGFR Primary ORR Median HR Agent Trial Population MET abnormalities Setting Arms N status endpoint (OR) (ms) [95% CI] Capmatinib Phase II NSCLC Mutated IHC MET-positive Acquired Capmatinib + 61 ORR 29% – – (2+ or 3+ in ≥50% resistance to Gefitinib of TC) or MET EGFR-TKIs amplification by FISH (GCN ≥4) NSCLC Mutated MET amplification Acquired Capmatinib + 36 ORR 47% – – by FISH (GCN ≥6) resistance to Gefitinib EGFR-TKIs NSCLC Mutated IHC MET-positive Acquired Capmatinib + 25 ORR 32% – – (2+ or 3+ in ≥50% resistance to Gefitinib of TC) EGFR-TKIs Emibetuzumab NCT01900652 NSCLC Mutated IHC MET-positive Pretreated Emibetuzumab; 28; 83 ORR 4.3%; – – (8); phase II (27% (2+ or 3+ in ≥10% Erlotinib + 3.0% T790M+) of TC) Emibetuzumab NSCLC Mutated High IHC; MET- Pretreated Emibetuzumab; 21; 53 ORR 4.8%; – – (27% positive (2+ or 3+ Erlotinib + 3.8% T790M+) in ≥60% of TC) Emibetuzumab Onartuzumab Phase II (9) NSCLC Mutated Unselected 2–3 lines Erlotinib + Placebo; 6; 7 OS* – NR; NR 2.2 Erlotinib + Onartuzumab; NSCLC Mutated IHC MET-positive 2–3 lines Erlotinib + Placebo; 2; 7 OS* – NR; NR 4.81E7 (2+ or 3+ in ≥60% Erlotinib + of TC) Onartuzumab; Transl LungCancerRes Transl METLung (10); NSCLC Mutated IHC MET-positive 2–3 lines Erlotinib + 28; 57 OS – 12.6; NE 4.68 phase III (2+ or 3+ in ≥60% Onartuzumab; [0.97–22.63] of TC) Erlotinib + Placebo Tivantinib MARQUEE Non-squamous Mutated Unselected Pretreated Erlotinib + Tivantinib; 56; 53 PFS – 13; 7.5 0.49 (11); phase III 109/1,048 Erlotinib + Placebo [0.31–0.77] (10.4%) 2018;7(Suppl 4):S312-S317 Table 1 (Continued) S313 © Translational lung cancer research. All rights reserved. tlcr.amegroups.com S314 Table 1 (Continued) EGFR Primary ORR Median HR Agent Trial Population MET abnormalities Setting Arms N status endpoint (OR) (ms) [95% CI] Tepotinib Phase II (12) NSCLC EGFR MET-positive Resistance to Tepotinib + Gefitinib; 31; 24 PFS – 4.9; 4.4 0.71 mutated; (2+ or 3+ or MET prior EGFR TKI Carboplatin/cisplatin [0.36–1.39] No T79M amplification by + pemetrexed ISH (GCN ≥5 and/ or MET/CEP ≥2) NSCLC EGFR High IHC 3+ Resistance to Tepotinib + Gefitinib; 19; 15 PFS – 8.3; 4.4 0.35 mutated; prior EGFR TKI Carboplatin/cisplatin [0.17–0.74] No T79M + pemetrexed NSCLC EGFR MET amplification Resistance to Tepotinib + Gefitinib; 12; 7 PFS – 21.2; 4.4 0.17 mutated; by ISH [GCN prior EGFR TKI Carboplatin/cisplatin [0.05–0.57] No T79M ≥5 and/or MET/ + pemetrexed CEP ≥2] *, the primary endpoint of the study was PFS, but only the OS outcome were reported for EGFR mutated population. CEP, chromosome enumeration probes; FISH, Fluorescence In situ hybridization; IHC, immunohistochemistry; ISH, in situ hybridization; GCN, gene copy number; ms, months; NR, not reported; ORR, overall response rate; OS, overall survival; PFS, progression free survival. patients whosetumorsharbor of activity, a higher response rate (47%) was observed in safety profile of theWith combination. regard to predictors response rate was 27%, with a generally well-tolerable of 29% was achieved. Combining both phases, overall study (400mgtwicedaily),andanoverallresponserate capmatinib at the dose identified in the phase I part of the the combination of gefitinib (250 mg per day) plus enrolled. In the phase II of the trial, 100 patients received the phase 1b part of the trial, in which 61 patients were MET MET fluorescence in situ hybridization (FISH) analysis ≥ with tumorsaGCN patients in seen was (PFS) survival progression-free a longer patients withIHC2+andGCN tumors, whichwascomparablewiththeobservedactivityin patients with immunohistochemistry (IHC) score 3+ a genecopynumber(GCN) targeted agents which were early stopped for unacceptable unacceptable for stopped early were which agents targeted suggested. in patientswith the hypothesisthatthiscombination wouldbetterwork in patients with acquired resistance to EGFR TKIs, and gefitinib seemstobeatleastcomparablewithchemotherapy and capmatinib of activity the comparison, indirect of an and PFS 4.6 months). Thus, although considering the bias in the plasma T790M negative population (ORR of 32% and a median PFS of 5.4 months, which were even lower received chemotherapy alone achieved an ORR of 34% with continuation of the gefitinib or placebo. Patients who to 6 cycles of cisplatin-pemetrexed chemotherapy together progressed on first-line gefitinib were randomized to up trial (15), non-squamous NSCLC patients who had now (14). With regard to chemotherapy, in the IMPRESS to belimitedintheoncogene-addicteddisease,atleastfor addition ofcheck-pointinhibitors,whoseefficacyappear preferentially investigatedthanthoseemergingfromthe In addition,thesepromisingearlydatadeservetobe platinum-based chemotherapy as standard treatment. to EGFRTKIs,who arecurrentlycandidatetoreceive with NSCLC patients EGFR strategy includingtheconcurrentinhibitionof the combinationofcapmatinibplusgefitinib. beshrankwith staining toidentifytumors morelikelyto (with acut-offofGCN 5 (7.29 months). Thus, the biomarker analysis prioritizes Conversely to other studies including combination of Conversely tootherstudies includingcombinationof These results,generatethehypothesisthatatherapeutic signaling could be conceivable for T790M
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