P59.01 Clinical Characteristics of Patients With MET Amplification-Positive NSCLC After EGFR-TKI Therapy

74 Background: c-MET gene amplified ( MET-amp) tumors have been identified as a rare but targetable subset of esophagogastric cancer (EGC). In a phase I study, patients with MET-amp EGC had a 50% response rate to the oral MET inhibitor AMG 337, with some responses exceeding a year (Kwak EL, GI ASCO 2015). We evaluate clinical characteristics and outcomes were evaluated in patients with MET amplified esophagogastric cancer to facilitate identification of patients and establishment of treatment paradigms. Methods: Patients with metastatic MET amplified EGC were identified. MET-amplification was identified by fluorescent in situ hybridization (FISH) on paraffin-embedded tissue, with a gene to control ratio of > 2.2 defined as positive. Clinical characteristics, treatment factors, and survival were recorded. A group of metastatic non- MET amplified patients identified during the same time period who had undergone tumor genotyping and treatment at our institution was evaluated as a comparison group. Results: 21 patients were identified with metastatic MET amplified EGC and 65 patients with metastatic non- MET amplified EGC. The majority of MET amplified tumors occurred in the distal esophagus. 4 patients had co-amplification of HER2, 1 patient had PIK3CA mutation and 1 patient had a TP53 mutation. Compared to non- MET amplified tumors, MET-amplified tumors were more likely to have poorly differentiated tumors. There was no difference in initial sites of metastatic disease. Progression-free survival (PFS) for first line therapy was substantially shorter for patients with MET (6.5 mo vs 14.3 mo, p = 0.0033). MET amplified patients trended towards a shorter overall survival (OS) as well (12.3 mo vs. 20.1 mo, p = 0.0523). Conclusions: MET amplified EGC represents a distinct clinical entity characterized by rapid progression and short survival. Given the efficacy seen with MET inhibition, patients need to be tested and identified early and directed to appropriate MET-targeted clinical trials.

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Rebiopsy of patients (pts) with acquired resistance to epidermal growth factor tyrosine kinase inhibitors (EGFR-TKIs) in non-small cell lung cancer (NSCLC)

Journal of Clinical Oncology ◽

10.1200/jco.2009.27.15_suppl.8025 ◽

2009 ◽

Vol 27 (15_suppl) ◽

pp. 8025-8025 ◽

Cited By ~ 3

Author(s):

M. E. Arcila ◽

G. J. Riely ◽

M. F. Zakowski ◽

M. G. Kris ◽

M. Ladanyi ◽

...

Keyword(s):

Median Time ◽

Progressive Disease ◽

Kinase Inhibitors ◽

Egfr Mutation ◽

Acquired Resistance ◽

Egfr Mutations ◽

Met Amplification ◽

Metastatic Sites ◽

Egfr Tki ◽

Egfr Tkis

8025 Background: The EGFR-TKIs erlotinib and gefitinib produce dramatic regressions of tumor in ∼ 70% of NSCLC patients with activating mutations in the EGFR-TK domain. After a median time to progression of ∼1 year, most pts have progressive disease. We undertook this study to search for mechanisms of “acquired resistance” to EGFR-TKIs, to determine the spectrum and frequency of secondary EGFR mutations which arose, and to determine the feasibility of rebiopsy in this setting. Methods: All pts had metastatic or recurrent NSCLC and prior treatment with EGFR-TKI and progressive disease while on EGFR-TKI. Pts must also have had an activating EGFR mutation OR radiographic response (RECIST or WHO) to EGFR-TKI OR significant and durable improvement in cancer-related symptoms as judged by patient's physician. Core biopsies were performed and studied for EGFR mutation (exons 18–21 including PCR-based test for T790M) and MET amplification. Results: From 8/04–12/08 98 pts were consented for rebiopsy and 85 underwent the procedure. Demographics Female/Male=59/39; median age 62 (range 28–88); smoking: never=59, former/current=39. Primary EGFR mutation was exon 19 del-39; exon 21 L858R-11, other/WT-28, pending-7. Median time on EGFR-TKI before biopsy was 12 months (7–28 months). Secondary EGFR mutations: T790M-33, other-2, none detected-31, indeterminate-10, pending-9. MET amplification in 2/16 studied to date. Conclusions: 1) Rebiopsy of patients with NSCLC and acquired resistance to EGFR TKIs is feasible and well-received by pts. 2) Knowledge of EGFR genotype including EGFR T790M and MET status can inform clinical trials of targeted therapies in this population 3) More complete annotation of MET status and exploratory analyses of profiles of specimens by metastatic sites and prior EGFR-TKI versus chemo and EGFR-TKI is ongoing. Supported by the Doris Duke Foundation, the LaBrecque Foundation, Steps for Breath, NIH, and an anonymous donor. No significant financial relationships to disclose.

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Genomic Profiling Identifies Outcome-Relevant Mechanisms of Innate and Acquired Resistance to Third-Generation Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Therapy in Lung Cancer

JCO Precision Oncology ◽

10.1200/po.18.00210 ◽

2019 ◽

pp. 1-14 ◽

Cited By ~ 2

Author(s):

Sebastian Michels ◽

Carina Heydt ◽

Bianca van Veggel ◽

Barbara Deschler-Baier ◽

Nuria Pardo ◽

...

Keyword(s):

Lung Cancer ◽

Acquired Resistance ◽

Growth Factor Receptor ◽

Third Generation ◽

Met Amplification ◽

Epidermal Growth ◽

Tki Treatment ◽

Egfr Mutant ◽

Egfr Tki ◽

Egfr Tkis

PURPOSE Third-generation epidermal growth factor receptor ( EGFR) tyrosine kinase inhibitors (TKIs) are effective in acquired resistance (AR) to early-generation EGFR TKIs in EGFR-mutant lung cancer. However, efficacy is marked by interindividual heterogeneity. We present the molecular profiles of pretreatment and post-treatment samples from patients treated with third-generation EGFR TKIs and their impact on treatment outcomes. METHODS Using the databases of two lung cancer networks and two lung cancer centers, we molecularly characterized 124 patients with EGFR p.T790M-positive AR to early-generation EGFR TKIs. In 56 patients, correlative analyses of third-generation EGFR TKI treatment outcomes and molecular characteristics were feasible. In addition, matched post-treatment biopsy samples were collected for 29 patients with progression to third-generation EGFR TKIs. RESULTS Co-occurring genetic aberrations were found in 74.4% of EGFR p.T790-positive samples (n = 124). Mutations in TP53 were the most frequent aberrations detected (44.5%; n = 53) and had no significant impact on third-generation EGFR TKI treatment. Mesenchymal-epithelial transition factor ( MET) amplifications were found in 5% of samples (n = 6) and reduced efficacy of third-generation EGFR TKIs significantly (eg, median progression-free survival, 1.0 months; 95% CI, 0.37 to 1.72 v 8.2 months; 95% CI, 1.69 to 14.77 months; P ≤ .001). Genetic changes in the 29 samples with AR to third-generation EGFR TKIs were found in EGFR (eg, p.T790M loss, acquisition of p.C797S or p.G724S) or in other genes (eg, MET amplification, KRAS mutations). CONCLUSION Additional genetic aberrations are frequent in EGFR-mutant lung cancer and may mediate innate and AR to third-generation EGFR TKIs. MET amplification was strongly associated with primary treatment failure and was a common mechanism of AR to third-generation EGFR TKIs. Thus, combining EGFR inhibitors with TKIs targeting common mechanisms of resistance may delay AR.

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Distinct Characteristics and Clinical Outcomes to Predict the Emergence of MET Amplification in Patients with Non-Small Cell Lung Cancer Who Developed Resistance after Treatment with Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors

Cancers ◽

10.3390/cancers13123096 ◽

2021 ◽

Vol 13 (12) ◽

pp. 3096

Author(s):

Beung-Chul Ahn ◽

Ji Hyun Lee ◽

Min Hwan Kim ◽

Kyoung-Ho Pyo ◽

Choong-kun Lee ◽

...

Keyword(s):

Kinase Inhibitors ◽

Growth Factor Receptor ◽

Small Cell ◽

Multivariate Logistic Regression ◽

Small Cell Lung ◽

Met Amplification ◽

Epidermal Growth ◽

Tki Treatment ◽

Egfr Mutant ◽

Egfr Tki

Objectives: Patients with epidermal growth factor receptor (EGFR) mutant non-small cell lung cancer (NSCLC) ultimately acquire resistance to EGFR tyrosine kinase inhibitors (TKIs) during treatment. In 5–22% of these patients, resistance is mediated by aberrant mesenchymal epithelial transition factor (MET) gene amplification. Here, we evaluated the emergence of MET amplification after EGFR-TKI treatment failure based on clinical parameters. Materials and Methods: We retrospectively analyzed 186 patients with advanced EGFR-mutant NSCLC for MET amplification status by in situ hybridization (ISH) assay after EGFR-TKI failure. We collected information including baseline patient characteristics, metastatic locations and generation, line, and progression-free survival (PFS) of EGFR-TKI used before MET evaluation. Multivariate logistic regression analysis was conducted to evaluate associations between MET amplification status and clinical variables. Results: Regarding baseline EGFR mutations, exon 19 deletion was predominant (57.5%), followed by L858R mutation (37.1%). The proportions of MET ISH assays performed after first/second-generation and third-generation TKI failure were 66.7% and 33.1%, respectively. The median PFS for the most recent EGFR-TKI treatment was shorter in MET amplification-positive patients than in MET amplification-negative patients (median PFS 7.0 vs. 10.4 months, p = 0.004). Multivariate logistic regression demonstrated that a history of smoking, short PFS on the most recent TKI, and less intracranial progression were associated with a high probability of MET amplification (all p < 0.05). Conclusions: Our results demonstrated the distinct clinical characteristics of patients with MET amplification-positive NSCLC after EGFR-TKI therapy. Our clinical prediction can aid physicians in selecting patients eligible for MET amplification screening and therapeutic targeting.

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A large real-world study on the effectiveness of the combined inhibition of EGFR and MET in EGFR-mutant advanced non-small cell lung cancer (NSCLC).

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.9043 ◽

2021 ◽

Vol 39 (15_suppl) ◽

pp. 9043-9043

Author(s):

Liu Li ◽

Jingjing Qu ◽

Jianfu Heng ◽

Chunhua Zhou ◽

Yi Xiong ◽

...

Keyword(s):

Real World ◽

Tp53 Mutation ◽

Objective Response ◽

Acquired Resistance ◽

Braf V600e ◽

Monotherapy Group ◽

Chemotherapy Group ◽

Met Amplification ◽

Egfr Mutant ◽

Egfr Tki

9043 Background: MET amplification is an important mechanism mediating acquired resistance to EGFR tyrosine kinase inhibitors (TKI). Until now, no consensus exists on the standard treatment strategy for this subset of patients due to the lack of clinical data from large cohort or controlled trials. In our clinical practice, three regimens were commonly administered to patients after MET amplification-mediated EGFR-TKI progression: EGFR-TKI and MET-TKI combination therapy, MET-TKI monotherapy, or chemotherapy. Our study aimed to compare the effectiveness of these three regimens. Methods: Seventy patients with EGFR-mutant advanced NSCLC who progressed from prior EGFR-TKI through the acquisition of MET amplification and received treatment between March 2015 and March 2020 were included in this study. Of them, 38 received EGFR-TKI plus crizotinib, 10 received crizotinib monotherapy, and 22 received platinum-based doublet chemotherapy. Somatic mutation profiling was performed on blood and tissue biopsy samples. Resistance mechanisms to the combination targeted therapy were also explored in 12 patients. Results: The objective response rate (ORR) and disease control rate (DCR) were 47.5% and 84.0% for EGFR-TKI+crizotinib group, 40.0% and 70.0% for crizotinib monotherapy group, and 18.2% and 50.0% for chemotherapy group, respectively. The EGFR-TKI+crizotinib group had significantly better ORR (P = 0.026) and DCR (P = 0.016) than the chemotherapy group but was not statistically different from the crizotinib monotherapy group (ORR, P = 0.73; DCR, P = 0.39). Progression-free survival (PFS) was significantly longer for the EGFR-TKI+crizotinib group than those who received crizotinib monotherapy (5.0 vs 2.3 months, P = 0.004) or chemotherapy (5.0 vs 2.9 months, P = 0.036), but overall survival was comparable (10.0 vs 4.1 vs 8.5 months, P = 0.088). TP53 mutation (58.5%) and EGFR amplifications (42.9%) were the two common concurrent mutations in the three cohorts. PFS was significantly longer for patients with either concurrent TP53 mutation (n = 17) (6.0 vs 2.3 vs 2.9 months, P = 0.009) or concurrent EGFR amplification (n = 13) (5.0 vs 1.2 vs 2.4 months, P = 0.016) who received EGFR-TKI+crizotinib. Potential molecular mechanisms of acquired resistance to EGFR-TKI+crizotinib therapy included EGFR T790M (n = 2), EGFR L718Q (n = 1), EGFR S645C (n = 1), MET D1228H (n = 1), BRAF V600E (n = 1), NRAS Q61H (n = 1), and amplifications in KRAS (n = 2), ERBB2 (n = 1), CDK4 (n = 1), and MYC (n = 2). Conclusions: Our study provides real-world clinical evidence, in the largest cohort to date, that simultaneous inhibition of EGFR and MET improves clinical outcomes of patients with EGFR-mutant NSCLC who acquired MET amplification from prior EGFR-TKI therapy, indicating that combinatorial regimen of EGFR-TKI and MET-TKI could be a more effective therapeutic strategy in this subset of patients.

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A phase Ib safety and tolerability study of a pan class I PI3K inhibitor buparlisib (BKM120) and gefitinib (gef) in EGFR TKI-resistant NSCLC.

Journal of Clinical Oncology ◽

10.1200/jco.2013.31.15_suppl.8107 ◽

2013 ◽

Vol 31 (15_suppl) ◽

pp. 8107-8107 ◽

Cited By ~ 12

Author(s):

Daniel Shao-Weng Tan ◽

Kiat Hon Lim ◽

Wai Meng Tai ◽

Aziah Ahmad ◽

Summer Pan ◽

...

Keyword(s):

Pi3k Pathway ◽

T790m Mutation ◽

Met Amplification ◽

Pet Ct ◽

Clinical Responses ◽

Cns Penetration ◽

Expansion Cohort ◽

Dose Levels ◽

Egfr Tki ◽

Egfr T790m

8107 Background: Overcoming EGFR TKI resistance (R) is a major clinical challenge; reported mechanisms include EGFR T790M mutation (mt), MET amplification (amp) and PIK3CA mt. As the PI3K pathway is a central convergent signaling node, we hypothesized that addition of buparlisib (BKM) could overcome EGFR TKI-R. Methods: Patients (pt) resistant to EGFR TKI (Jackman JCO 2010) were enrolled to determine safety, tolerability, pharmacokinetics (PK) and pharmacodynamics of BKM-gef. Using a “3+3” design, escalating doses of BKM were added to pt progressing on gef (Gp A). Pt not on gef preceding enrolment received a 2 wk run in (Gp B). Given the favorable CNS penetration of BKM, a CNS gp with brain metastases only was included. Pt had pretreatment biopsies and sequential PET-CT scans (baseline & d28). Results: 15 pt have been treated at 3 dose levels: BKM 80 mg/d (n=6), 100 mg/d (n=6), 80 mg 5d on 2d off (5/2, n=3), with gef 250 mg/d. Gp A (n=9, 1 CNS), B (n=6, 1 CNS), F:M (9:6), median age 63 (47-73) and majority >3 lines of therapy. DLT was G3 diarrhea observed in 2/6 pt at BKM100. Common adverse events (AE, all grades) include rash (80%), diarrhea (73%), fatigue (60%), anorexia (47%), mucositis (40%). Notably, 40% of pt had late (beyond DLT period) G3 toxicities such as rash and diarrhea. MTD is BKM 80/d and gef 250/d. To improve the overall safety profile, an intermittent schedule of BKM80 5/2 was also found to be feasible. In gp B, PET-CT done after 2 wk run-in of gef, 3/4 evaluable pt demonstrated reduction in SUVmax of which 1 had PR. With addition of BKM, reduction in SUVmax (>25%) was seen in 4/10 pt (gp A & B). Median PFS 2.8 m (95%CI 2.3 – 8.1), two pt in CNS gp had PFS of 2.8 and 10.7 m. Molecular analyses revealed 6/12 (50%) harbored T790M mt, 2/5 (40%) MET amp, 0/12 PI3KCA mt. In gp A, 4/9 pt (2 T790M; 1 MET amp) had clinical responses, including slight tumor shrinkage and reduced pleural effusion, but required dose reductions due to AE. PK profiles are being analyzed. Conclusions: MTD is gef 250-BKM 80/d. Antitumor activity has been observed with addition of BKM in EGFR TKI-R pt. In view of late toxicities and long t½ of BKM, exploring alternative schedules is warranted. A dose expansion cohort at MTD is currently ongoing. Clinical trial information: NCT01570296.

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Outcome of EGFR mutant patirnts included in a clinical trial after progression on EGFR TKI.

Journal of Clinical Oncology ◽

10.1200/jco.2017.35.15_suppl.e20555 ◽

2017 ◽

Vol 35 (15_suppl) ◽

pp. e20555-e20555

Author(s):

Nuria Pardo Aranda ◽

Jordi Remon ◽

Alex Martinez Marti ◽

Ana Maria Martinez de Castro ◽

Susana Cedres Perez ◽

...

Keyword(s):

Clinical Trial ◽

Clinical Trials ◽

Best Supportive Care ◽

Rank Test ◽

Common Mechanism ◽

Met Amplification ◽

Platinum Based Chemotherapy ◽

Egfr Mutant ◽

Nsclc Patients ◽

Egfr Tki

e20555 Background: EGFR mutant(EGFRm) NSCLC patients develop adquired resistance after 12 months on EGFR TKI. Acquired T790mutation(T790M) is the most common mechanism of resistance in around 60% of patients, followed by MET amplification in 20% of cases. Inclusion in a clinical trials at progression may have an impact in patients’ outcome. Methods: We retrospectively assessed the overall survival in EGFRm patients according to post-progression treatment on 1st/2nd generation EGFR TKI: standard vs. experimental (clinical trial). Also, we assessed the survival in the cohort of acquired T790M NSCLC patients(p). X2 test and long rank test P values are described. OS was defined since progression 1st/2nd generation EGFR TKI to death or last follow up Results: 42p EGFRm were enrolled. According to EGFRm subtype (24 p EGFR del19, 14p EGFR L858R, 1p EGFR exon18, 1 EGFR exon20 ,2p unknown). Median age was 58 (33-83) and 27 (64%) females. First-line EGFR TKI was 30% gefitinib / 58 % erlotinib /10 % afatinib/2% dacotinib At PD, in 51 biopsies (b) were performed,11p were biopsy twice.Tumor tissue for molecular determinations was available in in 86% of cases. Druggable molecular alterations were detected in 57% of cases: 20 acquired T790M and 4 MET amplification. According to these results all 24 p were enrolled in a clinical trial (NCT02108964,NCT01802632,NCT02147990,NCT02335944, NCT02151981), and 18p were screening failure; 8p (45%) of them due to abscense of adquired resistance mechanisms. 10 received platinum-based chemotherapy and 6 only received best supportive care. OS metastatic disease was 51 months for patients included in a clinical trial vs 22 months for those on standard treatment (p < 0.001; 95%CI: 14.4-47). OS was: 34 months vs 10 months for those included in a clinical trial vs standard, respectively (p < 0.001; 95%CI: 8.88-25). For T790M tumours, OS post-progression was 25 months Conclusions: Enrolling patients in clinical trials may allow personalised treatment according to mechanisms of resistance improving survival after 1st/2nd generation EGFR TK progression disease.

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