Abstract
In this retrospective study, MET inhibitor therapy demonstrated better survival outcomes compared with other treatments like chemotherapy and immunotherapy. Furthermore, MET ex14 skipping mutations and/or MET amplification typically occurred in the absence of other oncogenic driver mutations. With recent approvals of METi for patients with MET ex14 NSCLC, there is a need to identify more patients for treatment with METi to improve survival outcomes.
Background:
We evaluated the disease and patient characteristics, treatment, and MET testing patterns, predictive biomarkers and survival outcomes in patients with MET-dysregulated metastatic non–small-cell lung cancer (NSCLC) in a real-world setting.
Patients and Methods:
This was a multinational, retrospective, noninterventional chart review study. Data from medical records of patients with advanced/metastatic EGFR wild-type, MET-dysregulated NSCLC (December 2017-September 2018) were abstracted into electronic data collection forms.
Results:
Overall, 211 patient charts were included in this analysis; 157 patients had MET exon 14 skipping mutations (MET ex14; with or without concomitant MET amplification) and 54 had MET amplification only. All patients were tested for MET ex14, whereas MET amplification was evaluated in 168 patients. No overlap was reported between MET dysregulation and ALK, ROS1 or RET rearrangements, or HER2 exon 20 insertions. Overall, 56 of 211 patients (26.5%) received MET inhibitor (METi) therapy in any treatment-line setting (31.2% in the MET ex14 cohort; 13% in the MET-amplified only cohort). In the MET ex14 cohort, median OS in patients receiving METi was 25.4 months versus 10.7 months in patients who did not (HR [95% CI]: 0.532 [0.340–0.832]; P = .0055). In the MET-amplified only cohort, median OS was 20.6 months in patients treated with METi compared with 7.6 months in those without METi (HR [95% CI]: 0.388 [0.152–0.991]; P = .0479).
Conclusions:
MET alterations in NSCLC typically occur in the absence of other oncogenic driver mutations and are associated with poor survival outcomes. Notably, METi therapies are associated with improved survival outcomes in patients with MET-dysregulated NSCLC.
Keywords: Real-world study, MET mutations, Non-small cell lung cancer
Introduction
Genomic alterations leading to dysregulated MET signaling, including MET exon 14 skipping mutation (MET ex14), MET overexpression and MET amplification, are oncogenic drivers for patients with advanced non–small-cell lung cancer (NSCLC).1–3 MET ex14 skipping mutation occurs in ~3% of patients with NSCLC and is usually mutually exclusive with any other known driver mutations.4 MET amplification, the increase in the MET gene copy number (GCN), may occur de novo or as an acquired bypass resistance mechanism in patients with NSCLC treated with epidermal growth factor receptor (EGFR) inhibitors.5 The incidence of MET gene amplification decreases at higher levels of amplification and it is as low as 1% at very high levels of amplification.6 Both MET ex14 and MET amplification have been described as poor prognostic factors in patients with NSCLC,2, 7 and have been associated with poor response to cytotoxic anticancer therapies.8,9 Suboptimal responses to immune checkpoint inhibitor (ICI) therapy in MET ex14 patients have been reported, even when programmed death-ligand 1 (PD-L1) expression and mutation load are high, and this further limits the treatment options for these patients.9
Recently, 2 specific MET kinase inhibitors, capmatinib, and tepotinib, have been approved for the treatment of patients with NSCLC harboring MET ex14 skipping.10, 11 Capmatinib is an orally bioavailable, highly potent and selective MET inhibitor (METi), which received accelerated approval from the United States Food and Drug Administration (US FDA) in May 2020 for the treatment of adult patients with metastatic NSCLC whose tumors harbor a MET ex14 skipping mutation.12 Tepotinib, another METi received regulatory approval from the FDA13 for the treatment of patients with NSCLC harboring MET ex14 skipping mutation in February 2021. Both approvals were based on nonrandomized clinical trials and, consequently, no head-to-head comparisons of METi with other therapies such as chemotherapies or ICIs are available. Thus, the evaluation of real-world data is essential to learn more on the natural history, disease characteristics and treatment patterns of patients with NSCLC harboring MET ex14.14–16
Among patients with MET dysregulation, distinct biomarker signatures17 and clinical response to anticancer therapies have been reported in patients with MET ex14 skipping mutations and MET amplifications.18 Differential responses to chemotherapy and ICI therapy were reported in patients with MET ex14 and MET amplifications in a real-world study comprising 337 patients and the authors concluded that the survival benefit of ICI was lower in patients with MET ex14 compared to those with MET amplifications.18 Furthermore, a previously published study showed variable degrees of response to capmatinib in patients with MET ex14 compared to those with MET amplification, and between those who had GCN < 10 versus GCN ≥10.10 Therefore, characterizing biomarkers and clinical features to identify patients who are likely to benefit from METi versus ICI is of significant clinical relevance.
This study aimed to describe disease and patient characteristics, treatment and MET testing patterns, predictive biomarkers and survival outcomes in patients with MET-dysregulated metastatic NSCLC in a real-world setting.
Methods
Data Source for the Analysis
This was a multinational, multicenter, retrospective, noninterventional chart review study conducted at 11 oncology practices and hospitals in the United States, France, Germany, South Korea, and Japan. Anonymized patient-level data from medical records of patients with advanced/metastatic EGFR-wt, MET-dysregulated NSCLC were abstracted into an electronic data collection form (eDCF). The eDCF was designed by RTI Health Solutions (RTI-HS), A + A Research, Novartis, and the principal investigators from the participating study sites. Data collection started in December 2017 and concluded in September 2018 before the approval of any METi, with study index dates ranging from 2008 to 2018.
Patient Selection Criteria
Adult patients (≥18 years) with a confirmed diagnosis of advanced/metastatic (stage IIIb not amenable for definitive chemoradiotherapy, or stage IV), EGFR wild-type, and MET-dysregulated NSCLC, defined as MET ex14, or MET amplification determined as GCN ≥6 and/or gene/centromere ratio ≥2.2, were included in this analysis. In addition, patients were required to have a nonmissing study index date (ie, a known first date of diagnosis of or progression to advanced/metastatic NSCLC) and ≥12 months of postindex follow-up opportunity. Patients with postindex follow-up of < 12 months remained eligible for selection if progression on ≥1 prior line of systemic therapy occurred in the advanced/metastatic setting, or if death occurred < 12 months after the index date. Patients aged < 18 years at the initial diagnosis or missing MET status or missing medical records for abstraction were excluded from this analysis.
Study Size
Due to the rarity of patients with MET-dysregulated NSCLC, the planned sample size target for the study was set at approximately 100 patients. Given the availability of a relatively small number of patient records with MET dysregulation, the descriptive nature of the analysis, and the current lack of epidemiological data in this patient population, no a priori hypotheses and no formal sample size or statistical power calculations were used in this study.
Study Measures
The study assessed patient and disease characteristics, MET testing patterns and biomarkers, cancer-related treatment patterns, and overall survival (OS). Patient and disease characteristics at presentation, including age at the index date, sex, race/ethnicity, smoking history, tumor histology, Eastern Cooperative Oncology Group performance status (ECOG PS), disease stage, MET status (mutation, amplification) and site(s) of metastases at initial NSCLC diagnosis were assessed. MET testing patterns and biomarker analysis included the type of sample used in MET testing and the incidence of patients who were positive for other known tumor alterations. Cancer-related treatment patterns included patients’ overall anticancer treatment modalities from the study index date until the end of follow-up or death. OS (overall and by treatment types) was assessed from the initiation of first-line, second-line, or third-line systemic anticancer therapy for advanced or metastatic disease to the date of death due to any cause, or date of censoring if the patient was not deceased at last follow-up.
Ethics
This study underwent a project-level institutional review board (IRB) evaluation and clearance by the Research Triangle Institute Committee for the Protection of Human Subjects Research, as well as country-specific and local site-level IRB reviews and clearances where required. These IRB submissions resulted in expedited reviews, informed consent guidance (or waiver thereof as applicable by country- and site-level IRB policies), and, from the project-level IRB, study approval under applicable US regulations.
Statistical Analyses
All analyses were stratified by patients’ MET mutational status, ie, all patients with MET ex14 mutation with or without concomitant MET amplification or MET-amplified only with no concomitant MET mutation. No comparative test was performed across these groups; however, data are presented by mutational status to facilitate the interpretation of the results. Patient characteristics and treatment patterns are presented by mutational status: MET ex14 (with or without concomitant MET amplifications) and MET-amplified only (no mutation). OS from first diagnosis of advanced/metastatic NSCLC was reported by use of prior METi (received or not received). The METi class included cabozantinib, crizotinib, emibetuzumab, ficlatuzumab, foretinib, glesatinib, merestinib, onartuzumab, rilotumumab, SAR125844, sitravatinib, tepotinib, and tivantinib. Data on patient and clinical characteristics, MET testing patterns, treatment patterns, duration of available follow-up and survival outcomes were summarized using descriptive statistics (continuous data) or counts and proportions (categorical data); OS data were analyzed using the Kaplan-Meier method while the median follow-up data was calculated by reversed Kaplan-Meier method.
Results
Patient Characteristics
A total of 211 patient charts meeting the inclusion criteria were identified and included in this analysis, which exceeded the initial target. Of these 211 patients, 157 patients had MET ex14 (with or without concomitant MET amplification), and 54 had MET amplification only. Patient demographics for both cohorts are described in Table 1A. The median age was higher in MET ex14 cohort (73 years) than the MET-amplified only cohort (64 years). No apparent difference in gender distribution was noted in the MET ex14 patients in this study; however, there were fewer females in the MET-amplified cohort (39.9%). The proportion of patients who were current or former smokers was 56.1% in MET ex14 patients, and 88.9% in MET-amplified only patients. The median (range) follow-up time from the initial diagnosis of advanced or metastatic NSCLC was 12.0 (1.0–80.0) months and 7.9 (1.4–85.2) months in the MET ex14 and MET-amplified only patients, respectively. The median follow-up time from the first diagnosis of advanced or metastatic NSCLC for overall survival, as estimated via reversed Kaplan-Meier method was 25.0 (17.4–34.1) months for MET ex14 cohort and 26.8 (20.7, NR) months for MET-amplified only cohort. At the initial diagnosis of NSCLC, the proportion of patients with adenocarcinoma was higher in MET amplification only cohort (88.9%) than MET ex14 cohort (75.8%). The disease characteristics of the patients included in this study are described in Table 1B. In the overall study population, (67.3%; 142/211) had metastatic stage IV disease (MET ex14, 68.8%; MET-amplified only, 63.0%). The proportion of patients with ECOG PS 0 or 1 versus ≥2 at diagnosis was 61.1% versus 14.7% in MET ex14 patients and 72.3% versus 11.1% in MET-amplified only patients. Metastasis to bone at initial NSCLC diagnosis was more frequent in MET ex14 patients (59.3%) than in MET-amplified only patients (41.2%). Nearly one-third of all patients had brain metastasis at the time of diagnosis of metastatic NSCLC, with no apparent differences in the 2 cohorts.
Table 1A.
Patient Demographics
| Demographic Variable | METex14 (N = 157) | MET-Amplified Onlyc (N = 54) | All Patients (N = 211) | |
|---|---|---|---|---|
| Age, median (range) | Years | 73 (31–94) | 64 (27–88) | 70 (27–94) |
| Sex, n (%) | Female | 78 (49.7) | 21 (38.9) | 99 (46.9) |
| Male | 79 (50.3) | 33 (61.1) | 112 (53.1) | |
| Ethnicity, n (%) | Data not collected (France onlya) | 37 (23.6) | 3 (5.6) | 40 (19.0) |
| Caucasian | 78 (49.7) | 44 (81.5) | 122 (57.8) | |
| Asian | 35 (22.3) | 7 (13.0) | 42 (19.9) | |
| Pacific Islander | 1 (0.6) | - | 1 (0.5) | |
| Other | 2 (1.3) | - | 2 (1.0) | |
| Unknown | 4 (2.6) | - | 4 (1.9) | |
| Smoking status, n (%) | Current smoker | 27 (17.2) | 27 (50.0) | 54 (25.6) |
| Former smoker | 61 (38.9) | 21 (38.9) | 82 (38.9) | |
| Never smoked | 64 (40.8) | 5 (9.3) | 69 (32.7) | |
| Unknown | 5 (3.2) | 1 (1.9) | 6 (2.8) | |
| Follow-up time from the first diagnosis of advanced/metastatic NSCLC b | Median (range), months | 12.0 (1.0–80.0) | 7.9 (1.4–85.2) | 10.9 (1.0–85.2) |
| Follow-up time from the first diagnosis of advanced/metastatic NSCLC for overall survival, estimated via reverse Kaplan Meier | Median (range), months | 25.0 (17.4–34.1) | 26.8 (20.7, NR) | 26.6 (20.7, 34.5) |
Abbreviations: GCN = gene copy number; MET = mesenchymal epithelial transition factor; METex14 = MET exon 14 skipping mutation, NR = not reached.
Ethics regulations in France regarding data privacy prohibit the collection of ethnicities in retrospective studies.
Follow-up duration calculated as number of months between date of diagnosis of advanced/metastatic NSCLC and last available medical record.
MET amplification was defined as GCN ≥6 and/or gene/centromere ratio ≥2.2.
Table 1B.
Disease Characteristics
| Disease Characteristics | METex14 (N = 157) | MET-Amplified Onlyd (N = 54) | All Patients (N = 211) | |
|---|---|---|---|---|
| Tumor histology at initial diagnosis, n (%) | Adenocarcinoma | 119 (75.8) | 48 (88.9) | 167 (79.2) |
| Squamous cell carcinoma | 8 (5.1) | 3 (5.6) | 11 (5.2) | |
| Large cell carcinoma | 2 (1.3) | 1 (1.9) | 3 (1.4) | |
| Mixed histology | 2 (1.3) | - | 2 (1.0) | |
| Other | 17 (10.8) | 2 (3.7) | 19 (9.0) | |
| Disease stage at initial diagnosis, n (%) | Early (Stage IA, IB, IIA, IIB) | 21 (13.4) | 8 (14.8) | 29 (13.7) |
| Limited regional (Stage IIIA) | 12 (7.6) | 3 (5.6) | 15 (7.1) | |
| Locally advanced (Stage IIIB) | 15 (9.6) | 8 (14.8) | 23 (10.9) | |
| Metastatic (Stage IV) | 108 (68.8) | 34 (63.0) | 142 (67.3) | |
| (n = 108)c | (n = 34)c | (n = 142)c | ||
| Site of metastasesa at metastatic NSCLC diagnosis, n (%) | Bone | 64 (59.3) | 14 (41.2) | 78 (54.9) |
| Brain | 35 (32.4) | 10 (29.4) | 45 (31.7) | |
| Liver | 19 (17.6) | 4 (11.8) | 23 (16.2) | |
| ECOGb status at the initial diagnosis, n (%) | 0 | 33 (21.0) | 13 (24.1) | 46 (21.8) |
| 1 | 63 (40.1) | 26 (48.2) | 89 (42.2) | |
| 2 | 19 (12.1) | 4 (7.4) | 23 (10.9) | |
| 3 | 2 (1.3) | 2 (3.7) | 4 (1.9) | |
| 4 | 2 (1.3) | - | 2 (1.0) | |
| Unknown | 38 (24.2) | 9 (16.7) | 47 (22.3) |
Abbreviations: ECOG = Eastern Cooperative Oncology Group; GCN = gene copy number; MET = mesenchymal epithelial transition factor; METex14 = MET exon 14 skipping mutation; NSCLC = non–small-cell lung cancer.
Categories were not mutually exclusive, and proportions are estimated only among patients with metastatic stage IV disease at initial diagnosis.
ECOG was not recorded in 38 and 9 patients in the METex14 mutated and MET-amplified cohorts, respectively.
number of patients with metastatic stage IV disease.
MET amplification was defined as GCN ≥6 and/or gene/centromere ratio ≥2.2.
MET Testing Patterns and Biomarker Analysis
Tumor tissue biopsy was the most commonly used specimen type (172 [81.5%]), followed by cytology (29 [13.7%]) and blood samples (4[1.9%]), for determining the MET alteration status (Supplemental Table 1). Solid tissue biopsy was more frequently used in patients in the MET-amplified cohort (92.6%) than in the MET ex14 (77.7%) cohort. Among tissue biopsies, lung was the most common site of specimen acquisition (121 [57.4%]), regardless of the MET mutational status. The median time to MET test order from the initial NSCLC diagnosis was 1.7 months. All patients included in this study were tested for MET ex14 (n = 211), whereas MET amplification was evaluated in 79.6% (n = 168) of patients. The next-generation sequencing (NGS) of DNA was the most common testing method (40 [74.1%] patients) for the confirmation of MET mutation status in the MET-amplified only patients. The NGS using other techniques such as massive parallel sequencing, target NGS, DNA target capture, FoundationOne and Mirati NGS was used more frequently for detecting MET ex14 (65 [41.4%]). MET dysregulation was mutually exclusive with most other established molecular drivers (Table 2), ie, no overlap was reported between MET dysregulation and ALK translocations, ROS 1 or RET rearrangements, or HER2 exon 20 insertions. Among MET ex14 patients tested for KRAS mutations (n = 136), 11 (8.1%) cases tested positive. In the MET-amplified only cohort tested for KRAS mutations (n = 48), 9 (18.8%) patients tested positive. Among all patients tested for mutations in TP53 (n = 130), approximately one-third (36.9%) were TP53 positive; TP53 positivity (among those tested) was lower in MET ex14 patients (24.7%) than in MET-amplified only patients (60.0%). Among patients tested for PD-L1 expression (n = 90/211), PD-L1 expression ≥1% was observed in most patients (66.7%) and had similar incidence across MET mutational status cohorts. More than half of PD-L1 positive patients (55.6%, n = 35/63) had ≥50% tumor proportion score, which was more common in the MET ex14 cohort (61%, n = 25/41) than the MET-amplified only cohort (45.5%, n = 10/22).
Table 2.
Biomarker Analysis
| METex14 (N = 157) | MET-Amplified Onlya (N = 54) | All patients (N=211) | ||
|---|---|---|---|---|
| KRAS mutations, n (%) | Tested | 136 (86.6) | 48 (88.9) | 184 (87.2) |
| Positive | 11 (8.1) | 9 (18.8) | 20 (10.9) | |
| ROS-1 translocation, n (%) | Tested | 130 (82.8) | 39 (72.2) | 169 (80.1) |
| Positive | - | - | - | |
| EML4-ALK fusion, n (%) | Tested | 142 (90.5) | 46 (85.2) | 188 (89.1) |
| Positive | - | - | - | |
| BRAF mutation, n (%) | Tested | 133 (84.7) | 46 (85.2) | 179 (84.8) |
| Positive | 3 (2.3) | - | 3 (1.7) | |
| V600E status | (n = 3) | (n = 0) | (n=3) | |
| V600E positive | 1 (33.3) | - | 1 (33.3) | |
| Not V600E positive | 2 (66.7) | - | 2 (66.7) | |
| RET rearrangement, n (%) | Tested | 93 (59.2) | 35 (64.8) | 128 (60.7) |
| Positive | - | - | - | |
| HER2 exon 20 insertion | Tested | 82 (52.2) | 8 (14.8) | 90 (42.7) |
| Positive | - | - | - | |
| TP53 mutation | Tested | 85 (54.1) | 45 (83.3) | 130 (61.6) |
| Positive | 21 (24.7) | 27 (60.0) | 48 (36.9) | |
| PD-L1 expression, n (%) | Tested | 58 (36.9) | 32 (59.3) | 90 (42.7) |
| Positive | 41 (70.7) | 22 (68.8) | 63 (70.0) | |
| PD-L1 expression levels, n (%) | ≥1% | 38 (92.7) | 22 (100.0) | 60 (95.2) |
| ≥5% | 31 (75.6) | 19 (86.4) | 50 (79.4) | |
| ≥25% | 28 (68.3) | 14 (63.6) | 42 (66.7) | |
| ≥50% | 25 (61.0) | 10 (45.5) | 35 (55.6) | |
| Unknown | 3 (7.3) | - | 3 (4.8) |
Abbreviations: ALK = anaplastic lymphoma kinase; BRAF = proto-oncogene B-Raf; DNA = deoxyribose nucleic acid; HER2 = human epidermal growth factor receptor 2; KRAS = Kirsten rat sarcoma viral oncogene; MET = mesenchymal epithelial transition factor; METex14 = MET exon 14 skipping mutation; NGS = next generation sequencing; NSCLC = non–small-cell lung cancer; PD-L1 = programmed death-ligand 1; RET = Ret proto-oncogene; ROS1 = ROS proto-oncogene 1; TP53 = tumor protein p53.
MET amplification was defined as GCN ≥6 and/or gene/centromere ratio ≥2.2.
Anticancer Treatment
Overall, 138 out of 157 (87.9%) patients in the MET ex14 cohort and all patients in the MET-amplified only cohort received at least 1 line of systemic anticancer therapy following the diagnosis of advanced/metastatic disease. Of the 19 patients in the MET ex14 cohort who did not receive any systemic therapy, 15 died before the initiation of first-line anticancer therapy (Table 3, Figure 1). Nearly half of all patients in the MET ex14 cohort (n = 77) received multiple lines of systemic anticancer therapy. In patients included in the MET ex14 cohort (n = 157), platinum-based chemotherapy was the predominant first-line therapy (n = 86) followed by nonplatinum-based chemotherapy (n = 19); only 1 patient received chemotherapy in combination with ICI in the first-line setting. Among the 105 patients receiving either platinum- or non–platinum-based chemotherapy as first-line treatment, 16 (11.6%) patients received single-agent therapy. Overall, few patients (56/211 [26.5%]) received METi therapy in any treatment-line setting. Of these, 49 (31.2%) patients received METi therapy in at least 1 treatment line in the MET ex14 cohort. Comparatively, the proportion of patients who received METi therapy was lower in the MET-amplified only cohort (13%). Amongst all MET-amplified only patients who received METi therapy, METi was the first-line therapy. ICI in any treatment line was received by 62 (29.4%) patients overall, including 48 (30.6%) in the MET ex14 cohort and 14 (25.9%) in the MET-amplified only cohort. Ten patients received treatment with a tyrosine kinase inhibitor in this study, 9 of whom received erlotinib (8 in second-line and 1 in third-line) and 1 patient received afatinib in the third-line (Supplemental Table 2).
Table 3.
Anticancer Treatment Received in the Advanced/Metastatic Setting
| METex14 (N = 157) | MET-Amplified Onlyd (N = 54) | All Patients (N = 211) | ||
|---|---|---|---|---|
| Number of systemic treatment regimens received a , n (%) | Median (range) | 1 (0–7) | 1 (1–8) | 1 (0–8) |
| 0b | 19 (12.1) | - | 19 (9.0) | |
| 1 | 61 (38.9) | 29 (53.7) | 90 (42.7) | |
| 2 | 36 (22.9) | 11 (20.4) | 47 (22.3) | |
| 3 | 18 (11.5) | 7 (13.0) | 25 (11.9) | |
| ≤ 4 | 23 (14.7) | 7 (13.0) | 30 (14.2) | |
| Number of lines of MET inhibitorc therapy, n (%) | 0 | 108 (68.8) | 47 (87.0) | 155 (73.5) |
| 1 | 37 (23.6) | 7 (13.0) | 44 (20.9) | |
| 2 | 12 (7.6) | - | 12 (5.7) | |
| Received I/O in any treatment line, n (%) | No | 109 (69.4) | 40 (74.1) | 149 (70.6) |
| Yes | 48 (30.6) | 14 (25.9) | 62 (29.4) |
Abbreviations: MET = mesenchymal epithelial transition factor; METex14 = MET exon 14 skipping mutation; I/O = immuno-oncotherapy.
After first diagnosis of (or progression to) advanced/metastatic disease (index date).
Fifteen of the 19 patients who did not receive systemic treatment died before a first-line treatment could be initiated.
The use of the following MET inhibitors was noted in this study: crizotinib, emibetuzumab, ficlatuzumab, foretinib, glesatinib, merestinib, onartuzumab, rilotumumab, SAR125844, sitravatinib, tepotinib, tivantinib.
MET amplification was defined as GCN ≥6 and/or gene/centromere ratio ≥2.2.
Figure 1. Summary of treatment patterns in first 4 lines of systemic anticancer therapy following diagnosis of advanced/metastatic NSCLC in MET ex14 patients.
Overall Survival
Patients with MET-dysregulated NSCLC who did not receive METi therapy had poorer survival outcomes than those who did receive METi therapy (Table 4). Among the MET TKI treated patients with an OS event (n = 27), 18 patients exhibited MET ex14 only while 9 patients exhibited both MET ex14 and MET amplification. The median OS (min, max) in these cohorts were 2.3 (2.5, 53.0) months and 18.8 (3.3, 40.9) months, respectively. However, due to the small sizes of the cohorts, any statistical comparison of outcomes was not feasible. Among patients who were not treated with METi therapies, the median OS (95% CI) was 10.7 (7.8, 14.4) months in MET ex14 cohort and 7.6 (5.4, 9.9) months in MET-amplified only cohort. In the MET ex14 cohort, patients treated with ICI in the first-line setting generally had longer median OS compared to those who were treated with chemotherapy (Supplemental Table 3). In the MET ex14 cohort, the median OS (95% CI) was 25.4 (18.8, 40.9) months in patients treated with METi compared with 10.7 (7.8, 14.4) months in patients who did not receive METi therapy (HR [95% CI]: 0.532 [0.340, 0.832]; P = .0055). In the MET-amplified only cohort, the median OS (95% CI) was 20.6 (7.2, 85.2) months in patients treated with METi compared with 7.6 (5.4, 9.9) months in those not treated with METi (HR [95% CI]: 0.388 [0.152, 0.991]; P = .0479). The 12-month OS rate in MET ex14 patients was 78.7% in those receiving METi therapy and 46.4% in those without METi therapy (Figure 2). Likewise, the 12-month OS-rate in MET-amplified only cohort was 85.7% in patients on METi therapy and 30.7% in those who did not receive METi therapy. Overall, patients receiving METi generally had numerically longer OS and higher 12-month OS rates than those who did not receive METi, regardless of the MET mutational status.
Table 4.
Efficacy—KM Measure of OS From the Diagnosis of Advanced/Metastatic NSCLC as Per Treatment and MET Dysregulation Status
| METex14 (N = 157) | MET-Amplified Onlyb (N = 54) | All Patients (N = 211) | ||||
|---|---|---|---|---|---|---|
| Received METia Therapy (n = 49) | No METia Therapy (n = 108) | Received METia Therapy (n = 7) | No METia Therapy (n = 47) | Received METia Therapy (n = 56) | No METia Therapy (n = 155) | |
| Patients with an OS event, n (%) | 27 (55.1) | 72 (66.7) | 6 (85.7) | 41 (87.2) | 33 (58.9) | 113 (72.9) |
| Median (95% CI) OS, months | 25.4 (18.8, 40.9) | 10.7 (7.8, 14.4) | 20.6 (7.2, 85.2) | 7.6 (5.4, 9.9) | 25.3 (17.8, 38.7) | 8.9 (7.4, 11.5) |
| 6-month OS rate, % | 91.8 | 65.4 | 100.0 | 59.1 | 92.8 | 63.5 |
| 12-month OS rate, % | 78.7 | 46.4 | 85.7 | 30.7 | 79.5 | 41.5 |
Abbreviations: CI = confidence interval; KM = Kaplan–Meier; MET = mesenchymal epithelial transition factor; METex14 = MET exon 14 skipping mutation; METi = MET inhibitor; NSCLC = non–small-cell lung cancer; OS = overall survival.
For analysis of OS from first diagnosis of advanced/metastatic NSCLC, receipt of METi defined by treatment with a METi at any point after first diagnosis of (or progression to) advanced/metastatic disease; METi class includes: cabozantinib, crizotinib, emibetuzumab, ficlatuzumab, foretinib, glesatinib, merestinib, onartuzumab, rilotumumab, SAR125844, sitravatinib, tepotinib, tivantinib.
MET amplification was defined as GCN ≥6 and/or gene/centromere ratio ≥2.2.
Figure 2. Overall survival from first diagnosis of advanced/metastatic MET-dysregulated NSCLC CI, confidence interval; HR, hazard ratio; METi, MET inhibitor; OS, overall survival.
Discussion
This study represents assessments of patients with MET-dysregulated advanced or metastatic NSCLC before the approval of selective METi therapies. Our key objective was to descriptively compare patients with a confirmed diagnosis of advanced/metastatic NSCLC harboring MET ex14 skipping mutations or MET amplifications with respect to natural history, treatment patterns and survival outcomes in response to anticancer therapies. The baseline characteristics of patients with MET ex14 included in this chart review were consistent with the known patient profile from the clinical trials19, 20 (median age 73 years, and ~40% patients never smoked) and differed from MET-amplified only patients (median age 64 years, and ~9% patients never smoked). One-third of the patients in this study presented with brain metastasis at the time of diagnosis of advanced NSCLC.
Patients with MET-dysregulated NSCLC represent a challenging population with limited treatment options. Nearly 10% of the patients reviewed in the MET ex14 cohort died before receiving a first-line therapy and a similar percentage of patients only received single-agent chemotherapy as first-line treatment, suggesting that they were not candidates for doublet or triplet therapies. Previous studies have reported a range of 7% to 45% patients with NSCLC who did not receive any treatment.21 Most patients in the MET ex14 cohort received platinum-based chemotherapy (n = 86) followed by nonplatinum-based chemotherapy (n = 19) as first-line therapy suggesting that the use of METi therapy was delayed in the majority of the patients. This observation can be explained by the fact that this analysis was completed in September 2018, and at that time, selective METi capmatinib and tepotinib were not yet approved for the treatment of patients with MET ex14 NSCLC (FDA-approved in May 2020 and February 2021, respectively). The median time to MET test order from the initial NSCLC diagnosis (1.7 months) was quite long given the poor prognosis of these patients. This is expected to change with approved/available METi therapies. However, the turnaround time for upfront molecular testing remains a challenge in view of the often aggressive course of disease in this fragile patient population.
As reported previously in other studies evaluating the frequency of driver concomitant mutations in MET ex14 patients,22 MET alterations were mutually exclusive with ROS 1 translocations, EML4-ALK fusions, RET rearrangements, and HER2 exon 20 insertions. MET alterations co-occurred to varying degrees with KRAS, BRAF, and TP53 mutations. Concomitant mutations in TP53 were more frequently observed in the MET-amplified only patients (60%) compared with those in MET ex14 patients (24.7%), which is consistent with the real-world data published by Kron et al.18 More than half of the PD-L1 positive cases in this real-world study presented with PD-L1 expression ≥50%, which is in line with previous studies reporting similar PD-L1 expression in patients with NSCLC harboring MET ex14.8, 9
In this study, the median OS was 10.7 months in MET ex14 patients and 7.6 months in MET-amplified only patients who were not treated with METi. Treatment with ICI seemed to associate with longer OS compared to chemotherapy in the first-line setting, irrespective of the MET mutation status. This is in line with phase III study results in patients with advanced NSCLC and high PD-L1 expression but without known MET status.23 However, these results may be overestimated due to the low number of MET ex14 patients treated with ICI in the first-line setting (n = 5). By comparison, Kron et al.18 showed no survival benefit of ICI versus chemotherapy in MET ex14 patients, however, nearly all patients in this study received ICI after failure of chemotherapy.18 In the real-world setting, efficacy of ICI in patients with MET mutated NSCLC seemed similar to that in unselected NSCLC patients.24–26 In this regard, NCCN guidelines recommend the preferential use of targeted therapies rather than ICI in patients with metastatic NSCLC harboring an oncogenic driver.27 However, it has been unclear, whether METi therapies are superior to ICI or chemotherapy in the first-line setting. In this study, treatment with METi was associated with longer OS in patients with MET-dysregulated NSCLC, irrespective of the MET mutation status. In the MET ex14 cohort, longer OS was noted in patients treated with METi compared with those with no METi treatment (HR [95% CI] for OS: 0.532 [0.340, 0.832]; P = .0055). Likewise, the OS was longer in patients treated with METi compared with those with no METi treatment in the MET-amplified only cohort (HR [95% CI] for OS: 0.388 [0.152, 0.991]; P = .0479). In addition, the median OS of patients in the METi treated MET ex14 cohort was numerically longer than the MET-amplified only cohort (median OS: 20.6 months; 95% CI: 7.2, 85.2). It is noteworthy to mention that capmatinib showed limited efficacy in terms of response rates in patients with high MET amplification compared to those with MET ex14 skipping mutations.10 The median OS observed in the METex14 cohort treated with METi in this study is consistent with the median OS (20.8 months [95% CI: 12.4, not estimable]) observed in treatment-naïve patients with advanced METex14 treated with capmatinib in the GEOMETRY mono-1 study.28
The present study has several limitations. Data from this study need to be interpreted cautiously given the retrospective nature of this study in which treatment assignment was physician-determined as per routine practice and therefore nonrandomized. Results from this study provide descriptive data and has a small sample size, which prevents from conducting comparative analysis across the different cohorts and treatment groups. This analysis was based on retrospective review of medical records from selected academic institutions and may not be generalized to the broader NSCLC patient population harboring MET-dysregulation in the real-world clinical practice. Data were pooled from patients across different countries, which can have an effect on the diagnosis, testing modalities and treatment patterns. Any comparison of outcomes between naturally occurring treatment cohorts in this study must be made with caution as treatment assignment was not randomized and therefore may be confounded by uncontrolled and unobserved factors. This study was not designed to formally assess comparative effectiveness of alternative treatments. Patients in the METi received off-label METi therapies as these therapies were not yet approved for patients with MET ex14 before data collection in this study was completed. In future studies, it would be of significant clinical relevance to identify predictive markers of response to METi therapies in patients with MET-dysfunctional NSCLC, especially in those with high MET amplifications in the real-world practice settings.
Conclusion
In conclusion, this report based on real-world data serves as a crucial supplement to existing clinical data for METi therapies. Data from our study suggest that MET alterations in NSCLC typically occur in the absence of other oncogenic driver mutations and are associated with aggressive disease presentations. Most importantly, the results presented in this retrospective study show that METi therapies are associated with improved survival outcomes in the challenging cohort of patients with MET-dysregulated NSCLC. These results highlight the need for MET testing and using MET-targeted therapies compared with other systemic therapies.
Supplementary Material
Clinical Practice Points.
MET alterations in patients with advanced NSCLC have been associated with poor prognosis and suboptimal response to chemo- and immunotherapy.
In this real-world study, we observed that MET alterations (MET ex14 skipping and MET amp) in patients with advanced NSCLC occurred in the absence of other oncogenic driver mutations, including ALK, ROS1, or RET rearrangements or HER2 exon 20 insertions.
Treatment with MET inhibitors was associated with longer survival in both MET ex14 and MET amp cohorts compared with patients who did not receive METi.
This study emphasizes the need to identify patients with NSCLC harboring MET alterations through testing for better therapeutic outcomes with METi compared with alternative treatments, such as chemotherapy and immunotherapy.
Acknowledgments
This study was funded by Novartis Pharma AG, Basel, Switzerland. The authors thank Varunkumar Pandey, PhD, (Novartis Healthcare Pvt. Ltd., India) for providing medical writing/editorial support, which was funded by Novartis Pharma AG, in accordance with the Good Publication Practice (GPP3) guidelines (http://www.ismpp.org/gpp3).
Footnotes
Disclosure
J.W. received research support from Bristol Myers Squibb, Janssen Pharmaceuticals, Novartis, and Pfizer. He has served as consultant for Amgen, AstraZeneca, Bayer, Blueprint, Bristol Myers Squibb, Boehringer Ingelheim, Chugai Europe, Daiichi Sankyo, Ignyta, Janssen, Eli Lilly, Loxo, Merck Sharp & Dohme, Novartis, Nuvalent, Pfizer, Roche, Seattle Genetics, Takeda, and Turning Point. P.J.S. received grant support from Novartis. He also served as consultant, participated on data safety monitoring board and received honoraria from Novartis. K.G. received support for the present manuscript from Novartis Pharma K.K. He received grant support from Amgen, Amgen Astellas BioPharma K.K, AstraZeneca K.K, Bayer Yakuhin Ltd., Boehringer Ingelheim Japan, Bristol-Myers Squibb K.K., Blueprint Medicines, Chugai, Daiichi Sankyo, Eisai, Eli Lilly Japan, Haihe, Ignyta, Janssen Pharmaceutical K.K., Kissei, Kyowa Kirin, Life Technologies Japan, Loxo Oncology, Medical & Biological Laboratories, Merck Biopharma, Merus, MSD K.K., NEC, Novartis Pharma K.K., Ono, Pfizer Japan, Sumitomo Dainippon, Spectrum, Sysmex, Taiho, Takeda and Turning Point Therapeutics and received personal honoraria from Amgen, AstraZeneca K.K., Bayer Healthcare, Boehringer Ingelheim Japan, Bristol-Myers Squibb K.K., Daiichi Sankyo, Eisai, Eli Lilly Japan K.K., Guardant Health, Janssen Pharmaceutical K.K., Kyowa Kirin, Life Technologies Japan, Medpace Japan K.K., Merck Biopharma, MSD K.K., Novartis Pharma K.K., Ono, Otsuka, Pfizer Japan, Taiho, Takeda and grant support for institution from Chugai. He also participated on the data safety monitoring board or advisory board for Amgen, Bayer U.S., Eli Lily Japan K.K., Medpace Japan K.K., Janssen Pharmaceutical K.K. and Takeda. A.C. received grant support for institution from Merck and Roche. He served as consultant for AstraZeneca, Novartis and Roche and received honoraria from AstraZeneca, Bristol Myers Squibb, Merck Sharp & Dohme, Pfizer, Novartis, Takeda, Janssen and Roche. He also received travel support from Pfizer and Novartis and participated on the data safety monitoring board for Novartis. C.B. received consulting fees from AstraZeneca, Blueprint Medicines, Daiichi, Takeda, Turning-Point Therapeutics, Guardant Health, Pfizer, Jansen, Regeneron and Silverback Therapeutics. She also received research funding (funding to institution) from Spectrum, Turning Point Therapeutics, Daiichi Sankyo, AbbVie, AstraZeneca, Lilly, Loxo, Jansen, Rain Therapeutics, Pfizer, Blueprint Medicines. R.H. received grant support for institution from Abbvie, Agios, Corvus, Incyte, Daichii Sankyo, Novartis, Lilly, Mirati, Turning Point and Exelixis, and served as consultant for Abbvie, Daichii Sankyo, EMD Serono and Novartis. T.M.K. received research grants from AstraZeneca and Korea Health Industry Development Institute outside this work. He has served as consultant for AstraZeneca, Hanmi, Janssen, Novartis, Roche/Genentech and Takeda. He received personal honoraria from Janssen and Takeda. He also has other financial or nonfinancial interests with AstraZeneca/MedImmune, Bayer, Boehringer Ingelheim, Boryung, Genmab, Hanmi, Janssen, Merck Serono, Merck Sharp & Dohme, Novartis, Regeneron, Roche/Genentech, Sanofi and Takeda. J.W.N. received grant support from Abbvie, Genetech/Roche, Exelixis, Merck, Novartis, Boehringer Ingelheim, Nektar Therapeutics, Adaptimmune, GlaxoSmithKline, Janssen and Takeda. He received consulting fees from Amgen, AstraZeneca, Genetech/Roche, Exelixis, Jounce Therapeutics, Eli Lilly, Calithera Biosciences, Lovance Biotherapeutics, Blueprint, Natera, Sanofi/Regeneron Merck, D2G Oncology, Surface Oncology, Turning point Therapeutics and Takeda. A.M. received research support from Bristol Myers Squibb, Novartis and Verily, consulting fees from Rising Tide – grant reviewer ad TRIPTYCH Health Partners Expert Think Tank, honoraria from Janssen, Beigene, Chugai, Ideology Health LLC, Miami International Mesothelioma Symposium, Antoni van Leeuwenhoek Cancer Institute, Axis Medical Education, Johnson & Johnson Global Services, Intellisphere LLC and Answers in CME, participated on data safety monitoring board for Abbvie, AstraZeneca, Bristol Myers Squibb and Genentech/Roche, and served as nonremunerated Director for Mesothelioma Applied Research Foundation. J.Y.H. received grant support from Roche, Ono and Pfizer, consulting fees from AstraZeneca, Bristol Myers Squibb, Lilly and Merck, payment as honoraria from AstraZeneca, Bristol Myers Squibb, Merck and Novartis. She also participated on the data safety monitoring board for Abion and owns stocks or stock options of Yuhan. I.G., N.N. and M.G. are employees of Novartis. MG owns Novartis stock. K.L.D. is an employee of the RTI Health Solutions. M.W.L. was an employee of Novartis at the time of conduct of the study and development of this manuscript. M.M.A. reported serving as a consultant for Achilles, AbbVie, Neon, Maverick, Nektar, and Hegrui; receiving grants and personal fees from Genentech, Bristol-Myers Squibb, Merck, AstraZeneca, and Lilly; and receiving personal fees from Maverick, Blueprint Medicine, Syndax, Ariad, Nektar, Gritstone, ArcherDx, Mirati, NextCure, Novartis, EMD Serono, and NovaRx outside the submitted work.
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