Real World Experience with MET Inhibitors in MET Exon 14 Skipping Mutated Non-small Cell Lung Cancer: Largest Indian Perspective

Background: Patients with Non-small Cell Lung Cancer (NSCLC) presenting with Mesenchymal-epithelial transition exon 14 skipping mutation (MET ex14) have an unfavorable prognosis with traditional therapies. MET inhibitors have altered the therapeutic paradigm of NSCLC. MET ex14 skipping alteration is reported in 3-4% cases (N Engl J Med 383(10):944-957, 2020, Cancer Discov 5(8):842-9, 2015). Randomized controlled trials have reported noteworthy outcomes of selective MET tyrosine kinase inhibitors (TKIs), however real-world data from the Indian sub-continent is lacking.

Methods: The current study is a non-interventional retrospective multi-centre analysis reporting on real-world data of NSCLC patients with MET ex14 skipping alteration from two apex cancer centers from India. Data of 49 eligible NSCLC patients with MET ex14 mutations fulfilling the inclusion and exclusion criteria were reviewed and analysed. Kaplan Meier (KM) estimating method was used to estimate the overall survival (OS) and progression free survival (PFS). Log rank test was used to compare the survival curves between the groups. A p-value < 0.05 was considered clinically significant. Statistical analysis was performed using R studio.

Results: A total of 49 patients harboring MET ex14 alterations were included in the current study. Table 1. shows the clinico-pathological features of these patients. Treatment patterns were heterogeneous across therapy lines and included systemic therapy, MET TKIs and immunotherapy. Approximately 85.71% (42/49) patients opted for treatment. First line TKIs were offered to 14 patients; while chemotherapy was given to 28 patients. First-line TKIs doubled the PFS in comparison to chemotherapy arm (mPFS: 11.9 months vs. 5.9 months, p < 0.002*, HR for TKI: 0.3295. On multivariate analysis, male sex and TP53 co-mutation were factors influencing the first-line PFS (p < 0.06). Second line treatment was taken by 13/14 patients in the TKI arm of which 5 received sequential TKI, while 8 received chemotherapy. Similarly, 22/28 patients in the chemotherapy arm received second line treatment. Of these 22 patients, 14 received sequential TKIs, while 8 received next line systemic chemotherapy (TKIs: 14, chemotherapy: 8). PFS for 2nd line TKI was 7.7 months (95% CI, 2.8-14.8) vs. 4.6 months (95% CI, 2.1-9.8) for chemotherapy arm (HR for TKI: 0.3641, p < 0.04*). Around 57% (28/49) received MET TKI therapy at any given time point during the disease course. Median OS for patients treated with 1st line TKI and systemic chemotherapy was not reached (95% CI 9.2-NR months) and 20.7 months (95% CI 18.1-36.1 months) respectively at the study endpoint (p = 0.3). Table 1 Characteristics of the patients at baseline Clinicopathological Features n = 49 % Age (Years) Median: 70 (Range, 39-85) - ECOG PS  1 40 81.6  ≥2 9 18.4 Gender  Male 33 67.3  Female 16 32.7 Smoking Status  Ever smoker 34 69.3  Never smoker 15 30.7 Brain metastases  Present at diagnosis 4 8.3  Developed Later 12 24.4  Absent 33 67.3 Histology  Adenocarcinoma 33 67.3  Squamous cell carcinoma 8 16.3  Adenosquamous carcinoma 8 16.3 Co-mutations  TP53 12 24.4  KRAS 1 2.1  CTNNB1 1 2.1  MET Copy number gain 1 2.1  None 34 69.3 PDL1   < 1% 9 18.4  1-49% 20 40.8   > 49% 20 40.8 MET exon 14 skipping  DNA only 0 0  RNA only 30 61.2  Both DNA & RNA 19 38.8 CONCLUSION: The current study comprises of the largest MET ex14 mutated NSCLC patient cohort reporting on the real-world data of MET TKI therapy from the Indian subcontinent. MET TKI showed higher systemic and intracranial efficacy with manageable safety profile. The current study represents an unmet need for more clinical phase 3 study for rare genomic alterations as well as patient access programs in the Indian subcontinent.