Capmatinib in Treatment of Non-Small Cell Lung Cancer: Comparison
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Non-small cell lung cancer (NSCLC) is a leading cause of death. Capmatinib is a Type Ib MET TKI first discovered in 2011 and was FDA approved in August 2022 for advanced NSCLC with MET exon 14 skipping mutation. Clinical trials now involve combination therapy with capmatinib, including amivantamab, trametinib, and immunotherapy. Furthermore, new drug agents, particularly antibody–drug conjugates, are being developed to help treat patients with acquired resistance from capmatinib and other tyrosine kinase inhibitors (TKIs).

  • dysregulation
  • capmatinib
  • tyrosine kinase inhibitor
  • detection
  • NSCLC

1. Introduction

Non-small cell lung cancer (NSCLC) is a leading cause of death, accounting for an estimated 1.8 million deaths according to GLOBOCAN in 2020 [1]. Over the past decade, there has been tremendous progress in the discovery and development of targeted therapies for EGFR; KRAS G12C; BRAF V600E mutations; ALK, ROS1; RET gene rearrangements; MET alterations, including MET exon 14 skipping mutations, ERBB2 (HER2) mutations, and NTRK 1/2/3 gene mutations [2][3][4][5][6][7][8][9][10]. This has led to the personalization of medicine in NSCLC.
The mesenchymal–epithelial transition factor (MET) gene is located in human chromosome 7 (7q21–q31), comprising 21 exons and 21 introns, and encodes a protein that is approximately 120 kDa in size. The ligand for MET is hepatocyte growth factor (HGF), which is a soluble cytokine and is synthesized by mesenchymal cells, fibroblasts, and smooth muscle cells [11]. HGF will bind to MET, and this will trigger the autophosphorylation of Tyr-1234 and Tyr-1235 in the intracellular tyrosine kinase domain, which then undergoes further autophosphorylation of Tyr-1340 and Tyr-1356 in the C-terminal docking site [11][12]. This then facilitates the recruitment of intracellular effector molecules such as GRB2, SRC, PIK3, and GAB1, leading to the activation of downstream pathways. Normally, MET/HGF signaling pathway mediates embryogenesis, tissue regeneration, wound healing, and the formation of nerves and muscles [11][12][13].
In cancer, the MET proto-oncogene is abnormally activated and stimulates other signaling pathways in tumor cells, notably PI3K/AKT, JAK/STAT, Ras/MAPK, SRC, and Wnt/beta-catenin [11] (Figure 1). MET overexpression can be found in inflammation and hypoxia, leading to proliferation and migration, and is seen in a large variety of cancer types, including epithelial, mesenchymal, and hematological malignancies [14]. In NSCLC, it has been shown to be overexpressed in 35–72% of cases [14]. High levels of MET expression have been found to correlate with early disease recurrence [15]. MET dysregulation in NSCLC can present in a variety of ways—gene overexpression; HGF expression that can cause ligand-induced activation, leading to sustained or altered signaling; gene amplification, which can lead to overexpression and reduce the requirement for ligand activation, leading to sustained or altered signaling of the MET receptor; gene rearrangement, which may reduce or remove the requirement for ligand activation, leading to sustained altered signaling properties of the MET receptor; and downstream MET signaling alterations [11][12][15]. Notably, cigarette smoking can upregulate c-MET and the downstream Akt pathway [16]. It also affects the sensitivity of EGFR TKIs as cigarette smoke attenuates the AMP-activated protein-kinase (AMPK)-dependent inhibition of mTOR which then decreases the sensitivity of NSCLC cells with wild-type EGFR to TKI and thereby represses the expression of liver kinase B1 (LKB1) [17]. Finally, MET dysregulation can occur via gene mutation, most notably the MET exon 14 skipping mutation seen in about 3–4% of adenocarcinoma and 2% of squamous cell carcinoma but in higher frequencies in adenosquamous carcinoma (6%) and pulmonary sarcomatoid carcinoma (9–22%) [15][18].
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Figure 1. MET signaling pathway and blockade by MET inhibitors. In cancer, the MET proto-oncogene is abnormally activated and stimulates other signaling pathways in tumor cells, notably PI3K/AKT, JAK/STAT, Ras/MAPK, SRC, and Wnt/beta-catenin [11]. Type 1a inhibitor crizotinib blocks ATP binding to prevent the phosphorylation of the receptor, whereas type 1b inhibitors such as capmatinib are more specific and bind to a pocket adjacent to the ATP binding site. This figure was generated by BioRender.
MET exon 14 skipping mutations are processes in which the 47-amino-acid juxtamembrane domain is deleted, altered, or disrupted by intronic regions surrounding exon 14, leading to fusion in mature mRNA between exon 13 and exon 15 [19][20]. MET exon 14 skipping mutations have been shown to be exclusive from other driver mutations but coexist with other MET amplification or copy number gains [21]. Meanwhile, the amplification of the MET gene, which is defined as a gain in copy number (GCN), has been seen both de novo and as an acquired resistance mechanism [22]. MET amplification is seen in EGFR-acquired resistance and can occur with or without the loss of T790M [23]. In the analysis of resistance mechanisms in the AURA 3 study (n = 78), MET amplification was seen in (14/78,18%) of samples, EGFR C797S (14/78,18%) of cases, and 15 patients having >1 resistance-related genomic alteration [23][24]. MET amplification is also considered an acquired resistance mechanism of ALK inhibitors, as MET amplification has been observed in about 15% of next-generation ALK inhibitor resistance [25]. Both MET exon 14 skipping mutations and MET high-level amplification have been shown to portend poor prognosis [21]. Without the use of MET inhibitors, a retrospective study by Awad et al. showed that the median OS was 8.1 months [26]. MET exon 14 skipping mutations are seen more frequently in females than in males, and the median age of MET exon 14 skip mutation patients ranged from 71.4 to 76.7 years [6][18]. Compared with other driver mutations, MET exon 14 skip mutation patients tend to be smokers, with only about 36% being never smokers in a previous retrospective analysis [27].
MET tyrosine kinase inhibitors have been developed to treat MET-dysregulated NSCLC, classified as Type I, Type II, and Type III inhibitors. Type I inhibitors compete with ATP for the binding of the ATP-binding pocket of the active conformation of MET. Specifically, Type Ia inhibitors such as crizotinib interact with the Y1230 residue in the hinge region and are dependent on binding with the G1163 residue [28][29]. Type Ib inhibitors such as capmatinib, tepotinib, and savolitinib also connect with the Y1230 residue but are not dependent on G1163 binding [28][30][31][32]. Meanwhile, Type II inhibitors, which include cabozantinib, meresitinib, and gleasatanib, bind the ATP pocket in an inactive state [32][33][34][35]. Type III inhibitors bind to allosteric sites different from the ATP site and are not competitive; tivantinib has been studied in NSCLC but was not found to show any benefit in interim analysis and therefore was discontinued [32][34][36].

2. Pharmacodynamics/Pharmacokinetics

Capmatinib is a selective Type Ib ATP-competitive tyrosine kinase inhibitor targeting MET. Capmatinib has an average IC50 value of 0.13 nM and a cell-based IC50 of 0.3–0.7 nM in lung cancer cell lines [28][37] (Figure 2). Capmatinib has linear pharmacokinetics, with exposure increasing approximately dose-proportionally over a dose range of 200–400 mg. It is rapidly absorbed, with peak plasma concentration (Cmax) obtained about 1–2 h after a 400 mg dose is given. There is similar absorption when taken with and without food. The effective elimination half-life is 6.5 h. The plasma protein binding is 96% [38][39].
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Figure 2. Chemical structure of capmatinib; the asterisk (*) represents the chiral carbons that are part of the chemical structure.. The chemical name for capmatinib is 2-Fluoro-N-methyl-4-[7-(quinolin-6-ylmethyl)imidazo[1,2 b][1,2,4]triazin-2-yl]benzamide—hydrogen chloride—water (1/2/1). The molecular formula for capmatinib hydrochloride is C23H21Cl2FN6O2 [38].
Capmatinib is metabolized by CYP3A4 and aldehyde oxidase. In a single oral dose, 78% of total radioactivity was recovered in feces with 42% as unchanged and 22% recovered in urine. There are no specific significant effects on the pharmacokinetic parameters of capmatinib identified in the following covariates assessed: age, sex, race, mild-to-moderate renal impairment, and hepatic impairment [38][39]. In drug interaction studies, coadministration with itraconazole, a strong CYP3A inhibitor, increased capmatinib’s area under the curve (AUC0-INF) by 42%, with no change in Cmax. Coadministration with rifampicin, a strong CYP3A inducer, decreased capmatinib AUC0-INF by 67% and decreased Cmax by 56%. Coadministration with protein pump inhibitors (rabeprazole) decreased capmatinib by AUC0-INF 25% and decreased Cmax by 38%. Coadministration with rosuvastatin, a BRCP substrate, increased rosuvastatin AUC0-INF by 108% and increased Cmax by 204% [38][39].

3. GEOMETRY Mono-1 Trial

The GEOMETRY mono-1 trial was a multicohort Phase II study in patients with MET-dysregulated advanced NSCLC. The patients were either in Stage IIIB or IV NSCLC, had no EGFR mutation, and were negative for ALK rearrangement. All subjects took capmatinib 400 mg po b.i.d. A total of 364 patients were enrolled, with 97 having a MET exon 14 skipping mutation and 210 having MET amplification. There were seven cohorts to the study: In previously treated patients (1–2 lines of therapy), Cohort 1 consisted of MET amplification with (a) GCN ≥ 10 (n = 69) or (b) GCN 6–9 (n = 42); Cohort 2 consisted of MET amplification with GCN 4–5 (n = 54); Cohort 3 consisted of MET amplification with GCN < 4 (n = 30); Cohort 4 consisted of MET exon 14 skipping mutation with any GCN (n = 69); and Cohort 6 consisted of MET amplification with GCN > 10 (n = 3) or MET exon 14 skipping mutation with any GCN (n = 31) who had received one line of therapy (n = 34). In the untreated group, Cohort 5a consisted of MET amplification with GCN ≥ 10 (n = 15); Cohort 5b consisted of MET exon 14 skipping mutation with any GCN (n = 28); and Cohort 7 consisted of treatment-naïve MET exon 14 skipping mutation with any GCN (n = 23). MET exon 14 skipping mutation patients had a slightly higher median age (71 years) than patients with MET amplification (60–70 years) on diagnosis. Patients with MET exon 14 skipping mutation were more likely to be women and to have never smoked [6]. Among patients with MET exon 14 skip mutations, ORR was seen in 41% (95% CI 29–53) of 69 previously treated patients and 68% (95% CI 48–84) of 28 previously untreated patients. The median duration of response (DOR) was 9.7 months (95% CI 5.6–13.0) among the treated patients and 12.6 months (95% CI 5.6—not reached) in previously untreated patients. Most patients (82% in treated and 68% in untreated) had a response at the first tumor evaluation following the start of capmatinib therapy. The median PFS was 5.4 months (95% CI 4.2–7.0) in previously treated patients and 12.4 months (95% CI 8.2—not reached) in previously untreated patients. Notably, 12 of 13 patients with exon 14 skipping mutations who had brain metastasis had intracranial disease control. The primary reason for discontinuation was progressive disease (58% in previously treated patients and 46% in untreated patients) [6]. In patients with GCN < 10, the cohorts were closed due to futility, as PFS for GCN 6–9 and 4 or 5 was only 2.7 months. In GCN ≥ 10, there was activity; the ORR was 29% (95% CI 19–41) in previously treated patients and 40% (95% CI 16–68) in previously untreated patients, but this fell below the predefined clinical efficacy. The median DOR was 8.3 months (95% CI 4.2–15.4) in treated patients and 7.5 months (95% CI 2.6–14.3) in untreated patients. The median PFS was 4.1 months (95% CI 2.9–4.8) in treated patients and 4.2 months (95% CI 1.4–6.9) in untreated patients [6] (Table 1).
Table 1. Responses to capmatinib treatment relative to the cohort in GEOMETRY mono-1 trial (6).
Response NSCLC with MET Exon 14 Skipping Mutation     NSCLC with MET Amplification      
Best Response—No (%) Cohort 4 n = 69,

any GCN with 1–2 Lines of Therapy		 Cohort 5b n = 28, any GCN with No Previous Therapy Cohort 1a n = 69, GCN ≥ 10 with 1–2 Lines of Therapy Cohort 5a n = 15, GCN ≥ 10 with No Previous Therapy Cohort 1b n = 42, GCN 6–9 with 1–2 Lines of Therapy Cohort 2 n = 54, GCN 4 or 5 with 1–2 Lines of Therapy Cohort 3 n = 30, GCN < 4 with 1–2 Lines of Therapy
Complete response 0 1 (4) 1 (1) 0 0 0 0
Partial Response 28 (41) 18 (64) 19 (28) 6 (40) 5 (12) 5 (9) 2 (7)
Stable disease 25 (36) 7 (25) 28 (41) 4 (27) 17 (40) 20 (37) 14 (47)
In the GEOMETRY mono-1 trial, across all cohorts, the most reported adverse events were peripheral edema, nausea, and vomiting. Notably, 67% of patients had adverse events of Grade 3 or 4; the most frequent of these were peripheral edema, nausea, vomiting, and increased blood creatinine level. Treatment-related adverse events led to the discontinuation of treatment in 39 patients (11%), with treatment-related peripheral edema leading to discontinuation in 6 patients (2%) [6]. (Table 2)
Table 2. Adverse events in all cohorts (n = 364) in the GEOMETRY mono-1 trial [6].
Adverse Event Total Grade 3 or 4
 
Incomplete response or nonprogressive disease
Progression or death—No. of patients
60
Any event—No. (%) 355 (98) 244 (67)
17
Most common events—No. (%)  
1 (1)
Peripheral edema 186 (51) 33 (9) 1 (4) 1 (1) 0
Nausea1 (2) 0 0
163 (45) 9 (2) Unknown or could not be evaluated 9 (13)
Vomiting 102 (28) 9 (2) 28 19 20 6
Blood creatinine increased 89 (24) 0 5 5 2
Dyspnea 84 (23) 24 (7) Percent of patients (95% CI) 41 (29–53) 68 (48–84) 29 (19–41) 40 (16–68) 12 (4–26) 9 (3–20) 7 (1–22)
Fatigue 80 (22) 16 (4) Disease control              
2 (1)
Back Pain 54 (15) 3 (1)
Pyrexia 50 (14) 3 (1)
ALT increased 48 (13) 23 (6)
Asthenia 42 (12) 13 (4)
Pneumonia 39 (11) 17 (5)
Weight loss 36 (10) 2 (1)

4. Future Directions/Conclusions

Capmatinib, a Type Ib MET TKI that is not dependent on G1163, as crizotinib is, has proven to have efficacy, as shown in the GEOMETRY mono-1 study. Subsequent post hoc analyses have shown similar efficacy regardless of the prior treatment used and patient-reported improvement in quality of life. In addition, real-world analysis has shown similar efficacy with a promising intracranial response. The Foundation One CDx assay has been shown to be a reliable companion assay and remains the only FDA-approved assay for MET-targeted therapies. However, there have been no completed Phase III studies comparing capmatinib to first-line chemotherapy and immunotherapy or second-line chemotherapy. Furthermore, there was a notable percentage of Grade 3–4 toxicities. Future studies include investigations of capmatinib with MEK inhibition, combination therapy with amivantamab, and new classes of drugs, particularly ADCs. (Table 3) Capmatinib’s role in a perioperative setting in early-stage NSCLC may provide further treatment options for early stage patients with MET exon 14 skipping NSCLC, but the sequencing of these drugs and tolerability will be key factors, along with finding a more reliable biomarker. 
Table 3. Current key ongoing studies involving capmatinib.
Clinical Trial Number Phase Purpose
NCT04427072 Phase III Previously treated advanced NSCLC patients with MET exon 14 skipping mutation treated with capmatinib versus docetaxel
NCT04926831 Phase II Efficacy and safety of neoadjuvant and adjuvant capmatinib
Noncardiac chest pain
NCT05435846 0 8 (12) 1 (7) 4 (10) 8 (15) 8 (27)
Overall response              
No. of patients with overall response
Decreased appetite 76 (21) 3 (1)
No. of patients with disease control 54 27 49
Constipation 66 (18)10 23 25 16
3 (1) Percent of patients (95% CI) 78 (67–87) 96 (82–100) 71 (59–81) 67 (38–88) 55 (39–70) 46 (33–60)
Diarrhea53 (34–72)
64 (18) 2 (1) Duration of Response              
Cough 58 (16) No. of events/No. of patients with response 23/28 11/19 15/20 6/6 3/5 4/5 2/2
Median duration of response (95% CI)—mo 9.7 (5.6–13.0) 12.6 (5.6–NE) 8.3 (4.2–15.4) 7.5 (2.6–14.3) 24.9 (2.7–24.9) 9.7 (4.2–NE) 4.2 (4.2–4.2)
Progression-free survival      
35 (10) 4 (1)
Phase I/Ib Serious adverse event—No. (%) 184 (51) 152 (42)
Capmatinib plus trametinib in patients with MET exon 14 skipping mutation
NCT04677595 Phase II Chinese patients who are EGFR wt and ALK rearrangement negative with MET exon 14 skipping mutation        
58 15 34 50 22
Median progression-free survival (95% CI)—mo 5.4 (4.2–7.0) 12.4 (8.2–NE)
Event leading to discontinuation—No. (%) 56 (15) 35 (10)

3

NCT05110196
Phase IV
Indian patients with MET exon 14 skipping mutation
NCT05488314 Phase I/II Combination therapy of capmatinib and amivantamab in unresectable Stage IV NSCLC in patients with MET exon 14 skipping mutations or MET amplification
NCT05642572 Phase II Combination therapy of capmatinib with osimertinib +/− ramucirumab in EGFR mutant, MET-amplified, Stage IV or recurrent NSCLC
4.1 (2.9–4.8)
4.2 (1.4–6.9)
2.7 (1.4–3.1)
2.7 (1.4–4.1)
3.6 (2.2–4.2)

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