Crizotinib for c-MET –amplified advanced NSCLC: a single-center experience

Abstract

Introduction:

Lung cancer is the most common cause of cancer-related death in the world. Changes in the treatment of metastatic lung cancer in recent years have made targetable mutations gain importance. MET alteration is one of these driver mutations and crizotinib is a tyrosine kinase inhibitor used in therapy.

Methods:

In our study, data of patients with c-MET amplification who received crizotinib treatment between July 2017 and November 2020 in the Medical Oncology Clinic of Bakırköy Dr. Sadi Konuk Training and Research Hospital were retrospectively analyzed. c-MET scanning was performed by the fluorescent in situ hybridization method by using Cytotest MET/CCP7 probe kit by evaluating 100 tumor cells and the threshold value for positivity was accepted as above 20%.

Results:

Eight of 28 patients who received crizotinib treatment had c-MET amplification. Seven of these patients were male and one was female. Progression-free survival and overall survival in these eight patients were 9.4 and 10.9 months, respectively, and objective response rate was 50%. Grade 4 nausea was observed in only one patient; there was no grade 4–5 toxicity and no patient discontinued the drug due to toxicity.

Conclusion:

Crizotinib is an effective treatment option other than cytotoxic chemotherapy in the limited number of patients with MET amplification in the stage 4 lung adenocarcinoma subgroup. It is important to investigate this amplification, which can be detected especially in smoking patients in the appropriate patient group, and to use appropriate tyrosine kinase inhibitors in treatment.

Keywords

lung cancer crizotinib

Introduction

Lung cancer is the most common cause of cancer death worldwide.¹ According to data of the World Health Organization, in 2018, the countries with the highest incidence were Turkey, Japan, China, the United States, and the United Kingdom.² Approximately 1.6 million people worldwide die each year of lung cancer.³ Lung cancer is divided into two different histologic subgroups: small cell lung cancer and non-small cell lung cancer (NSCLC). Many patients diagnosed with NSCLC have advanced stage disease at the time of diagnosis. The standard treatment for advanced-stage lung cancer has been platinum-based doublet chemotherapy for many years. In recent years, there have been significant changes in NSCLC treatment through immune checkpoint inhibitors. Also, in the past decade, driver mutations that cause tumor growth, mainly in the adenocarcinoma subtype of NSCLC, have been identified and targeted treatment agents have been used for these mutations. The most prominent of these targetable mutations are mutations in the epidermal growth factor receptor (EGFR) gene, the BRAF V600E mutation, and rearrangements in the anaplastic lymphoma kinase (ALK) and ROS1 genes. With the discovery of an increasing number of molecular subgroups over the past few years, additionally, c-MET alterations, changes in NTRK, and RET translocations have been identified as targetable mutations.⁴

The c-MET gene is located on chromosome 7q21-31 and encodes a protein tyrosine kinase belonging to the HGF (hepatocyte growth factor) receptor family. HGF has an important role in regulating processes such as differentiation, proliferation, cell cycle, motility, and apoptosis, which are important for cellular processes.⁵

Crizotinib is a multitargeted tyrosine kinase inhibitor (TKI) that was originally developed as a MET inhibitor. PROFILE 1014 and PROFILE 1007 studies of crizotinib demonstrated superiority in the first and second lines of treatment compared to conventional chemotherapy in the ALK-positive NSCLC patient group. These studies showed higher response rates and longer progression-free survival with crizotinib treatment and were subsequently approved by the US Food and Drug Administration (FDA) for the treatment of patients with NSCLC with ALK or ROS1 fusion.^6,7

In preclinical tumor xenograft studies, it has been shown that crizotinib inhibits cell growth stimulated by HGF by decreasing c-MET phosphorylation and preventing the survival of cells. Crizotinib has also been observed to induce apoptosis in lung cancer cell lines with MET amplification and inhibit the phosphorylation of the kinase regulated by extracellular signaling.⁴

In this study, we retrospectively evaluated the efficacy of crizotinib in metastatic NSCLC with c-MET amplification.

Materials and Methods

We retrospectively analyzed the files of patients who received crizotinib treatment with a diagnosis of metastatic or locally advanced NSCLC between July 2017 and November 2020 in the Medical Oncology Clinic of Bakırköy Dr. Sadi Konuk Training and Research Hospital and recorded their information. We included patients with c-MET amplification and receiving crizotinib 2×250 mg/d for treatment. c-MET scanning was performed by the fluorescent in situ hybridization (FISH) method by using cytotest MET/CCP7 probe kit by evaluating 100 tumor cells and the threshold value for positivity was accepted as above 20%. Treatment response evaluation was done according to Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1) guideline criteria. The patients continued with crizotinib therapy until progressive disease or unacceptable toxicity developed.

Statistical Analyses

Progression-free survival (PFS) was defined as the time from crizotinib onset to the date of progression or death. Overall survival (OS) was defined as the time elapsed from the onset of crizotinib to death. OS and PFS were estimated using the Kaplan-Meier method. Categorical variables were presented as percentages. PFS and OS were presented as median value with 2-sided 95% confidence interval (CI). Objective response rate (ORR) was obtained from Clopper-Pearson (exact) test. A p value of <0.05 was considered statistically significant. The clinical data were analyzed using SPSS version 24.0.

Results

In our study, electronic records and files of 28 patients who received crizotinib with a diagnosis of metastatic lung adenocarcinoma were examined. Twenty patients were ALK mutation-positive; c-MET amplification was detected by the FISH method in eight patients. It was determined that one of the patients with c-MET amplification was previously treated with erlotinib and osimertinib due to EGFR exon 19 mutation and amplification emerged as a TKI resistance mechanism. Seven of eight patients had stage 4 disease at the time of diagnosis; only one had stage 3 disease at the time of diagnosis. Seven of the patients were male and one was female. The mean age was 66 years (range, 60–72). The demographic and clinical characteristics of the patients are summarized in Table 1.

Table 1.

Patient characteristics.

Patient	Age, y	Sex	ECOG PS	Smoking	Stage at diagnosis	Brain metastasis	Metastatic sites	Line of crizotinib	Prior systemic therapies	c-MET (%MET/CCP)	Best response to crizotinib	PFS, mo	OS, mo
1	65	M	0	Yes	IV	Yes	Adrenal, bone	2	Carboplatin + pemetrexed	38	PR	11	12
2	67	M	1	No	IV	Yes	Lung, bone	2	Carboplatin + paclitaxel	24	PR	16	17
3	64	M	0	Yes	IV	No	Adrenal, bone	1	No	42	PD	3	3.5
4	72	M	2	No	IV	Yes	Lung, bone	2	Carboplatin + paclitaxel	NE	PR	19	38
5	60	M	1	Yes	IV	Yes	Lung, bone	1	No	74	PR	11	12
6	63	M	1	Yes	IV	No	Bone	1	No	35	PD	1	1
7	65	M	0	Yes	IV	Yes	Lung, liver	2	Carboplatin + paclitaxel	32	PD	1	1
8	72	F	1	No	III	No	Lung, bone	4	Cisplatin + gemcitabine, erlotinib, osimertinib	86	PD	2	3

ECOG PS: Eastern Cooperative Oncology Group Performance Status; NE: not evaluable; OS: overall survival; PD: progressive disease; PFS: progression-free survival; PR: partial response.

All patients are deceased.

When the radiologic responses of 8 patients who received crizotinib treatment in our study were evaluated, partial response was found in 4 patients and progressive disease in 4 patients. ORR was 50% (95% CI 0.15–0.84), median PFS was 9.4 months (95% CI 4.20–14.61) (Figure 1), median OS was 10.9 months (95% CI 2.31–19.57) (Figure 2), and median follow-up time was 25 months (range, 18–39 months). Eight patients died during the follow-up.

Figure 1.

Kaplan-Meier graphic for progression-free survival (PFS). CI: confidence interval.

Figure 2.

Kaplan-Meier graphic for overall survival (OS). CI: confidence interval.

Considering drug-related side effects, diarrhea was the most common, at 37% (grade 1–2); edema, fatigue, nausea, elevated transaminases, and creatinine were also observed. Two patients (25%) had grade 1 visual impairment, 3 (37%) patients had nausea (2 patients grade 2, 1 patient grade 4), and there were no grade 4–5 side effects (Table 2). There were no patients who discontinued the drug or underwent dose modification due to drug-induced toxicity.

Table 2.

Treatment-related adverse events.

Adverse events	Any grade (%)	>3 Grade (%)
Fatigue	3 (37.5)	0
Diarrhea	3 (37.5)	0
Edema	3 (37.5)	0
Nausea	3 (37.5)	1 (12.5)
Elevated aminotransferases	3 (37.5)	0
Elevated creatinine	3 (37.5)	0
Vision disorder	2 (25)	0
Vomiting	2 (25)	0
Upper respiratory infection	2 (25)	0
Decrease appetite	1 (12.5)	0
Constipation	1 (12.5)	0
Abdominal pain	1 (12.5)	0
Headache	1 (12.5)	0
Neuropathy	1 (12.5)	0
Cough	1 (12.5)	0
Pyrexia	1 (12.5)	0
Dizziness	1 (12.5)	0
Thrombocytopenia	1 (12.5)	0
Stomatitis	1 (12.5)	0

Discussion

Abnormal activation of the MET pathway in NSCLC can occur by various mechanisms. MET alteration may be due to the increased MET copy number, MET amplification, and MET exon 14 skip mutation.⁸ MET gene amplification is seen in 2%–4% of previously untreated NSCLCs and is responsible for 5%–20% of acquired resistance to EGFR TKIs in EGFR-mutant patients.^9,10 Whereas MET is a targeted therapeutic pathway for patients with MET alteration in previously untreated NSCLC, it is also a therapeutic option for acquired MET amplification for patients with EGFR-mutant NSCLC treated with anti-EGFR.¹¹

It has been reported that unlike other targetable mutations such as EGFR, ALK, and ROS-1, c-MET amplification can also be detected positively in patients with a smoking history. In phase 2 AcSé and METROS studies, the majority of patients with c-MET alteration were men, and many patients had a history of smoking.^12,13 Similarly, in our study, seven of eight patients were male and three patients were former smokers.

Approximately 60% of acquired resistance against first-generation anti-EGFR agents is due to the T790M mutation. MET gene amplification is also one of the other important acquired resistance mechanisms, along with HER-2 amplification and transformation to small cell cancer. In a retrospective study by Wang et al.,¹⁴ 18 patients with EGFR-mutant NSCLC demonstrated the resistance mechanism acquired after anti-EGFR treatment and c-MET amplification by the FISH method. Eight patients were given crizotinib and the ORR was 50%, median PFS 6 months, and median OS 17.2 months in these patients. The only female patient in our study was prescribed erlotinib first because of EGFR exon 19 mutation positivity, and then osimertinib with the demonstration of the T790M mutation. Molecular analysis performed after osimertinib resistance revealed c-MET amplification and the patient was started on crizotinib, but the patient was able to use this treatment for only 2 months and died due to disease progression.

Following the demonstration of the effectiveness of crizotinib in c-MET exon 14 mutant tumors in preclinical studies, it was shown for the first time that a response to crizotinib was obtained in patients with lung cancer with MET exon 14 alteration in retrospective case series.^15,16 Phase 1 PROFILE 1001 study is the first prospective study to demonstrate efficacy with a MET inhibitor in patients with NSCLC with MET exon 14 alteration. A total of 69 c-MET exon 14 skip mutation-positive patients were included in this study; the response rate to crizotinib was 32% and the median PFS was 7.3 months.¹⁷ In the 2018 update of this study, 37 patients with MET amplification were identified, and the best response rate was observed in 20 patients with high-level MET amplification (MET/CEP7 ratio ⩾5).¹⁸

Caparica et al.¹⁹ have reported two cases of MET inhibitor-sensitive NSCLC harboring high-level MET amplification (MET/CEP7 ratio ⩾5) without coincident exon 14 alterations with a commercial next-generation sequencing assay and they suggested that these two methods of MET activation can produce independent MET-addicted states.

In a retrospective multicenter study, 61 patients with NSCLC with MET exon 14 mutants were evaluated. A total of 27 of these patients were given at least first-line MET inhibitor (crizotinib, glesatinib, capmatinib, and ABBV399) treatment, and the median OS was found to be 24.6 months in these patients; 22 of these patients received crizotinib and the median PFS was 7.3. Median OS was 8.1 months in 34 patients who were not treated with MET inhibitors.²⁰ In another retrospective study, the efficacy of crizotinib was evaluated in patients with MET alteration and the median PFS was 7.3 months.²¹ We found median PFS of 9.4 months in our study.

In the retrospective study by Song et al.,²² the crizotinib responses of 47 patients with MET amplification were evaluated and the median PFS was 6.5 months, the median OS was 31 months, and the ORR was 73%. In this study, in which those who previously received anti-EGFR treatment were not included, 22.5% of the patients had brain metastasis. In our study, ORR was 50% and median OS was 10.9 months shorter compared to this study. However, half of our patients had brain metastases, and the low efficacy of crizotinib in intracranial disease may explain this difference.

In a meta-analysis performed by Vuong et al.,²³ the ORR was found to be 40.6%, median PFS 5.2 months, and median OS 12.7 in patients with NSCLC with MET alteration and crizotinib treatment. Responses to crizotinib and median OS in our study were similar to this study.

In the PROFILE 1014 study, for which crizotinib was approved by the FDA in ALK-positive patients, the most common side effects were vision disorders, elevated transaminases, diarrhea, and nausea.²⁴ In the meta-analysis performed by Vuong et al.,²³ the most common side effects were vision impairment (43.7%), edema (42.9%), and fatigue (40.1%). In our study, 25% vision impairment, 25% fatigue, 37% edema, 37% nausea, and 37% hepatotoxicity were observed. No patient required dose modification or discontinuation of the drug due to side effects.

Our study has some limitations. First, this is a retrospective observational study. Also, patients are relatively few in number and consist of a heterogeneous group. The crizotinib treatment line differs between patients, making it difficult to evaluate data on drug efficacy. Despite these limitations, it should be emphasized that c-MET amplification should be investigated in patients with advanced NSCLC and crizotinib may be an effective treatment option in these patients.

In the past decade, metastatic NSCLC treatment has changed dramatically with the widespread use of immunotherapy agents and TKIs for targetable mutations. After the Geometry Mono-1 study, the FDA approved the use of capmatinib for patients with NSCLC MET exon 14 skip mutation. Capmatinib was found to be effective in patients with MET amplification in this study.²⁵

As of the 2020 4th version of the National Comprehensive Cancer Network guideline, it is recommended to examine MET exon 14 skip mutation in patients with metastatic NSCLC at the category 2A level.²⁶ Historically, the mean survival for metastatic NSCLC was around 1 year when only cytotoxic drugs were used in treatment. Survival times started to increase after the use of targetable mutations with a personalized treatment model. MET alterations are also candidates to gain more importance with the demonstrated efficacy of different TKIs in the future.

Footnotes

Declaration of conflicting interests

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The authors received no financial support for the research, authorship, and/or publication of this article.

ORCID iDs

Seher Yildiz Tacar

Mesut Yilmaz

Deniz Tural

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