In patients with pulmonary sarcoma-like carcinoma, MET inhibitors bring new options to treatment

*For medical professionals only

Wonderful case sharing~

Lung sarcoma-like carcinoma (PSC) is a rare class of low-differentiated non-small cell lung cancers (NSCLCs) that account for less than 1% of all lung cancers. Compared with other NSCLC subtypes, PSCs are more aggressive and have a worse prognosis. According to an analysis by the National Cancer Database (NCDB) and the Surveillance, Epidemiology, and Outcomes Database (SEER), the median overall survival (OS) of patients with stage IV PSC was only 3.0 to 5.4 months. Moreover, patients with PSC are susceptible to resistance to a variety of chemotherapy drugs, and treatment options are very limited.

With the development of genetic testing technology, the gene map of PSC has gradually become clear. The incidence of EXON-jump mutations in META14 has been reported to be as high as 31.8% in patients with PSC[1]. MET has become a promising therapeutic target for patients with PSC. In this article, I would like to share a case of MET inhibitors treating PSC patients with EXON-hopping mutations in MET14 [2].

Case profile

The 75-year-old male presented in September 2017 with symptoms of cough, dyspnea, and intermittent chest pain. The patient had a 40-year history of smoking and took 40 cigarettes per day.

CT shows a lesion with a maximum diameter of 5.6 cm in the lower right lobe, enlarged right hilar lymph nodes, and multiple metastatic foci of the right pleura. Biopsy pathology of lung lesions suggests stage IV (T3N1M1) sarcoma-like carcinoma, which may be transformed by adenocarcinoma.

Second-generation sequencing (NGS) of lung biopsy samples showed exon jump mutations (NM_000245: c.3028+3A>G) with a variable allele frequency (VAF) of 73.9%, which may lead to selective splicing of MET proteins. In addition, NGS showed MET amplification, TP53 (V173M) mutations, FBXW7 (G459R) mutations, but no EGFR, KRAS, ALK, and ROS1 gene mutations were detected.

The patient refused chemotherapy and participated in a Phase II clinical trial of the MET inhibitor sevotinib for patients with exon-jumping mutations in META14 or metastatic PSCs or other NSCLCs.

In November 2017, the patient was treated with the MET inhibitor sivotinib. After 6 weeks of treatment, the first tumor evaluation showed that the tumor achieved partial remission according to the RECIST v1.1 criteria (the diameter of the target lesion was reduced from 5.6 cm to 3 cm at baseline) (Figure 1); and the patient's ECOG physical condition score improved from 1 to 0. In a second tumor evaluation conducted at week 12, a partial response was confirmed.

All treatment-related adverse events (AEs) reported by patients were Grade 1, including decreased white blood cell count, nausea, diarrhea, and rash. According to the Adverse Event Common Terminology Standard version 4.03, AEs are grades 1 to 2. During treatment, the patient interrupted the administration of the drug for 5 days due to fever (not related to treatment), but the dose was not reduced due to adverse events.

After 36 weeks of treatment, the patient developed the disease (PD), the diameter of the target lesion increased to 3.8 cm, so the treatment was discontinued. After treatment with MET inhibitors, the patient achieved a 36-week progression-free survival (PFS).

Figure 1: Imaging findings at baseline, at 6 weeks (PR), and at 36 weeks (PD).

Exploration of MET inhibitor drug resistance biomarkers

From baseline to disease progression, the researchers continuously took samples of the patient's plasma circulating tumor DNA (ctDNA) throughout treatment and took tumor biopsy samples as the disease progressed. And, the researchers used an NGS panel containing 422 cancer-associated genes to explore DNA changes in tumor biopsies and plasma samples.

The analysis found that at baseline, the patients' ctDNA showed a low-level META14 exon-skipping mutation (c.3028+3A>G) with a VAF of 0.6%. After 6 weeks of treatment, as the tumor volume shrinks, the VAF of the MET mutation falls below the limit for detection; the MET mutation is not detected in subsequent cycles (18 weeks, 24 weeks, 30 weeks) or even at the time of progression (36 weeks). No somatic mutations were found in the ctDNA sample except for the META14 exon-jumping mutation.

Tumor biopsies performed at the time of disease progression showed that the mutation sites in the MET, TP53, and FBXW7 genes were the same as those found prior to MET inhibitor therapy. In addition, NGS tests performed at the time of disease progression found moderate levels of EGFR (GCN=5.7), FGFR1 (GCN=5.8), and KRAS (GCN=4.5) gene copy numbers, which were further confirmed by fluorescence in situ hybridization techniques (Figure 2). This result suggests that amplification of acquired genes may be associated with MET inhibitor resistance. Interestingly, NGS testing on tumor biopsy samples at the time of disease progression found no MET amplification (Figure 2).

Figure 2: Copy number signatures of tumor tissue. Left column: baseline; right column: at disease progression after 36 weeks.

Case discussion

In this case, tumor remission was rapid and long-lasting, and the overall performance of the patient improved after treatment, showing the efficacy of MET inhibitors in patients with EXON-jumping mutations in MET14. Moreover, during treatment, the patient was well tolerated, the safety was acceptable, no ≥ grade 3 AEs were reported, and dose reduction was not required. Previous studies have found that MET inhibitors have antitumor activity against lung adenocarcinomas, including PSCs. This case further demonstrates that PSCs also respond to MET inhibitors if the MET target is effectively suppressed. This suggests that the MET14 exon-jumping mutation may be a driver gene for NSCLC, regardless of its histopathological subtype.

In this case, the MET14 exon-jump mutation is the only somatic mutation detected in ctDNA samples, and vaF decreases significantly when partial remission is reached. Trends in VAF are consistent with changes in tumor size, suggesting that it can be used as an indicator of tumor remission in the clinic. The absence of an increase in VAF in MET mutations at the time of disease progression may be due to the occurrence of acquired resistance driving tumor growth (independent of MET gene status), at which point MET inhibitors still effectively inhibit MET.

Regarding the mechanism of drug resistance that occurs in NSCLC patients with EXON-hopping mutations in META14, two have been previously identified. One is target-dependent resistance, that is, secondary variation of the MET kinase domain, such as D1228N and Y1230S; the other is the bypass effect, such as KRAS amplification. A bypass effect was observed in this case: FGFR1, EGFR, and KRAS amplification at the time of disease progression. Therefore, amplification of the FGFR1, EGFR, and KRAS genes at the time of disease progression may be responsible for resistance to MET inhibitors in this case. However, whether these genetic changes occur in the same tumor cells or in different tumor cells, and whether FGFR1, EGFR, or MAPK pathway inhibition can restore the sensitivity of MET inhibitor therapy, further research is needed.

Interestingly, in this case, mutations in the TP53 gene were detected both before treatment and at the time of disease progression. TP53 is the most common genetic mutation in many cancers, including PSC. In general, tumors carrying TP53 mutations typically exhibit high chromosomal instabilities, particularly those located in the DNA-binding domain, such as V173M in patients in this case. Thus, chromosomal instability may be associated with multiple gene amplifications such as EGFR, KRAS, and FGFR1 during TREATMENT with MET inhibitors, leading to acquired resistance. However, further research is needed to validate this association.

brief summary

In this case report, a patient with PSC with exon-jump mutation OF MET14 achieved clinical remission with a MET inhibitor for 36 weeks, suggesting that the MET inhibitor could provide clinical benefit in such patients.

Resources:

[1] Tong J H,Yeung S F,Chan A W H,et al. MET amplification and exon 14 splice site mutation define unique molecular subgroups of non–small cell lung carcinoma with poor prognosis[J]. Clinical Cancer Research,2016,22(12):3048-3056.

[2] Han S,Fang J,Lu S,Wang L,Li J,Cheng M,Ren Y,Su W.Response and acquired resistance to savolitinib in a patient with pulmonary sarcomatoid carcinoma harboring MET exon 14 skipping mutation:a case report[J]. Onco Targets Ther.2019;12:7323-7328.doi:10.2147/OTT. S210365.

3]2021 Edition of The Chinese Society of Clinical Oncology (CSCO) Guidelines for the Diagnosis and Treatment of Non-Small Cell Lung Cancer.

Approval number: CN-91826

This material is provided by AstraZeneca and is intended for healthcare professionals only

*This information is for medical and scientific reference only and does not constitute a recommendation or promotion of any drug or treatment regimen. The information contained in this article should not be a substitute for medical advice provided by healthcare professionals.