Case report: Salvage capmatinib therapy in KIF5B-MET fusion-positive lung adenocarcinoma with resistance to telisotuzumab vedotin.

Telisotuzumab vedotin is a MET-targeting antibody-drug conjugate that has demonstrated a good treatment response in patients with EGFR wild-type MET-overexpressing non-squamous non-small cell lung cancer. However, patients have been reported to acquire resistance to this drug, and the subsequent therapy has not been standardized. Here, we present a case of a 56-year-old woman diagnosed with KIF5B-MET fusion-positive non-small cell lung cancer who had a durable response to capmatinib after acquired resistance to telisotuzumab vedotin.

Introduction

Telisotuzumab vedotin, previously named ABBV-399, is an antibody-drug conjugate, which comprises a human MET-targeting antibody, ABT-700, and a cytotoxic microtubule inhibitor, monomethyl auristatin E, through a valine-citrulline linker (1). Preliminary results from a phase 2 trial demonstrated that telisotuzumab vedotin yielded an objective response rate of 53.8% in patients with epidermal growth factor receptor (EGFR) wild-type MET-overexpressing non-squamous non-small cell lung cancer (NSCLC) (2). However, the subsequent treatment strategy after acquiring resistance to telisotuzumab vedotin remains under investigation. Here, we present the case of a patient with KIF5B-MET fusion-positive advanced NSCLC who exhibited a durable response to capmatinib after acquiring resistance to telisotuzumab vedotin. To the best of our knowledge, this is the first case report to describe the clinical benefit of capmatinib in patients with NSCLC with MET fusion.

Case presentation

In October 2019, a 56-year-old woman was diagnosed with poorly differentiated stage IIIC pulmonary adenocarcinoma. The tumor involved the right upper lobe and mediastinal lymph nodes. Polymerase chain reaction analysis revealed wild-type EGFR, and the immunohistochemical staining for ALK and ROS1 was negative. Concurrent chemoradiotherapy followed by 12-month durvalumab consolidation was administered, and the tumor showed significant shrinkage. Eleven months after completion of durvalumab therapy, the patient experienced disease progression with enlargement of the left axillary lymph node. Sonography-guided biopsy revealed an adenocarcinoma. Next-generation sequencing (NGS) by the QIAact Lung All-in-One assay revealed KIF5B-MET fusion ( ), PDGFRA mutation, and RICTOR amplification ( ). She was then enrolled in a phase 2 clinical trial with telisotuzumab vedotin, and subsequent chest computed tomography revealed partial regression of the axillary lymph node. During the administration of telisotuzumab vedotin, the patient experienced grade 2 blurred vision and grade 1 pneumonitis.

Figure 1

Next-generation sequencing of tissue before and after Telisotuzumab Vedotin. (A) The RNA-based NGS by QIAact Lung All-in-One assay revealed a KIF5B-MET (K24;M15) fusion. (B) The DNA-based NGS by FoundationOne® CDx after Telisotuzumab Vedotin still revealed KIF5B-MET fusion. The data was provided by the Department of Research and Development, Foundation Medicine Inc. (C) The diagram of KIF5B-MET fusion. NGS, next-generation sequencing.

Table 1

Results from NGS testing before and after Telisotuzumab Vedotin.

Before Telisotuzumab Vedotin*		After Telisotuzumab Vedotin**
Gene	Genomic alteration	Gene	Genomic alteration
MET	KIF5B-MET fusion (AF: 6.25%)	MET	KIF5B-MET fusion
MET	Amplification	PIK3CA	amplification
PDGFRA	D842A (AF: 5.02%)	CCNE1	amplification
RICTOR	Amplification	KEL	rearrangement intron 14
		MUTYH	splice site 892-2A>G
		TP53	M169fs*16

*Next-generation sequencing testing was performed by QIAact Lung All-in-One assay and revealed wild-type sequences in hotspots of the following genes: ALK, AKT1, DDR2, EGFR, ERBB2, ESR1, FGFR1, KRAS, KIT, MAP2K1, MET, NRAS, NTRK1, PDGFRA, PIK3CA, PTEN, and ROS1.

**Next-generation sequencing testing was performed by FoundationOne® CDx.

However, 8 months later, the patient experienced disease progression again with new-onset left chest wall metastasis. Re-biopsy showed adenocarcinoma, and NGS using FoundationOne® CDx revealed KIF5B-MET fusion without other oncogenic driver mutations ( and ), which implies a potential response to MET tyrosine kinase inhibitor (TKI). Thus, capmatinib was administered, and further imaging showed a dramatic response after 3 months of therapy. The therapeutic response was determined based on the radiographic evidence according to Response Evaluation Criteria in Solid Tumors version 1.1 (3). The patient has been on capmatinib for more than nine months, and no significant adverse events have developed. The treatment course is summarized in .

Figure 2

Summary of treatment courses mentioned in this case report. The yellow arrowhead indicate the target lesion at disease progression after consolidation therapy with durvalumab, whereas the red arrowhead indicates the target lesion at disease progression after the use of Telisotuzumab Vedotin. ALK, anaplastic lymphoma kinase; CCRT, concurrent chemoradiotherapy; CT, computed tomography; EGFR, epidermal growth factor receptor; IHC, immunohistochemical; NGS, next-generation sequencing; PCR, polymerase chain reaction; ROS1, ROS proto-Oncogene 1.

Discussion

MET fusion is a rare oncogenic driver mutation in NSCLC, which comprises only 0.5% of the total number of patients with lung cancer (4, 5). This may be underestimated if the genomic test is carried out using DNA-based NGS (6). Several fusion of MET gene partners have been described in lung adenocarcinomas, including KIF5B, HLA-DRB1, UBE2H, CD47, ATXN7L1, SPECC1L, and CAV1 (7, 8). Similar to the MET exon 14 skipping mutation, MET fusion induces ligand-independent activation of downstream signaling pathways, resulting in cellular proliferation, survival, migration, and angiogenesis (6). In addition, depending on the breakpoint of each fusion gene, MET fusion might also result in overexpression of MET protein on the cell surface. In a study conducted by Gow et al., there were two NSCLC cases with the KIF5B-MET rearrangement, which is a fusion between exons 1-24 of KIF5B and exons 15-21 of MET. The loss of exon 14 in MET results in a lack of the juxtamembrane domain of the MET protein, leading to its overexpression during immunohistochemical staining, which is secondary to failure of ubiquitin-dependent protein degradation (4). Our patient also harbored a KIF5B-MET rearrangement with a fusion between exons 1-24 of KIF5B and exons 15-21 of MET ( ), which is associated with MET protein overexpression and a potentially higher response rate to telisotuzumab vedotin (2). In addition, the KIF5B-MET rearrangement also contain the exon 1-15 of the KIF5B, which preserves the kinesin motor and coiled-coil domains that mediate homodimerization and subsequent activation of MET signaling pathway (9). The KIF5B is also an active promoter, which had been reported to activate and enhance the downstream oncogenic pathway of ALK and RET (10, 11).

The therapeutic strategy after acquiring resistance to telisotuzumab vedotin remains to be standardized. In our case report, NGS of the re-biopsied tumor revealed KIF5B-MET fusion, and no other oncogenic driver mutation was discovered, which implies that the tumor might be responsive to targeted therapy. In a in vivo study, the lung cancer xenograft model of KIF5B-MET fusion exhibited a good treatment response to crizotinib, a type Ia MET-TKI (4). Several case reports also demonstrated a good treatment response to crizotinib among NSCLC patients with de noo MET fusion (5, 8, 12–15). In addition, MET fusion could also be a resistance mechanism in patients with EGFR-mutant NSCLC who experience disease progression after treatment with EGFR-TKI. The combination of EGFR-TKIs and MET-TKIs can provide clinical benefits (5, 16, 17). Recently, targeted therapies with type Ib MET-TKIs, including tepotinib and capmatinib, have demonstrated their effectiveness and have been approved to treat patients with MET exon 14 skipping mutation-positive NSCLC (18). Capmatinib has a higher potency for MET protein binding based on an in vitro study (19); however, there are no reports on capmatinib treatment in patients with MET fusion. In the present case report, our patient experienced significant tumor shrinkage after receiving capmatinib, which implies that capmatinib could be a potential salvage therapy for patients with NSCLC with MET fusion and acquired resistance to telisotuzumab vedotin.

In summary, our case report highlights that patients with MET fusion could potentially respond to capmatinib treatment. More importantly, it could be used as salvage therapy for patients with acquired resistance to telisotuzumab vedotin. Further prospective clinical trials are warranted to validate these results.

Data availability statement

The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.

Ethics statement

This study was reviewed and approved by The Review Board and Ethics Committee of National Cheng Kung University Hospital. The patient provided their written informed consent to participate in this study.

Author contributions

C-YL, S-HW, and P-LS had full access to data in this case report and takes responsibility for the integrity and accuracy of data analysis. Y-LC and C-LH contributed to the genomic data analysis. C-TL, S-YW, C-LH, DP, P-LS, and C-CL contributed to the scientific review and final approval of this manuscript. All authors contributed to the article and approved the submitted version.

Funding

The present study was funded by grant no. MOST 110-2314-B-006-102, MOST 111-2314-B-006 -092-MY3 from the Ministry of Science and Technology, Taiwan, and grant no. NCKUH-11102019 from National Cheng Kung University Hospital, Taiwan.

Acknowledgments

The patient involved in this case report gave his informed consent authorizing use and disclosure of his health information. We also thank the Molecular Medicine Core Laboratory, Clinical Medicine Research Center, National Cheng Kung University Hospital for technical support, experimental design, and data analysis with the GeneReader NGS system.

Conflict of interest

DP is employed by Foundation Medicine Inc.

The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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