The approval and mainstreaming of targeted therapies have decreased the mortality of non-small cell lung cancers (NSCLC). Notably, MET exon 14 (METex14) skipping mutations constitute driver alterations that occur in 3-4% of these cancers and capmatinib, a MET inhibitor, arrests cell proliferation when this mutation occurs; however, this agent has also shown antiviral activity against coronaviruses in preclinical studies.

An 82-year-old man admitted with epileptic seizures and loss of consciousness was diagnosed with stage IVB NSCLC, harboring a METex14 skipping mutation. He underwent locoregional treatment for his brain metastases and systemic chemotherapy. The patient later developed a SARS-CoV-2 infection concomitant to his worsening NSCLC. He was then treated with remdesivir and capmatinib and eventually recovered from SARS-CoV-2 along with radiological and clinical NSCLC regression within two months of initiating capmatinib.

This case highlights the clinical benefit of capmatinib in NSCLC with METex14 mutations in patients with SARS-CoV- 2 and the importance of testing for METex14 with DNA- and RNA-based methods as early as possible following advanced NSCLC diagnosis.

worldwide, with an estimated 1.8 million fatalities reported each year [1]. Non-small cell lung cancer (NSCLC) accounts for nearly 85% of all cases, and despite improvements in early detection and the development of novel treatments, the overall 5-year survival rate is still below 25% [2]. Among the molecular subtypes of NSCLC, alterations in the mesenchymal-epithelial transition (MET) gene—particularly MET exon 14 (METex14) skipping mutations—are detected in approximately 3–4% of cases and are associated with poor prognosis [3,4].

Capmatinib, a selective MET inhibitor, has demonstrated clinically meaningful activity in METex14-positive advanced NSCLC, with overall response rates of around 40–68

In January 2024, an 82-year-old man was admitted to the Livorno Hospital following an epileptic seizure with loss of consciousness (see Table 1 for detailed findings throughout the development of the case). The patient’s NSCLC was stage IVB based on imaging scans showing two lesions on the right and left frontal brain lobes with perilesional edema, a right lung lesion, and mediastinal lymphadenopathies (Figure 1). Pathologic and molecular testing indicated adenocarcinoma histology and programmed cell death ligand 1 (PD-L1) expression of 40%. Next-generation sequencing (NGS) revealed a MET exon 15 mutation. Subsequent RNA-based NGS analysis detected a METex14 skipping mutation [4].

In January 2024, the patient underwent stereotactic radiosurgery for his brain lesions. He started first-line chemotherapy with gemcitabine combined with carboplatin in February 2024. Consequently, he experienced nausea (grade 3), asthenia (grade 2), anemia (grade 3), and thrombocytopenia (grade 2). In May, imaging showed a pleural effusion, the lung lesion (Figure 2B), and three new brain lesions (Figure 3 A1, A2, A3). The patient’s clinical condition declined with intense asthenia, anorexia, and dyspnea on light exertion.

In June 2024, the patient was admitted to the emergency room due to fever and persistent cough. A SARS-CoV-2 infection was diagnosed and he was treated with oxygen therapy and remdesivir. During this hospitalization, imaging revealed a diffuse parenchymal thickening in the right lung (Figure 2C). Thus, concomitant capmatinib was initiated. After five days, he tested negative for SARS-CoV-2 and in the following weeks, his dyspnea and cough significantly improved. His capmatinib dose was reduced due to nausea (grade 2), peripheral edema (grade 2), and elevated serum creatinine (grade 2). In August 2024, two months after initiating capmatinib, imaging revealed the lung lesion with partial remission and significantly reduced brain metastases (Figures 2D and 3B2).

In November 2024, imaging showed further reductions in the target lesions. The patient survives in good overall health, without signs of disease progression, and is still being treated and in follow-up.

Table 1: Detailed case information and findings throughout the development of the case.

Figure 1: Chest (A) and brain (B) computed tomography (CT) images on January 2024. The chest CT shows a lesion close to the right costal pleura (40 x 43 x 43 mm) and multiple mediastinal lymphadenopathies. The brain CT shows two focal lesions on the right and left frontal brain lobes with perilesional edema.

Figure 2: Chest CT images from January 2024 (A) and in May 2024 (B), three months after starting chemotherapy; (C) shows CT images of the chest before (June 2024) and after (August 2024 (D)) starting treatment with capmatinib. The largest diameter of the right lung lesion is 43.12 mm in A, 45.02 mm in B, 47.09 in C, and 15.26 in D. Figure B shows the right-sided pleural effusion in addition to the lung lesion. Figure C, shows a diffuse confluent parenchymal thickening in the right lung that could have been due to COVID-19, cancer progression, or both.

Figure 3: CT images of the brain before (June 2024, A) and two months after (August 2024, B) starting treatment with capmatinib. A1 shows the small right frontal lesion, A2 shows the largest lesion which was located in the left frontal lobe (largest diameter, 12.61 mm), and A3 a small right parietal lesion. B1 and B3 show no lesions and B2 shows the left frontal lesion greatly decreased in size (largest diameter, 7 mm).

One of NSCLC’s known driver alterations is the METex14 skipping mutation, occurring in 3-4% of them. The exon 14 of the MET gene encodes the juxtamembrane domain, preventing MET receptors’ from over-signaling; thus, skipping mutations increase oncogenicity. [3] These mutations usually occur in older patients with lung squamous carcinoma and adenocarcinoma, with or without smoking history, and are associated with poor prognosis. [3]

In our case, the DNA-based NGS revealed a point mutation in the exon 15 of the MET gene. Only subsequent RNA- based analysis showed that this mutation was associated with exon 14 skipping, which as reported by Davies et al., identifies a higher percentage of METex14 skipping than amplicon-mediated DNA-based testing. This results from overcoming an inherent limitation of DNA-based approaches where primer design does not detect all METex14 events. [4] For this reason, DNA- and RNA-based NGS using hybrid capture-mediated target enrichment are preferred to avoid the allele dropout issue often seen with amplicon-based methods. [3]

Capmatinib, a potent and selective MET receptor inhibitor, has antitumor activity against MET-dysregulated NSCLC and crosses the blood-brain barrier with relatively low-grade toxicity. [5] Indeed, in the phase II GEOMETRY mono-1 trial, the overall response rate and median progression-free survival were 41% and 5.4 months in previously-treated patients and 68% and 12.4 months in treatment-naive patients.5 Capmatinib also showed promising intracranial activity and predictable and reversible adverse events consisting of mostly grade 1 or 2 peripheral edema, nausea, vomiting, and increased serum creatinine. [5]

Our patient received capmatinib concomitantly with remdesivir for a SARS-CoV-2 infection in the context of NSCLC progression because the lung’s parenchymal thickenings on his chest CT could have represented either SARS-CoV-2 infection signs or further NSCLC progression. In addition to this rationale, the decision was based on reports of capmatinib’s possible antiviral activity. For instance, Reza et al. showed that capmatinib can be active against selected SARS-CoV-2 proteins [6] and Jade et al. found that capmatinib binds to SARS-CoV-2’s RNA-dependent RNA polymerase, essential for viral replication, and can thus limit the viral infection by inhibiting RNA synthesis. [7] Therefore, we can reasonably hypothesize that in our case capmatinib could have exerted antiviral action in addition to antitumor activity, and perhaps interacted synergistically with remdesivir, 

Our case highlights the clinical benefit of capmatinib against NSCLC with METex14 skipping mutations and the importance of early molecular testing using DNA- and RNA-based methods. This case also underlines capmatinib’s safety profile and efficacy even in patients with SARS-CoV-2, on which it may contribute to treating this infection. This potential role of capmatinib deserves further investigation.

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

All the authors declare that the they do not have any conflicts of interest to disclose.

The authors declare that the following manuscript was realized with the support of Novartisand prefer that the journal assigns the reviewers for their manuscript.