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Corresponding author. Address for correspondence: Samuel J. Klempner, MD, The Angeles Clinic and Research Institute, Cedars-Sinai Medical Center, 11818 Wilshire Blvd., Los Angeles, CA 90025.
The Angeles Clinic and Research Institute, Los Angeles, CaliforniaSamuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, California
Chao Family Comprehensive Cancer Center, Department of Medicine, Division of Hematology-Oncology, University of California Irvine School of Medicine, Orange, California
A significant portion of NSCLCs with MET proto-oncogene, receptor tyrosine kinase gene (MET) exon 14 skipping alterations are sensitive to small-molecule mesenchymal-epithelial transition tyrosine kinase inhibitors. However, the incidence and management of brain metastases in this molecular subset is unknown and represents an unmet clinical need.
Methods
Hybrid capture–based comprehensive genomic profiling identified a patient with a MET exon 14 skipping alteration, and serial magnetic resonance imaging was utilized to follow intracranial disease during crizotinib and subsequent cabozantinib therapy.
Results
Intracranial progression developed in the context of ongoing extracranial disease control during crizotinib therapy. Rapid intracranial response was observed after change to cabozantinib.
Conclusions
This report provides the first detailed description of brain metastases in MET exon 14–positive NSCLC and provides preliminary support for the intracranial activity of cabozantinib. Prospective study is warranted and needed to refine the management of intracranial disease in MET exon 14–positive NSCLC.
Genomic alterations in the MNNG HOS Transforming gene (MET) leading to an exon 14 skipping (METex14)-positive result in constitutive activation and identify a unique subset of NSCLCs responsive to mesenchymal-epithelial transition (MET) tyrosine kinase inhibitors (TKIs).
Ongoing trials and published reports have demonstrated extracranial systemic responses to type I (crizotinib and capmatinib) and type II (cabozantinib) inhibitors in METex14–positive NSCLC.
Differing intracranial TKI activity informs treatment decisions in anaplastic lymphoma receptor tyrosine kinase gene (ALK)-driven NSCLC, but the incidence and optimal management of brain metastases is unknown in METex14–positive NSCLC.
Safety and activity of alectinib against systemic disease and brain metastases in patients with crizotinib-resistant ALK-rearranged non-small-cell lung cancer (AF-002JG): results from the dose-finding portion of a phase 1/2 study.
Here we report the first detailed description of brain metastases and intracranial activity of cabozantinib in METex14–positive NSCLC.
Methods
Patients with advanced NSCLC and available tissue specimens were subjected to hybrid capture–based comprehensive genomic profiling as previously described.
Appropriate patients were enrolled into the METex14–positive expansion cohort of a phase I clinical trial of crizotinib (NCT00585195). Serial computed tomography and magnetic resonance imaging (MRI) were utilized to monitor extrancranial and intracranial disease activity, respectively.
Results
Recurrent metastatic NSCLC developed in a 65-year-old white male never-smoker 17 months after lobectomy for stage IA (pT1apN0cM0) disease. Recurrence was characterized by multifocal hepatic metastases and small left and right parietal brain metastases (Fig. 1A and C). Upon metastatic recurrence the original specimen was subjected to comprehensive genomic profiling (FoundationOne, Foundation Medcine, Inc., Cambridge, MA) that identified a MET exon 14 splice site mutation (MET 2929_3028 + 212del312) without concurrent MET amplification or alternate putative driver mutations. The initial two brain metastases received stereotactic radiosurgery in a dose to 18 Gy with lasting effect (see Fig. 1A–C). The patient was enrolled into the METex14–positive expansion cohort of a phase I clinical trial of crizotinib (NCT00585195), but grade 4 transaminitis developed after 4 weeks, requiring discontinuation of crizotinib and the clinical trial (Fig. 2). A repeat MRI scan demonstrated the appearance of multiple new subcentimeter brain metastases with ongoing response in extracranial disease during an increase in transaminase level (see Fig. 1B and C). His liver enzymes recovered to grade I and cabozantinib, 60 mg orally daily, was given on the basis of demonstrated activity in METex14–positive NSCLC at this dose.
In an effort to avoid whole brain radiotherapy, close MRI monitoring was planned, and imaging 4 weeks after the patient started receiving cabozantinib demonstrated a complete intracranial response and ongoing systemic response. He tolerated cabozantinib without changes in transaminase level and continues to receive the drug (see Figs. 1B and 2).
Figure 1Intracranial and systemic response to cabozantinib in a patient with metastatic NSCLC positive for MNNG HOS Transforming gene (MET) exon 14 skipping alterations. (A) Two small brain metastases at presentation and response to stereotactic radiosurgery. Red arrows refer to brain metastases at presentation. (B) Axial postcontrast imaging showing multiple new small enhancing brain metastases that developed and subsequently responded to cabozantinib. Yellow arrows refer to new brain metastases responsive to cabozantinib. (C) Hepatic metastatic disease demonstrated ongoing response during crizotinib and cabozantinib.
Figure 1Intracranial and systemic response to cabozantinib in a patient with metastatic NSCLC positive for MNNG HOS Transforming gene (MET) exon 14 skipping alterations. (A) Two small brain metastases at presentation and response to stereotactic radiosurgery. Red arrows refer to brain metastases at presentation. (B) Axial postcontrast imaging showing multiple new small enhancing brain metastases that developed and subsequently responded to cabozantinib. Yellow arrows refer to new brain metastases responsive to cabozantinib. (C) Hepatic metastatic disease demonstrated ongoing response during crizotinib and cabozantinib.
Figure 2Trend in hepatic function tests during crizotinib and subsequent cabozantinib therapy in a patient with NSCLC positive for MNNG HOS Transforming gene (MET) exon 14 skipping alterations. Abbreviations: AST, aspartate aminotransferase; ALT, alanine aminotransferase.
The presence of brain metastases is a poor prognostic factor in NSCLC and a major driver of patient morbidity and mortality. Among ALK-rearranged NSCLCs, intracranial progression is well described for the type I inhibitor crizotinib and central nervous system (CNS) activity is a key distinguishing feature among later-generation anaplastic lymphoma kinase TKIs.
Whether an analogous situation exists in METex14–positive NSCLC is altogether unknown at this point. Among all published series describing clinicopathologic features of METex14–positive NSCLC, the incidence of CNS disease has not been captured.
Although systemic response to MET TKIs is well documented, the intracranial activity was not reported in a capmatinib-sensitive patient with known brain metastases.
Ongoing trials of type I MET TKIs, including capmatinib (NCT02750215), tepotinib (NCT02864992), and crizotinib (NCT00585195), will add to our understanding of the initial incidence of CNS metastases and the frequency of intracranial failure in METex14–positive patients while they are receiving type I MET TKIs. Although intracranial progression in our patient is partly due to the 4-week interruption of crizotinib during LFT elevation, we demonstrate for the first time that the type II MET TKI cabozantinib has CNS activity in patients with METex14–positive NSCLC.
Cabozantinib may overcome the dominant failure mechanisms plaguing crizotinib in ALK-rearranged (and likely METex14–positive) NSCLC, namely, acquired resistance mutations and intracranial progression. Emerging data suggest that METex14–positive disease shares some features with other oncogene-driven NSCLCs in that secondary mutations can underlie clinical resistance. Mutations at MET codons D1228 and Y1230 are known to confer resistance to type I MET TKIs, including crizotinib, and have been recently described clinically.
A drug resistance screen using a selective MET inhibitor reveals a spectrum of mutations that partially overlap with activating mutations found in cancer patients.
LY2801653 is an orally bioavailable multi-kinase inhibitor with potent activity against MET, MST1R, and other oncoproteins, and displays anti-tumor activities in mouse xenograft models.
Differing from crizotinib, cabozantinib is a multitarget type II MET TKI with nanomolar inhibitory concentrations against MET, and it has demonstrated preclinical intracranial penetration in mouse whole brain lysates and clinical responses in glioblastoma.
Cabozantinib is currently being studied in a brain metastasis–specific trial (NCT02260531), which may further refine our understanding of CNS penetration. Beyond crizotinib, nothing is known about CNS penetration among type I MET inhibitors (capmatinib, tepotinib, savolitinib, and AMG337) or type II compounds (cabozantinib, glesatinib, and merestinib). Although we cannot definitively conclude what the mechanism of intracranial progression is in our case, the observation that a non–cross-resistant type II inhibitor (cabozantinib) has intracranial penetration and clinical activity after exposure to a type I inhibitor (crizotinib) is novel and therapeutically important.
Notably, grade 3 or 4 transaminitis occurs in 16% of ALK-positive NSCLC treated with crizotinib, and death has occurred. As reported, grade 3 or 4 increase in aminotransferase level occured in only 2% of patients taking cabozantinib in the METEOR trial.
The safety of alternate TKI therapy after prior grade 4 hepatotoxicity is not well studied, and we suggest that cabozantinib appears safe after crizotinib.
Overall, this case provides the first detailed description of brain metastases in METex14–positive NSCLC and provides preliminary clinical support for intracranial penetration and activity of cabozantinib. Further studies characterizing the incidence, radiographic pattern, and TKI sensitivity of brain metastases in METex14–positive NSCLC are needed to expand on our observation.
References
Frampton G.M.
Ali S.M.
Rosenzweig M.
et al.
Activation of MET via diverse exon 14 splicing alterations occurs in multiple tumor types and confers clinical sensitivity to MET inhibitors.
Safety and activity of alectinib against systemic disease and brain metastases in patients with crizotinib-resistant ALK-rearranged non-small-cell lung cancer (AF-002JG): results from the dose-finding portion of a phase 1/2 study.
A drug resistance screen using a selective MET inhibitor reveals a spectrum of mutations that partially overlap with activating mutations found in cancer patients.
LY2801653 is an orally bioavailable multi-kinase inhibitor with potent activity against MET, MST1R, and other oncoproteins, and displays anti-tumor activities in mouse xenograft models.
Disclosure: Dr. Klempner has received honoraria from Foundation Medicine, Inc. Dr. Ali is an employee of and holds equity in Foundation Medicine, Inc. The remaining authors declare no conflict of interest.
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