Keywords NSCLC - Met Exon 14 Skip - NGS - Capmatinib
Introduction
Lung cancer is the poster child of precision oncology, which views cancer through
the lens of single oncogenic alteration and is also known as driver mutation. Current
clinical research is focused on improving outcomes by targeting its mutant protein,
namely, epidermal growth factor receptor (EGFR), ALK, ROS1, BRAF, Her2, etc. In this
existing paradigm, mutations other the driver mutation are considered as passengers
with little to no impact on clinical outcomes. We present a case with coexisting EGFR
L858R and MET Exon 14 skipping mutation and not responding to single agent EGFR tyrosine
kinase inhibitor (TKI).
Hence, we advocate next-generation sequencing (NGS) panel testing at outset.
Case History
A 44-year-old, nonsmoker woman presented with a 3-month history of chest pain, cough,
and dyspnea. Her Eastern Cooperative Oncology Group performance status (ECOG PS) was
1. CT scan showed 8.8 × 8.3 × 9.4 cm mass in the right lung upper lobe. There was
evidence of lymphangitis carcinomatosis in the right middle and lower lobe ([Fig. 1 ] A). These findings were suggestive of stage IV disease as per the 8th edition of
the American Joint Committee on Cancer. Histopathology established the diagnosis as
TTF1 positive lung adenocarcinoma. Subsequent Sanger sequencing detected p.L858R pathogenic
mutation in exon 21 of the EGFR gene. Patient was started on Gefitinib 250 mg/day,
within 15 days of which the patient developed progressive dyspnea and new onset cervical
lymphadenopathy. Positron emission tomography (PET) scan confirmed disease progression
([Fig. 1 ] B). Her ECOG PS now (“at progression”) was 4 and she required admission in hospital.
She also developed grade 2 acneiform rash as per common terminology criteria for adverse
events (CTCAE) version 5.0 and grade 2 paronychia ([Fig. 2 ] A, B).
Fig. 1 Contrast chest CT axial images (upper panels) and coronal images (lower panels) during
initial diagnosis (A ); follow-up visit when the patient was unresponsive to Gefitinib (B ); and next follow-up 4.5 months after Capmatinib along with Gefitinib (C ). Persistent response seen at the end of on combination of Gefitinib and Capmatinib
(D ).
Fig. 2 (A )Adverse effect—acneiform rash (common terminology criteria for adverse events [CTCAE]
v5.0). Left—grade 3 within 15 days of starting Gefitinib. Right—grade 2 after 8 months
of Gefitinib plus Capmatinib. (B )Adverse effect—paronychia grade 2 (CTCAE v5.0) at end of 8 months of Gefitinib plus
Capmatinib combination.
As a part of the institutional protocol, multigene testing by NGS was performed on
tissue for initial diagnosis. The test includes single nucleotide variations in EGFR,
ALK, KRAS, BRAF, MET, RET and ERBB2, copy number variants of MET, and gene fusions
of ALK and ROS1. NGS reports of this patient detected MET Exon 14 skipping along with
EGFR p. L858R ([Fig. 3 ] A, B). Based on this, we added Capmatinib, a type Ib MET inhibitor. The patient
was enrolled in a managed access program by Novartis. Capmatinib was given 400 mg
twice daily along with Gefitinib (250 mg). This dose was determined on the basis of
RP2D from a phase Ib/II trial.[1 ] After 14 days of therapy, dyspnea and cervical lymph nodes resolved. Acneiform rash,
which developed on Gefitinib, remained stable despite the introduction of Capmatinib.
An early response evaluation PET scan at 6 weeks showed partial response (PR) with
significant reduction in metabolic activity of the previously noted right lung mass.
At the end of 4.5 months, with same dose of Gefitinib and Capmatinib, the patient
continued to respond ([Fig. 1 ] C). She has no adverse effects except grade 2 skin rash and grade 1 paronychia ([Fig. 2 ] A, B)
Fig. 3 (A, B ) Next-generation sequencing (NGS) report showing epidermal growth factor receptor
(EGFR) p.L858R and MET exon 14 splice mutations. Total mapped fusion panel reads—329059.
Read counts of MET Exon skipping = 833.
The follow-up scan ([Fig. 1 ] D) at the end of 8 months showed only a right lung mass measuring 5.5 × 5.0 cm and
mediastinal nodes reduced further in size, suggestive of continued combination therapy
at full doses ([Table 1 ]).
Table 1
Radiographic response
Time points
15/8/19
11/10/19
28/11/19
22/2/20
9/6/20
Abbreviations: CR, complete response; SUV, specific uptake value; LN, lymph node;
N/A, not applicable, Gef, Gefitinib; Cap, Capmatinib
a All sizes are in cm.
b Pretreatment scan on August 15, 2019, was a multidetector CT scan with no metabolic
scan done at that time. Hence, SUV was unknown before therapy initiation.
Treatment
Pretreatment
15 days Gefitinib
6 weeks Gef + Capmatinib
4.5 months
Gef + Cap
8 months
Gef + Cap
Right lung mass
Size
8.8 × 8.3 a
10.5 × 10
6.5 × 6.0
5.4 × 6
5.4 × 5.5
SUV
N/A b
18.52
4.40
2.13
1.58
Right para-tracheal LN
Size
4.3 × 2.8
3.5 × 2.5
2.2 × 1.5
1.9 × 2.1
1.5 × 2.1
SUV
N/A b
9.61
4.13
3.07
2.92
Right adrenal
Size
2.6 × 3.0
5.8 × 5.2
CR
CR
CR
SUV
b
22.58
Pleural effusion
None
Moderate
Minimal
None
None
Discussion
MET Exon 14 skip mutations are present in 3 to 4% of nonsmall cell lung cancer (NSCLC)
with higher frequency in elderly, smokers, and sarcomatoid histology.[2 ] Of all MET alterations, Exon 14 skip mutations are the best predictive biomarkers
of response to MET inhibitors, and a RNA-based NGS is preferable to capture these
mutations. These mutations are mutually exclusive with other driver mutations, although
coexisting MET amplification is reported.[2 ]
[3 ] Barring some anecdotal cases, this is the first case of lung adenocarcinoma with
de novo co-existing EGFR L858R and MET Exon 14 skip mutation successfully treated
with a combination of Gefitinib and Capmatinib.[4 ]
[5 ] The duration of response to targeted therapy is affected by development of acquired
resistance, which is the Achilles heel of precision oncology. In our case, there was
significant reduction in the size and metabolic activity as early as 6 weeks, and
this response is still sustained until 8 months. In similar cases reported earlier,
adverse effects to combination of EGFR TKI and MET inhibitors warranted dose adjustments.
In this case, the patient is still on full dose of Gefitinib and Capmatinib with no
added toxicities. Limitations in this case was not reconfirming MET alteration by
reverse transcription polymerase chain reaction (RT-PCR) and administering first-generation
TKI Gefitinib instead of third-generation TKI-Osimertinib, which is the current standard
of care in first-line treatment.[6 ] This can be explained by the lower gross domestic product (GDP) of our country,
with most patients paying out of pocket. However, it is unlikely that that this patient
would have responded if given Osimertinib instead of Gefitinib. Studies exploring
acquired resistance mechanisms to first-line Osimertinib show incidence of MET alterations
which is, in fact, higher than Gefitinib.
Lung cancer research has been successful in prolonging median progression-free survival
(PFS) from 9 months to 18 months.[6 ] However, the overall response rates (ORR) with Gefitinib (76%) is not very different
from Osimertinib arm (80%). Today, NGS is utilized more on progression after the first-line
TKI, because of the heterogenous mechanisms of resistance and concurrent mutations.
But our case emphasizes the need of NGS even at baseline. In the FLAURA study, patients’
tissue biopsies were done at baseline. Doing liquid biopsies at baseline will uncover
more coexisting mutations along with EGFR, as it allows more comprehensive analysis
of tumor heterogeneity. A cfDNA analysis of 1122 EGFR mutant NSCLC showed the incidence
of concurrent mutations was as high as 92%.[7 ] This study defined new pathways of limiting EGFR TKI response, including Wnt/Beta
catenin and CDK 4/6 cell cycle genes. Another multivariate analysis by Kim et al showed
that mutations in TP53, RB1, PTEN and MDM2 were poor prognostic factors in patients
on Osimertinib.[8 ] Categorizing cases as one described in this case report as TKI refractory and treating
them with conventional chemotherapy will take us back 15 to 20 years in terms of prognosis.
NSCLC with EGFR mutations is a heterogenous subgroup, with varying responses to TKI,
based on coexisting mutations. We would like to propose a new classification, as depicted
in [Fig. 4 ].
Fig. 4 New proposed pragmatic classification for nonsmall cell lung cancer (NSCLC) with
epidermal growth factor receptor (EGFR) mutations.
Conclusion
This case emphasizes the importance of NGS over single gene testing as it can find
concurrent mutations which can strongly influence the response of targeted therapy
to the primary driver mutation leading to improved treatment outcomes.
