If you don't remember your password, you can reset it by entering your email address and clicking the Reset Password button. You will then receive an email that contains a secure link for resetting your password
If the address matches a valid account an email will be sent to __email__ with instructions for resetting your password
Corresponding author. Address for correspondence: Sai-Hong Ignatius Ou, MD, PhD, University of California Irvine School of Medicine, Depart of Medicine, Division of Hematology-Oncology, Chao Family Comprehensive Cancer Center, 101 City Drive, Bldg. 56, RT81, Rm 241, Orange, California 92868.
We analyzed a large set of EGFR-mutated (EGFR+) NSCLC to identify and characterize cases with co-occurring kinase fusions as potential resistance mechanisms to EGFR tyrosine kinase inhibitors (TKIs).
Methods
EGFR+ (del 19, L858R, G719X, S768I, L851Q) NSCLC clinical samples (formalin-fixed paraffin-embedded tumor and blood) were analyzed for the presence of receptor tyrosine kinase (RTK) and BRAF fusions. Treatment history and response were obtained from provided pathology reports and treating clinicians.
Results
Clinical samples from 3505 unique EGFR+ NSCLCs were identified from June 2012 to October 2017. A total of 31 EGFR+ cases had concurrent kinase fusions detected: 10 (32%) BRAF, 7 (23%) ALK receptor tyrosine kinase (ALK), 6 (19%) ret proto-oncogene (RET), 6 (19%) fibroblast growth factor receptor 3 (FGFR3), 1 (3.2%) EGFR, and 1 (3.2%) neurotrophic receptor tyrosine kinase 1 (NTRK1), including two novel fusions (SALL2-BRAF and PLEKHA7-ALK). Twenty-seven of 31 patients had either a known history of EGFR+ NSCLC diagnosis or prior treatment with an EGFR TKI before the fusion+ sample was collected. Twelve of the 27 patients had paired pre-treatment samples where the fusion was not present before treatment with an EGFR TKI. Multiple patients treated with combination therapy targeting EGFR and the acquired fusion had clinical benefit, including one patient with osimertinib resistance due to an acquired PLEKHA7-ALK fusion achieving a durable partial response with combination of full-dose osimertinib and alectinib.
Conclusions
RTK and BRAF fusions are rare but potentially druggable resistance mechanisms to EGFR TKIs. Detection of RTK and BRAF fusions should be part of comprehensive profiling panels to determine resistance to EGFR TKIs and direct appropriate combination therapeutic strategies.
Matching treatment to underlying oncogenic drivers has produced enormous patient benefit, particularly in advanced NSCLC. However, the duration of response to targeted therapies including tyrosine kinase inhibitors (TKIs) is inevitably limited by the emergence of acquired resistance (AR). As such, identifying the precise mechanism(s) of AR may lead to subsequent lines of rationally matched treatment. An example of AR is the emergence of intragenic secondary (T790M) and tertiary (C797S and others) EGFR mutations during treatment with first-, second-, and third-generation EGFR TKIs in EGFR+ NSCLC.
Emergence of novel and dominant acquired EGFR solvent-front mutations at Gly796 (G796S/R) together with C797S/R and L792F/H mutations in one EGFR (L858R/T790M) NSCLC patient who progressed on osimertinib.
Similar intragenic mutations driving AR have been observed in NSCLC harboring ALK receptor tyrosine kinase (ALK) fusions and mesenchymal epithelial transition factor receptor gene (MET) exon 14 splice alterations in patients who have progressed on matched targeted therapy.
Circulating tumor DNA identifies EGFR coamplification as a mechanism of resistance to crizotinib in a patient with advanced MET-amplified lung adenocarcinoma.
Emergence of RET rearrangement co-existing with activated EGFR mutation in EGFR-mutated NSCLC patients who had progressed on first- or second-generation EGFR TKI.
Metastatic EML4-ALK fusion detected by circulating DNA genotyping in an EGFR-mutated NSCLC patient and successful management by adding ALK inhibitors: a case report.
Despite these promising initial reports, the prevalence and characteristics of AR kinase fusions in NSCLC remain poorly defined.
Herein, we conducted a retrospective analysis of a large database of EGFR+ NSCLC cases that had undergone hybrid-capture based next-generation sequencing (NGS). Our primary objective was to broadly identify and assess the significance of kinase fusions in the setting of acquired resistance, with a focus on targetable alterations that could improve clinical management.
Patients and Methods
Population
NSCLC cases with classical activating EGFR mutations (del exon 19, L858R, G719X, S768I, and L851Q) were identified from the Foundation Medicine, Inc., database. Cases with co-occurring receptor tyrosine kinase (RTK) and non-RTK rearrangements were selected, and those without identified fusion partners or in which the kinase domain was not retained were excluded. Treatment history was obtained from the provided pathology report or test requisition form, or through contacting the treating physician. Approval for this study, including a waiver of informed consent and a Health Insurance Portability and Accountability Act waiver of authorization, was obtained from the Western Institutional Review Board (protocol no. 20152817).
Genomic Analysis
Hybrid-capture–based comprehensive genomic profiling (CGP) was performed prospectively on submitted tumor tissue in a Clinical Laboratory Improvement Amendments–certified, College of American Pathologists–accredited, New York State–regulated reference laboratory (Foundation Medicine, Inc., Cambridge, Massachusetts) to identify genomic alterations, including base substitutions, insertions/deletions, copy number alterations, and rearrangements. At least 50 ng of DNA per specimen was extracted from clinical formalin-fixed paraffin-embedded, consecutively submitted NSCLC specimens from the primary tumor or a metastatic lesion; NGS was performed on hybridization-captured, adaptor ligation-based libraries to high, uniform coverage (>500x) for all coding exons of 236 plus detection of 19 genes fusions or 315 cancer-related genes plus detection of 28 gene fusions.
Baiting for rearrangements discussed in this study for each version of the CGP assay is detailed in Supplemental Table 1, and the version used for each sample tested in this study is detailed in Supplemental Table 2. Tumor mutational burden (TMB) was calculated as the total number of relevant mutations divided by the coding region target territory of the test (0.83 megabase [Mb] for version 1 and 1.14 Mb for version 2), and is characterized as the number of somatic base substitution or indel alterations per Mb after filtering to remove known somatic and deleterious mutations.
Additionally, since May 2016, hybrid-capture–based NGS was performed on circulating tumor DNA (ctDNA) as previously described.
Briefly, two 10-mL aliquots of peripheral whole blood were collected in cell-free DNA blood collection tubes. A double-spin protocol was used to isolate plasma, and 50 to 100 ng of ctDNA was extracted to create adapted sequencing libraries before hybrid-capture and sample-multiplexed sequencing on an Illumina HiSeq 2500 sequencer (Illumina, San Diego, California). The FoundationACT ctDNA test covers 62 genes to ×5000 unique coverage and includes intron baiting for rearrangements of six genes (ALK, EGFR, fibroblast growth factor receptor 3 [FGFR3], platelet derived growth factor receptor alpha [PDGFRA], ROS1, and ret proto-oncogene [RET]) (see also Supplemental Table 1).
A total of 3,503 EGFR+ NSCLC tumor samples, prospectively tested between June 2012 and October 2017, and 453 EGFR+ blood-based ctDNA samples, prospectively tested between May 2016 and October 2017 (total of 3956 samples), were submitted for testing during routine clinical care, representing 3505 unique NSCLC patients. Of the 3505 unique cases, 3111 patients had 1 sample tested (2815 tissue and 296 blood) and the remaining patients had >1 sample tested (688 tissue and 157 blood) (Fig. 1).
These 3505 cases include 52% EGFR del exon 19 (n = 1830), 37% L858R (n = 1300), 5.8% G719X (n = 203), 3.1% L861Q (n = 109), 1.8% S768I (n = 62), and one sample with G719S + L861Q (Supplemental Fig. 1A and B). A total of 31 EGFR+ cases (0.9%) had concurrent kinase fusions detected. In comparison, other known resistance alterations including the T790M mutation and MET amplification were detected in 19% (n = 662) and 3.3% (n = 117) of EGFR+ NSCLC cases, respectively. Fourteen cases had concurrent EGFR T790M and MET amplification.
Molecular Characteristics of Kinase Fusions in EGFR+ NSCLC
Twenty-seven of the 31 patients with co-occurring BRAF or RTK fusions identified had either a history of EGFR+ NSCLC diagnosis and/or prior treatment with an EGFR TKI before the fusion+ sample was collected (Fig. 2). Twelve patients had paired pre- and post- EGFR TKI samples available where the pre-treatment sample was negative for the fusion that was acquired in the post-treatment sample (Fig. 2 and Table 1).
Figure 2Treatment timeline for 31 NSCLC patients with EGFR mutations + BRAF or RTK fusions. Includes available records of EGFR targeted therapy and other therapy received during the relevant interval between EGFR molecular testing. Tick marks indicate 2 months. Grey boxes indicate unknown or approximate duration of treatment. Negative ALK FISH test results are noted when appropriate. Green arrow: known time of CGP. Red arrow: known time of local molecular testing. Orange circle: approximate time of local molecular testing. Pink arrows: radiation therapy.
*CGP was performed retrospectively on an initial biopsy at the time of progression on EGFR targeted therapy.
#CGP of ctDNA at this time would not have detected the BRAF fusion that was later detected in a tissue sample, so this is not considered a case with a paired pre-treatment sample.
C, carboplatin; p, pemetrexed; b, bevacizumab; cis, cisplatin; n, navelbine; ab, cetuximab; d, docetaxel; A, alectinib; a, afatinib; e, erlotinib; z, crizotinib; osi, osimertinib; bri, brigatinib; cabo, cabozantinib; t, clinical trial of EGFR unspecified inhibitor; N, nivolumab; r, rocelitinib; WT, wild-type; ALK, ALK receptor tyrosine kinase; FISH, fluorescent in situ hybridization; CGP, comprehensive genome profiling; RTK, receptor tyrosine kinase.
Table 1Characteristics and Genomic Alterations in 12 Cases of EGFR+ NSCLC With Matched Pre- And Post-Treatment Samples and Acquired RTK or BRAF Fusions
Case
Age/Sex
First CGP
Time Between Samples (d)
Second CGP
Interval Treatment History, Duration and Clinician Assessed Response
Among these 31 cases, fusions represented involved 32% BRAF (n = 10), 23% ALK (n = 7), 19% RET (n = 6), 19% FGFR3 fusion (n = 6), 3.2% EGFR (n = 1), and 3.2% neurotrophic receptor tyrosine kinase 1 (NTRK1) (n = 1) (Fig. 3 and Supplemental Fig. 1C and D). Nine unique BRAF fusion partners were identified in 10 BRAF fusion+ cases, including ArfGAP with GTPase domain, Ankyrin repeat and PH domain 3 (AGAP3), acylglycerol kinase (AGK) (n = 2), armadillo repeat containing 10 (ARMC10), dedicator of cytokinesis 4 (DOCK4), epidermal growth factor receptor pathway substrate 15 (EPS15), growth hormone receptor (GHR), KIAA1549, spalt like transcription factor 2 (SALL2), and tripartite motif containing 24 (TRIM24). Partners identified in the 7 ALK fusion+ cases included echinoderm microtubule associated protein like 4 (EML4) (n = 4), striatin (STRN) (n = 1), TRK-fused gene (TFG) (n = 1), and one novel fusion partner, pleckstrin homology domain containing A7 (PLEKHA7). Partners in the 6 RET fusion+ cases included coiled-coil domain containing 6 (CCDC6) (n = 3), nuclear receptor coactivator 4 (NCOA4) (n = 1), and TRIM24 (n = 2). All six FGFR3 fusions identified were FGFR3-TACC3. The single EGFR fusion–positive case harbored EGFR–fibroblast growth factor receptor 1 (FGFR1), and the lone NTRK1 fusion+ case harbored tropomyosin 3 (TPM3)–NTRK1.
Figure 3Schematic of the genomic rearrangements of all the RTK- and BRAF- fusions. Included exons are numbered and the involved kinase is colored purple (ALK), orange (FGFR3), pink (RET), teal (BRAF), green (NTRK1), or blue (EGFR). Exons encoding a portion of the kinase domain are colored in red. *Breakpoint within the indicated exon. RTK, receptor tyrosine kinase; ALK, ALK receptor tyrosine kinase; RET, ret proto-oncogene; NTRK1, neurotrophic receptor tyrosine kinase 1.
Twelve of the 31 patients had paired samples tested (tumor/tumor [n = 5]; tumor/plasma [n = 5]; and plasma/plasma [n = 2]). The RTK or BRAF fusion was detected after first-generation EGFR TKI (erlotinib, n = 3), second-generation EGFR TKI (afatinib, n = 2), third-generation EGFR TKI (osimertinib, n = 2; ASP8273 n = 1), second-generation EGFR TKI + EGFR antibody (afatinib + cetuximab, n = 1), first- and second-generation EGFR TKIs (erlotinib then afatinib, n = 1), first- and third-generation EGFR TKIs (erlotinib then osimertinib, n = 1), or first-, second-, and third-generation EGR TKIs (erlotinib, afatinib, osimertinib, n = 1) but was not present before EGFR-targeted therapy. Of the three patients with EGFR T790M detected by CGP in the first sample, all of whom were treated with a third-generation EGFR TKI, the emergence of RTK or BRAF fusions also corresponded with the disappearance of T790M on repeat analysis. Except for two blood samples with ALK fusions harboring co-occurring BRAF V600E or multiple EGFR resistance mutations (cases 7 and 28 shown in Tables 1 and 2), no known mechanisms of resistance were found to co-occur with the fusions in any of the post-treatment samples examined. The TMB in evaluable cases with acquired fusions was also low (median 3.5 mutations/Mb) consistent with EGFR-mutated NSCLCs. Detailed clinical and molecular characteristics and treatment history of the 12 patients are shown in Table 1 and Figure 2.
Table 2Characteristics and Genomic Alterations in 14 Cases of EGFR+ NSCLC With Acquired RTK or BRAF Fusions
Case
Age/Sex
Blood/Tissue
CGP
Interval Treatment History, Duration, and Clinician Assessed Response
Erlotinib PR, EGFR targeted therapy trial, osimertinib 8 mo PR, progression suspected on osimertinib, but was continuing on osimertinib for a total of almost 13 mo at time fusion+ sample was collected
ALK fusions
26
68/M
Tissue
L747_A755>SRD
STRN-ALK
1.7
—
Erlotinib 5 mo PR (T790M+ by outside testing), CO-1686 4 mo with liver metastasis shrinkage, osimertinib 6 mo PR (apparent T790M dropout)
The molecular profiling and treatment history of the remaining 19 patients without paired pre-treatment samples testing using CGP are shown in Table 2 and Figure 2. One patient (case 16) with paired plasma/tumor samples had a BRAF fusion detected in the post-progression tumor sample, but because the current ctDNA platform used does not include intron baiting for BRAF fusions we could not conclusively determine that the BRAF fusion was not present pre-progression, and thus this case is not included with the paired samples in Table 1.
Among the 31 cases in this series, treatment data following detection of the acquired kinase fusion was available from the treating physician for 14 patients. Of these, 5 passed away without receiving any further targeted therapy, 3 are currently being treated with standard chemotherapy or immunotherapy, 2 received single agent fusion-directed therapy, and 4 received an EGFR TKI in combination with fusion-directed therapy (2 with concurrent radiation therapy).
Case With a Novel PLEKHA7-ALK Fusion as Resistance Mechanism to Osimertinib, Responding to Osimertinib + Alectinib
This patient is a 70-year-old Asian female never-smoker with an initial diagnosis of metastatic lung adenocarcinoma. CGP of the primary tumor revealed EGFR L858R mutation but no RTK rearrangement (case 10, Table 1). She received erlotinib and achieved a partial response (PR) for 12 months. At the time of disease progression, testing of a urine liquid biopsy detected the original L858R mutation at 144 copies/100,000 genome equivalents (geq) as well as the T790M mutation at 22 copies/100,000 geq.
She received afatinib for 2 months but had mild disease progression. Subsequently, she achieved a PR for 10 months with osimertinib 80 mg once daily. Upon progression on osimertinib, blood-based ctDNA testing showed the original EGFR L858R mutation, but T790M was absent. In addition, CGP revealed a novel in-frame PLEKHA7-ALK fusion (Fig. 4A). Alectinib (600 mg twice daily) was added to full-dose osimertinib. The patient had a dramatic and confirmed PR and a duration of response of 6 months (Fig. 4B and C). The only adverse effects were grade 1 myalgia and grade 2 elevation of creatinine phosphokinase that resolved by day 50 (Supplemental Fig. 2). Notably, repeat blood-based ctDNA testing after 4 months of the combination treatment did not detect any evidence of ctDNA in the blood.
Figure 4Treatment evolution and genomic profiling in a patient with EGFR+ NSCLC with an acquired PLEKHA7-ALK fusion. (A) Schema of the PLEKHA7-ALK fusion protein. (B) Radiographic response to osimertinib + alectinib. Pre- (left) and 16 weeks post- (right) initiation of combination treatment with osimertinib + alectinib. ALK, ALK receptor tyrosine kinase; WW, tryptophan tryptophan; TKI, tyrosine kinase inhibitor.
Case With NCOA4-RET Fusion as a Resistance Mechanism to Afatinib, Responding to Afatinib + Cabozantibib
This patient is a 62-year-old female former smoker diagnosed initially with stage IIIA resected lung adenocarcinoma. The patient was enrolled on a clinical trial (E1505) and received adjuvant cisplatin/pemetrexed based chemotherapy for 4 cycles plus bevacizumab/placebo for 1 year. Disease recurrence occurred 2 years after completing adjuvant therapy, and at this time EGFR hotspot testing revealed the EGFR L858R mutation and the patient received afatinib for 20 months with stable disease (SD). Upon subsequent progression, a right lung biopsy was sent for CGP which revealed the primary EGFR L858R mutation as well as an in-frame NCOA4-RET fusion (case 23). No additional drivers or resistance mutations were detected. Cabozantinib (20 mg daily then tapered to every other day due to asymptomatic transient 2- to 3-fold transaminase and bilirubin elevation which promptly returned to normal upon dose adjustment), a multi-kinase inhibitor with RET activity, was then added to afatinib (20 mg daily). Following initiation of combination therapy, the patient had SD for an additional 7 months with no signs of progression in the brain or other sites.
Discussion
We conducted the largest retrospective analysis to our knowledge on the emergence of kinase fusions as resistance mechanisms to EGFR TKIs to date, and identified both RTK and BRAF fusions as recurrent AR mechanisms in advanced NSCLC.
These fusions occurred after treatment with first-, second-, or third-generation EGFR TKIs, or combination of afatinib plus cetuximab. Although it is generally considered that EGFR mutations and ALK or ROS1 fusions don’t co-occur in the same tumor sample,
Metastatic EML4-ALK fusion detected by circulating DNA genotyping in an EGFR-mutated NSCLC patient and successful management by adding ALK inhibitors: a case report.
In this study 12 cases had paired pre-treatment samples tested using CGP confirming the absence of the fusion, but, in the remaining 27 samples (with the possible exception of case 26, in which ALK fluorescent in situ hybridization was negative at diagnosis) we cannot say definitively that the fusion was not present de novo.
Furthermore, in the three patient cases with EGFR T790M detected by CGP, the emergence of RTK or BRAF fusions after progression on a third-generation EGFR TKI coincided with the disappearance (“drop out”) of T790M. In a fourth patient (case 10, Table 1), T790M was detected in a urine sample collected post-erlotinib but drop out was observed when a subsequent sample was tested using CGP at the time of progression on osimertinib. Additionally, in multiple cases without paired pre-treatment samples, T790M was noted to have been detected previously by outside prior testing and drop out is thus highly suspected (Table 2). In all of these cases, the original activating mutations in EGFR were retained. This is consistent with retrospective analyses of a series of EGFR T790M+ NSCLC patients who progressed on osimertinib and had drop out of T790M, but all retained the original activating EGFR mutation, and some acquired FGFR3 or RET fusions.
Furthermore, patents who had drop out of T790M on liquid biopsy at osimertinib progression had the shortest progression-free survival while on osimertinib (median, 2.6 months), and shortest post-osimertinib (median, 5.0 months) and overall survival from start of osimertinib treatment (9.3 months) among the groups of patients analyzed.
As such, identifying mechanisms of resistance indicates a possible treatment pathway for these patients.
Significantly, neither of the two patients with EGFR+ NSCLC who received single-agent targeted therapy alone matched to their acquired fusion, without concurrent combination with an EGFR TKI, had clinical benefit. The first patient (case 2, Table 1) with a CCDC6-RET fusion acquired post-erlotinib had no significant benefit to single-agent treatment with alectinib at 600 mg twice daily (also a putative RET inhibitor albeit at a dose lower than necessary to inhibit RET). A second patient (case 26, Table 2) with a STRN-ALK fusion acquired post-osimertinib in the setting of T790M drop out failed to respond to single-agent full-dose crizotinib. Conversely, two patients (cases 10 and 23, Tables 1 and 2) receiving concurrent combination treatment with an EGFR inhibitor and targeted therapy matched to their acquired fusion had clinical benefit. A patient with an acquired ALK fusion who progressed on osimertinib subsequently derived significant ongoing clinical benefit from the continuation of full-dose osimertinib with the addition of full-dose alectinib (case 10, Table 1). This is also the first report describing a novel PLEKHA7-ALK fusion which retains the PLEKHA7 protein interaction domains and the ALK kinase domain (Fig. 4A).
A second patient with lung adenocarcinoma initially positive for EGFR L858R (case 23, Table 2) had SD for 7 months on afatinib before CGP performed at disease progression detected the L858R mutation and a NCOA4-RET fusion. Because CGP was not performed initially before afatinib was initiated, we cannot definitely conclude the RET fusion was acquired in the setting of resistance; however, the patient had an additional 7 months of SD after initiating combination therapy with afatinib + cabozantinib (a multi-targeted RET inhibitor).
These cases provide additional proof of concept for the need to target both the retained primary EGFR driver alteration and the AR fusion concurrently. The combination of osimertinib and crizotinib has also been successful in overcoming resistance to osimertinib in another proof of principle case where MET amplification was determined as the resistance mechanism to osimertinib.
Tolerable and effective combination of full-dose crizotinib and osimertinib targeting MET amplification sequentially emerging after T790M positivity in EGFR-mutant non–small cell lung cancer.
All these cases indicated that simultaneously inhibiting both the primary driver mutation and the putative driver resistance mutation is important in achieving clinical benefit.
Two additional patients with EGFR+ NSCLC and acquired ALK fusions in this series (cases 9 and 11, Table 1) had clinical benefit from combined EGFR and ALK inhibition, but interpretation of these cases is confounded by concurrent radiation therapy. In case 9 (Table 1), an acquired EML4-ALK fusion was detected in combination with EGFR exon 19 deletion in a blood sample upon progression on afatinib. After radiation to the single progressive bony lesion, the patient was placed on a combination of afatinib and crizotinib, which has been ongoing for 4 months with good tolerance and SD. However, we are currently unable to discern whether the clinical benefit in this case is due to the radiation treatment or the combination targeted therapy, or both. In case 11 (Table 1), with an EML4-ALK fusion acquired in the context of EGFR L858R post-erlotinib and afatinib, there was no observed benefit with single-agent full-dose crizotinib given for approximately 1 month; however, some benefit was observed when treatment was switched to brigatinib (180 mg), a TKI with both ALK and EGFR activity, given for approximately 4 months, with a 1-week dose interruption for radiation and an additional week at 90 mg dosing.
BRAF rearrangement with diverse fusion partners has been identified in multiple solid tumor origins.
Of the nine unique partners identified among 10 cases with BRAF fusions in this report, aspartylglucosaminidase (AGA)–BRAF and Arf-GAP with GTPase, ANK repeat and PH domain-containing protein 3 (AGAP3)-BRAF fusions have been reported in NSCLC, whereas KIAA1549-BRAF was identified in other tumors. Among the recently reported 21 distinct BRAF partners in NSCLC
, SALL2-BRAF is a novel fusion not reported previously. SALL2 contains four separate zinc finger domains which can bind to DNA and function as a transcription repressor as well as interact with SV40 large T antigen.
The ability to assay for diverse BRAF fusions is of utmost importance in providing a comprehensive approach to deciphering resistance to EGFR TKIs, and developing effective combination anti-EGFR and anti-BRAF therapy. It is currently unknown whether specific BRAF fusion partners may affect the drug sensitivity profile or development of resistance, although this has been suggested for other kinase fusions including RAF1 and ALK, respectively.
Although we did not have a patient treated with combination anti-EGFR and anti-BRAF therapy, BRAF fusions alone have been successfully treated with BRAF/pan-RAF and MEK inhibitors.
Moreover, it has been shown pre-clinically that FGFR3-TACC3 provides signaling escape from EGFR/erb-b2 receptor tyrosine kinase 3 (HER3) blockade in a model of head and neck squamous cell carcinoma.
There are now TKIs in active clinical trials against RET, FGFR3, and NTRK, and some multikinase inhibitors approved in other indications have RET and/or FGFR3 activity.
Safety and antitumor activity of the multitargeted pan-TRK, ROS1, and ALK inhibitor entrectinib: combined results from two phase I trials (ALKA-372-001 and STARTRK-1).
It is anticipated that each of these RTK fusions will eventually have a matched inhibitor approved. Future studies allowing the combination of EGFR TKIs with an inhibitor of the acquired fusion will be important for patients to obtain access to effective combination regimens.
Thus, while T790M, C797S and other adjacent second site mutations, as well as MET amplification and small cell transformation are major resistance alterations to EGFR TKIs, our report expands the knowledge that a diverse set of RTK and BRAF fusions can function as acquired and potentially actionable resistance mechanisms to EGFR TKIs and addresses an unmet need for patients.
Acquired resistance of EGFR-mutant lung cancer to a T790M-specific EGFR inhibitor: emergence of a third mutation (C797S) in the EGFR tyrosine kinase domain.
Cis-oriented solvent-front EGFR G796S mutation in tissue and ctDNA in a patient progressing on osimertinib: a case report and review of the literature.
High MET amplification level as a resistance mechanism to osimertinib (AZD9291) in a patient that symptomatically responded to crizotinib treatment post-osimertinib progression.
Given this, use of tissue or blood-based CGP is necessary in clinical care, particularly upon treatment progression, to detect all classes of genomic alterations (base substitutions, indels, copy number changes, and rearrangements) and identify appropriate matched targeted therapies. Further, the identification of these fusions in the context of primary EGFR driver mutations underscores the need for further investigation of combination treatment with EGFR TKIs and other RTK or BRAF/MEK inhibitors in the clinical setting.
The elevation and resolution of creatinine phosphokinase (CPK) after the addition of full dose alectinib 600 mg twice daily to osimertinib 80 mg once daily in case 10.
Emergence of novel and dominant acquired EGFR solvent-front mutations at Gly796 (G796S/R) together with C797S/R and L792F/H mutations in one EGFR (L858R/T790M) NSCLC patient who progressed on osimertinib.
Circulating tumor DNA identifies EGFR coamplification as a mechanism of resistance to crizotinib in a patient with advanced MET-amplified lung adenocarcinoma.
Emergence of RET rearrangement co-existing with activated EGFR mutation in EGFR-mutated NSCLC patients who had progressed on first- or second-generation EGFR TKI.
Metastatic EML4-ALK fusion detected by circulating DNA genotyping in an EGFR-mutated NSCLC patient and successful management by adding ALK inhibitors: a case report.
Tolerable and effective combination of full-dose crizotinib and osimertinib targeting MET amplification sequentially emerging after T790M positivity in EGFR-mutant non–small cell lung cancer.
Safety and antitumor activity of the multitargeted pan-TRK, ROS1, and ALK inhibitor entrectinib: combined results from two phase I trials (ALKA-372-001 and STARTRK-1).
Acquired resistance of EGFR-mutant lung cancer to a T790M-specific EGFR inhibitor: emergence of a third mutation (C797S) in the EGFR tyrosine kinase domain.
Cis-oriented solvent-front EGFR G796S mutation in tissue and ctDNA in a patient progressing on osimertinib: a case report and review of the literature.
High MET amplification level as a resistance mechanism to osimertinib (AZD9291) in a patient that symptomatically responded to crizotinib treatment post-osimertinib progression.
Drs. Schrock and Zhu contributed equally to this paper.
Disclosure: Drs. Schrock, Madison, Ross, Miller, and Ali are employees and have equity interest in Foundation Medicine, Inc. Dr. Zhu has received personal fees from Astra Zeneca, Roche/Genentech, Takeda, Biocept, and TP Therapeutics. Dr. Klempner has received personal fees from Foundation Medicine, Inc.; and has consulting/advisory roles with Lilly Oncology, Astellas, and Boston Biomedical. Dr. Ou has received personal fees from Foundation Medicine, Inc., Roche/Genentech, Takeda/ARIAD, Pfizer, and Astra Zeneca. The remaining authors declare no conflict of interest.
This work was partially presented at World Conference Lung Conference, Yokohama, Japan 2017: Ou et al. Abstract MA 12.03.
30674-9&id=gr1.jpg){kind=link}
30674-9&id=gr2.jpg){kind=link}
30674-9&id=gr3.jpg){kind=link}
30674-9&id=gr4.jpg){kind=link}