Background
EGFR-activating mutations are pivotal therapeutic targets in non–small cell lung cancer (NSCLC).1 EGFR-targeting tyrosine kinase inhibitors (TKIs) have significantly improved patient outcomes.1 However, resistance to these therapies can develop through various on- and off-target mechanisms.2,3 Next-generation sequencing (NGS) enables high-throughput genomic profiling, facilitating the identification of actionable genetic alterations. EGFR T790M and C797S are common EGFR secondary mutations. EGFR T790M is the primary cause of resistance to first- and second-generation EGFR-TKIs, which can often be effectively addressed with third-generation TKIs.4 In contrast, EGFR C797S, either in cis (on the same allele as T790M) or in trans (on a different allele), is prevalent in patients who progress on third-generation TKIs, posing additional challenges for treatment.5,6
Activation of bypass signaling pathways is another significant cause of resistance to EGFR-TKIs.7,8 MET amplification has long been recognized as a key acquired resistance mechanism that can lead to the failure of EGFR-targeted therapies.9 Studies such as SAVANNAH, TATTON, and INSIGHT 2 have demonstrated the efficacy of co-inhibiting EGFR and MET pathways in overcoming resistance. This strategy is recommended for patients with MET amplification whose disease progressed on EGFR-TKIs.10–12 Several EGFR-MET bispecific antibodies have shown promise in addressing MET-driven resistance in preclinical and clinical studies. Among these, amivantamab has recently been approved for NSCLC based on results of the phase III PAPILLON study.13 NTRK gene fusions are rare oncogenic drivers in solid tumors, with a reported prevalence of only 0.2% to 3.3% in NSCLC.14 First-generation tropomyosin receptor kinase (TRK) TKIs, such as larotrectinib and entrectinib, have proven effective in treating solid tumors with NTRK fusions and have received FDA approval for tumor-agnostic use.15,16 Next-generation TRK inhibitors have demonstrated effectiveness in inhibiting TRK receptor signaling and overcoming resistance to first-generation TRK inhibitors. Among these, repotrectinib has received FDA approval for NTRK fusion–positive solid tumors.17 Recent studies provide early insights into the potential correlation between NTRK fusions and lack of response to EGFR-TKIs.18,19 The diverse mechanisms complicate the treatment landscape for patients with NSCLC that fails to respond to EGFR-TKIs, underscoring the need for standard clinical management of EGFR-TKI resistance involving multiple pathways.7,8
This report presents a challenging case of bone-metastatic NSCLC featuring the concurrence of a novel POT1::NTRK3 fusion and MET amplification, which rendered EGFR-TKIs ineffective. To our knowledge, this is the first reported case of a patient with advanced NSCLC and acquired EGFR-TKI resistance achieving a response to EGFR/NTRK/MET triple inhibition. This case highlights the value of NGS-guided precision treatment in tailoring effective treatment strategies for complex resistance mechanisms.
Case Description
In May 2020, a 58-year-old Asian male with no history of smoking or familial cancer presented with left hip pain lasting 1 year and a cough for 2 months. The severity of localized hip pain was assessed using the Numeric Rating Scale (NRS; scale 0–10), a simple and commonly used tool for evaluating pain intensity, with an initial rating of 3.20 Serum CEA and cytokeratin 19 fragment 21-1 (CYFRA21-1) levels were significantly elevated (see Supplementary Figure S1, available online in the supplementary material). Enhanced CT scans revealed a mass in the lower lobe of right lung causing atelectasis, enlarged mediastinal lymph nodes, and bony destruction in the T5 and T11 vertebrae, left ilium, and right acetabulum. A biopsy of the left ilium showed immunochemical positivity for thyroid transcription factor 1 (TTF-1), Napsin A, and cytokeratin 7 (CK7), indicating metastatic adenocarcinoma (Figure 1). The patient was diagnosed with stage IV right lung adenocarcinoma (cT2N3M1c) and had an ECOG performance status of 2. At the time of diagnosis, the patient also had deep vein thrombosis and pulmonary embolism. Two additional pulmonary embolism events were confirmed in May 2022 and April 2023, each treated appropriately. Given multiple occurrences, the patient has been taking rivaroxaban for prevention as of the time of writing. The patient underwent tissue and liquid biopsies analyzed with NGS targeting 769 cancer-related genes (Genecast Biotechnology Co., Ltd.). Before NGS results were available, the patient received 1 cycle of pemetrexed (500 mg/m2, intravenously guttae, day 1, every 3 weeks) and cisplatin (25 mg/m2, intravenously guttae, days 1–3, every 3 weeks). NGS identified an EGFR L858R mutation, with variant allele frequencies (VAFs) of 44.93% in tissue and 13.32% in plasma. In July 2020, the patient began treatment with dacomitinib (30 mg, orally, daily), which was later reduced to 15 mg due to grade 2 paronychia. Denosumab and zoledronic acid were administered to mitigate the risk of skeletal-related events. The patient reported symptom relief and achieved partial response (PR). Follow-up CT scans showed significant reduction of the primary lung lesion and osteoblastic transformation of the osteolytic lesion in the left ilium (Figure 2).
Histopathologic findings of the left ilium biopsy. (A) Hematoxylin-eosin staining, and immunochemical stains of (B) Napsin A, (C) thyroid transcription factor 1 (TTF-1), and (D) cytokeratin 7 (CK7) (original magnification ×200 for all). All consistent with metastatic adenocarcinoma.
Citation: Journal of the National Comprehensive Cancer Network 2025; 10.6004/jnccn.2024.7070
Clinical treatment history and serial imaging data of the patient. Timeline of events, including systemic and localized treatments and disease progression, is shown at the top. Cross-sectional CT images at the bottom indicate the development, progression, and shrinkage of representative lesions in lung and pelvis during the treatment course.
Abbreviations: OR, overall response; PFS, progression-free survival; PR, partial response; SD, stable disease.
Citation: Journal of the National Comprehensive Cancer Network 2025; 10.6004/jnccn.2024.7070
In October 2021, the patient reported worsening left hip pain. CT scans revealed enlarged extraosseous soft tissue around the left ilium (Figure 2). Palliative radiotherapy (30 Gy/10 fractions) was administered, resulting in slight pain improvement. However, follow-up CT in March 2022 showed further growth of the left iliac lesion and new metastases to sacrum and right ilium, indicating a progression-free survival (PFS) of 20.2 months with dacomitinib. To address the progression, CT-guided 125I implantation was performed in the left pelvis. Despite this, the pain persisted. Plasma-based NGS detected the emergence of EGFR T790M (VAF 19.11%). Treatment was switched to third-generation EGFR-TKI almonertinib (110 mg, orally, daily), and CT re-evaluation suggested stable disease (SD).
In October 2022, the patient experienced new soreness in the right hip. CT scans revealed gradual progression of pelvic metastases. Another round of radiotherapy (30 Gy/10 fractions) was administered, but symptoms did not improve. Plasma-based NGS detected EGFR T790M-trans-C797S (VAF 0.83%; PFS, 6.4 months). Gefitinib (250 mg, orally, daily) was added to the regimen, and the overall response was subsequently evaluated as SD once again.
By May 2023, the patient reported increased hip pain (NRS score 4). CT revealed a new osteolytic lesion in the right ilium (Figure 2; PFS, 4.4 months). Plasma-based NGS identified EGFR T790M-cis&trans-C797S mutations (c.2389T>A VAF 0.35%, c.2390G>C VAF 0.6%) and a POT1::NTRK3 fusion (VAF, 0.54%) (Figure 3). In June 2023, larotrectinib (100 mg, orally, twice daily) was added to the previous regimen. However, the patient developed grade 3 dermatitis, leading to a reduction of gefitinib to twice weekly and eventual discontinuation after 1 month. Thereafter, the dermatitis gradually resolved to grade 1, the NRS score decreased from 4 to 2, and therapeutic efficacy was evaluated as SD.
Dynamic changes of the variant allele frequencies of mutations over 6 time points. Fish plots at top and bottom show the evolving frequencies of gene alterations of interest in blood and tissue, respectively. To enhance visualization, we applied logarithmic transformation to the actual frequencies. The middle panel illustrates the relative frequencies by the sizes of circles, and the numbers within circles represent the actual frequencies detected by NGS. Filled circles and outlined circles indicate results from plasma- and tissue-based NGS analysis, respectively.
Abbreviations: delins, deletion-insertion; NGS, next-generation sequencing.
*Copy number of MET amplification.
Citation: Journal of the National Comprehensive Cancer Network 2025; 10.6004/jnccn.2024.7070
In July 2023, the patient reported persistent hip pain and underwent bilateral internal iliac artery chemoembolization with gemcitabine (60 mg). Despite this, he experienced pain exacerbation (NRS score 6) and left hip swelling. In September 2023, CT scans revealed new metastases near the left ilium and in the left hilum and left erector spinae muscle (Figure 2), indicating multiorgan progression (PFS, 3.2 months). NGS analysis of the nodule near the left ilium and paired plasma revealed the emergence of MET amplification (copy number 4.21 in tissue, 3.83 in plasma), and the POT1::NTRK3 fusion was again detected in blood (VAF, 0.59%). Thus, the patient was started on a combination therapy of osimertinib (80 mg, orally, daily), larotrectinib (100 mg, orally, twice daily), and capmatinib (400 mg, orally, twice daily). Despite grade 2 paronychia, immediate symptom relief was observed within 2 days, with dramatic shrinkage of new measurable metastases, evaluated as a PR (Figure 2). Plasma-based NGS performed after treatment initiation showed that both MET amplification and the NTRK3 fusion had become undetectable, and the frequencies of EGFR L858R and T790M had also decreased significantly. Additionally, a new MET insertion-deletion mutation (p.D1228_Y1230delinsHLN) (VAF, 0.79%) was identified. At the last follow-up in January 2024, after being monitored for 44 months, the patient continued to demonstrate a PR.
Discussion
EGFR C797S, which can occur either in cis or trans with EGFR T790M, is an important on-target resistance mechanism to third-generation EGFR-TKIs. EGFR T790M-trans-C797S is sensitive to combined first- and third-generation EGFR-TKIs, whereas patients harboring EGFR T790M-cis-C797S may benefit from combination therapy with brigatinib and cetuximab.21–25 In our case, we first detected the trans configuration and started combined treatment with gefitinib and almonertinib. Notably, the allelic configuration of EGFR T790M/C797S can shift during treatment, which is associated with the development of drug resistance.23,26 After dual EGFR-TKI therapy, we detected a conversion from EGFR T790M-trans-C797S to T790M-cis&trans-C797S (Figure 3). The cis&trans configuration accounts for approximately 10% of C797S-mutated cases and correlates with the worst prognosis compared with other subtypes.26 Currently, there are no effective therapies for this patient subgroup.27,28 In our case, an NTRK fusion was identified concomitantly. Given the patient’s tolerability, only larotrectinib was added to the previous treatment regimen. However, severe adverse events occurred during the combined regimen. Therefore, the safety profile of dual EGFR-TKIs in combination with other targeted agents warrants attention.
The novel POT1::NTRK3 fusion we detected has not been previously documented in the literature. Both DNA- and RNA-based NGS offer the advantage of identifying the fusion partner with high specificity and are recommended for detecting NTRK rearrangements.29 In our case, despite the low frequency of the fusion, DNA-based NGS successfully identified the POT1::NTRK3 fusion event (Figure 4A). To further confirm expression, we performed a tissue-based RNA sequencing; however, it did not detect the fusion, which we propose could be due to the spatiotemporal heterogeneity of tumor. Recently, based on acquired NTRK1 fusions detected after patients progressed on EGFR-TKIs, preliminary evidence suggests that NTRK1 fusions can emerge as acquired resistance mechanisms to both first- and third-generation EGFR-TKIs, even at a low frequencies.18,19,30 In patients with EGFR-mutated NSCLC harboring NTRK1 fusions, 4 of 7 NTRK1 fusion genes were detected with a frequency of ≤1%.19 However, current reports on NTRK3-related EGFR-TKI resistance are scarce. In our case, the NTRK3 fusion was detected after progression on combined first- and third-generation EGFR-TKIs, indicating its potential role in EGFR-TKI resistance. Although the underlying mechanism remains unclear, dysregulation of receptor tyrosine kinases may compensate for the inhibited EGFR signaling through the abnormal activation of convergent downstream signaling pathways, such as those mediated by MET amplification.31 Similarly, given that NTRK signaling and EGFR signaling converge on the PI3K/Akt and MAPK pathways, NTRK fusions may induce EGFR-TKI resistance via compensatory activation of downstream molecules.32–34 Despite the overall low frequency of NTRK fusions in patients with lung cancer, a substantial proportion of detected fusions co-occur with primary and secondary EGFR mutations.19,35 In this clinical context, co-targeting EGFR and the acquired fusion may offer clinical benefits.30,36 The novel fusion we detected contains the full-length tyrosine kinase domain of NTRK3 and conforms to an in-framestructure (Figure 4B,C), suggesting its sensitivity to first-generation TRK-TKIs. Larotrectinib induces a response in 75% of patients in a pan-cancer cohort.15 However, its efficacy remains uncertain in patients with an EGFR mutation, particularly those harboring secondary EGFR mutations and resistant to EGFR-TKIs. In our case, although the addition of larotrectinib resulted in pain relief and improved mobility, it showed suboptimal efficacy in reducing tumor burden. We speculate that this could be due to progression driven by untargeted activated pathways, such as EGFR T790M-cis&trans-C797S, or other undetected genetic alterations. However, the possibility that the NTRK3 fusion did not drive the major resistance events cannot be ruled out.
Illustration of the POT1::NTRK3 fusion event. (A) Identification of POT1::NTRK3 fusion in plasma-based next-generation sequencing analysis. (B) Circos plot showing interchromosomal translocations between POT1 and NTRK3 represented by a colored line linking 2 genes. (C) Schematic diagram depicting the in-frame POT1::NTRK3 (P7;N15) fusion event. The fusion contains the full-length kinase domain of NTRK3 (exons 15–19).
Citation: Journal of the National Comprehensive Cancer Network 2025; 10.6004/jnccn.2024.7070
After the multiorgan progression, MET amplification was identified as a crucial contributing factor through matched NGS. Because continued inhibition of EGFR and NTRK was required, the patient was treated with concomitant EGFR/NTRK/MET inhibition. This triplet therapy induced a robust response and rapid symptom relief. Subsequent NGS revealed >80% reductions in EGFR L858R and T790M mutations and undetectable levels of NTRK3 fusion and MET amplification (Figure 3). As previously noted, genetic alterations of EGFR, MET, and NTRK promote cancer initiation and progression by engaging multiple common downstream signaling pathways.32,34,37 MET amplification can mediate resistance to EGFR-TKIs and TRK inhibitors via convergent activation of the PI3K/Akt and MAPK pathways, respectively.9,38 Thus, it is possible that the triplet therapy synergistically suppressed these downstream molecules, contributing to its remarkable efficacy. Overall, this case highlights the efficacy and safety of concurrent multipathway inhibition in heavily treated patients with TKI-resistant NSCLC. Further research is needed to explore the interaction between pathways and its impact on combination therapy. Notably, an atypical insertion-deletion at MET D1228_Y1230 was detected in the latest plasma-based NGS analysis. MET D1228 and Y1230 point mutations are common resistance mechanisms to type I MET inhibitors while sensitive to type II MET inhibitors.39,40 The clinical significance of this insertion-deletion variant deserves increased focus.
Bone metastases are detected in >60% of patients with NSCLC harboring EGFR L858R mutations.41 In this case, the patient experienced multiple metastases to major weight-bearing bones, with gradual progression causing worsening pain and elevated tumor markers. The efficacy of localized therapy is limited. Currently, systemic targeted therapy remains the primary treatment for bone metastases. In the detection of treatable targets, tissue-based NGS demonstrates higher sensitivity compared with plasma-based NGS. As a complementary approach, liquid biopsy better captures tumor heterogeneity and offers the advantages of being minimally invasive and real-time.42–44 However, concordance rates between liquid and tissue biopsies for molecular genotyping vary across studies and mutation types.7,45,46 Therefore, matched NGS may provide a more comprehensive characterization of the cancer genome, facilitating the identification of targetable genetic alterations. In our case, emerging MET amplification was identified by matched NGS, suggesting its critical role in disease progression. Plasma-based NGS expanded the range of potentially actionable targets and revealed the presence of EGFR C797S and NTRK3 fusion (Figure 5), which may exist in subclonal-resistant populations. Overall, in the framework of precision medicine, matched NGS represents an informative strategy to aid optimal clinical decision-making.
Mutation profiles over 6 time points. Matched plasma- and tissue-based next-generation sequencing revealed the complex and evolving mutational landscape of the patient during treatment. Paired results of tissue and plasma are shown at timepoint 1 and timepoint 5. Numbers within the squares represent frequencies of the mutation.
*Copy number.
Citation: Journal of the National Comprehensive Cancer Network 2025; 10.6004/jnccn.2024.7070
Conclusions
This case reports a novel, targetable POT1::NTRK3 fusion in a patient with NSCLC and acquired EGFR L858R/T790M/C797S mutations, which may serve as a resistance mechanism to EGFR-TKIs. It also highlights the rare co-occurrence of the POT1::NTRK3 fusion and MET amplification, which may contribute to disease progression. The triple inhibition of EGFR, NTRK, and MET resulted in a dramatic therapeutic response and was well tolerated. This case underscores the importance of real-time, matched NGS in complex clinical scenarios. Further studies are expected to explore the role of NTRK fusions in EGFR-TKI resistance and to determine the optimal treatment combinations and follow-up strategies for patients with EGFR-mutated NSCLC who develop resistance in a stepwise manner.
Acknowledgments
The authors thank the patient and his family. They also extend thanks to Genecast Biotechnology Co., Ltd. (Wuxi), which participated in gene sequencing and data bioinformatic analysis.
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