| 23 |
2024 |
A phase II study of tepotinib in patients with advanced solid cancers harboring MET exon 14 skipping mutations or amplification (KCSG AL19-17)
Abstract
Background
We evaluated the efficacy and safety of tepotinib in patients with various solid cancers harboring MET exon 14 skipping mutation (METex14) or MET gene amplification.
Patients and methods
A phase II, multicenter study was conducted in patients with advanced or metastatic solid cancers who progressed after standard treatment, harboring either METex14 or MET amplification detected in tissue-based next-generation sequencing (NGS). The primary endpoint was objective response rate (ORR). For exploratory analyses, we analyzed the gene profiles using plasma NGS test.
Results
Thirty-five patients were enrolled. The ORR was 57.6% for all patients, 52.2% for those with METex14, and 70% for those with MET amplification. Median progression-free survival (PFS) was 8 months [95% confidence interval (CI) 4.5-11.5 months] and median overall survival (OS) was 14 months (95% CI 7.8-20.2 months) in all patients. For patients with non-small-cell lung cancer with METex14, the median PFS was 9 months (95% CI 4.7-13.4 months) and the median OS was 17 months [95% CI not applicable (NA)-NA]. For patients with MET amplification, the median PFS was 7 months (95% CI 1.5-12.5 months) and the median OS was 10 months (95% CI 5.8-14.2 months). The ORR of patients with MET dysregulation detected by plasma NGS was 72.2%, whereas the ORR was 30% in those without detection. The most common adverse events were peripheral edema, asthenia, transaminase elevation, and anorexia, mostly grade 1 or 2.
Conclusions
Tepotinib demonstrated consistent antitumor activity in patients with METex14, and promising antitumor activity in various cancers with MET amplification. Detection of MET dysregulation by plasma NGS may predict the response to tepotinib.
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ESMO Open |
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| 22 |
2024 |
Varlitinib and Paclitaxel for EGFR/HER2 Co-expressing Advanced Gastric Cancer: A Multicenter Phase Ib/II Study (K-MASTER-13)
Abstract
Purpose
Varlitinib is a
pan-human epidermal growth factor receptor (HER) inhibitor targeting epidermal
growth factor receptor (EGFR), human epidermal growth factor receptor 2 (HER2),
and HER4. We present a phase Ib/II study of a combination of varlitinib and weekly
paclitaxel as a second-line treatment for patients with EGFR/HER2 co-expressing
advanced gastric cancer (AGC).
Materials and
Methods
Patients whose
tumors with EGFR and HER2 overexpression by immunohistochemistry (≥ 1+) were
enrolled. Varlitinib and paclitaxel were investigated every 4 weeks. After
determining the recommended phase II dose (RP2D) in phase Ib, a phase II study
was conducted to evaluate the antitumor activity.
Results
RP2D was treated
with a combination of varlitinib (300 mg twice daily) and paclitaxel. Among 27
patients treated with RP2D, the median progression-free survival and overall
survival (OS) were 3.3 months (95% confidence interval [CI], 1.7 to 4.9) and
7.9 months (95% CI, 5.0 to 10.8), respectively, with a median follow-up of 15.7
months. Among 16 patients with measurable disease, the objective response rate
(ORR) and disease control rate were 31% and 88%, respectively. Patients with
strong HER2 expression (n=8) had a higher ORR and longer OS, whereas those with
strong EGFR expression (n=3) had poorer outcomes. The most common adverse
events (AEs) of any grade were neutropenia (52%), diarrhea (27%), aspartate
aminotransferase/alanine transaminase elevation (22%), and nausea (19%). No
treatment-related deaths or unexpected AEs resulting fr|om treatment cessation
were observed in patients with RP2D.
Conclusion
A combination of
varlitinib and paclitaxel displayed manageable toxicity and modest antitumor
activity in patients with EGFR/HER2 co-expressing AGC who progressed after
first-line chemotherapy.
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Cancer Research and Treatment |
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| 21 |
2024 |
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Annals of Laboratory Medicine |
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| 20 |
2024 |
Concordance of ctDNA and tissue genomic profiling in advanced biliary tract cancer
Abstract
Background
& Aims
Recent advances in
molecular profiling have enabled the identification of potential therapeutic
targets for biliary tract cancer (BTC). However, in patients with BTC,
molecular profiling is hindered by challenges in obtaining adequate tissue
samples. Circulating tumor DNA (ctDNA) may offer an alternative to tissue-based
analysis. Herein, we aimed to assess the concordance between ctDNA and tissue
genomic profiling in a large cohort of Asian patients with advanced BTC, and to
evaluate the feasibility of liquid biopsy in BTC treatment.
Methods
This study
included patients with systemic treatment-naive advanced BTC, treated at CHA
Bundang Medical Center between January 2019 and December 2022. We enrolled
patients with available baseline tissue-based next-generation sequencing, and
sufficient plasma samples for ctDNA analysis (AlphaLiquid®100 fr|om IMBdx).
Results
Among 102 enrolled
patients, 49.0% had intrahepatic cholangiocarcinoma, 26.5% extrahepatic
cholangiocarcinoma, and 24.5% gallbladder cancer. The concordance between
intra-patient ctDNA and tumor tissue mutations revealed a sensitivity of 84.8%,
and positive predictive value of 79.4%. ctDNA revealed targetable alterations
in 34.3% of patients – including FGFR2 fusions, IDH1 mutations, microsatellite
instability-high, ERBB2 amplifications, PIK3CA mutations, BRCA1/2 mutations,
and MET amplifications. Notably, a novel FGFR2-TNS1 fusion was identified in
ctDNA, which was not targeted in the tissue NGS panel. A high maximum somatic
variant allele frequency in ctDNA was associated with poor prognosis after
gemcitabine/cisplatin-based chemotherapy, in terms of both overall survival (p
= 6.9 × 10−6) and progression-free survival (p = 3.8 × 10−7
).
Conclusions
Among patients
with advanced BTC, ctDNA-based genotyping showed acceptable concordance with
tissue genomic profiling. Liquid biopsy using ctDNA could be a valuable
complement to tissue-based genomic analysis in BTC.
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Journal of Hepatology |
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| 19 |
2024 |
Clinical utility and predictive value of cerebrospinal fluid cell-free DNA profiling in non-small cell lung cancer patients with leptomeningeal metastasis
Abstract
Leptomeningeal
metastasis (LM) is a challenging complication of non-small cell lung cancer
(NSCLC). Cerebrospinal fluid (CSF) cell-free DNA (cfDNA) analysis using
next-generation sequencing (NGS) offers insights into resistance mechanisms and
potential treatment strategies. We conducted a study fr|om February 2022 to
April 2023 involving patients fr|om five hospitals in Taiwan who had recurrent
or advanced NSCLC with LM. These patients underwent CSF cfDNA analysis using a
118-gene targeted panel for NGS, with comprehensive clinical data collected.
Among 25 enrolled patients, 22 (88.0 %) had EGFR mutations, while three (12.0
%) had EML4-ALK fusion, KIF5B-RET fusion, and ERBB2 A775_G776insSVMA. CSF cfDNA
sequencing of 27 samples (fr|om 25 patients) all confirmed their original driver
mutations. Of total cohort, 18 patients (72.0 %) underwent intrathecal
pemetrexed (ITP), with a median survival time of 7.4 months (95.0 % confidence
interval, 3.3–11.6) fr|om the initiation of ITP to death. Among them, ten
individuals (55.6 %) survived beyond 6 months. Notably, MET copy number gain
(CNG) correlated significantly with survival time exceeding 6 months after ITP
(p = 0.007). The coexistence of EGFR T790M and EGFR-independent resistance
alterations was associated with shorter survival times after ITP, with a median
survival time of 1.9 months compared to 9.9 months for those without EGFR T790M
(p = 0.010). Our results highlight CSF cfDNA NGS's potential in LM resistance
understanding and ITP efficacy prediction. MET CNG positively impacts survival for
ITP recipients, whereas the coexistence of EGFR T790M and EGFR-independent
resistance mechanisms leads to poor outcomes.
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Neoplasia |
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