Activity of Tepotinib in Hepatocellular Carcinoma With High-Level MET Amplification: Preclinical and Clinical Evidence.

PURPOSE: MET amplification (METamp) has been reported in 1%-5% of patients with hepatocellular carcinoma (HCC) and may be sensitive to MET inhibition. Tepotinib, a selective MET inhibitor, has shown promising activity in HCC with MET overexpression. We investigated the preclinical and clinical activity of tepotinib in HCC with METamp (MET gene copy number [GCN] ≥5), including high-level METamp (MET GCN ≥10). METHODS: Preclinical antitumor activity of tepotinib 100 mg/kg (orally, days 1-5, every 7 days, 3-5 weeks; 3-12 replicates) was evaluated according to METamp status, as determined using the nCounter platform (NanoString), in 37 HCC patient-derived xenografts (PDXs) in immunodeficient mice. Clinical outcomes were evaluated in patients with METamp by fluorescence in situ hybridization who received tepotinib 500 mg (450 mg active moiety) in two phase Ib/II trials in HCC with MET overexpression. RESULTS: Across the PDX models, tepotinib induced complete or near-complete tumor regression in the only two models with high-level METamp. Median tumor volume reductions were 100% and 99.8% in models with MET GCN 47.1 and 44.0, respectively. Across the two clinical trials, 15/121 patients had METamp. Disease control was achieved by 11/15 patients with METamp (complete response [CR], n = 1; partial response [PR], n = 4; stable disease [SD], n = 6) and 4/4 with high-level METamp (CR, n = 1; PR, n = 2; SD, n = 1). All three patients with high-level METamp and objective response received treatment for >1 year, including one patient who received first-line tepotinib for >6 years. CONCLUSION: High-level METamp may be an oncogenic driver in HCC that is sensitive to MET inhibitors such as tepotinib.

Hyper-Dependence on NHEJ Enables Synergy between DNA-PK Inhibitors and Low-Dose Doxorubicin in Leiomyosarcoma.

PURPOSE: Leiomyosarcoma (LMS) is an aggressive sarcoma for which standard chemotherapies achieve response rates under 30%. There are no effective targeted therapies against LMS. Most LMS are characterized by chromosomal instability (CIN), resulting in part from TP53 and RB1 co-inactivation and DNA damage repair defects. We sought to identify therapeutic targets that could exacerbate intrinsic CIN and DNA damage in LMS, inducing lethal genotoxicity. EXPERIMENTAL DESIGN: We performed clinical targeted sequencing in 287 LMS and genome-wide loss-of-function screens in 3 patient-derived LMS cell lines, to identify LMS-specific dependencies. We validated candidate targets by biochemical and cell-response assays in vitro and in seven mouse models. RESULTS: Clinical targeted sequencing revealed a high burden of somatic copy-number alterations (median fraction of the genome altered =0.62) and demonstrated homologous recombination deficiency signatures in 35% of LMS. Genome-wide short hairpin RNA screens demonstrated PRKDC (DNA-PKcs) and RPA2 essentiality, consistent with compensatory nonhomologous end joining (NHEJ) hyper-dependence. DNA-PK inhibitor combinations with unconventionally low-dose doxorubicin had synergistic activity in LMS in vitro models. Combination therapy with peposertib and low-dose doxorubicin (standard or liposomal formulations) inhibited growth of 5 of 7 LMS mouse models without toxicity. CONCLUSIONS: Combinations of DNA-PK inhibitors with unconventionally low, sensitizing, doxorubicin dosing showed synergistic effects in LMS in vitro and in vivo models, without discernable toxicity. These findings underscore the relevance of DNA damage repair alterations in LMS pathogenesis and identify dependence on NHEJ as a clinically actionable vulnerability in LMS.

Overcoming MET-mediated resistance in oncogene-driven NSCLC.

This study evaluates the efficacy of combining targeted therapies with MET or SHP2 inhibitors to overcome MET-mediated resistance in different NSCLC subtypes. A prevalence study was conducted for MET amplification and overexpression in samples from patients with NSCLC who relapsed on ALK, ROS1, or RET tyrosine kinase inhibitors. MET-mediated resistance was detected in 37.5% of tissue biopsies, which allow the detection of MET overexpression, compared to 7.4% of liquid biopsies. The development of drug resistance by MET overexpression was confirmed in EGFRex19del-, KRASG12C-, HER2ex20ins-, and TPM3-NTRK1-mutant cell lines. The combination of targeted therapy with MET or SHP2 inhibitors was found to overcome MET-mediated resistance in both in vitro and in vivo assays. This study highlights the importance of considering MET overexpression as a resistance driver to NSCLC targeted therapies to better identify patients who could potentially benefit from combination approaches with MET or SHP2 inhibitors.

Discovery of Cycloalkyl[c]thiophenes as Novel Scaffolds for Hypoxia-Inducible Factor-2α Inhibitors.

Hypoxia-inducible factors (HIFs) are heterodimeric transcription factors induced in diverse pathophysiological settings. Inhibition of HIF-2α has become a strategy for cancer treatment since the discovery that small molecules, upon binding into a small cavity of the HIF-2α PAS B domain, can alter its conformation and disturb the activity of the HIF dimer complex. Herein, the design, synthesis, and systematic SAR exploration of cycloalkyl[c]thiophenes as novel HIF-2α inhibitors are described, providing the first chemotype featuring an alkoxy-aryl scaffold. X-ray data confirmed the ability of these inhibitors to induce perturbation of key amino acids by appropriately presenting key pharmacophoric elements in the hydrophobic cavity. Selected compounds showed inhibition of VEGF-A secretion in cancer cells and prevention of Arg1 expression and activity in IL4-stimulated macrophages. Moreover, in vivo target gene modulation was demonstrated with compound 35r. Thus, the disclosed HIF-2α inhibitors represent valuable tools for investigating selective HIF-2α inhibition and its effect on tumor biology.

The Preclinical Pharmacology of Tepotinib-A Highly Selective MET Inhibitor with Activity in Tumors Harboring MET Alterations.

The mesenchymal-epithelial transition factor (MET) proto-oncogene encodes the MET receptor tyrosine kinase. MET aberrations drive tumorigenesis in several cancer types through a variety of molecular mechanisms, including MET mutations, gene amplification, rearrangement, and overexpression. Therefore, MET is a therapeutic target and the selective type Ib MET inhibitor, tepotinib, was designed to potently inhibit MET kinase activity. In vitro, tepotinib inhibits MET in a concentration-dependent manner irrespective of the mode of MET activation, and in vivo, tepotinib exhibits marked, dose-dependent antitumor activity in MET-dependent tumor models of various cancer indications. Tepotinib penetrates the blood-brain barrier and demonstrates strong antitumor activity in subcutaneous and orthotopic brain metastasis models, in-line with clinical activity observed in patients. MET amplification is an established mechanism of resistance to EGFR tyrosine kinase inhibitors (TKI), and preclinical studies show that tepotinib in combination with EGFR TKIs can overcome this resistance. Tepotinib is currently approved for the treatment of adult patients with advanced or metastatic non-small cell lung cancer harboring MET exon 14 skipping alterations. This review focuses on the pharmacology of tepotinib in preclinical cancer models harboring MET alterations and demonstrates that strong adherence to the principles of the Pharmacological Audit Trail may result in a successful discovery and development of a precision medicine.

DNA-Dependent Protein Kinase Inhibitor Peposertib Potentiates the Cytotoxicity of Topoisomerase II Inhibitors in Synovial Sarcoma Models.

Synovial sarcoma is a rare and highly aggressive subtype of soft tissue sarcoma. The clinical challenge posed by advanced or metastatic synovial sarcoma, marked by limited treatment options and suboptimal outcomes, necessitates innovative approaches. The topoisomerase II (Topo II) inhibitor doxorubicin has remained the cornerstone systemic treatment for decades, and there is pressing need for improved therapeutic strategies for these patients. This study highlights the potential to enhance the cytotoxic effects of doxorubicin within well-characterized synovial sarcoma cell lines using the potent and selective DNA-PK inhibitor, peposertib. In vitro investigations unveil a p53-mediated synergistic anti-tumor effect when combining doxorubicin with peposertib. The in vitro findings were substantiated by pronounced anti-tumor effects in mice bearing subcutaneously implanted tumors. A well-tolerated regimen for the combined application was established using both pegylated liposomal doxorubicin (PLD) and unmodified doxorubicin. Notably, the combination of PLD and peposertib displayed enhanced anti-tumor efficacy compared to unmodified doxorubicin at equivalent doses, suggesting an improved therapeutic window-a critical consideration for clinical translation. Efficacy studies in two patient-derived xenograft models of synovial sarcoma, accurately reflecting human metastatic disease, further validate the potential of this combined therapy. These findings align with previous evidence showcasing the synergy between DNA-PK inhibition and Topo II inhibitors in diverse tumor models, including breast and ovarian cancers. Our study extends the potential utility of combined therapy to synovial sarcoma.

ATR represents a therapeutic vulnerability in clear cell renal cell carcinoma.

Metastatic clear cell renal cell carcinomas (ccRCCs) are resistant to DNA-damaging chemotherapies, limiting therapeutic options for patients whose tumors are resistant to tyrosine kinase inhibitors and/or immune checkpoint therapies. Here we show that mouse and human ccRCCs were frequently characterized by high levels of endogenous DNA damage and that cultured ccRCC cells exhibited intact cellular responses to chemotherapy-induced DNA damage. We identify that pharmacological inhibition of the DNA damage-sensing kinase ataxia telangiectasia and Rad3-related protein (ATR) with the orally administered, potent, and selective drug M4344 (gartisertib) induced antiproliferative effects in ccRCC cells. This effect was due to replication stress and accumulation of DNA damage in S phase. In some cells, DNA damage persisted into subsequent G2/M and G1 phases, leading to the frequent accumulation of micronuclei. Daily single-agent treatment with M4344 inhibited the growth of ccRCC xenograft tumors. M4344 synergized with chemotherapeutic drugs including cisplatin and carboplatin and the poly(ADP-ribose) polymerase inhibitor olaparib in mouse and human ccRCC cells. Weekly M4344 plus cisplatin treatment showed therapeutic synergy in ccRCC xenografts and was efficacious in an autochthonous mouse ccRCC model. These studies identify ATR inhibition as a potential novel therapeutic option for ccRCC.

Validation of the newly introduced CASTLE Score for predicting successful CTO recanalization.

BACKGROUND: The new EuroCTO CASTLE Score was validated against the widely adopted Japanese Multicenter CTO Registry (J-CTO) score in predicting technical success in percutaneous coronary intervention (PCI) for coronary chronic total occlusions (CTO). METHODS: A total of 463 patients treated by CTO PCI were included in a retrospective analysis. Result: The mean CASTLE score was 2.23 ± 1.1 and J-CTO score was 2.84 ± 1.0. The overall technical success rate was 83.2%. At 30 days follow up, a primary composite safety endpoint showed a low proportion of stent thrombosis (0.2%) and re-hospitalization (0.4%). Moreover, an improvement of clinical symptoms was found in 83% of patients. Receiver operating characteristic analysis (ROC) demonstrated a comparable overall discriminatory performance in predicting technical outcome: CASTLE score, area under the ROC curve (AUC) 0.668, 95% CI: 0.606-0.730; J-CTO score AUC 0.692, 95% CI: 0.631-0.752; Comparison of AUCs: p = 0.324. Those findings were even consistent in more complex procedures CASTLE Score ≥ 4 and J-CTO score ≥ 3: CASTLE Score AUC 0.514, 95% CI: 0.409-0.619; J-CTO score, AUC 0.617, 95% CI: 0.493-0.741; Comparison of AUCs: p = 0.211. Furthermore, increasing score values are accompanied by a longer examination and fluoroscopy time, more contrast medium and a higher dose area product. CONCLUSION: Compared to the widely accepted J-CTO score, the new introduced EuroCTO CASTLE score demonstrated a comparable overall discriminatory performance in predicting technical outcomes in CTO PCI.

Dual lumen microcatheters for recanalisation of chronic total occlusions: a EuroCTO Club expert panel report.

Dual lumen microcatheters (DLMC) have become indispensable tools in the setting of percutaneous coronary intervention (PCI) of chronic total occlusion (CTO). Other than allowing preservation and treatment of bifurcated coronary branches within or in the proximity of the CTO body, they enable the use of modified parallel wiring, antegrade dissection and re-entry, collateral selection and retrograde negotiation of the distal CTO cap. This EuroCTO consensus document describes current DLMC and suggests a practical guide to anatomies and techniques in which these devices are applicable.

Sensitivity and Resistance of Oncogenic RAS-Driven Tumors to Dual MEK and ERK Inhibition.

Oncogenic mutations in RAS family genes arise frequently in metastatic human cancers. Here we developed new mouse and cellular models of oncogenic HrasG12V-driven undifferentiated pleomorphic sarcoma metastasis and of KrasG12D-driven pancreatic ductal adenocarcinoma metastasis. Through analyses of these cells and of human oncogenic KRAS-, NRAS- and BRAF-driven cancer cell lines we identified that resistance to single MEK inhibitor and ERK inhibitor treatments arise rapidly but combination therapy completely blocks the emergence of resistance. The prior evolution of resistance to either single agent frequently leads to resistance to dual treatment. Dual MEK inhibitor plus ERK inhibitor therapy shows anti-tumor efficacy in an HrasG12V-driven autochthonous sarcoma model but features of drug resistance in vivo were also evident. Array-based kinome activity profiling revealed an absence of common patterns of signaling rewiring in single or double MEK and ERK inhibitor resistant cells, showing that the development of resistance to downstream signaling inhibition in oncogenic RAS-driven tumors represents a heterogeneous process. Nonetheless, in some single and double MEK and ERK inhibitor resistant cell lines we identified newly acquired drug sensitivities. These may represent additional therapeutic targets in oncogenic RAS-driven tumors and provide general proof-of-principle that therapeutic vulnerabilities of drug resistant cells can be identified.

Long-term serial functional evaluation after implantation of the Fantom sirolimus-eluting bioresorbable coronary scaffold.

BACKGROUND: Quantitative flow ratio (QFR) has been validated as an accurate surrogate of standard wire-based fractional flow reserve. The clinical and angiographic outcomes of the Fantom sirolimus-eluting bioresorbable coronary scaffold (BRS) have been previously studied and reported. We investigate the functional performance of the Fantom BRS. METHODS: The FANTOM II trial prospectively enrolled 240 patients with stable coronary artery disease or unstable angina, of which 235 patients received the Fantom BRS and were included in the present analysis. We performed an independent serial QFR analysis of the target vessel at baseline, post-percutaneous coronary intervention (PCI), and at 6- or 9-month and 24-month follow-up, using a QFR threshold ≤0.80 to define functional ischemia. RESULTS: QFR was analyzable in 178 patients at baseline, 185 post-PCI, 178 at 6- or 9-month follow-up, and 30 at 24-month follow-up. At baseline, 119 patients (66.9%) had a QFR ≤0.80, whereas 12 (6.5%) post-PCI, 13 (7.3%) at 6- or 9-month follow-up, and 3 (10.0%) at 24-month follow-up had a QFR ≤0.80. QFR improved from baseline to post-PCI, and decreased from post-PCI up to 24-month follow-up. During follow-up period, 28 patients (11.9%) had target vessel revascularization, of which 21 had analyzable QFR and 16 patients (76.1%) had QFR ≤0.80 at the time of revascularization. CONCLUSIONS: Off-line serial QFR assessment demonstrated that around 30% patients did not have functionally significant lesions at baseline and the time with target vessel revascularization. PCI with the Fantom BRS improved functional ischemia with a slight decrease in QFR values over 24 months.

FANTOM II Trial: safety and performance study of the fantom sirolimus-eluting bioresorbable coronary scaffold: first report on initial 48-month outcomes

BACKGROUND: Bioresorbable vascular scaffolds (BRS) provide temporary mechanical support and may help restore normal vessel reactivity, positive remodeling, and reduce chronic inflammation. The Fantom scaffold (REVA Medical) is a sirolimus-eluting BRS, with a TyroCoreTM radiopaque tyrosine analog polymer. METHODS: FANTOM II is a prospective, multi-center, safety and performance study of patients with myocardial ischemia or a positive functional study. The study included patients with single de novo lesions in native coronary vessels ranging in diameter from 2.5 to 3.5 mm and lesion lengths up to 20 mm. The primary objective of the study is to demonstrate safety and performance of the Fantom sirolimus-eluting bioresorbable scaffold by assessing the incidence of Major Adverse Cardiac Events (MACE) and Late Lumen Loss at 6 months. RESULTS: FANTOM II enrolled 240 patients across 28 clinical centers in 8 countries. Two separate sequential cohorts followed patients with a 6-month (Cohort A, N=117) versus 9-month (Cohort B, N=123) angiographic assessment. A sub-set of Cohort A patients, returned for serial angiographic follow-up at 24-month. We report 24-month adjudicated clinical endpoints. Acute technical success, acute procedural success, and clinical procedural success were 95.8%, 99.1% and 99.6%, respectively. The primary safety endpoint of MACE at 24 months was 5.0%. Late Lumen Loss at 6 months in the Cohort A was 0.25 ± 0.35mm In-Scaffold and 0.17 ± 0.29mm In-Segment. At 24-months the subset of Cohort A patients (n=36) demonstrated stable late lumen loss values of 0.23 ± 0.49mm In-Scaffold and 0.21 ± 0.49mm In-Segment. CONCLUSION: FANTOM II demonstrates safe and stable performance of the REVA BRS at 24-months. (AU)

Long-Term serial functional evaluation after implantation of the fantom sirolimus-eluting bioresorbable coronary scaffold: the FANTOM II study

BACKGROUND: The Fantom sirolimus-eluting bioresorbable coronary scaffold (BRS) (REVA Medical, San Diego, California) was previously studied with angiographic late lumen loss at 6, 9, and 24 months with clinical events being followed through 36 months. However, a functional evaluation has not previously been performed. The aim of this study was to assess serial functional changes after percutaneous coronary intervention (PCI) with the Fantom BRS implantation. METHODS: The FANTOM II trial was a prospective, multicenter, single-arm study that enrolled 240 patients with stable coronary artery disease or unstable angina and single de novo native coronary lesions, of which 235 patients received the Fantom BRS and are included in the present analysis. Serial quantitative flow ratio (QFR) analysis was performed in an independent core laboratory at baseline, after PCI, and at 6- or 9-month and 24-month follow-up. RESULTS: QFR was analyzable in 178 patients at baseline, 185 post-PCI, 178 at 6- or 9-month follow-up, and 31 at 24-month follow-up. At baseline, 59 patients (33.1%) had QFR >0.80, whereas 12 (6.5%) at post-PCI, 13 (7.3%) at 6- or 9-month followup, and 3 (9.7%) at 24-month follow-up had QFR _0.80. In the paired analyses, QFR was significantly increased from baseline to post-PCI (0.73 _ 0.12 vs. 0.94 _ 0.07; p < 0.001), while it decreased from post-PCI to 6- or 9-month follow-up (0.94 _ 0.07 vs. 0.92 _ 0.08; p < 0.001) and from 6- or 9-month to 24-month follow-up (0.93 _ 0.07 vs. 0.91 _ 0.09; p » 0.03). CONCLUSION: Serial angiographic analysis showed significant increase in QFR values between baseline and post-PCI. A slight decrease was observed in QFR values with the Fantom BRS over 24 months. (AU)

Clinical and Angiographic Outcomes With a Novel Radiopaque Sirolimus-Eluting Bioresorbable Vascular Scaffold.

Background A novel bioresorbable scaffold, the sirolimus-eluting Fantom, incorporates a radiopaque polymer, struts with a thickness of 125 µm, and a crossing profile of 1.35 mm. The purpose of this study was to evaluate the 9-month angiographic and 12-month clinical outcomes of the FANTOM scaffold in a larger patient population. Methods and Results The FANTOM II study (Safety & Performance Study of the Fantom Sirolimus-Eluting Bioresorbable Coronary Scaffold - First Report on Initial 24 Month Outcomes) was a prospective, multicenter trial which enrolled 240 patients with single de novo coronary stenosis with reference vessel diameter 2.5 to 3.5 mm diameter and lesion length ≤20 mm. Major adverse cardiac events through 12-month follow-up were assessed. Angiographic follow-up was performed in consecutive patient cohorts at 6 months (n=117) and 9 months (n=123). Acute delivery success, acute technical success, acute procedural success, and clinical procedural success rates as defined in the clinical protocol were 97.9% (235/240), 95.8% (230/240), 99.1% (228/230), and 99.6% (227/228), respectively. The mean in-stent late lumen loss at 6 months and 9 months were 0.25±0.40 mm and 0.33±0.36 mm, respectively, and in-segment binary restenosis occurred in 2.0% and 7.6% of patients, respectively. Major adverse cardiac events and target lesion failure through 12 months occurred in 4.2% of 240 patients; scaffold thrombosis developed in only one patient (0.4%). Conclusions The Fantom sirolimus-eluting bioresorbable coronary scaffold demonstrated favorable safety and effectiveness performance at 12-month follow-up. Longer-term follow-up is ongoing to examine the late outcomes with this novel device. Clinical Trial Registration URL: https://www.clinicaltrials.gov . Unique identifier: NCT02539966.

Clinical and angiographic outcomes with a novel radiopaque sirolimus-eluting bioresorbable vascular scaffold

BACKGROUND A novel bioresorbable scaffold, the sirolimus-eluting Fantom, incorporates a radiopaque polymer, struts with a thickness of 125 microm, and a crossing profile of 1.35 mm. The purpose of this study was to evaluate the 9-month angiographic and 12-month clinical outcomes of the FANTOM scaffold in a larger patient population. METHODS and RESULTS The FANTOM II study (Safety & Performance Study of the Fantom Sirolimus-Eluting Bioresorbable Coronary Scaffold - First Report on Initial 24 Month Outcomes) was a prospective, multicenter trial which enrolled 240 patients with single de novo coronary stenosis with reference vessel diameter 2.5 to 3.5 mm diameter and lesion length

Mechanical performance and healing patterns of the novel sirolimus-eluting bioresorbable Fantom scaffold: 6-month and 9-month follow-up by optical coherence tomography in the FANTOM II study.

Objectives: We aimed to evaluate the mechanical properties and healing patterns 6 and 9 months after implantation of the sirolimus-eluting Fantom bioresorbable scaffold (BRS). Background: The Fantom BRS (Reva Medical, San Diego, USA) has differentiating properties including radiopacity, strut thickness of 125 µm, high expansion capacity and has demonstrated favourable mid-term clinical and angiographic outcomes. Methods and results: FANTOM II was a prospective, single arm study with implantation of the Fantom BRS in 240 patients with stable angina pectoris. Guidance by optical coherence tomography (OCT) was encouraged and was repeated at 6-month (cohort A) or 9-month follow-up (cohort B). Matched baseline and follow-up OCT recordings were available in 152 patients. In-scaffold mean lumen area in cohort A was 6.8±1.7 mm2 and 5.7±1.4 mm2 at baseline and follow-up (p<0.0001) and was 7.2±1.6 mm2 and 5.6±1.4 mm2 in cohort B (p<0.0001). Mean scaffold area remained stable from 7.1±1.5 mm2 at baseline to 7.2±1.4 mm2 at 6 months (p=0.12), and from 7.4±1.5 mm2 to 7.3±1.4 mm2 at 9 months. Strut malapposition was median 0.8 (IQR 0.0;3.5)% and 1.8 (IQR 0.3;6.0)% at baseline and was 0.0 (IQR 0.0;0.0)% in both groups at 6-month and 9-month follow-up. Strut tissue coverage was 98.1 (IQR 95.9;99.4)% at 6 months and 98.9 (IQR 98.3;100.0)% at 9 months. Conclusions: The novel Fantom BRS had favourable healing patterns at 6-month and 9-month follow-up as malapposition was effectively resolved and strut coverage was almost complete. The scaffold remained stable through follow-up with no signs of systematic late recoil.

Mechanical performance and healing patterns of the novel sirolimus-eluting bioresorbable Fantom scaffold: 6-month and 9-month follow-up by optical coherence tomography in the FANTOM II study

OBJECTIVES: We aimed to evaluate the mechanical properties and healing patterns 6 and 9 months after implantation of the sirolimus-eluting Phantom bioresorbable scaffold (BRS). BACKGROUND: The Phantom BRS (Reva Medical, San Diego, USA) has differentiating properties including radiopacity, strut thickness of 125 µm, high expansion capacity and has demonstrated favorable mid-term clinical and angiographic outcomes. METHODS AND RESULTS: FANTOM II was a prospective, single arm study with implantation of the Phantom BRS in 240 patients with stable angina pectoris. Guidance by optical coherence tomography (OCT) was encouraged and was repeated at 6-month (cohort A) or 9-month follow-up (cohort B). Matched baseline and follow-up OCT recordings were available in 152 patients. In-scaffold mean lumen area in cohort A was 6.8±1.7 mm2 and 5.7±1.4 mm2 at baseline and follow-up (p<0.0001) and was 7.2±1.6 mm2 and 5.6±1.4 mm2 in cohort B (p<0.0001). Mean scaffold area remained stable from 7.1±1.5 mm2 at baseline to 7.2±1.4 mm2 at 6 months (p=0.12), and from 7.4±1.5 mm2 to 7.3±1.4 mm2 at 9 months. Strut malposition was median 0.8 (IQR 0.0;3.5)% and 1.8 (IQR 0.3;6.0)% at baseline and was 0.0 (IQR 0.0;0.0)% in both groups at 6-month and 9-month follow-up. Strut tissue coverage was 98.1 (IQR 95.9;99.4)% at 6 months and 98.9 (IQR 98.3;100.0)% at 9 months. CONCLUSIONS: The novel Phantom BRS had favorable healing patterns at 6-month and 9-month follow-up as malposition was effectively resolved and strut coverage was almost complete. The scaffold remained stable through follow-up with no signs of systematic late recoil. (AU)

Intravascular ultrasound findings of the Fantom sirolimus-eluting bioresorbable scaffold at six- and nine-month follow-up: the FANTOM II study.

AIMS: FANTOM II is a prospective multicentre trial assessing the safety and efficacy of the Fantom sirolimus-eluting bioresorbable coronary scaffold (BRS). The present substudy focuses on the six- and nine-month IVUS findings. METHODS AND RESULTS: A total of 240 patients with de novo coronary artery lesions presenting with stable or unstable disease were included in two sequential cohorts (cohort A [n=117] and cohort B [n=123]) in which angiographic follow-up was performed at either six or nine months, respectively. Matched IVUS data were available for 35 paired cases in cohort A and 26 paired cases in cohort B. At six months, mean and minimum scaffold area (SA) decreased from 6.09±1.08 mm2 to 5.88±1.07 mm2, p=0.009, and 5.27±0.99 mm2 to 5.05±0.99 mm2, p=0.01, respectively. At nine months, no significant change in mean scaffold and minimum scaffold area was observed (6.46±1.11 mm2 to 6.38±0.96 mm2; p=0.35, and 5.45±1.00 mm2 to 5.36±0.86 mm2; p=0.32, respectively). Neointimal hyperplasia area was low at both six (0.11±0.12 mm2) and nine months (0.20±0.21 mm2), as was in-scaffold obstruction volume (1.94±2.25% at six months, and 3.40±4.11% at nine months). CONCLUSIONS: The use of the Fantom BRS in stable coronary artery disease was associated with low rates of neointimal hyperplasia volume and in-scaffold volume obstruction at both six and nine months.