Introduction

Risankizumab (RZB) is a P19 subunit blocking anti-IL-23 agent that has been shown to be effective in CD in a recent Phase 3 trial (Ferrante et al., Lancet 2022). Compassionate use has been possible since June 2022. The aim of this work was to investigate whether RZB levels correlate with biomarker-based remission.

Aims & Methods

Any CD patient on RZB (compassionate use or open-label phase 3 study) was eligible for the study. All patients were treated with a regimen of RZB (600mg/IV S0, S4 and S8) followed by 360 mg/sc every 8 weeks starting at S12. Patients who had received other regimens were excluded. Before each infusion or SC injection, fecal calprotectin, CRP and RZB levels were measured using an ELISA test. The assays were blinded to clinical and biomarker datas. Clinical remission was defined as CDAI score < 150 Conversly, clinical activity was definied by a CDAI score > 220. Biomarker remission was defined as fecal calprotectin levels below 250 µg/ml and CRP < 5 mg/l.

Results

26 patients (mean age: 42 years, sex ratio M/F: 1.3) with 97 maintenance RZB samples (360mg/sc every 8S) were eligible. In 37 cases, RZB samples were taken while biomarkers were in remission. During, maintenance, mean RZB levels were significantly higher in cases of clinical remission than in the absence of clinical remission (22.5 versus 6.1 µg/ml; p<0.0001)(Figure 1). Mean RZB levels were similar between patients in clinical remission and patients in clinical and biomarker remissions (22.5 versus 19.6 µg/ml; p<0.0001). The higher RZB trough level quartiles tended to be associated with greater rates of clinical response [p = 0.001]. Clinical remission rates were 4% if RZB trough levels were ≤4.9 μg/mL [quartile 1] and 88% if RZB trough levels were >19.6 μg/mL [quartile 4] (Figure 2).

Conclusion

RZB levels are significantly higher in patients with clinical remission in CD. Trough concentration of RZB above 10.6µg/mL should be recommended in clinical practice.

References

Ferrantet et al., Lancet 2022

Introduction

Etrasimod is an oral, once-daily, selective sphingosine 1‑phosphate (S1P)_1,4,5 receptor modulator for the treatment of moderately to severely active ulcerative colitis (UC). In patients with moderately to severely active UC, treatment guidelines recommend early use of advanced therapies rather than gradual step up after failure of 5-aminosalicylate (5-ASA).¹

Aims & Methods

This prespecified subgroup analysis assessed the efficacy of etrasimod vs placebo in patients in ELEVATE UC 52 (NCT03945188) with, and without, prior oral 5-ASA failure only (defined as inadequate response, loss of response or intolerance to previous treatment with oral 5-ASA but not to any other previous UC medication). Efficacy endpoints assessed at Weeks 12 and 52 included clinical remission, endoscopic improvement, symptomatic remission and composite histological endpoints.

Results

In total, 45 and 29 patients receiving etrasimod and placebo, respectively, had prior 5-ASA failure only and 244 and 115 patients did not. At Weeks 12 and 52, among those who had failed prior 5-ASA only, significantly more patients receiving etrasimod vs placebo achieved clinical remission (Week 12, % difference [Δ]: 38.3%, p < 0.001; Week 52, Δ: 45.0%, p < 0.001), endoscopic improvement (Week 12, Δ: 54.7%, p < 0.001; Week 52, Δ: 47.8%, p < 0.001), symptomatic remission (Week 12, Δ: 38.6%, p < 0.001; Week 52, Δ: 45.0%, p < 0.001) and endoscopic improvement-histologic remission (Week 12, Δ: 35.6%, p < 0.001; Week 52, Δ: 31.1%, p < 0.001; Table). Significantly more patients receiving etrasimod vs placebo in this subgroup achieved endoscopic normalisation-histologic remission (Week 12, Δ: 19.9%, p = 0.002; Week 52, Δ: 24.3%, p < 0.001) and disease clearance (Week 12, Δ: 15.6%, p = 0.008; Week 52, Δ: 27.8%, p < 0.001). Among those who had failed other therapies, significantly more patients receiving etrasimod vs placebo also achieved all endpoints at Weeks 12 and 52 (p < 0.01).

Conclusion

Etrasimod demonstrated robust efficacy as first-line advanced therapy in patients who had failed oral 5-ASA only, across all evaluated endpoints including stringent composite histological endpoints, consistent with the overall ELEVATE UC population. Etrasimod shows efficacy when used early in the UC treatment algorithm.

References

1. Singh S et al. Gastroenterology 2024; 167: 1307–1343.
Pfizer’s generative artificial intelligence tool MAIA was used to assist production of the abstract first draft. Authors reviewed/edited and take responsibility for the content.

Disclosure

DTR received grant support from Takeda; consultancy fees from AbbVie, Abivax SA, Altrubio, Avalo Therapeutics, Bausch Health, Bristol Myers Squibb, Buhlmann Diagnostics Corp, Celltrion, ClostraBio, Connect BioPharma, Douglas Pharmaceuticals, Eli Lilly & Co., Foresee, Genentech (Roche) Inc., Image Analysis Group, InDex Pharmaceuticals, Iterative Health, Janssen Pharmaceuticals, Odyssey Therapeutics, Pfizer Inc, Sanofi, Takeda Pharmaceuticals, Throne and Vedanta.
CWL received speaker fees from AbbVie, Dr Falk, Ferring, Hospira, Janssen, MSD, Pfizer Inc, Shire, Takeda and Warner-Chilcott; consultancy fees from AbbVie, Dr Falk, Gilead, GSK, Hospira, Iterative Scopes, Janssen, MSD, Oshi Health, Pfizer Inc, Pharmacosmos, Takeda, Topivert, Trellus Health and Vifor Pharma; research funding from AbbVie and Gilead.
FB received research/grant support from AbbVie, Amgen, Eurogenerics, Janssen and Takeda; lecture fees/speaker’s bureau from AbbVie, Arena Pharmaceuticals, Celltrion, Ferring, Galapagos, Janssen, Merck Sharp & Dohme, Pfizer Inc and Takeda; consultancy fees from AbbVie, Abivax, Amgen, Arena Pharmaceuticals, Celgene, Celltrion, Ferring, Fresenius Kabi, Janssen, Merck Sharp & Dohme, Pfizer Inc and Sandoz.
MK is an employee and shareholder of Pfizer Inc.
AB is an employee of Pfizer Healthcare India Private Ltd and shareholder of Pfizer Inc.
KL is an employee of Pfizer AG and shareholder of Pfizer Inc.
MG is an employee of Pfizer AG and shareholder of Pfizer Inc.
AMM is an employee and shareholder of Pfizer Inc.
KW is an employee of Pfizer Canada Inc and shareholder of Pfizer Inc.
JKM is an advisory committee/board member on AbbVie, Alimentiv, Amgen, AstraZeneca, Bausch Health, Bristol Myers Squibb, Celltrion, Ferring, Fresenius Kabi, Janssen, Lilly, Lupin, Organon, Paladin, Pfizer Inc, Pharmascience, Qu Biologics, Roche, Sandoz, SCOPE, Takeda, Teva and Viatris; receives lecture/speaker fees from AbbVie, Amgen, Bausch Health, Ferring, Fresenius Kabi, Janssen, Organon, Pfizer Inc, Pharmascience, Roche, Takeda and Viatris.

Introduction

T1 colorectal cancer can be managed either by surgery or interventional endoscopy. High-risk features after endoscopic resection (G3, submucosal invasion >1000 µm, lympho-vascular invasion, tumour budding+, or R1 resection) increase the risk of lymphnode metastasis (10-15%), often requiring additional surgery. However, the benefits of surgery versus endoscopic resection alone remain unclear, particularly in elderly or frail patients.

Aims & Methods

The aim of the study is to assess recurrence rate and overall survival in patients underwent surgery, endoscopy or both. Secondary endpoints is to evaluate incidence of adverse events and length of hospital stay
All consecutive patients diagnosed with T1 colorectal cancer from 2018 to 2024 in our institution were enrolled in this retrospective study. We divided this cohort in 3 groups: endoscopic resection plus surgery (ER-S), upfront surgery (SR), or endoscopic resection alone (ER). Demographics data, mortality, cancer recurrence rate, disease free survival and AEs were recorded.

Results

One-hundred and thirty-three patients were enrolled in the study: 34 (72 years±10) in the SR group, 65 (65 years±11) in the ER-S group and 34 (77 years±11) in ER, respectively.
Lesions were similar (p-value 0.30) for dimension: 31±15 mm (ER) vs 23±12 mm (ER-S) vs 30±13 mm (ER) such as follow-up (23 vs 24 vs 21 months) for the three groups (p-value 0.428). Hospital stay after the procedure was significantly lower in the ER group (1 day median) vs SR (median 9 days;p-value 0.0001) and ER-S group (7 days median;p-value 0.003). Cumulative 30 days adverse events were higher in the SR group (62%; p-value 0.0001) and in the ER-S group (22%; p-value 0.001) compared to ER alone (12%). During the study period, no endoscopic/radiological recurrence occurred in the SR group whereas 1 patient in the ER-S group and 2 in the ER group showed recurrence non suitable for further treatments.
Five patients in SR group died after a median of 18 months (1 for early surgical complication); 2 died in the ER-S group after a median of 34 months and 3 died in the ER group after a median of 24 months (1 for rectal cancer progression) (p-value 0.365).
Overall survival was comparable among the three groups with no significant difference (p-value 0.718) with a median of 40 months (SR), 28 (ER-S) and 26 (ER) months.

Conclusion

Endoscopic resection alone appears to be a reasonable option for high-risk T1 CRC patients, especially those with increased surgical risk due to low rate of recurrence, low adverse events and a comparable overall survival in short-mid term.

References

1. Quénéhervé, L.; Pioche, M.; Jacques, J. Curative Criteria for Endoscopic Treatment of Colorectal Cancer. Best Pract. Res. Clin. Gastroenterol. 2024, 101883, doi:10.1016/j.bpg.2024.101883.
2. Chen, Y.; Jing, W.; Chen, M.; Wang, Z.; Wu, J.; Yang, J.; Yang, L.; Deng, K. Long-Term Outcomes of Local Resection versus Surgical Resection for High-Risk T1 Colorectal Cancer: A Systematic Review and Meta-Analysis. Gastrointest. Endosc. 2023, 97, 1016-1030.e14, doi:10.1016/j.gie.2023.02.027.
3. Spadaccini M, Bourke MJ, Maselli R, et al. Clinical outcome of non-curative endoscopic submucosal dissection for early colorectal cancer. Gut. Published online January 20, 2022. doi:10.1136/gutjnl-2020-323897
4. Corre, F.; Albouys, J.; Tran, V.-T.; Lepilliez, V.; Ratone, J.-P.; Coron, E.; Lambin, T.; Rahmi, G.; Karsenti, D.; Canard, J.-M.; et al. Impact of Surgery after Endoscopically Resected High-Risk T1 Colorectal Cancer: Results of an Emulated Target Trial. Gastrointest. Endosc. 2023, S0016-5107(23)02933-4, doi:10.1016/j.gie.2023.09.027.
5. UICC. TNM. Classification of malignant tumours. eighth ed. Wiley; 2016. p. 272

Disclosure

Giuseppe Grande is consultant for Olympus, Boston Scientific, ERBE, Fujifilm

Introduction

Self-expandable metallic stents (SEMS) are commonly used to relive malignant gastric outlet obstruction (GOO). However, SEMS with high radial force can occurs tissue proliferation caused by mechanical injury. To overcome these problems, drug-eluting stents using antiproliferative drugs have been developed. Specially, everolimus have demonstrated efficacy in reducing restenosis rates in arteries, but their potential application in the gastrointestinal tract remains unexplored. Additionally, recent studies have reported that stents with thinner struts have a reduced risk of clinical restenosis compared to stents with thicker struts. However, the application of everolimus-coated laser-cut stents, which offer robust antiproliferative properties, has not yet been investigated or established in the gastrointestinal tract.

Aims & Methods

This study aims to investigate the efficacy and safety of everolimus-coated laser-cut SEMS in suppressing stent-induced tissue hyperplasia in a rat gastric outlet model.
Everolimus-coated laser-cut SEMS were prepared using ultrasonic spray technology, and the characteristics of the SEMS before and after coating process were evaluated. Twelve male rats were randomly divided into two groups: control (laser-cut SEMS, n = 6) and everolimus (everolimus-coated laser-cut SEMS, n = 6). The effectiveness of everolimus-coated laser-cut SEMS were assessed by comparing results of fluoroscopy, endoscopy, and histopathological analyses.

Results

Everolimus were uniformly coated onto the surface of the laser-cut SEMS and approximately 80% of everolimus was slowly released for a week. Stent placement was successful in all rats. Stent-induced tissue hyperplasia variables were significantly lower in the everolimus group compared to the control group (all p < 0.05). The luminal diameter was significantly larger in the everolimus group than in the control group (p < 0.05). The degrees of α-SMA-, Ki-67-, and BrdU-positive deposition were significantly lower in the everolimus group (p < 0.001), while the degree of TUNEL-positive deposition was significantly higher than in the control group (p < 0.001).

Conclusion

Everolimus-coated laser-cut SEMS effectively suppressed stent-induced tissue hyperplasia in a rat gastric outlet model. Local treatment with everolimu via laser-cut SEMS was safe and effective to maintain the stent patency and has therapeutic potential in the prevention of restenosis after stent placement in the gastrointestinal tract.

Disclosure

No disclosure