Introduction

Given the natural history of Crohn’s disease (CD), the beneficial effects of treatments may wane over time and result in loss of response. Treatment escalation may aid in re-capturing clinical benefit and improving markers of inflammation. Upadacitinib (UPA) is an oral reversible Janus kinase inhibitor that demonstrated efficacy compared with placebo in 2 phase 3 induction studies and 1 maintenance study, U‑ENDURE, in CD^1-3 and is approved for patients with moderately to severely active CD.⁴ In this post hoc analysis, we evaluated the effect of UPA 30 mg therapy among patients who experienced loss of response to UPA 15 mg maintenance treatment or upon treatment withdrawal.

Aims & Methods

Patients who achieved clinical response (≥ 30% decrease in average daily very soft/liquid stool frequency [SF] and/or abdominal pain score [APS], neither worse than baseline) to 12 weeks of UPA 45 mg once daily (QD) induction therapy were re-randomized to receive UPA 30 mg, UPA 15 mg, or placebo QD in U‑ENDURE (NCT03345823). Beginning at week 4, patients who experienced loss of response and required medical treatment could receive open‑label (OL) UPA 30 mg QD. Loss of response was defined as having clinical symptoms (average daily very soft/liquid SF ≥ 4.0 and/or average daily APS ≥ 2.0) plus an objective marker of inflammation (protocol-specified criteria for high‑sensitivity C-reactive protein [hsCRP], fecal calprotectin [FCP], or Simple Endoscopic Score for CD). Outcomes were assessed at 12 and 24 weeks after initiation of OL UPA 30 mg QD therapy and included clinical remission and clinical response (both per CD Activity Index [CDAI] and SF/APS), enhanced clinical response, and FCP and hsCRP levels. Safety was also assessed. Analyses were based on as observed data without imputation.

Results

Patients who received OL UPA 30 mg QD therapy had, at baseline, a mean CD duration of 10 years, mean CDAI of 304, median hsCRP of 14.3 mg/L, and median FCP of 1550 µg/g; 83.5% had prior biologic failure. At 12 weeks after initiation of OL UPA 30 mg QD, regardless of group during blinded maintenance, 84.4%–87.6% of patients achieved SF/APS clinical response, 77.2%–78.9% achieved enhanced clinical response, 63.3%–71.3% achieved CDAI clinical response, and 46.7%–53.8% achieved SF/APS or CDAI clinical remission (Table). Reponses were sustained through 24 weeks. Median hsCRP and FCP levels decreased after initiation of OL UPA 30 mg QD therapy. Adverse event rates in either group were consistent with those in the overall population. One major adjudicated cardiovascular event in the placebo group and 2 events of non-melanoma skin cancer in the UPA 15-mg group were reported after receiving UPA 30 mg.

Conclusion

Among patients with CD who responded to UPA 45 mg induction therapy and subsequently lost response during maintenance when randomized to placebo or UPA 15 mg QD, most regained clinical response and many achieved clinical remission 12 weeks after initiating UPA 30 mg QD therapy. These improvements were sustained through 24 weeks. No new safety signals were observed.

References

1. Colombel JF, et al. Gastroenterology. 2022;162:S1394.
2. Loftus EV Jr. United European Gastroenterol J. 2022;10;103–104.
3. Panés J, et al. Am J Gastroenterol. 2022;117:S10.
4. RINVOQ. Summary of Product Characteristics. AbbVie Deutschland GmbH & Co. KG; 2023. Accessed 24 April 2023. https://www.ema.europa.eu/en/documents/product-information/rinvoq-epar-product-information_en.pdf.

Disclosure

RP has received consultancy and/or speaking honoraria from Abbott, AbbVie, Alimentiv (formerly Robarts), Amgen, Arena Pharmaceuticals, AstraZeneca, Biogen, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Celltrion, Cosmos, Eisai, Elan, Ferring, Galapagos, Fresenius Kabi, Genentech, Gilead, GSK, JAMP Bio, Janssen, Lilly, Merck, Mylan, Novartis, Oppilan Pharma, Organon, Pandion, Pendopharm, Pfizer, Progenity, Prometheus, Protagonist, Roche, Sandoz, Satisfai Health, Shire, Sublimity, Takeda, Theravance, Trellus, Viatris, and Ventyx, and has received research funding from Abbvie, Janssen, Pfizer, and Takeda.
JOL has received consulting and/or speaker fees from AbbVie, Bristol-Myers Squibb, Celgene, Celltrion, Ferring, Galapagos, Gilead, GSK, Janssen, Lilly, Napp, Pfizer, Shire, Takeda, and Vifor Pharma; and investigator-led research grants from AbbVie, Gilead, Pfizer, Shire, and Takeda.
JP has received financial support for research from AbbVie and Pfizer; consultancy fees/honorarium from AbbVie, Arena, Athos, Atomwise, Boehringer Ingelheim, Celgene, Celsius, Celltrion, Ferring, Galapagos, Genentech/Roche, GSK, Janssen, Mirum, Morphic, Nestlé, Origo, Pandion, Pfizer, Progenity, Prometheus, Protagonist, Revolo, Robarts, Sanofi, Takeda, Theravance, and Wasserman; reports payment for lectures, including service on speaker bureaus, from Abbott, Ferring, Janssen, Pfizer and Takeda; and reports payment for development of educational presentations from Abbott, Janssen, Pfizer, Roche and Takeda.
PS has received honoraria for consulting and/or speaking activities from AbbVie, Ferring, Janssen, Lilly, Roche, Pfizer, and Takeda. He has served as an investigator for clinical trials sponsored by Abbvie, Gilead, Janssen, Pfizer, and Takeda.
MNR has been a principal investigator for studies sponsored by AbbVie.
MDM-A has received consulting and/or speaker fees from AbbVie, Galapagos, Janssen, Pfizer, Takeda, and Tillotts, and has received research funding from AbbVie, Janssen, and Pfizer.
FB has served as an investigator for clinical trials sponsored by AbbVie and Janssen.
APL, ED, SF, SA, and TF are employees or contractors of AbbVie, and may own AbbVie stock and/or stock options.
GD'H has received honoraria for consulting and/or speaking activities from AbbVie, Alimentiv, Boehringer Ingelheim, Celltrion, Ferring, Galapagos, GSK, Gossamer Bio, Janssen, Lilly, Pfizer, Progenity, Takeda, and Tillotts.
Funding
AbbVie Inc. funded this study and participated in the study design, research, analysis, data collection, interpretation of data, reviewing, and approval of the abstract. All authors had access to relevant data and participated in the drafting, review, and approval of this abstract. No honoraria or payments were made for authorship. AbbVie and authors thank all the trial investigators and the patients who participated in this clinical trial. Medical writing support was provided by Lisa M Pitchford, PhD, of JB Ashtin, and funded by AbbVie.

Introduction

Gastric fundus is a technically difficult area for endoscopic submucosal dissection(ESD), even for experienced endoscopists, due to its anatomic features, thin wall, and abundant blood supply.

Aims & Methods

To evaluate the feasibility a novel ESD technique, the “topflight ESD” for the gastric fundus tumors resection.
Topflight ESD procedure: marking dots are applied 5 mm outside the lesion margins, using the tip of the ESD knife; a mucosal incision is made in the distal esophagus, ca 3 cm above gastroesophageal junction; a tunnel is created into the gastric wall; subepithelial injection is performed using an endoscopic needle and the water flush from the ESD knife; extensive dissection of the submucosal space in the fundus and proximal corpus is performed; the tumor is isolated from the surrounding tissues; the endoscope is removed from the submucosal tunnel and is inserted into the gastric lumen; mucosal incision is performed outside the dots rim using the ESD knife; en bloc resection is obtained, the specimen is retrieved; finally, the esophageal incision is closed using conventional through-the-scope clips.

Results

An 81-year-old male patient with history of a coronary bypass surgery, right lung lobectomy and MALT lymphoma, was referred to us. On a previous gastroscopy, a 6 cm flat lesion with no ulcer(Paris 0-IIa+b), was identified in the gastric fundus and greater curvature of the proximal body. Biopsies revealed a mixed type, moderately differentiated adenocarcinoma. After multidisciplinary team conference a decision for ESD resection was made. The ESD was performed according to the steps described above. After lesion characterization, marks were placed around the lesion. Then, an incision was made in the distal esophagus and a wide tunnel was created, dissecting the submucosa under the lesion. Then, a mucosal incision from the luminal side was made. During this stage there was a 3mm perforation, highlighting the risk of perforation when the cutting is done from the luminal side. That perforation was effectively closed with the use of through-the-scope clips. En bloc resection was achieved. The esophageal incision was closed. The obtained specimen was 75x50mm in size. Oral liquids were started on day 1 and the patient was discharged asymptomatic, on day 2. The pathological examination confirmed the presence of a mixed type, moderately differentiated adenocarcinoma SM2L0V0R0, pT1b. The patient was under clopidogrel and was admitted at day 10 due to bleeding from the ESD ulcer, treated endoscopically, and remains asymptomatic 2 months after.

Conclusion

We demonstrate a novel and minimally invasive endoscopic option that uses conventional ESD devices. To our best knowledge, this is the first report of gastric fundus epithelial tumor resection using this technique. The Topflight ESD might be considered in such cases in the future.

References

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