Introduction

Prognosis in advanced pancreatic ductal adenocarcinoma (aPDAC) is particularly poor. Few patients benefit from second-line chemotherapy, while most experience side effects, highlighting the need for biomarkers. The PREDICT trial examined in aPDAC patients whether first-line time-to-treatment failure (TTF1) predicts second-line treatment failure (TTF2) but found no association. In our translational study we hypothesized that the responsiveness of the tumor immune microenvironment (TiME) might determine second-line therapy outcome and examined whether treatment-naive tissue immune features are also reflected in the peripheral blood after one line of chemotherapy.

Aims & Methods

In the PREDICT trial, patients received 5-FU/LV plus nanoliposomal irinotecan second-line after gemcitabine/nab-paclitaxel (Gem-nabPac) first-line therapy. We stratified PREDICT patients by shortest vs. longest TTF2. Treatment-naive primary tumor tissues from 20 patients were analyzed by NanoString transcriptomic profiling and multiplexed immunohistochemistry to characterize differences in the TiME. Peripheral blood mononuclear cells (PBMCs) were obtained immediately before second-line therapy from 82 patients and analyzed using multiparameter flow cytometry with an automated gating procedure and gene expression profiling via RT-qPCR. A feature selection and machine learning pipeline integrated PBMC and clinical data to derive a minimal predictor for TTF2 outcome and prognosis that was validated across different treatment regimens on an independent external cohort of 30 patients with aPDAC.

Results

Treatment-naive tumors of patients in the long-TTF2 group exhibited an immune-active (“hot”) TiME with CXCR3⁺ CD8⁺ cytotoxic T cell infiltration into the cancer cell compartment via CXCR3-dependant inflammatory chemokine signaling. Analysis of PBMCs obtained directly before second-line therapy showed that these immune features were sustained over one line of treatment and reflected in PBMCs. A PBMC-based machine learning model (“TTF2Pred”) identified a 7-feature immune signature that accurately distinguished long vs. short TTF2 patient groups outperforming multivariate clinical data or CA19-9 benchmark models. TTF2Pred robustness was confirmed by external validation and showed the best overall performance post-Gem-nabPac first-line treatment. Among the seven TTF2Pred features, long-TTF2 patients exhibited more circulating CXCR3⁺ activated T cells and plasmacytoid dendritic cells, while short-TTF2 patients had more circulating platelet–leukocyte (platelet-monocyte, platelet-neutrophil) aggregates and exhausted T cells.

Conclusion

PDAC patients with an immune-active, treatment-naïve TiME have a better outcome on second-line therapy, and these tissue characteristics are reflected in circulating PBMCs after one line of chemotherapy. A parsimonious circulating PBMC-based signature offers a minimally invasive predictor of second-line outcome that could inform personalized therapy.

Introduction

Upadacitinib (UPA) is an oral, reversible JAK inhibitor that recently demonstrated efficacy compared with placebo (PBO) in 2 double-blind, multicenter induction studies, U-EXCEED and U-EXCEL, and 1 maintenance study, U-ENDURE.^1-3 UPA is approved for the treatment of patients with moderately to severely active Crohn’s disease (CD).^4,5 The updated STRIDE-II guidelines recommend symptomatic control and mucosal healing as short- and long-term goals, respectively, of therapy.⁶ This post hoc analysis evaluated the durability of clinical, biomarker, and endoscopic improvements in patients with moderately to severely active CD treated with maintenance UPA.

Aims & Methods

In the phase 3 induction studies, U-EXCEL (NCT03345849) and U-EXCEED (NCT03345836), patients with moderately to severely active CD were randomized 2:1 to receive either UPA 45 mg or PBO once daily for 12 weeks. Clinical responders to UPA at week 12 were re-randomized 1:1:1 to the phase 3 maintenance study, U-ENDURE (NCT03345823), in which they received UPA 30 mg, UPA 15 mg, or PBO once daily for an additional 52 weeks. The 52‑week durability (achievement of an outcome at maintenance week 0 and at 52 weeks) of clinical, biomarker, and endoscopic outcomes was assessed amongst patients achieving the specified outcome at the end of induction. Endpoints evaluated included enhanced clinical response (per stool frequency [SF]/abdominal pain score [APS]) , clinical response (CR-100), clinical remission (per SF/APS and CD activity index [CDAI]), endoscopic response, endoscopic remission, achievement of normalized high-sensitivity C-reactive protein (hs-CRP), and achievement of normalized fecal calprotectin (FCP).

Results

Across all endpoints studied, maintenance UPA treatment with both UPA doses provided greater maintenance of response compared with PBO (Table). Compared with PBO, a greater proportion of patients receiving UPA achieved maintenance of CR-100 (UPA 30 mg, 60.8%; UPA 15 mg, 48.8%; PBO, 17.9%; nominal P < .0001 for both doses). Similarly, a greater proportion of patients maintained enhanced clinical response with UPA vs PBO (UPA 30 mg, 61.1%; UPA 15 mg, 44.0%; PBO, 21.8%; nominal P < .0001 for both doses). Maintenance of clinical remission was greater with UPA vs PBO (CDAI: UPA 30 mg, 65.2%; UPA 15 mg, 49.5%; PBO, 21.2%; SF/APS: UPA 30 mg, 60.0%; UPA 15 mg, 50.5%; PBO, 19.6%; nominal P < .0001 for all). Likewise, maintenance of endoscopic response was greater with UPA vs PBO, as was maintenance of endoscopic remission. A greater proportion of patients maintained biomarker normalization with UPA 15 mg or 30 mg vs PBO at week 52.

Conclusion

Maintenance therapy with both UPA doses results in durable clinical, biomarker, and endoscopic improvements amongst patients with moderately to severely active CD. Patients receiving UPA 30 mg QD maintenance achieved key endpoints at a numerically higher rate than did patients receiving UPA 15 mg QD.

References

1. Loftus E, et al. United European Gastroenterol J. 2022;10:OP129.
2. Colombel JF, et al. Gastroenterology. 2022;162:867f.
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.
5. Electronic Medicines Compendium. Rinvoq (upadacitinib) 30 mg prolonged-release tablets: summary of product characteristics. Updated March 16, 2023. Accessed March 27, 2023. https://www.medicines.org.uk/emc/product/12830/smpc/
6. Turner D, et al. Gastroenterology. 2021;160:1570–1583.

Disclosure

RP has served as consultant for Abbott, AbbVie, Abbivax, Alimentiv, Amgen, Arena Pharmaceuticals, AstraZeneca, Biogen, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Celltrion, Cosmos Pharmaceuticals, Eisai, Elan, Ferring, Galapagos, Fresenius Kabi, Genentech, Gilead Sciences, Glaxo-Smith Kline, JAMP Bio, Janssen, Lilly, Merck, Mylan, Novartis, Oppilan Pharma, Organon, Pandion Pharma, Pendopharm, Pfizer, Progenity, Prometheus Biosciences, Protagonist Therapeutics, Roche, Sandoz, Satisfai Health, Shire, Sublimity Therapeutics, Takeda, Theravance Biopharma, Trellus, Viatris, Ventyx, and UCB; speakers fees from AbbVie, Amgen, Arena Pharmaceuticals, Bristol-Myers Squibb, Celgene, Ferring, Fresenius Kabi, Gilead Sciences, Janssen, Lilly, Merck, Organon, Pfizer, Roche, Sandoz, Shire, and Takeda; and has received research grants from AbbVie, Janssen, Pfizer, Takeda, and Ventyx.
MTA has served as a consultant for AbbVie, Arena Pharmaceuticals, Bristol-Myers Squibb, Celsius, Focus Medical, Gilead, Janssen, Microba, Lilly, Pfizer, Prometheus Biosciences, UCB, and WebMD Global.
RA has served as a speaker or consultant, or received research grants from AbbVie, Amgen, Arena Pharmaceuticals, Biogen, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Celltrion Healthcare, Falk Foundation, Ferring, Galapagos, Gilead, InDex Pharmaceuticals, Janssen-Cilag, Kiniksa, Lilly, MSD, Novartis, Pandion Therapeutics, Pfizer, Roche Pharma, Samsung Bioepis, Takeda, Tillots Pharma, and Viatris
PB has received financial support for research from AbbVie, Amgen, Celltrion, Mylan, Pfizer, and Takeda; lecture fees from AbbVie, Celltrion, Janssen, Lilly, and Takeda; and consulting fees AbbVie, Arena Pharmaceuticals, Bristol-Myers Squibb, Celltrion, Dr Falk, Galapagos, Janssen, Lilly, Pentax, PSI-CRO, Roche, Takeda, and Tetrameros.
SDL has served as a consultant for Cornerstones, Janssen, Lilly, Pfizer, and UCB; and received grant and research support from AbbVie, Arena, Celgene, Janssen, Shield Therapeutics, Takeda, Tetherex, and UCB.
GAD reports no conflicts of interest
EL has received research grants from Janssen, Pfizer, and Takeda; received educational grants from AbbVie, Janssen, MSD, and Takeda; received speaker fees from AbbVie, Dr Falk Pharma, Ferring, Hospira, Janssen, MSD, Pfizer, and Takeda; served on advisory boards for AbbVie, Arena, Celgene, Ferring, Galapagos, Gilead, Hospira, Janssen, MSD, Pfizer, and Takeda; and served as a consultant for AbbVie.
ST has received research funding from AbbVie.
APL, ED, CJ, and AG are employees of AbbVie and may own stock and/or options.
JP has received financial support for research from AbbVie and Pfizer; received lecture fees from AbbVie, Ferring, Janssen, and Takeda; and received consultancy fees from AbbVie, Arena Pharmaceuticals, Athos, Boehringer Ingelheim, Celltrion, Ferring, Galapagos, Genentech, GSK, Janssen, Mirum, Morphic, Origo, Pandion, Pfizer, Protagonist, Revolo, Robarts, Roche, Takeda, Theravance, and Wassermann.
Funding
AbbVie Inc. funded this study and participated in the study design, research, analysis, data collection, interpretation of data, reviewing, and approval of this 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 the authors thank the patients who participated in the study and all study investigators for their contributions. AbbVie funded the research for this study and provided writing support for this abstract. Medical writing assistance, funded by AbbVie, was provided by Spencer Hughes, PhD, of JB Ashtin.