Golidocitinib combined with CHOP in treatment-Naïve monomorphic epitheliotropic intestinal T-cell lymphoma: Preliminary results from A phase 2 multicenter, single-arm goal study

Abstract Background Monomorphic epitheliotropic intestinal T-cell lymphoma (MEITL) is a rare and highly aggressive subtype of peripheral T-cell lymphoma (PTCL) with a dismal prognosis and limited therapeutic options. The standard first-line treatment, CHOP (Cyclophosphamide, doxorubicin, vincristine, and prednisone), yields suboptimal outcomes, highlighting a critical unmet need. Pathogenetically, constitutive activation of the JAK/STAT signaling pathway is a key driver of lymphomagenesis in MEITL. Golidocitinib is a potent, selective JAK1 inhibitor with a unique gastrointestinal (GI)-enriched property, making it an ideal candidate for treating intestinal lymphomas. Prior clinical studies have demonstrated golidocitinib's promising anti-tumor activity and manageable safety in other PTCL subtypes, providing a strong rationale for its investigation in MEITL. Methods This multicenter, single-arm, phase 2 study (GOAL; NCT06701344) evaluated golidocitinib plus CHOP in treatment-naïve MEITL patients (pts). Eligible pts received oral golidocitinib at 150 mg once daily, in combination with a standard CHOP regimen every 21 days for 6 cycles. The CHOP regimen consisted of intravenous cyclophosphamide 750 mg/m², doxorubicin 50 mg/m², and vincristine 1.4 mg/m² (capped at 2 mg) on day 1, plus oral prednisone 60 mg/m² on days 1-5. Tumor response was assessed by PET-CT at baseline, after 3 cycles (interim), and at the end of treatment (EOT), according to the Lugano criteria. The primary endpoint was the complete response rate (CRR) at EOT. Secondary endpoints included overall response rate (ORR), duration of response (DOR), progression-free survival (PFS), overall survival (OS), and safety. Results Between Aug 2, 2024, and Apr 14, 2025, 8 pts were screened for eligibility. One patient withdrew informed consent prior to treatment. A total of 7 treatment-naïve MEITL pts were enrolled and received at least one dose of the study treatment. The median age of the cohort was 60 years (range, 39-73), and 6 pts (85.7%) were male. At baseline, 4 pts (57.1%) had advanced disease (Lugano stage IV). A high proportion of pts (6/7, 85.7%) had a poor performance status (ECOG ≥ 2). The median number of extranodal sites was 1 (range, 1-2), with the gastrointestinal (GI) tract being universally involved. Two pts (28.6%) had elevated lactate dehydrogenase (LDH) levels at baseline. One patient had undergone surgery prior to enrollment. As of the data cutoff on July 31, 2025, with a median follow-up of 6.2 months, all 7 enrolled pts were evaluable for efficacy in an intent-to-treat analysis. The combination demonstrated profound clinical activity. Among 7 evaluable pts, 5 achieved a complete response (CR), 1 achieved a partial response (PR), and 1 had progressive disease (PD), resulting in an overall response rate (ORR) of 85.7% (6/7) and a complete response rate (CRR) of 71.4% (5/7 pts). Correlative biomarker analyses provided strong mechanistic insights. Targeted sequencing on 3 of the 7 pts (2 CR, 1 PR) revealed that all 3 (100%) harbored activating mutations in the JAK/STAT pathway (JAK3, n=2; STAT5B, n=1). This was further validated by single-cell RNA sequencing on 4 baseline tumors (2 CR, 1 PR, 1 PD), which identified two key determinants of response. First, at the tumor-intrinsic level, malignant T cells from responders exhibited a significantly stronger baseline JAK/STAT activation signature compared to the non-responder. Second, at the microenvironment level, responders' tumors displayed a diverse, “hot” TME, rich with infiltrating immune cells, while the non-responder's tumor was an immune-desert. These data suggest that response to golidocitinib plus CHOP is co-determined by both a tumor's dependence on the JAK/STAT pathway and a pre-existing, immunocompetent microenvironment. The most common Grade ≥3 treatment-emergent adverse events were hematologic toxicities. Notable non-hematologic events included severe GI events (bleeding/perforation, n=2) and CMV reactivation (n=2). Conclusions The combination of golidocitinib and CHOP demonstrates profound clinical activity in treatment-naïve MEITL, representing a significant therapeutic advance over conventional chemotherapy. Preliminary single-cell analysis identifies a baseline JAK/STAT activation signature in malignant cells and a non-immunosuppressive tumor microenvironment as potential biomarkers of response. This regimen represents a highly promising new therapeutic strategy for this aggressive lymphoma.