Efficacy and safety of geptanolimab (GB226) for relapsed or refractory peripheral T cell lymphoma: an open-label phase 2 study (Gxplore-002)

Yuankai Shi, Jianqiu Wu, Zhen Wang, Liling Zhang, Zhao Wang, Mingzhi Zhang, Hong Cen, Zhigang Peng, Yufu Li, Lei Fan, Ye Guo, Liping Ma, Jie Cui, Yuhuan Gao, Haiyan Yang, Hongyu Zhang, Lin Wang, Weihua Zhang, Huilai Zhang, Liping Xie, Ming Jiang, Hui Zhou, Yuerong Shuang, Hang Su, Xiaoyan Ke, Chuan Jin, Xin Du, Xin Du, Li Liu, Yaming Xi, Zheng Ge, Ru Feng, Yang Zhang, Shengyu Zhou, Fan Xie, Qian Wang, Yuankai Shi, Jianqiu Wu, Zhen Wang, Liling Zhang, Zhao Wang, Mingzhi Zhang, Hong Cen, Zhigang Peng, Yufu Li, Lei Fan, Ye Guo, Liping Ma, Jie Cui, Yuhuan Gao, Haiyan Yang, Hongyu Zhang, Lin Wang, Weihua Zhang, Huilai Zhang, Liping Xie, Ming Jiang, Hui Zhou, Yuerong Shuang, Hang Su, Xiaoyan Ke, Chuan Jin, Xin Du, Xin Du, Li Liu, Yaming Xi, Zheng Ge, Ru Feng, Yang Zhang, Shengyu Zhou, Fan Xie, Qian Wang

Abstract

Background: Peripheral T cell lymphoma (PTCL) is a rare disease and recent approved drugs for relapsed/refractory (r/r) PTCL provided limited clinical benefit. We conducted this study to evaluate the efficacy and safety of geptanolimab (GB226), an anti-PD-1 antibody, in r/r PTCL patients.

Methods: We did this single-arm, multicenter phase 2 study across 41 sites in China. Eligible patients with r/r PTCL received geptanolimab 3 mg/kg intravenously every 2 weeks until disease progression or intolerable toxicity. All patients who received at least one dose of geptanolimab and histological confirmed PTCL entered full analysis set (FAS). The primary endpoint was objective response rate (ORR) in FAS assessed by the independent radiological review committee (IRRC) per Lugano 2014 criteria.

Results: Between July 12, 2018, and August 15, 2019, 102 patients were enrolled and received at least one dose of geptanolimab. At the data cutoff date (August 15, 2020), the median follow-up was 4.06 (range 0.30-22.9) months. For 89 patients in FAS, 36 achieved objective response (40.4%, 95% CI 30.2-51.4), of which 13 (14.6%) were complete response and 23 (25.8%) had partial response assessed by IRRC. The median duration of response (DOR) was 11.4 (95% CI 4.8 to not reached) months per IRRC. Patients with PD-L1 expression ≥ 50% derived more benefit from geptanolimab treatment compared to < 50% ones (ORR, 53.3% vs. 25.0%, p = 0.013; median PFS 6.2 vs. 1.5 months, p = 0.002). Grade ≥ 3 treatment-related adverse events occurred in 26 (25.5%) patients, and the most commonly observed were lymphocyte count decreased (n = 4) and platelet count decreased (n = 3). Serious adverse events were observed in 45 (44.1%) patients and 19 (18.6%) were treatment related.

Conclusions: In this study, geptanolimab showed promising activity and manageable safety profile in patients with r/r PTCL. Anti-PD-1 antibody could be a new treatment approach for this patient population.

Trial registration: This clinical trial was registered at the ClinicalTrials.gov (NCT03502629) on April 18, 2018.

Keywords: Immunotherapy; PD-1 inhibitor; T cell lymphomas.

Conflict of interest statement

FX and QW are employees of Genor Biopharma Co., Ltd., China. The other authors declared no competing interests.

Figures

Fig. 1
Fig. 1
Patient disposition of all screened patients. IRRC, independent radiological review committee. Note Pathological diagnosis was done by study site pathologists for study enrolment and patient eligibility was determined by site investigators. Central pathology review was conducted retrospectively upon patient consent. Retrospectively pathological confirmation per central pathology review was not available in 13 patients, leaving 89 patients entering FAS
Fig. 2
Fig. 2
a Duration of treatment for full analysis set population (N = 89). b Best percentage change from baseline in target lesion size for full analysis set population based on an independent radiological review committee assessment (N = 74). CR, complete response; PR, partial response; SD, stable disease; CPD, confirmed progressive disease; UE, unevaluable; UPD, unconfirmed progressive disease; PD, progressive disease.Note Out of 89 patients in the full analysis set, five patients did not have measurable target lesion at baseline per central review, eight patients withdrew before first response assessment and two patients had disease progression on the basis of physical examination by investigators without radiographic record
Fig. 3
Fig. 3
a Kaplan–Meier estimated duration of response in full analysis set population based on an independent radiological review committee (IRRC) assessment of patients (N = 36). b Kaplan–Meier estimated progression-free survival in full analysis set population based on an IRRC assessment (N = 89). NR, not reached; CI, confidence interval
Fig. 4
Fig. 4
a Post-hoc analysis of objective response rate and b Kaplan–Meier estimated of progression-free survival by PD-L1 expression based on an independent radiological review committee assessment. PD-L1, programmed death-ligand 1; CI, confidence interval; NR, not reached. Note Responders were response-evaluable patients with PD-L1 assessed who achieved a complete or partial response as best overall response per 2014 Lugano lymphoma response criteria. PD-L1 expression was assessed with a cutoff of 50%

References

    1. Swerdlow SH, Campo E, Pileri SA, Harris NL, Stein H, Siebert R, et al. The 2016 revision of the World Health Organization classification of lymphoid neoplasms. Blood. 2016;127(20):2375–2390.
    1. Sun J, Yang Q, Lu Z, He M, Gao L, Zhu M, et al. Distribution of lymphoid neoplasms in China: analysis of 4,638 cases according to the World Health Organization classification. Am J Clin Pathol. 2012;138(3):429–434.
    1. Vose J, Armitage J, Weisenburger D, International TCLP International peripheral T-cell and natural killer/T-cell lymphoma study: pathology findings and clinical outcomes. J Clin Oncol. 2008;26(25):4124–4130.
    1. Li X, Cui Y, Sun Z, Zhang L, Li L, Wang X, et al. DDGP versus SMILE in newly diagnosed advanced natural Killer/T-Cell lymphoma: a randomized controlled, multicenter, open-label study in China. Clin Cancer Res. 2016;22(21):5223–5228.
    1. Feyler S, Prince HM, Pearce R, Towlson K, Smith IM, Schey S, et al. The role of high-dose therapy and stem cell rescue in the management of T-cell malignant lymphomas: a BSBMT and ABMTRR study. Bone Marrow Transplant. 2007;40(5):443–450.
    1. Smith SM, Burns LJ, van Besien K, Lerademacher J, He W, Fenske TS, et al. Hematopoietic cell transplantation for systemic mature T-cell non-Hodgkin lymphoma. J Clin Oncol. 2013;31(25):3100–3109.
    1. Reimer P, Rudiger T, Geissinger E, Weissinger F, Nerl C, Schmitz N, et al. Autologous stem-cell transplantation as first-line therapy in peripheral T-cell lymphomas: results of a prospective multicenter study. J Clin Oncol. 2009;27(1):106–113.
    1. d'Amore F, Relander T, Lauritzsen GF, Jantunen E, Hagberg H, Anderson H, et al. Up-front autologous stem-cell transplantation in peripheral T-cell lymphoma: NLG-T-01. J Clin Oncol. 2012;30(25):3093–3099.
    1. Gui L, Shi YK, He XH, Lei YH, Zhang HZ, Han XH, et al. High-dose therapy and autologous stem cell transplantation in peripheral T-cell lymphoma: treatment outcome and prognostic factor analysis. Int J Hematol. 2014;99(1):69–78.
    1. O'Connor OA, Pro B, Pinter-Brown L, Bartlett N, Popplewell L, Coiffier B, et al. Pralatrexate in patients with relapsed or refractory peripheral T-cell lymphoma: results from the pivotal PROPEL study. J Clin Oncol. 2011;29(9):1182–1189.
    1. Piekarz RL, Frye R, Prince HM, Kirschbaum MK, Zain J, Allen SL, et al. Phase 2 trial of romidepsin in patients with peripheral T-cell lymphoma. Blood. 2011;117(22):5827–5834.
    1. Coiffier B, Pro B, Prince HM, Foss F, Sokol L, Greenwood M, et al. Results from a pivotal, open-label, phase II study of romidepsin in relapsed or refractory peripheral T-cell lymphoma after prior systemic therapy. J Clin Oncol. 2012;30(6):631–636.
    1. O'Connor OA, Horwitz S, Masszi T, Hoof AV, Brown P, Doorduijn J, et al. Belinostat in patients with relapsed or refractory peripheral T-cell lymphoma: results of the pivotal phase II BELIEF (CLN-19) study. J Clin Oncol. 2015;33(23):2492–2499.
    1. Olsen EA, Kim YH, Kuzel TM, Pacheco TR, Foss FM, Parker S, et al. Phase IIb multicenter trial of vorinostat in patients with persistent, progressive, or treatment refractory cutaneous T-cell lymphoma. J Clin Oncol. 2007;25(21):3109–3115.
    1. Shi Y, Dong M, Hong X, Zhang W, Feng J, Zhu J, et al. Results from a multicenter, open-label, pivotal phase II study of chidamide in relapsed or refractory peripheral T-cell lymphoma. Ann Oncol. 2015;26(8):1766–1771.
    1. Shi Y, Jia B, Xu W, Li W, Liu T, Liu P, et al. Chidamide in relapsed or refractory peripheral T cell lymphoma: a multicenter real-world study in China. J Hematol Oncol. 2017;10(1):69.
    1. Pro B, Advani R, Brice P, Bartlett NL, Rosenblatt JD, Illidge T, et al. Five-year results of brentuximab vedotin in patients with relapsed or refractory systemic anaplastic large cell lymphoma. Blood. 2017;130(25):2709–2717.
    1. Horwitz SM, Advani RH, Bartlett NL, Jacobsen ED, Sharman JP, O'Connor OA, et al. Objective responses in relapsed T-cell lymphomas with single-agent brentuximab vedotin. Blood. 2014;123(20):3095–3100.
    1. Pardoll DM. The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer. 2012;12(4):252–264.
    1. Chen R, Zinzani PL, Fanale MA, Armand P, Johnson NA, Brice P, et al. Phase II study of the efficacy and safety of pembrolizumab for relapsed/refractory classic hodgkin lymphoma. J Clin Oncol. 2017;35(19):2125–2132.
    1. Ramchandren R, Domingo-Domenech E, Rueda A, Trněný M, Feldman TA, Lee HJ, et al. Nivolumab for newly diagnosed advanced-stage classic Hodgkin lymphoma: safety and efficacy in the phase II CheckMate 205 study. J Clin Oncol. 2019;37(23):1997–2007.
    1. Melani C, Major A, Schowinsky J, Roschewski M, Pittaluga S, Jaffe ES, et al. PD-1 Blockade in mediastinal gray-zone lymphoma. N Engl J Med. 2017;377(1):89–91.
    1. Chapuy B, Stewart C, Dunford AJ, Kim J, Wienand K, Kamburov A, et al. Genomic analyses of PMBL reveal new drivers and mechanisms of sensitivity to PD-1 blockade. Blood. 2019;134(26):2369–2382.
    1. Shi Y, Su H, Song Y, Jiang W, Sun X, Qian W, et al. Safety and activity of sintilimab in patients with relapsed or refractory classical Hodgkin lymphoma (ORIENT-1): a multicentre, single-arm, phase 2 trial. Lancet Haematol. 2019;6(1):e12–e19.
    1. Ansell SM, Minnema MC, Johnson P, Timmerman JM, Armand P, Shipp MA, et al. Nivolumab for Relapsed/Refractory Diffuse Large B-Cell Lymphoma in Patients Ineligible for or Having Failed Autologous Transplantation: A Single-Arm. Phase II Study J Clin Oncol. 2019;37(6):481–489.
    1. Barta SK, Zain J, MacFarlane AWt, Smith SM, Ruan J, Fung HC, et al. Phase II study of the PD-1 inhibitor pembrolizumab for the treatment of relapsed or refractory mature T-cell lymphoma. Clin Lymphoma Myeloma Leuk 2019; 19(6): 356–64 e3.
    1. Bennani NN, Pederson LD, Atherton P, Micallef I, Colgan JP, Thanarajasingam G, et al. A phase II study of nivolumab in patients with relapsed or refractory peripheral T-cell lymphoma. Blood. 2019;134(Supplement_1):467.
    1. Cheson BD, Fisher RI, Barrington SF, Cavalli F, Schwartz LH, Zucca E, et al. Recommendations for initial evaluation, staging, and response assessment of Hodgkin and non-Hodgkin lymphoma: the Lugano classification. J Clin Oncol. 2014;32(27):3059–3068.
    1. Thompson JA, Schneider BJ, Brahmer J, Andrews S, Armand P, Bhatia S, et al. Management of immunotherapy-related toxicities, Version 1.2019. J Natl Compr Canc Netw. 2019;17(3):255–289.
    1. Panjwani PK, Charu V, DeLisser M, Molina-Kirsch H, Natkunam Y, Zhao S. Programmed death-1 ligands PD-L1 and PD-L2 show distinctive and restricted patterns of expression in lymphoma subtypes. Hum Pathol. 2018;71:91–99.
    1. Wartewig T, Kurgyis Z, Keppler S, Pechloff K, Hameister E, Öllinger R, et al. PD-1 is a haploinsufficient suppressor of T cell lymphomagenesis. Nature. 2017;552(7683):121–125.
    1. Ratner L, Waldmann TA, Janakiram M, Brammer JE. Rapid progression of adult T-cell leukemia-lymphoma after PD-1 inhibitor therapy. N Engl J Med. 2018;378(20):1947–1948.
    1. Lesokhin AM, Ansell SM, Armand P, Scott EC, Halwani A, Gutierrez M, et al. Nivolumab in patients with relapsed or refractory hematologic malignancy: preliminary results of a phase Ib study. J Clin Oncol. 2016;34(23):2698–2704.
    1. Shi Y, Cai Q, Jiang Y, Huang G, Bi M, Wang B, et al. Activity and Safety of Geptanolimab (GB226) for patients with unresectable, recurrent or metastatic alveolar soft part sarcoma: a phase 2 single-arm study. Clin Cancer Res. 2020;26(24):6445–6452.
    1. Nishino M, Giobbie-Hurder A, Hatabu H, Ramaiya NH, Hodi FS. Incidence of programmed cell death 1 inhibitor-related pneumonitis in patients with advanced cancer: a systematic review and meta-analysis. JAMA Oncol. 2016;2(12):1607–1616.
    1. Wang PF, Chen Y, Song SY, Wang TJ, Ji WJ, Li SW, et al. Immune-related adverse events associated with anti-PD-1/PD-L1 treatment for malignancies: a meta-analysis. Front Pharmacol. 2017;8:730.

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