Background Pembrolizumab monotherapy showed 9.6% ORR and did not significantly improve OS as 2L or 3L treatment for mTNBC compared to standard chemotherapy in phase 3 study (KEYNOTE-119) leading to high unmet needs of a new drug that could enhance the activity of pembrolizumab when it is combined with. Higher lymphocyte count is an independent factor which correlates with better response to checkpoint blockade in cancer patients. Based on the MoA of GX-I7, which induces increase of T cells in both the tumor microenvironment and peripheral blood, combining GX-I7 with pembrolizumab can potentially enhance the anti-tumor effect.

Methods This is an open-label, phase 1b/2 study in patients with refractory or recurrent TNBC who failed standard chemotherapy from 1st to 3rd line treatment in metastasis setting. Patients pretreated with cyclophosphamide received GX-I7 from 360 µg/kg up to 1,440 µg/kg every 12 weeks and pembrolizumab 200 mg every 3 weeks (n=21). Patients without cyclophosphamide pretreatment received GX-I7 from 720 µg/kg up to 1,440 µg/kg every 9 weeks or 12 weeks and pemrbolizumab 200 mg every 3 weeks (n=24). The objectives were dose limiting toxicities (DLTs), safety, pharmacodynamic markers including lymphocyte increase and ORR.

Results GX-I7 and pembrolizumab were given to 45 patients (pts) (median age 50 years [29–75], ECOG PS 1 [42.2%]). 1 DLT (skin rash, Gr 3) was reported in the 1,440 µg/kg cohort. Treatment-related AEs occurred in 97.8% of pts with Gr 1–2, 15.6% with Gr 3 and 2.2% with Gr 4. Common TEAEs were injection site reaction (75.6%), rash (40.0%), pyrexia (40.0%) which were manageable. GX-I7 treatment induced up to 7-fold increase in absolute lymphocyte counts in all dose levels ranging from 360 µg/kg to 1,440 µg/kg with or without cyclophosphamide. A total of 33 evaluable mTNBC pts showed ORR of 0/3 in 360 µg/kg, 1/9 in 720 µg/kg, 2/9 in 960 µg/kg and, 4/12 in 1,200 µg/kg. Interestingly, 4 out of 6 pts received 1,200 µg/kg of GX-I7 with cyclophosphamide achieved SD and, thus, 1,200 µg/kg of GX-I7 regimens have been selected as candidates for RP2D. The tumor assessment for 1,440 µg/kg with or without cyclophosphamide is ongoing.

Conclusions GX-I7 in combination with pembrolizumab with or without cyclophosphamide was safe and well tolerated in most study participants. GX-I7 significantly increased T cell numbers in combination with pembrolizumab at doses from 360 µg/kg to 1,440 µg/kg. These results suggested GX-I7 in combination with pembrolizumab show promise as a potential treatment option for patients with metastatic TNBC.

Trial Registration ClinicalTrials. gov Identifier: NCT03752723

Ethics Approval The study was approved by the Samsung Medical Center, Gachon University Gil Medical Center, National Cancer Center, Korea University Anam Hospital, Korea University Guro Hospital, Severance Hospital, Ajou University Hospital, Seoul National University Bundang Hospital, Ewha Womans University Mokdong Hospital, Asan Medical center, Catholic Medical Center and Gangnam Severance Hospital Institutional Review Board, protocol number GX-I7-CA-006 (KEYNOTE-899).

References

1. Cortes J, Lipatov O, Im S-A. KEYNOTE-119: Phase III study of pembrolizumab (pembro) versus single-agent chemotherapy (chemo) for metastatic triple negative breast cancer (mTNBC). Ann. Oncol 2019;30:suppl 5:859–960

2. Sohn J, Park KH, Ahn HK. Preliminary safety and efficacy of GX-I7, a long-acting interleukin-7, in combination with pembrolizumab in patients with refractory or recurrent metastatic triple negative breast cancer (mTNBC): Dose escalation period of Phase Ib/II study (KEYNOTE-899). J. Clin. Oncol 2020;38:15_suppl.1072