• CX-072 (pacmilimab), a Probody (®) PD-L1 inhibitor, in advanced or recurrent solid tumors (PROCLAIM-CX-072): an open-label dose-finding and first-in-human study

      Naing, A.; Thistlethwaite, Fiona C; De Vries, E. G. E.; Eskens, F.; Uboha, N.; Ott, P. A.; LoRusso, P.; Garcia-Corbacho, J.; Boni, V.; Bendell, J.; et al. (2021)
      Background: Probody® therapeutics are antibody prodrugs that are activated in the tumor microenvironment by tumor-associated proteases, thereby restricting the activity to the tumor microenvironment and minimizing 'off-tumor' toxicity. We report dose-escalation and single-agent expansion phase data from the first-in-human study of CX-072 (pacmilimab), a Probody checkpoint inhibitor directed against programmed death-ligand 1 (PD-L1). Methods: In the dose-escalation phase of this multicenter, open-label study (NCT03013491), adults with advanced solid tumors (naive to programmed-death-1/PD-L1 or cytotoxic T-lymphocyte-associated antigen 4 inhibitors) were enrolled into one of seven dose-escalation cohorts, with pacmilimab administered intravenously every 14 days. The primary endpoints were safety and determination of the maximum tolerated dose (MTD). In the expansion phase, patients with one of six prespecified malignancies (triple-negative breast cancer [TNBC]; anal squamous cell carcinoma [aSCC]; cutaneous SCC [cSCC]; undifferentiated pleomorphic sarcoma [UPS]; small bowel adenocarcinoma [SBA]; and thymic epithelial tumor [TET]); or high tumor mutational burden (hTMB) tumors were enrolled. The primary endpoint was objective response (Response Evaluation Criteria In Solid Tumors v.1.1). Results: An MTD was not reached with doses up to 30 mg/kg. A recommended phase 2 dose (RP2D) of 10 mg/kg was chosen based on pharmacokinetic and pharmacodynamic findings in the expansion phase. Ninety-eight patients enrolled in the expansion phase: TNBC (n=14), aSCC (n=14), cSCC (n=14), UPS (n=20), SBA (n=14), TET (n=8), and hTMB tumors (n=14). Of 114 patients receiving pacmilimab at the RP2D, grade ≥3 treatment-related adverse events (TRAEs) were reported in 10 patients (9%), serious TRAEs in six patients (5%), and treatment discontinuation due to TRAEs in two patients (2%). Grade ≥3 immune-related AEs occurred in two patients (rash, myocarditis). High PD-L1 expression (ie, >50% Tumor Proportion Score) was observed in 22/144 (19%) patients. Confirmed objective responses were observed in patients with cSCC (n=5, including one complete response), hTMB (n=4, including one complete response), aSCC (n=2), TNBC (n=1), UPS (n=1), and anaplastic thyroid cancer (n=1). Conclusions: Pacmilimab can be administered safely at the RP2D of 10 mg/kg every 14 days. At this dose, pacmilimab had a low rate of immune-mediated toxicity and showed signs of antitumor activity in patients not selected for high PD-L1 expression.
    • Efficacy, safety, and quality of life (QoL) with futibatinib in patients (pts) with intrahepatic cholangiocarcinoma (iCCA) harboring FGFR2 fusions/rearrangements: FOENIX-CCA2

      Furuse, J.; Goyal, L.; Meric-Bernstam, F.; Hollebecque, A.; Valle, Juan W; Morizane, C.; Karasic, T. B.; Abrams, T. A.; Kelley, R. K.; Cassier, P. A.; et al. (2020)
      Background: iCCA has a poor prognosis and its incidence is higher in Asian vs Western countries. Futibatinib is an oral, highly selective, irreversible FGFR1e4 inhibitor that demonstrated safety and preliminary efficacy in pts with iCCA harboring FGFR2 aberrations. This study evaluated safety, efficacy, and QoL with futibatinib treatment in pts with iCCA and FGFR2 fusions/rearrangements. Methods: FOENIX-CCA2 (NCT02052778), a global phase II study, enrolled pts with unresectable/metastatic iCCA harboring an FGFR2 fusion/rearrangement and disease progression after 1 line of systemic therapy (including gemcitabineecisplatin) but no prior FGFR inhibitors. Pts received futibatinib 20 mg once daily until disease progression/ intolerability. The primary endpoint was objective response rate (ORR) per independent central radiology review and RECIST v1.1; secondary endpoints were disease control rate (DCR), duration of response (DOR), progression-free survival (PFS), safety, and patient-reported outcomes (PROs). ORRs of subgroups by baseline demographic, fusion partner, and other molecular alteration (eg, TP53) were also determined. Results: Of 103 enrolled pts, planned interim data are reported for 67 pts (54% white, 24% Asian) with 6mo of follow-up; 55% of pts received 2 prior therapy lines, and 82% had tumors harboring an FGFR2 fusion (BICC1, n¼15). ORR was 37.3%, DCR was 82.1%, and median DOR was 8.3 mo. Objective responses occurred regardless of baseline characteristic (subgroup: 65 y, ORR: 57.1%), FGFR2 fusion partner (BICC1, 33.3%), or other genetic mutation (TP53, 16.7%). Median PFS was 7.2 mo. The most common treatment-related adverse events (TRAEs; any grade/grade 3) were hyperphosphatemia (81%/27%), diarrhea (37%/0%), and dry mouth (33%/0%); no grade 4e5 TRAEs occurred. TRAEs were managed with dose interruption/reduction (55%/51%); only 1 pt discontinued due to a TRAE. PROs were stable through 273 days (13 cycles) of treatment. Conclusions: Futibatinib resulted in durable objective responses in pts with iCCA and FGFR2 fusions/rearrangements, including within pt subgroups. Adverse events were manageable, and QoL was maintained.