Cancer Res Treat.  2024 Apr;56(2):590-601. 10.4143/crt.2023.1117.

A Phase 1b/2a Study of GC1118 with 5-Fluorouracil, Leucovorin and Irinotecan (FOLFIRI) in Patients with Recurrent or Metastatic Colorectal Cancer

• Lee KW
• Han SW
• Kim TW
• Ahn JB
• Baek JY
• Cho SH
• Lee H
• Kim JW
• Kim JW
• Kim TY
• Hong YS
• Beom SH
• Cha Y
• Choi Y
• Kim S
• Bang YJ

• KMID: 2554348
• DOI: http://doi.org/10.4143/crt.2023.1117

Abstract

Purpose
GC1118 is a novel antibody targeting epidermal growth factor receptor (EGFR) with enhanced blocking activity against both low- and high-affinity EGFR ligands. A phase 1b/2a study was conducted to determine a recommended phase 2 dose (RP2D) of GC1118 in combination with 5-fluorouracil, leucovorin, and irinotecan (FOLFIRI) (phase 1b) and to assess the safety and efficacy of GC1118 plus FOLFIRI as a second-line therapy for recurrent/metastatic colorectal cancer (CRC) (phase 2a).
Materials and Methods
Phase 1b was designed as a standard 3+3 dose-escalation study with a starting dose of GC1118 (3 mg/kg/week) in combination with biweekly FOLFIRI (irinotecan 180 mg/m²; leucovorin 400 mg/m²; 5-fluorouracil 400 mg/m² bolus and 2,400 mg/m² infusion over 46 hours) in patients with solid tumors refractory to standard treatments. The subsequent phase 2a part was conducted with objective response rate (ORR) as a primary endpoint. Patients with KRAS/NRAS/BRAF wild-type, EGFR-positive, recurrent/metastatic CRC resistant to the first-line treatment were enrolled in the phase 2a study.
Results
RP2D of GC1118 was determined to be 3 mg/kg/wk in the phase 1b study (n=7). Common adverse drug reactions (ADRs) observed in the phase 2a study (n=24) were acneiform rash (95.8%), dry skin (66.7%), paronychia (58.3%), and stomatitis (50.0%). The most common ADR of ≥ grade 3 was neutropenia (33.3%). ORR was 42.5% (95% confidence interval [CI], 23.5 to 62.0), and median progression-free survival was 6.7 months (95% CI, 4.0-8.0).
Conclusion
GC1118 administered weekly at 3 mg/kg in combination with FOLFIRI appears as an effective and safe treatment option in recurrent/metastatic CRC.

Keyword

GC1118; Colorectal neoplasms; ErbB receptors; Monoclonal antibody; Irinotecan; FOLFIRI

Figure

• 

  Fig. 1. Study scheme. (A) The dose escalation phase of the phase 1b study followed a 3+3 design. A red circle indicates a patient with dose-limiting toxicity, which was grade 4 neutropenia that lasted ≥ 7 days. (B) Phase 2a study was conducted following Simon’s optimal two-stage design. DMC, data monitoring committee; FOLFIRI, 5-fluorouracil, leucovorin, and irinotecan; ORR, objective response rate; RP2D, recommended phase 2 dose.

• 

  Fig. 2. Waterfall plots showing individual patient’s maximum percent change in tumor size from baseline in phase 1b (A) and phase 2a (B). CR, complete response; NE, not evaluable; PD, progressive disease; PFS, progression-free survival; PR, partial response; SD, stable disease; SLD, the sum of the longest diameter of target lesions. Each dashed line above and below 0 indicates a 20% increase and a 30% decrease in SLD from baseline, respectively.

• 

  Fig. 3. Kaplan-Meier curves of progression-free survival (A) and overall survival (B) from phase 2a. CI, confidence interval; NR, not reached.

Reference

References

1. Baidoun F, Elshiwy K, Elkeraie Y, Merjaneh Z, Khoudari G, Sarmini MT, et al. Colorectal cancer epidemiology: recent trends and impact on outcomes. Curr Drug Targets. 2021; 22:998–1009.

2. Ferlay J, Colombet M, Soerjomataram I, Parkin DM, Pineros M, Znaor A, et al. Cancer statistics for the year 2020: an overview. Int J Cancer. 2021; 149:778–89.

3. Biller LH, Schrag D. Diagnosis and treatment of metastatic colorectal cancer: a review. JAMA. 2021; 325:669–85.

4. Martinelli E, De Palma R, Orditura M, De Vita F, Ciardiello F. Anti-epidermal growth factor receptor monoclonal antibodies in cancer therapy. Clin Exp Immunol. 2009; 158:1–9.

5. Yewale C, Baradia D, Vhora I, Patil S, Misra A. Epidermal growth factor receptor targeting in cancer: a review of trends and strategies. Biomaterials. 2013; 34:8690–707.

6. Messersmith WA, Ahnen DJ. Targeting EGFR in colorectal cancer. N Engl J Med. 2008; 359:1834–6.

7. Bronte G, Silvestris N, Castiglia M, Galvano A, Passiglia F, Sortino G, et al. New findings on primary and acquired resistance to anti-EGFR therapy in metastatic colorectal cancer: do all roads lead to RAS? Oncotarget. 2015; 6:24780–96.

8. Zhou J, Ji Q, Li Q. Resistance to anti-EGFR therapies in metastatic colorectal cancer: underlying mechanisms and reversal strategies. J Exp Clin Cancer Res. 2021; 40:328.

9. Lim Y, Yoo J, Kim MS, Hur M, Lee EH, Hur HS, et al. GC1118, an Anti-EGFR antibody with a distinct binding epitope and superior inhibitory activity against high-affinity EGFR ligands. Mol Cancer Ther. 2016; 15:251–63.

10. Park WS, Han S, Lee J, Hong T, Won J, Lim Y, et al. Use of a target-mediated drug disposition model to predict the human pharmacokinetics and target occupancy of GC1118, an antiepidermal growth factor receptor antibody. Basic Clin Pharmacol Toxicol. 2017; 120:243–9.

11. Park JE, Jin MH, Hur M, Nam AR, Bang JH, Won J, et al. GC1118, a novel anti-EGFR antibody, has potent KRAS mutation-independent antitumor activity compared with cetuximab in gastric cancer. Gastric Cancer. 2019; 22:932–40.

12. Lee HW, Son E, Lee K, Lee Y, Kim Y, Lee JC, et al. Promising therapeutic efficacy of GC1118, an anti-EGFR antibody, against KRAS mutation-driven colorectal cancer patient-derived xenografts. Int J Mol Sci. 2019; 20:5894.

13. Lee K, Koo H, Kim Y, Kim D, Son E, Yang H, et al. Therapeutic efficacy of GC1118, a novel anti-EGFR antibody, against glioblastoma with high EGFR amplification in patient-derived xenografts. Cancers (Basel). 2020; 12:3210.

14. Oh DY, Lee KW, Han SW, Kim JW, Shin JW, Jo SJ, et al. A first-in-human phase I study of GC1118, a novel anti-epidermal growth factor receptor antibody, in patients with advanced solid tumors. Oncologist. 2019; 24:1037–e636.

15. Simon R. Optimal two-stage designs for phase II clinical trials. Control Clin Trials. 1989; 10:1–10.

16. Peeters M, Price TJ, Cervantes A, Sobrero AF, Ducreux M, Hotko Y, et al. Randomized phase III study of panitumumab with fluorouracil, leucovorin, and irinotecan (FOLFIRI) compared with FOLFIRI alone as second-line treatment in patients with metastatic colorectal cancer. J Clin Oncol. 2010; 28:4706–13.

17. Hecht JR, Cohn A, Dakhil S, Saleh M, Piperdi B, Cline-Burkhardt M, et al. SPIRITT: a randomized, multicenter, phase II study of panitumumab with FOLFIRI and bevacizumab with FOLFIRI as second-line treatment in patients with unresectable wild type KRAS metastatic colorectal cancer. Clin Colorectal Cancer. 2015; 14:72–80.

18. Chung TK, Lee HA, Park SI, Oh DY, Lee KW, Kim JW, et al. A target-mediated drug disposition population pharmacokinetic model of GC1118, a novel anti-EGFR antibody, in patients with solid tumors. Clin Transl Sci. 2021; 14:990–1001.