Managing Refractory Metastatic Colorectal Cancer With Fruquintinib

Colorectal cancer (CRC) is the fourth most frequently diagnosed cancer in the United States. In 2020, the estimated number of people expected to die from the disease was 53,200.¹

Current treatments for metastatic CRC (mCRC) include fluoropyrimidine-, oxaliplatin-, and irinotecanbased chemotherapy with or without anti–vascular endothelial growth factor (VEGF) or anti–epidermal growth factor receptor (EGFR) therapies.² Other treatment approaches are available for patients with HER2 amplification, BRAF V600E mutation, and microsatellite instability–high (MSI-H) or mismatch repair–deficient (dMMR) tumors.

Patients who progress after receiving 2 lines of systemic therapy often continue to have good performance status, but subsequent treatment options are limited. In the United States, those options include regorafenib (Stivarga; Bayer) and the trifluridine and tipiracil combination (Lonsurf; Taiho Oncology).² Outside the United States, fruquintinib (Elunate; Hutchison China MediTech Limited, Eli Lilly and Company) is used as a third- or later-line therapy, but it is only authorized for use and available in China.

In June 2020, the FDA granted a fast track designation to fruquintinib for patients with mCRC who were previously treated with fluoropyrimidine-, oxaliplatin-, and irinotecanbased chemotherapy; VEGF-directed therapy; and, if RAS wild type, EGFRtargeted therapy.³ Following this announcement, recruitment began for the global phase 3 FRESCO-2 trial (NCT04322539), which aims to assess the overall survival (OS) of fruquintinib in patients with refractory mCRC.⁴

Fruquintinib is an oral, highly selective small molecule inhibitor of VEGF receptor -1, -2, and -3.⁵ Because of its kinase selectivity, the risk of off-target toxicity is lower than with multikinase inhibitors such as regorafenib. The typical dose of fruquintinib is 5 mg once daily for 21 days followed by 7 days off, in 28-day cycles.6 Doses may be taken with or without food, and following administration the maximum plasma concentration is reached in 2 to 4 hours.5 Fruquintinib has a low volume of distribution, a terminal elimination half-life of about 42 hours, and is excreted in the urine (60%) and feces (30%).

In 2018, the National Medical Products Administration of China approved fruquintinib for patients with refractory mCRC based on the results of the phase 3 FRESCO study (NCT02314819).³

In that trial, 416 patients received either fruquintinib (n = 278) or matching placebo (n = 138).⁶ At a median follow-up of 13.3 months, fruquintinib was demonstrated to have significantly prolonged OS (9.3 vs 6.6 months; HR, 0.65; 95% CI, 0.51-0.83; P < .001) and progression-free survival (3.7 vs 1.8 months; HR, 0.26; 95% CI, 0.21-0.34; P < .001). Compared with patients who received placebo, patients treated with fruquintinib also demonstrated a significantly higher objective response rate (4.7% vs 0%; P = .01) and disease control rate (62.2% vs 12.3%; P < .001).

Investigators saw at least 1 treatment-related adverse effect (AE) in 266 patients (95.7%) in the fruquintinib group and in 97 (70.8%) in the placebo group. The mean relative dose intensity was 92% and 98%, respectively.7 In the fruquintinib group, the most common treatment-related AEs were hypertension (55.4%), palmar-plantar erythrodysesthesia syndrome (also known as hand-foot skin reaction [HFSR]; 49.3%), and proteinuria (42.1%). The most common grade 3 or greater AEs were hypertension (21.2%), HFSR (10.8%), and proteinuria (3.2%); the median time to onset of these events was 10, 21, and 20 days, respectively.⁷

The FRESCO trial had the following limitations:⁶

1. Only Chinese patients were enrolled in the study.
2. Only one-third of patients had received prior treatment with anti-VEGF or anti-EGFR antibodies.
3. No patient had received prior treatment with regorafenib or trifluridine/tipiracil.
4. MSI status was not defined.

The global FRESCO-2 trial, which will address these limitations, is a randomized (2:1 ratio), double-blind study comparing the efficacy and safety of fruquintinib vs placebo.⁴ Investigators aim to enroll 520 patients who have progressed on or had resistance to chemotherapy, biologics, and trifluridine/tipiracil or regorafenib. For patients whose tumors are MSI-H or dMMR, progression on an immune checkpoint inhibitor is also required. Eligible patients must be at least age 18 years with good performance status and histologically or cytologically documented mCRC.4 Patients must also have documented RAS, BRAF, MSI, or MMR status.

Patients with uncontrolled hypertension, a history of or active gastric or duodenal ulcer, ulcerative colitis, or active hemorrhaging of an unresected gastrointestinal tumor will be excluded. Additional exclusion criteria include patients with an absolute neutrophil count of less than 1.5 x 109/L, a platelet count of less than 100 x 109/L, and a hemoglobin level of less than 9.0 g/dL.

The projected completion date for FRESCO-2 is July 2022.

KELLY M. BRUNK, PHARMD, BCOP, is a clinical oncology pharmacist at The University of Kansas Cancer Center in Kansas City. He received his doctor of pharmacy degree from the University of Kansas School of Pharmacy in Lawrence. He is an active member of the American Society of Health-System Pharmacists and the Hematology/Oncology Pharmacy Association.

REFERENCES

1. Cancer stat facts: colorectal cancer. National Cancer Institute. Accessed December 14, 2020. https://seer.cancer.gov/statfacts/html/colorect.html
2. Chiorean EG, Nandakumar G, Fadelu T, et al. Treatment of patients with latestage colorectal cancer: ASCO Resource-Stratified Guideline. JCO Glob Oncol. 2020;6:414-438. doi:10.1200/JGO.19.00367
3. Chi-Med announces fruquintinib granted U.S. FDA fast track designation for metastatic colorectal cancer. GlobeNewswire. June 18, 2020. Accessed March 1, 2021. https://www.globenewswire.com/news-release/2020/06/18/2049893/0/en/Chi-Med-Announces-Fruquintinib-Granted-U-S-FDA-Fast-Track-Designation-for-Metastatic-Colorectal-Cancer.html
4. A study of efficacy and safety of fruquintinib (HMPL-013) in patients with metastatic colorectal cancer (FRESCO-2). ClinicalTrials.gov. Updated September 14, 2020. Accessed December 14, 2020. https://clinicaltrials.gov/ct2/show/NCT04322539
5. Shirley M. Fruquintinib: first global approval. Drugs. 2018;78(16):1757-1761. doi:10.1007/s40265-018-0998-z
6. Li J, Qin S, Xu RH, et al. Effect of fruquintinib vs placebo on overall survival in patients with previously treated metastatic colorectal cancer: the FRESCO randomized clinical trial. JAMA. 2018;319(24):2486-2496. doi:10.1001/jama.2018.7855
7. Li J, Guo W, Bai Y, et al. Safety profile and adverse events of special interest for fruquintinib in Chinese patients with previously treated metastatic colorectal cancer: analysis of the phase 3 FRESCO trial. Adv Ther. 2020;37(11):4585-4598. doi:10.1007/s12325-020-01477-w