Analysis of fruquintinib adverse events of special interest from phase 3 of the FRESCO-2 study

3601 Background: Fruquintinib (F) is a highly selective and potent inhibitor of VEGFRs-1, -2 & -3 designed with improved kinase selectivity to minimize potential off-target toxicities. In the phase 3 FRESCO-2 study (NCT04322539), F demonstrated a statistically significant improvement vs placebo (P) in overall survival (hazard ratio, HR = 0.66) and progression-free survival (HR = 0.32), with a manageable toxicity profile and without deterioration in quality of life in heavily pre-treated patients (pts) with metastatic colorectal cancer (mCRC). Here we report the treatment-emergent adverse events of special interest (AESI). Methods: FRESCO-2 was a double-blind, P-controlled multiregional study with 2:1 randomization to F + best supportive care (BSC) or P + BSC. F or P was given 5 mg PO, QD, 3 weeks (w) on, 1 w off, in a 28-day (d) cycle. AEs were coded using MedDRA v25.0 and graded (G) by NCI-CTCAE v5.0. Clinically relevant class toxicities were grouped into respective AESI categories. Results: The safety population had 686 pts (F: 456 vs P: 230); 47% were ≥ 65 yrs, 56.9%/43.1% with ECOG 1/0, 71.6% with hepatic metastases, and 50.5% with medical history of hypertension (HTN) at baseline. The median number of prior lines of anti-cancer treatment for metastatic disease F vs P was 4 (2, 16) vs 4 (2, 12); 96.4% with prior anti-VEGF agent; 91.6% with prior TAS-102; and 47.8% with prior regorafenib. Median duration of exposure was longer with F 3.06 months (m) (range, 1.84-5.5) vs P 1.84 m (range, 0.95-2.27). 368 pts (80.7%) on F and 122 pts (53.0%) on P had an AESI. The most frequent AESIs (all G) in ≥ 25% of pts (F vs P) were HTN (38.4% vs 8.7%), dermatological toxicity (34.4% vs 11.7%), and thyroid dysfunction (27.0% vs 1.7%). G ≥ 3 AESIs in ≥ 5% of pts in the F vs P, were HTN (14.0% vs 0.9%), hepatic function abnormal (8.3% vs 9.1%), dermatological toxicity (6.8% vs 0.4%), and infections (6.6% vs 5.7%). AESIs (F vs P) that led to dose reductions (DR) occurred in 13.6% vs 0.9% of pts, drug discontinuation (DD) in 8.3% vs 6.1% of pts. AESIs leading to death were 1.8% vs 1.3% of pts, with infections (1.1% vs 0.4%) being most common. The median time to first occurrence of HTN AESI was in cycle (C) 1, with hypertension (96%) being the most common AE reported. In pts with HTN AESI, 9.7% vs 0.6% had dose reduction (DR) and 1.7% vs 0% had DD. The median time to first occurrence of dermatological toxicity was C1, with palmar plantar erythrodysesthesia (PPE) being most common AE reported (56.1%); 27.3% vs 0% had DR and 3.4% vs 0% had DD. The median time to first occurrence of thyroid dysfunction was C2, with hypothyroidism (76.4%) being most common and none with DR or DD. Conclusions: F was well tolerated in heavily pretreated pts and despite underlying medical conditions. AESIs including HTN, PPE and thyroid dysfunction were manageable with low rates of dose reductions and dose discontinuation, which further supports F as a potential safe and new treatment option for refractory mCRC. Clinical trial information: NCT04322539 .