Effective treatment options are limited for patients (pts) with refractory metastatic colorectal cancer (mCRC).

Fruquintinib (F), a highly selective, potent, oral tyrosine kinase inhibitor of VEGFR-1, -2, and -3, was approved in China in the 3L+ mCRC setting based on results from the FRESCO trial (NCT02314819).

FRESCO-2 (NCT04322539) evaluated F in more heavily pre-treated pts reflecting current global practices.

FRESCO-2 was a randomized, double-blind, placebo (P)-controlled, phase 3 MRCT conducted in the US, Europe, Japan & Australia, comparing F + best supportive care (BSC) with P + BSC.

F or P was given 5 mg PO, QD, 3 wks on, 1 wk off, in 28-d cycles.

Key criteria: Prior chemotherapy, anti-VEGF therapy, and, if RAS wild type (WT), anti-EGFR therapy; if BRAFV600E mutant (MT) or MSI-H, ≥1 targeted regimen; & prior exposure to trifluridine/tipiracil (T) and/or regorafenib (R).

Pts were randomized 2:1 to F + BSC or P + BSC and stratified by: prior therapy T, R or both; RAS status (WT, MT) & duration of metastatic disease (≤18, >18 months [m]).

The primary endpoint was overall survival (OS). Key secondary endpoints were progression-free survival (PFS), objective response rate (ORR), disease control rate (DCR) & safety. Final analysis was after 480 OS events.

From 2Sep2020 to 14Dec2021, 691 pts were randomized; F:461 vs P:230. Baseline characteristics were balanced.

F significantly improved OS (median: 7.4 m vs 4.8 m P; HR=0.66; [95% CI: 0.55, 0.80]; p<0.001) & PFS (median: 3.7 m vs 1.8 m P; HR=0.32; [95% CI: 0.27, 0.39]; p<0.001).

The median duration of follow-up was 11.3 m F vs 11.2 m P.

Subsequent anti-cancer therapies were 29.4% F vs 34.3% P. DCR was 55.5% F vs 16.1% P & ORR was 1.5% F vs 0% P.

Grade ≥3 adverse events were 62.7% F vs 50.4% P; those occurring in ≥5% on F were hypertension (13.6% vs 0.9% P), asthenia (7.7% vs 3.9% P) & hand-foot syndrome (6.4% vs 0% P).

F had a significant and clinically meaningful improvement in OS in pts with refractory mCRC.

F was well tolerated, with a safety profile consistent with the established profile for F monotherapy.

FRESCO-2 results are consistent with FRESCO and should support a new treatment option in refractory mCRC.

Dasari NA, Lonardi S, Garcia-Carbonero R et al. FRESCO-2: A Global Phase 3 Multiregional Clinical Trial Evaluating the Efficacy and Safety of Fruquintinib in Patients With Refractory Metastatic Colorectal Cancer. Abstract presented at: ESMO Congress 2022, September 9-13, 2022.

Funding supported by Takeda Oncology. Content independently developed by OncLive®.

Videos

Arvind Dasari, MD, MS, presents data from the FRESCO-2 clinical trial evaluating fruquintinib in patients with refractory metastatic colorectal cancer, and provides insights on the clinical implications of the results.

FRESCO-2: A Global Phase 3 Multiregional Clinical Trial Evaluating the Efficacy and Safety of Fruquintinib in Patients With Refractory Metastatic Colorectal Cancer

Nageshwara Arvind Dasari, MD, associate professor, the Department of Gastrointestinal Medical Oncology, the Division of Cancer Medicine, the University of Texas MD Anderson Cancer Center, discusses the patient population observed in the phase 3 FRESCO-2 trial (NCT04322539) in metastatic colorectal cancer (mCRC).

The global, randomized, placebo-controlled FRESCO-2 trial randomly assigned patients 2:1 to received fruquintinib (Elunate) vs placebo, Dasari says. Fruquintinib was dosed at 5 mg daily for 3-weeks-on/1-week-off schedule, and both arms received best supportive care, Dasari adds. The primary end point of the trial was overall survival. Progression-free survival served as a key secondary end point, and other secondary end points included objective response rate, disease control rate, and safety, Dasari continues.

Heavily pretreated patients with mCRC who progressed on all available therapies, including chemotherapy, targeted therapies, trifluridine/tipiracil (TAS-102; Lonsurf), and regorafenib (Stivarga), were enrolled on the study, Dasari explains.

Nageshwara Arvind Dasari, MD, discusses the patient population observed in the phase 3 FRESCO-2 trial in metastatic colorectal cancer.


Dr. Dasari on the Investigation of Fruquintinib in mCRC

Circulating tumor DNA (ctDNA)–based molecular residual disease has the potential to select patients who may benefit more from standard-of-care adjuvant chemotherapy by accurately assessing recurrence-risk post-surgery and by evaluating adjuvant colon cancer therapy (ACT) efficacy.

CIRCULATE-Japan project is a large platform enrolling patients with clinical stage II–IV resectable colorectal cancer (CRC) to evaluate the clinical utility of ctDNA minimal residual disease analysis. The study comprises 1 observational (GALAXY study) and 2 randomized phase 3 trials (VEGA and ALTAIR trials).

The GALAXY study utilizes a personalized, tumor-informed ctDNA assay (Signatera bespoke multiplex polymerase chain reaction next-generation sequencing) based on whole-exome sequencing of tumor tissue and matched normal sample.

The blood samples are collected before surgery and 4, 12, 24, 36, 48, 72, and 96 weeks after surgery.

Investigators can receive the results of the ctDNA assay in a timely manner and consider patients for enrollment in associated interventional phase 3 trials, such as VEGA and ALTAIR.

Association of ctDNA dynamics with a short-term clinical outcome and ACT efficacy are being investigated.

Patients enrolled in VEGA and ALTAIR trials were excluded from this analysis.

Even with an extended follow-up time, post-op 4-week positivity was significantly associated with inferior disease-free survival (DFS), consistent with previous results.

6- and 12-month DFS rates by ctDNA dynamics from post-op 4 to 12 weeks were significantly different between “positive to negative” and “positive to positive” groups with a hazard ratio of 15.8.

Among post-op 4-week ctDNA-positive patients, ACT was able to clear ctDNA in 68% of ctDNA-positive patients by post-op 24 weeks, and a 6-month DFS rate was significantly higher in patients with ACT vs without ACT across all stages.

2 of 3 post-op 4-week ctDNA-positive patients even with stage I or low-risk stage II recurred.

Patients who were post-op 4-week ctDNA-negative patients did not derive significant benefit from ACT, with an HR of 1.3 in high-risk stage II and III.

This study shows that stratifying postsurgical treatment decisions using the assay can identify patients likely to benefit from ACT across all stages.

ctDNA dynamics from post-op 4-week ctDNA-positive to 12 weeks could become a new surrogate end point beyond DFS.

ctDNA-guided adjuvant strategy will further be established by ongoing randomized VEGA and ALTAIR studies and will be presented at future conferences.

Insight on the observational GALAXY study, which analyzed the relationship between circulating tumor DNA and clinical outcomes in the adjuvant management of colorectal cancer. 

Rapid Readout: ctDNA Dynamics and Clinical Outcomes in the Adjuvant Management of Colorectal Cancer (GALAXY Study)

Nageshwara Arvind Dasari, MD, an associate professor in the Department of Gastrointestinal Medical Oncology, Division of Cancer Medicine at The University of Texas MD Anderson Cancer Center, discusses the eligibility criteria for the phase 3 FRESCO-2 trial (NCT04322539), which examined the use of fruquintinib in patients with metastatic colorectal cancer (CRC).

Patients who have documented advanced CRC who have previously received treatment with fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy, in addition to an anti-VEGF agent, will be included on the FRESCO-2 trial, according to Dasari. If a patient had 

 wild-type disease, they should have received a prior anti-EGFR therapy, while those who are microsatellite instability high should have received immunotherapy and those with 

-mutant disease needed to have received a BRAF-targeted agent, Dasari explains.

Additionally, in order to enroll on the study, patients needed to have experienced progression on, or intolerance to, trifluridine and tipiracil (Lonsurf) and/or regorafenib (Stivarga), Dasari concludes.

Nageshwara Arvind Dasari, MD, discusses the eligibility criteria for the phase 3 FRESCO-2 trial, which examined the use of fruquintinib in patients with metastatic colorectal cancer.

Dr. Dasari on Eligibility Criteria for the FRESCO-2 trial With Fruquintinib in CRC

Nageshwara Arvind Dasari, MD, associate professor, Department of Gastrointestinal Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, discusses the rationale to evaluate fruquintinib (Elunate) in the ongoing, phase 3 FRESCO-2 trial (NCT04322539) in patients with metastatic colorectal cancer (mCRC). 

Fruquintinib is a potent, highly selective, oral VEGF1/2/3 TKI, says Dasari. The drug was initially developed in China, where it is currently approved to treat patients with mCRC who have been previously treated with fluoropyrimidine, oxaliplatin, and irinotecan.

The regulatory decision, made by the China National Medical Products Administration, was based on findings from the placebo-controlled, phase 3 FRESCO trial, Dasari explains. The pivotal study showed a statistically significant improvement in overall survival and progression-free survival with fruquintinib compared with placebo in previously treated patients with mCRC.

In the United States, the FDA granted a fast track designation to fruquintinib for the treatment of patients with mCRC who have received prior fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy, VEGF-directed therapy, and if 

 wild-type, EGFR-directed therapy. The agent is currently being evaluated in the ongoing FRESCO-2 trial in patients with mCRC from the United States, Europe, and Japan.

Nageshwara Arvind Dasari, MD, discusses the rationale to evaluate fruquintinib in the ongoing, phase 3 FRESCO-2 trial in patients with metastatic colorectal cancer.  



Dr. Dasari on the Rationale for the FRESCO-2 Trial With Fruquintinib in mCRC 

Nageshwara Arvind Dasari, MD, associate professor, Department of Gastrointestinal Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, discusses the potential clinical implications with fruquintinib (Elunate) in metastatic colorectal cancer (mCRC). 

Results of the ongoing phase 3 FRESCO-2 trial (NCT04322539), which was presented virtually during the 2021 Gastrointestinal Cancers Symposium, is evaluating the efficacy and safety of fruquintinib, an investigational oral VEGF TKI, versus placebo in patients with mCRC. 

Currently, patients with relapsed/refractory mCRC have limited treatment options following progression, says Dasari. Although it is early, fruquintinib could provide patients who progress on later-line therapies, such as TAS-102 (trifluridine/tipiracil; Lonsurf) or regorafenib (Stivarga) with an additional option. Although the trial is still enrolling, Dasari is hopeful that the data will demonstrate an improvement in overall survival with fruquintinib compared with placebo. Additionally, the phase 3 data could echo previously reported safety findings with fruquintinib, which suggest the agent is well tolerated among this patient population. If so, combination regimens with fruquintinib could be on the horizon, concludes Dasari. 

Nageshwara Arvind Dasari, MD, discusses the potential clinical implications with fruquintinib in metastatic colorectal cancer.  



N. Arvind Dasari, MD, MS

Articles

FRESCO-2: A Global Phase 3 Multiregional Clinical Trial Evaluating the Efficacy and Safety of Fruquintinib in Patients With Refractory Metastatic Colorectal Cancer

Dr. Dasari on the Investigation of Fruquintinib in mCRC

Rapid Readout: ctDNA Dynamics and Clinical Outcomes in the Adjuvant Management of Colorectal Cancer (GALAXY Study)

Dr. Dasari on Eligibility Criteria for the FRESCO-2 trial With Fruquintinib in CRC

Dr. Dasari on the Rationale for the FRESCO-2 Trial With Fruquintinib in mCRC

Dr. Dasari on the Potential Clinical Implications of Fruquintinib in mCRC