Abstract
On November 8, 2023, the FDA approved fruquintinib, an inhibitor of vascular endothelial growth factor receptors (VEGFR)-1, −2, and −3, for the treatment of patients with metastatic colorectal cancer (mCRC) who have been previously treated with fluoropyrimidine‑, oxaliplatin‑, and irinotecan‑based chemotherapy, an anti‑VEGF therapy, and, if RAS wild‑type and medically appropriate, an anti EGFR therapy. Approval was based on Study FRESCO-2, a globally-conducted, double-blind, placebo-controlled randomized trial. The primary endpoint was overall survival (OS). The key secondary endpoint was progression-free survival (PFS). A total of 691 patients were randomized (461 and 230 into the fruquintinib and placebo arms, respectively). Fruquintinib provided a statistically significant improvement in OS with a hazard ratio (HR) of 0.66 (95% CI: 0.55, 0.80; p<0.001). The median OS was 7.4 months (95% CI: 6.7, 8.2) in the fruquintinib arm and 4.8 months (95% CI: 4.0, 5.8) for the placebo arm. Adverse events observed were generally consistent with the known safety profile associated with inhibition of the VEGFR. The results of FRESCO-2 were supported by the FRESCO study, a double-blind, single country, placebo-controlled, randomized trial in patients with refractory mCRC who have been previously treated with fluoropyrimidine‑, oxaliplatin‑, and irinotecan‑based chemotherapy. In FRESCO, the OS HR was 0.65 (95% CI: 0.51, 0.83; p<0.001). FDA concluded that the totality of the evidence from FRESCO-2 and FRESCO supported an indication for patients with mCRC with prior treatment with fluoropyrimidine, oxaliplatin-, and irinotecan-based chemotherapy, an anti-VEGF biological therapy, and if RAS wild‑type and medically appropriate, an anti-EGFR therapy.
Introduction
Colorectal cancer (CRC) is the fourth most common cancer and the second most common cause of cancer mortality in the United States. In 2024, approximately 152,810 people in the U.S. were diagnosed with CRC and 53,010 will die from the disease (1). There is both a higher incidence and higher mortality from CRC in both American Indian/Alaskan American (AI/AN; 48.6 and 18.6 per 100,000, respectively) and Non-Hispanic Black (NHB; 41.7 and 17.6 per 100,000, respectively) populations relative to the overall population of patients with CRC (35.9 and 13.1 per 100,000) (2). In the United States, over the last few decades, there has been a decrease in the incidence of later-onset colorectal cancer (those diagnosed in patients ≥ 50 years old) and an increase in the incidence of early-onset colorectal cancer (those diagnosed in patients < 50 years old) (3).
Standard of care for first- and second line treatment for patients with unresectable or metastatic disease includes combination chemotherapy with a fluoropyrimidine, oxaliplatin, and/or irinotecan. Biologics targeting the vascular endothelial growth factor (VEGF) pathway, including bevacizumab products, ramucirumab, and ziv-aflibercept are generally administered in combination with chemotherapy. For patients with tumors that are RAS wild-type, antibodies targeting the endothelial growth factor receptor (EGFR) pathway (cetuximab and panitumumab) are available in combination with chemotherapy or as single agents in the refractory setting if the antibodies were not previously used. In addition, targeted therapies are available for patients with microsatellite instability-high (MSI-H) or BRAF V600E-mutated tumors. In the refractory setting, trifluridine/tipiracil (with or without a bevacizumab product) or regorafenib are both approved for patients with metastatic CRC who have been previously treated with fluoropyrimidine-, oxaliplatin- and irinotecan-based chemotherapy, an anti-VEGF biological therapy, and if RAS wild-type, an anti-EGFR therapy (4,5). Under accelerated approval, patients with HER2-positive tumors may receive treatment with the combination of anti-HER2 agents tucatinib and trastuzumab.
This article summarizes the FDA’s review of the marketing application for fruquintinib for the treatment of adults with metastatic colorectal cancer (mCRC) who have been previously treated with fluoropyrimidine‑, oxaliplatin‑, and irinotecan‑based chemotherapy, an anti‑VEGF therapy, and, if RAS wild‑type and medically appropriate, an anti EGFR therapy. Results of these studies have been previously published (6,7).
Mechanism of Action
Fruquintinib inhibits the vascular endothelial growth factor receptors (VEGFR)-1, −2, and −3. VEGFR signaling is implicated in tumor angiogenesis, growth, and progression in a variety of solid tumors. The established pharmacologic class for fruquintinib is kinase inhibitor. When evaluated using a [32P-ATP] incorporation assay, fruquintinib inhibited VEGFR-1, −2, and −3 with half maximal inhibitory concentrations (IC50s) of 33, 35, and 0.5 nM, respectively. This assay also showed that fruquintinib moderately inhibited RET and FGFR1 with IC50s of 128 and 181 nM, respectively.
Clinical Pharmacology
The FDA reviewed subject-level pharmacokinetic data collected from the pivotal trial and several other studies to characterize pharmacokinetics, food effect, and drug–drug interactions. Following oral administration, median time to peak fruquintinib plasma concentration was 2 hours. Fruquintinib mean elimination half-life was 42 hours. Steady-state plasma levels were reached within 14 days. A single-dose food effect study in healthy subjects indicated that a high-fat meal had no effect on the mean peak plasma concentration of fruquintinib. No clinically meaningful effects on pharmacokinetics were observed on the basis of age, sex, race, body weight, mild or moderate renal impairment, or mild hepatic impairment. The pharmacokinetics of fruquintinib in patients with severe renal impairment or severe hepatic impairment has not been studied. Fruquintinib is not recommended for use in patients with severe hepatic impairment due to hepatotoxicity. No dosage modifications are recommended for patients with renal impairment as renal excretion is not a major excretion pathway of fruquintinib.
Fruquintinib is metabolized by CYP450 and non-CYP450 (i.e., sulfation and glucuronidation) pathways. Concomitant use of strong or moderate CYP3A4 inducers will decrease fruquintinib plasma concentrations. No clinically significant differences in fruquintinib pharmacokinetics were observed when used concomitantly with strong CYP3A inhibitors or proton pump inhibitors. No clinically significant differences in the pharmacokinetics of P-gp or BCRP substrates were observed when used concomitantly with fruquintinib.
Clinical Trial Design
Two randomized, double-blind, placebo-controlled clinical trials, along with a safety database of patients exposed to fruquintinib across multiple studies were submitted to support the approval of fruquintinib in the United States. Study 2019–013-GLOB1 (FRESCO-2) was considered to be the pivotal study and Study 2013–013-00CH1 (FRESCO) was considered supportive.
FRESCO-2 was a multiregional, double-blind, placebo-controlled randomized trial in patients with mCRC who had been previously treated with fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy, an anti-VEGF biological therapy, and in the refractory setting, regorafenib and/or tipiracil/trifluridine. In addition, to be eligible, patients for whom targeted therapy with anti-EGFR antibodies, immune checkpoint inhibitors, and BRAF inhibitors were indicated should have received such therapies. Patients were excluded from study participation if they had uncontrolled hypertension (defined as systolic blood pressure ≥ 140 mmHg and/or diastolic blood pressure ≥ 90 mmHg), proteinuria ≥ 2+ or 24-hour urine protein ≥ 1.0 g/24 hours, conditions that could result in gastrointestinal hemorrhage, a history of thromboembolic events or arterial embolic events, tumor invasion of a large vascular structure, or brain metastases.
Randomization was stratified by prior use of therapy in the refractory setting (tipiracil/trifluridine vs. regorafenib vs. tipiracil/trifluridine and regorafenib), RAS status (wild-type vs. mutated), and duration of metastatic disease (≤ 18 months vs. > 18 months). Patients were randomized in a 2:1 ratio to receive either fruquintinib 5 mg orally (PO) daily (QD) on Days 1–21 of each 28-day cycle or matching placebo. Treatment was administered until disease progression or intolerable toxicity. Disease response and progression were assessed radiographically at baseline and every 8 weeks. The primary endpoint was overall survival (OS). The key secondary endpoint was investigator-assessed progression-free survival (PFS) using RECIST 1.1
The planned sample size was 687 patients and with 480 OS events, the study had 90% power to detect a hazard ratio (HR) of 0.73 for OS using a stratified log-rank test at a 1-sided significance level of 0.025, assuming a median OS of 5 months in the placebo arm. The efficacy analyses were conducted in the intention-to-treat population (ITT), defined as all patients who were randomly assigned to treatment. Stratified log-rank test was used to compare OS and PFS between arms and a stratified Cox proportional hazard model was used to estimate the HRs. The Kaplan–Meier (KM) method was applied to further summarize OS and PFS.
Study 2013–013-00CH1 (FRESCO) was a single country (China), double-blind, placebo-controlled randomized trial in patients with mCRC who had been previously treated with fluoropyrimidine, oxaliplatin-, and irinotecan-based chemotherapy. Prior treatment with anti-VEGF or anti-EGFR biologics was allowed but not mandated. Other than the required prior therapies, eligibility criteria in FRESCO were similar to that of FRESCO-2.
In FRESCO, randomization was stratified by prior use of VEGF inhibitors (yes vs. no) and KRAS status (wild-type vs. mutated). Patients were randomized in a 2:1 ratio to receive either fruquintinib or matching placebo as described above. Treatment was administered until disease progression or intolerable toxicity. The primary endpoint was overall survival (OS). A secondary endpoint was investigator-assessed progression-free survival (PFS) using RECIST 1.1
The planned sample size was 400 patients and with 280 OS events, the study had 80% power to detect a hazard ratio (HR) of 0.7 for OS using a stratified log-rank test at a 2-sided significance level of 0.05 assuming a median OS of 6.3 months in the placebo arm. The efficacy analyses were conducted in the intention-to-treat population (ITT), defined as all patients who were randomly assigned to treatment. Stratified log-rank test was used to compare OS between arms and a stratified Cox proportional hazard model was used to estimate the HRs. The KM method was applied to summarize OS.
Results
In the FRESCO-2 study, a total of 691 patients were randomized (461 and 230 patients into fruquintinib and placebo arms, respectively) at 124 study sites in the North American (18%), European (72%), and Asia Pacific (10%) regions. Black or African American and Latino/Hispanic patients were underrepresented in the trial (3% and 4.9% respectively) as compared with the proportion of Black or African American patients with mCRC in the U.S. Demographics and baseline disease characteristics of the study population were balanced between the treatment arms (Table 1).
Table 1:
Demographic and Clinical Characteristics
| FRESCO-2 | FRESCO | |||
|---|---|---|---|---|
| Fruquintinib + BSC N=461; n (%) |
Placebo + BSC N=230; n (%) |
Fruquintinib + BSC N=278; n (%) |
Placebo + BSC N=138; n (%) |
|
| Median age, years (range) | 64 (25, 82) | 64 (30, 86) | 55 (23,75) | 57 (24, 74) |
| Age ≥ 65 years old | 214 (46) | 111 (48) | 50 (18) | 28 (20) |
| Male sex | 245 (53) | 140 (61) | 158 (57) | 97 (70) |
| ECOG PS 0/1 | 196 (43)/ 265 (57) | 102 (44)/ 128 (56) | 77 (28)/ 201 (72) | 37 (27)/ 101 (73) |
| Race | ||||
| Asian | 43 (9) | 18 (8) | 278 (100) | 138 (100) |
| Black or African American | 13 (3) | 7 (3) | 0 | 0 |
| White | 367 (80) | 192 (83) | 0 | 0 |
| Multiple Races/Other/Not Reported/Unknown | 38 (8) | 13 (6) | 0 | 0 |
| Hispanic or Latino Ethnicity | 20 (4) | 14 (6) | 0 | 0 |
| Right- vs Left-sided Primary | 97 (21)/335 (73) | 53 (23)/162 (70) | 56 (20)/214 (77) | 21 (15)/115 (83) |
| RAS-WT/RAS-Mut 1 | 170 (37)/291 (63) | 85 (37)/145 (63) | 157 (56)/121 (44) | 74 (54)/64 (46) |
| Prior VEGF Inhibitor | 445 (97) | 221 (96) | 84 (30) | 41 (30) |
| Prior EGFR Inhibitor | 180 (39) | 88 (38) | 40 (14) | 19 (14) |
| Prior Therapy with TAS-102 and/or regorafenib | ||||
| Prior regorafenib | 221 (48) | 109 (47) | 0 | 0 |
| Prior trifluridine/tipiracil | 421 (91) | 212 (92) | 13 (5) | 3 (2) |
| Both trifluridine/tipiracil and regorafenib | 181 (39) | 91 (40) | 0 | 0 |
In FRESCO-2 KRAS and NRAS were tested. In FRESCO only KRAS was tested.
Source: FDA analysis
In the FRESCO study, a total of 416 patients were randomized (278 and 138 patients into the fruquintinib and placebo arms, respectively) at 28 study sites in China. The demographics and baseline disease characteristics of the study population were balanced between the treatment arms (Table 1).
Efficacy
With a data cutoff June 24, 2022, and a median follow up of 11.3 months in the fruquintinib arm and 11.2 months in the placebo arm, 490 deaths and 605 PFS events had occurred in FRESCO-2. In this study, treatment with fruquintinib provided a statistically significant improvement in OS compared with placebo in a heavily pretreated population. The OS HR was 0.66 (95% CI: 0.55, 0.80; p<0.001) with a median OS of 7.4 months (95% CI: 6.7, 8.2) in the fruquintinib arm and 4.8 months (95% CI: 4.0, 5.8) for the placebo arm. The PFS HR was 0.32 (95% CI: 0.27, 0.39; p<0.001) with a median PFS of 3.7 months (95% CI: 3.5, 3.8) in the fruquintinib arm and 1.8 months (95% CI: 1.8, 1.9) in the placebo arm. Table 2 summarizes the efficacy results and Figure 1 displays the Kaplan Meier OS curve. A total of 7 (1.5%) patients treated with fruquintinib had an objective response. No responses were observed in the placebo arm.
Table 2:
Efficacy Results
| FRESCO-2 | FRESCO | |||
|---|---|---|---|---|
| Fruquintinib + BSC N=461; n (%) |
Placebo + BSC N=230; n (%) |
Fruquintinib + BSC N=278; n (%) |
Placebo + BSC N=138; n (%) |
|
| Overall Survival | ||||
| Number of events (%) | 317 (69%) | 173 (75%) | 188 (68%) | 109 (79%) |
| Median in months (95% CI) | 7.4 (6.7, 8.2) | 4.8 (4.0, 5.8) | 9.3 (8.2, 10.5) | 6.6 (5.9, 8.1) |
| HRa (95% CI), Pb | 0.66 (0.55, 0.80), <0.001 | 0.65 (0.51, 0.83), <0.001 | ||
| PFS | ||||
| Number of events (%) | 392 (85%) | 213 (93%) | 235 (85%) | 125 (91%) |
| Median in months (95% CI) | 3.7 (3.5, 3.8) | 1.8 (1.8, 1.9) | 3.7 (3.7, 4.6) | 1.8 (1.8, 1.8) |
| HRa (95% CI), Pbc | 0.32 (0.27, 0.39), <0.001 | 0.26 (0.21, 0.34), -- | ||
: Adjusted for stratification factors.
: 2-sided P-value computed from stratified log-rank test.
: P-value for the PFS analysis in FRESCO was not included due to the lack of multiplicity adjustment for this analysis
Source: FDA analysis
Figure 1:
Kaplan-Meier curves for overall survival in FRESCO-2 (A) and FRESCO (B).
BSC: best supportive care.
Source: FDA analysis
With a data cutoff January 17, 2017, and a median follow up of 13.3 months in the fruquintinib arm and 13.2 months in the placebo arm, 297 deaths and 360 PFS events had occurred in FRESCO. In this study, treatment with fruquintinib provided a statistically significant and clinically meaningful improvement in OS compared with placebo in a heavily pretreated population. The OS HR was 0.65 (95% CI: 0.51, 0.83; p<0.001) with a median OS of 9.3 months (95% CI: 8.2, 10.5) in the fruquintinib arm and 6.6 months (95% CI: 5.9, 8.1) for the placebo arm. The secondary endpoint of PFS was not formally tested due to lack of control of Type-I error rate for testing PFS hypothesis. In exploratory PFS analyses, the HR was 0.26 (95% CI: 0.21, 0.34) with a median PFS of 3.7 months (95% CI: 3.7, 4.6) in the fruquintinib arm and 1.8 months (95% CI: 1.8, 1.8) in the placebo arm. A total of 13 (4.7%) patients had an objective response with fruquintinib versus zero patients in the placebo arm.
Safety
The safety analysis was based on 1101 patients who received at least one dose of fruquintinib (N=734) or placebo (N=367) in the FRESCO-2 and FRESCO studies. The median duration of treatment with fruquintinib was 12 weeks (0 to 82 weeks) in the FRESCO-2 study and 15 weeks (0 to 95 weeks) in the FRESCO study. In FRESCO-2 grading of adverse events (AE) was based upon CTCAE v5.0 with adverse events classified and coded using MedDRA version 25.0. In FRESCO, AEs were graded based upon CTCAE v4.03 and coded using MedDRA version 19.1.
The adverse reaction profile observed in patients receiving fruquintinib in the FRESCO-2 and FRESCO studies is generally consistent with the known safety profile associated with VEGF receptor inhibition (Table 3). The most common Grade 3–4 adverse events in patients treated with fruquintinib in FRESCO-2 were hypertension (14%), fatigue (12%), and palmar-plantar erythrodysesthesia (6%). In FRESCO, the most common Grade 3–4 adverse events in patients treated with fruquintinib were hypertension (23%), palmar plantar erythrodysesthesia (11%), and proteinuria (5%).
Table 3:
Most Common Any Grade Adverse Events (>10%)
| FRESCO-2 | FRESCO | |||
|---|---|---|---|---|
| Any Grade AEs | Fruquintinib + BSC N=456; (%) |
Placebo + BSC N=230; (%) |
Fruquintinib + BSC N=278; (%) |
Placebo + BSC N=137; (%) |
| General | ||||
| Fatigue1 | 53 | 39 | 25 | 13 |
| Vascular | ||||
| Hypertension1 | 38 | 9 | 61 | 17 |
| Hemorrhage1 | 13 | 9 | 28 | 14 |
| Gastrointestinal | ||||
| Stomatitis1 | 31 | 8 | 33 | 3 |
| Diarrhea1 | 24 | 11 | 25 | 5 |
| Endocrine Disorders | ||||
| Hypothyroidism | 21 | <1 | 17 | 2 |
| Skin Disorders | ||||
| Palmar-plantar erythrodysesthesia | 19 | 3 | 49 | 3 |
| Renal | ||||
| Proteinuria1 | 18 | 5 | 55 | 30 |
| Respiratory | ||||
| Dysphonia1 | 18 | 5 | 38 | 1 |
| Musculoskeletal | ||||
| Musculoskeletal pain1 | 16 | 7 | 22 | 6 |
| Arthralgia | 11 | 4 | 13 | 2 |
Represents a composite of multiple related terms.
Source: FDA analysis
In the FRESCO-2 study, fatal TEAEs were reported in 14 (3%) patients on the fruquintinib arm and 10 (4%) patients on the placebo arm. In the FRESCO study, fatal TEAEs were reported in 7 (3%) patients on the fruquintinib arm and 2 (1%) patients on the placebo arm. There was no common safety signal or toxicity pattern associated with fatal events and it was difficult to attribute the majority of these events to treatment versus the underlying disease.
Regulatory Considerations
Treatment with fruquintinib in FRESCO-2 and FRESCO showed a statistically significant, modest, improvement in survival in patients with mCRC who had been previously treated with fluoropyrimidine, oxaliplatin-, and irinotecan-based chemotherapy. The study results are robust and consistent across most subgroups of patients. The effect on OS was supported by an equally modest but statistically significant effect on PFS in FRESCO-2. One key regulatory issue identified during the review of the application was whether the data submitted supported an indication in patients who did not receive prior trifluridine/tipiracil and/or regorafenib. At the time of the FRESCO trial conduct, regorafenib and tipiracil/trifluridine were not available in China and the use of biological therapies targeting the VEGF and EGFR pathways appears to have not been as widespread as in the US (Table 1). However, the magnitude of effect observed in FRESCO-2 and FRESCO, as well as subgroup analyses support the conclusion that the activity of fruquintinib appears independent of prior treatment with a VEGF(R) inhibitor.
Drug development is an increasingly global enterprise. However, while FDA can accept foreign clinical data to support efficacy, data derived solely from a single foreign country can be problematic given potential intrinsic and extrinsic differences from the U.S. population (8). FRESCO was conducted in a single-region that enrolled an all-Asian population, in a disease that is not uncommon in the U.S. Given the differences in prior therapy described above, FRESCO may not have been adequate for registration in the U.S. as a stand-alone study, however, the results of the FRESCO study were supportive and consistent with the primary results and exploratory subgroup analyses of the pivotal multiregional FRESCO-2 study. Therefore, the review team concluded that the clinical data was suitable to support a U.S. population and that the evidence supported broadening the indication beyond the population enrolled in FRESCO-2 (i.e., not requiring prior trifluridine/tipiracil or regorafenib).
Accruing a diverse population more representative of U.S. patients remains a challenge in cancer clinical trials (9). Despite being a multiregional trial, a limitation of FRESCO-2 was that a mere 20 of 691 patients (2.9%) enrolled in the trial were Black or African American and only 34 of 691 patients (4.9%) were Hispanic or Latino. In the United States, underrepresented populations are disproportionately affected by mCRC with respect to both incidence and mortality (2). Based upon the limited inclusion of underrepresented minorities in the FRESCO-2 study, FDA requested and the Applicant agreed to, a postmarketing study to characterize the effects of fruquintinib in underrepresented racial and ethnic subgroups.
Conclusions
In summary, fruquintinib for the treatment of refractory mCRC has a favorable benefit-risk profile, with a modest statistically significant improvement in OS demonstrated in the FRESCO-2 and FRESCO studies. The safety profile was generally consistent with the known safety profile associated with VEGF receptor inhibition with no new safety signals identified (Table 3). This approval provides an additional treatment option for patients with refractory mCRC.
The application was reviewed under various FDA programs designed to expedite the review of applications for patients with serious diseases including fast track designation and priority review. This application was also submitted to other global regulatory agencies through FDA’s Project Orbis, including the Australian Therapeutic Goods Administration (TGA), Health Canada, Israel Ministry of Health (IMoH), Singapore’s Health Sciences Authority (HSA), Switzerland’s Swissmedic, and United Kingdom’s Medicines and Healthcare products Regulatory Agency (MHRA).
Footnotes
Disclosure of Potential Conflicts of Interest: The authors report no financial interests or relationships with the commercial sponsors of any products discussed in this report.
This is a U.S. Government work. There are no restrictions on its use.
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