FRUZAQLA®▼
(fruquintinib) Prescribing Information

FRUZAQLA®▼ (fruquintinib): Clinically proven – with generally consistent results across two pivotal phase 3 trials1–3

FRUZAQLA is an oral, targeted treatment for people living with previously treated mCRC.3 It is a highly selective small molecule tyrosine kinase inhibitor that works by inhibiting VEGF receptors 1, 2, and 3.3

FRUZAQLA is indicated for the treatment of adult patients with metastatic colorectal cancer (mCRC) who have been previously treated with available therapies, including fluoropyrimidine-, oxaliplatin-, and irinotecan- based chemotherapy, with or without anti-VEGF therapy, and, if RAS wild type and medically appropriate, an anti-EGFR therapy.3

In two pivotal, multicentre, randomised, double-blind, placebo-controlled phase 3 trials, FRUZAQLA demonstrated a significant improvement in median OS (P<0.001) compared with placebo.1–3

This page explores the data from these pivotal trials – FRESCO and FRESCO 2.

*This does not apply to all mCRC patients, as treatment responses may vary.

 Study design

FRESCO was a single-country (China), multicentre, randomised, double-blind, placebo-controlled phase 3 trial1

FRESCO study design1

FRESCO study design

Inclusion criteria (see paper for full criteria)1

  • Histologically or cytologically diagnosed with mCRC (stage IV)
  • Aged 18–75
  • ECOG PS 0–1
  • Had failed at least second-line standard chemotherapies including fluoropyrimidine, oxaliplatin, irinotecan regimens

Exclusion criteria (see paper for full criteria)4

  • Any systemic therapy <4 weeks preceding the study
  • Any prior VEGFR inhibitor treatment
  • Absolute neutrophil count <1.5 x 109/L, or blood platelet count <100 x 109/L, or haemoglobin <90 g/L; blood transfusion within 1 week before enrolment for the purpose of enrolment
  • Serum total bilirubin >1.5 x ULN; ALT and/or AST >2.5 x ULN (subject to the normal value at each site); or ALT and/or AST >5 x ULN for patients with liver metastases
  • CrCl rate <50 mL/min
  • Uncontrolled hypertension

Stratification1

  • Prior VEGF inhibitor therapy (e.g. bevacizumab and aflibercept; yes vs no)
  • K-RAS mutational status (wild type vs mutant)
 Baseline characteristics

FRUZAQLA was studied in a robust clinical trial that included a population of patients who had received ≥2 prior lines of therapy1

Table detailing the baseline characteristics of patients in FRESCO

Adapted from Li J et al., 2018.

*All eligible patients had ECOG PS 0 or 1 (0=fully active, able to carry on all pre-disease activities without restriction; 1=restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature).1
†Referred to caecum.1
‡Included 120 patients who had received bevacizumab (FRUZAQLA arm, 83; placebo arm, 37) and 5 patients who had received aflibercept (FRUZAQLA arm, 1; placebo arm, 4).1
§Cetuximab.1
¶No patients received VEGFR inhibitors.1

 Overall survival

In a study of FRUZAQLA + BSC vs placebo + BSC in patients with previously treated mCRC:

FRUZAQLA demonstrated significant OS benefit1

Approaching a three-month improvement in median OS vs placebo (ITT population)

Primary endpoint: Median OS in patients
with previously treated mCRC3

Kaplan Meir curves of overall survival for FRUZAQLA vs placebo over 24 months in FRESCO

Primary endpoint: Median OS in patients
with previously treated mCRC3

Adapted from FRUZAQLA Summary of Product Characteristics.

The median follow-up time was 13.3 months (95% CI: 12.1–14.7) for the FRUZAQLA group and 13.2 months (95% CI: 10.6–19.6) for the placebo group.1

Consistent OS effect was observed across
a majority of pre-specified subgroups1*

Table with forest plot showing overall survival across pre-specified subgroups from FRESCO

Consistent OS effect was observed across
a majority of pre-specified subgroups1*

Adapted from Li J et al., 2018.

*This study was not powered to show significance in OS across these specified groups.

 Progression-free survival

In a study of FRUZAQLA + BSC vs placebo + BSC in patients with previously treated mCRC:

FRUZAQLA more than doubled median PFS1

Secondary endpoint: Median PFS in
patients with previously treated mCRC1

Kaplan Meir curves of progression-free survival for FRUZAQLA vs placebo over 24 months in FRESCO

Secondary endpoint: Median PFS
in patients with previously treated mCRC1*

Adapted from Li J et al., 2018.

Consistent PFS effect was observed across
all pre-specified subgroups1*

Table with forest plot showing progression-free survival across prespecified subgroups from FRESCO

Consistent PFS effect was observed across
all pre-specified subgroups1*

Adapted from Li J et al., 2018.

*This study was not powered to show significance in PFS across these specified groups.

Disease control rate (DCR) observed in FRESCO (secondary endpoint)1*

62%

n=173/278
DCR with FRUZAQLA + BSC

12%

n=17/138
DCR with placebo + BSC

This study was not powered to show significance in DCR.

The median follow-up time was 13.3 months (95% CI: 12.1–14.7) for the FRUZAQLA group and 13.2 months (95% CI: 10.6–19.6) for the placebo group.1

*DCR was defined as a complete response, partial response, or stable disease for ≥8 weeks after randomisation.1

 Safety summary

In FRESCO, FRUZAQLA demonstrated a generally manageable safety profile1

Overview of treatment-emergent
adverse events (TEAEs)1

Table of treatment-emergent adverse events reported in FRESCO

Overview of treatment-emergent adverse events (TEAEs)1

Adapted from Li J et al., 2018.

Treatment-related treatment-emergent
adverse events occurring in >10% of patients1

Table of treatment-emergent adverse events occurring in >10% of patients in FRESCO

Treatment-related treatment-emergent adverse
events occurring in >10% of patients1

Adapted from Li J et al., 2018.

Adverse events leading to dose modifications:1

  • Dose interruption or dose reduction: FRUZAQLA 47.1% (n=131/278); placebo 13.1% (n=18/137)
  • Treatment discontinuation: FRUZAQLA 15.1% (n=42/278); placebo 5.8% (n=8/137)

In the FRUZAQLA arm:1

  • Most common TEAEs leading to dose interruption or reduction: hand–foot skin reaction/palmar–plantar erythrodysaesthesia syndrome (HFSR/PPES) (13.3%), proteinuria (9.7%), and decreased platelet counts (5.4%)
  • Most common TEAE leading to dose discontinuation: proteinuria (2.2%)

Refer to the SmPC for full information on the safety profile of FRUZAQLA

*Specific causes in the FRUZAQLA arm (all n=1) included gastrointestinal haemorrhage, death not otherwise specified, lung infection, fungal lower respiratory tract infection, multiple organ dysfunction syndrome, sudden death, bacterial infection, cerebral infarction, and haemoptysis.1

 Study design

FRESCO 2 was a global, randomised, double-blind, multicentre phase 3 study2

FRESCO 2 study design2

FRESCO 2 study design

Inclusion criteria (see paper for full criteria)2

  • Histologically or cytologically diagnosed with metastatic CRC (stage IV)
  • 18 years or older
  • ECOG PS 0–1
  • Progression during or after prior treatment with at least two lines of fluoropyrimidine-, oxaliplatin-, or irinotecan-based chemotherapy, an anti-VEGF biological therapy, and if RAS wild type, an anti-EGFR biological therapy
  • Progression during or after prior treatment with trifluridine-tipiracil, regorafenib, or both

Exclusion criteria (see paper for full criteria)5

  • Absolute neutrophil count <1.5 x 109/L; platelet count <100 x 109/L; haemoglobin <9.0 g/dL
  • Serum total bilirubin >1.5 x ULN; ALT/AST >2.5 x ULN (patients without hepatic metastases); ALT/AST >5 x ULN (patients with hepatic metastases)
  • Serum creatinine >1.5 x ULN/CrCl <60 mL/min

Stratification2

  • Prior therapy (trifluridine-tipiracil vs regorafenib vs trifluridine-tipiracil and regorafenib)†
  • RAS mutational status (wild type vs mutant)
  • Duration of metastatic disease (≤18 months vs >18 months)

*Best supportive care was determined by local clinical practice.2
†To prevent unintentional enrichment, the number of patients treated with previous regorafenib was limited to 50% of the total randomly assigned patients.2

 Baseline characteristics

FRUZAQLA was studied in a large clinical trial that included a heterogeneous patient population2

Table detailing baseline characteristics of patients from FRESCO 2

Adapted from Dasari A et al., 2023.

*ECOG PS scores range from 0 to 5, with 0 indicating fully active and higher scores indicating greater disability.2
†Duration of metastatic disease=(date of randomisation – date of diagnosis of metastatic disease)/30.4375.2

 Overall survival

In a study of FRUZAQLA + BSC vs placebo + BSC in patients with previously treated mCRC:

FRUZAQLA demonstrated significant OS benefit2

Approaching a three-month improvement in median OS vs placebo (ITT population)

Primary endpoint: Median OS in patients
with previously treated mCRC2

Kaplan Meir curves of overall survival for FRUZAQLA vs placebo over 24 months in FRESCO 2

Primary endpoint: Median OS in patients
with previously treated mCRC2

Adapted from Dasari A et al., 2023, and FRUZAQLA Summary of Product Characteristics. 

Consistent OS effect was observed across
a majority of pre-specified subgroups1*

Table with forest plot showing overall survival across pre-specified subgroups from FRESCO 2

Consistent OS effect was observed across
a majority of pre-specified subgroups1*

Adapted from Dasari A et al., 2023.

*This study was not powered to show significance in OS across these specified groups.

Percentage of patients alive at 9 months2*

41%

of FRUZAQLA patients
(n=189/461; CI: 36–46)

28%

of placebo patients
(n=64/230; CI: 22–34)2

*This study was not powered to show significance for this endpoint.

Median follow-up was 11.3 months (IQR 9.0–14.2) in the FRUZAQLA group and 11.2 months (IQR 8.7–15.5) in the placebo group.2

 Progression-free survival

In a study of FRUZAQLA + BSC vs placebo + BSC in patients with previously treated mCRC:

FRUZAQLA more than doubled median PFS2

Secondary endpoint: Median PFS in
patients with previously treated mCRC2

Kaplan Meir curves of progression-free survival for FRUZAQLA vs placebo over 24 months in FRESCO 2

Secondary endpoint: Median PFS in
patients with previously treated mCRC2

Adapted from Dasari A et al., 2023, and FRUZAQLA Summary of Product Characteristics.

Consistent PFS effect was observed across
a majority of pre-specified subgroups2*

Table with forest plot showing progression-free survival across prespecified subgroups from FRESCO 2

Consistent PFS effect was observed across
a majority of pre-specified subgroups2*

Adapted from Dasari A et al., 2023.

*This study was not powered to show significance in PFS across these specified groups.

Disease control rate (DCR) observed in FRESCO 2 (secondary endpoint)2*

56%

n=256/451
DCR with FRUZAQLA + BSC

16%

n=37/230
DCR with placebo + BSC

This study was not powered to show significance in DCR.

Median follow-up was 11.3 months (IQR 9.0–14.2) in the FRUZAQLA group and 11.2 months (IQR 8.7–15.5) in the placebo group.2

*DCR was defined as the proportion of patients with a best overall response of confirmed complete response, partial response, or stable disease for ≥7 weeks.2

 Safety summary

In FRESCO 2, FRUZAQLA demonstrated a generally manageable safety profile2,5

Overview of TEAEs5*

Table of treatment-emergent adverse events reported in FRESCO 2

Overview of TEAEs5*

Adapted from Dasari A et al., 2023.

Most common treatment-related AEs2

Table of most common treatment emergent adverse events occurring in FRESCO 2

Most common treatment-related AEs2

Adapted from Dasari A et al., 2023.

In the FRUZAQLA arm:2

  • Most common TEAEs leading to dose reduction: HFSR/PPES (5.3%), hypertension (3.7%), and asthenia (3.5%)
  • Most common TEAE leading to dose discontinuation: asthenia (1.5%)

Adverse events leading to dose modifications:5

  • Dose interruption: FRUZAQLA 47% (n=213/456); placebo 27% (n=61/230)
  • Dose reduction: FRUZAQLA 24% (n=110/456); placebo 4% (n=9/230)
  • Dose discontinuation: FRUZAQLA 20% (n=93/456); placebo 21% (n=49/230)

Refer to the SmPC for full information on the safety profile of FRUZAQLA

*Of 5 patients assigned to the FRUZAQLA arm, 3 did not receive FRUZAQLA treatment and 2 received placebo instead; 2 patients assigned to the placebo arm did not receive treatment.2
†Disease progression was the most frequently reported term leading to death in each arm (FRUZAQLA: 7%, placebo: 13%).2

2L, second line; 3L, third line; AE, adverse event; ALT, alanine aminotransferase; AST, aspartate aminotransferase; BSC, best supportive care; CI, confidence interval; CRC, colorectal cancer; CrCl, creatinine clearance; DCR, disease control rate; ECOG, Eastern Cooperative Oncology Group; EGFR, epidermal growth factor receptor; HFSR/PPES, hand–foot skin reaction/palmar–plantar erythrodysaesthesia syndrome; HR, hazard ratio; IQR, interquartile range; ITT, intention-to-treat; mCRC, metastatic colorectal cancer; OS, overall survival; PS, performance status; PFS, progression-free survival; QoL, quality of life; TEAE, treatment-emergent adverse event; TRAE, treatment-related adverse event; TSH, thyroid-stimulating hormone; ULN, upper limit of normal; VEGF, vascular endothelial growth factor; VEGFR, vascular endothelial growth factor receptor.

1. Li J et al. JAMA. 2018:319(24):2486–2496; 2. Dasari A et al. Lancet. 2023;402(10395):41–53; 3. FRUZAQLA Summary of Product Characteristics; 4. Li J et al. JAMA. 2018: 319(24):2486–2496 (supplementary appendix); 5. Dasari A et al. Lancet. 2023;402 (10395):41–53 (supplementary appendix).

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