Early Local Community Data on Safety and Efficacy of Fruquintinib in Metastatic Colorectal Cancer

Hong Kong J Radiol 2024 Sep;27(3):e147-55 | Epub 16 September 2024

 

 

¹ Department of Oncology, Princess Margaret Hospital, Hong Kong SAR, China

² Department of Clinical Oncology, Tuen Mun Hospital, Hong Kong SAR, China

³ Cluster Quality and Safety Division, Tuen Mun Hospital, Hong Kong SAR, China

 

  Full Article in PDF

Globally, colorectal cancer is the third most common type of cancer and the second leading cause of cancer-related deaths.[1] In Hong Kong, colorectal cancer was not only the second most common cancer but also the second most common cause of cancer-related deaths in 2020.[2]

 

The primary treatment for metastatic colorectal cancer (mCRC) is chemotherapy, often supplemented by targeted therapy and, in certain cases, immunotherapy for patients with mismatch repair deficient tumours. For chemotherapy, standard chemotherapy regimens include 5-fluorouracil (or its oral prodrug capecitabine) plus either oxaliplatin or irinotecan, or both.[3] [4] Targeted therapy agents include bevacizumab and aflibercept, which target the vascular endothelial growth factor (VEGF) pathway; and cetuximab and panitumumab, which target the epidermal growth factor receptor (EGFR) pathway.[3] [4] Later-line treatment regimens include trifluridine-tipiracil[5] and regorafenib.[6] These two agents offer only modest improvements in overall survival (OS) and progression-free survival. However, even after failure on multiple different treatment strategies, patients may still maintain good performance status. This underscores the necessity for more safe and effective treatment options.

 

Fruquintinib is a selective inhibitor of vascular endothelial growth factor receptor (VEGFR)-1, -2, and -3 tyrosine kinases.[7] In the phase III FRESCO randomised clinical trial (Fruquintinib Efficacy and Safety in 3+ Line Colorectal Cancer Patients), fruquintinib significantly improved the median overall survival (mOS) compared with that of the placebo group (9.3 months [95% confidence interval (CI) = 8.2-10.5] vs. 6.6 months [95% CI = 5.9-8.1]) in Chinese patients with mCRC who progressed after at least two prior chemotherapy regimens (i.e., third- or later-line use).[8] It was approved in Mainland China in 2018 and was granted a fast-track designation by the US Food and Drug Administration in June 2020 for the above indication.[9] Another recent phase III FRESCO-2 randomised clinical trial also showed significant improvement in mOS with fruquintinib compared with placebo (7.4 months [95% CI = 6.7-8.2] vs. 4.8 months [95% CI = 4.0-5.8]).[10] Fruquintinib received its approval from the US Food and Drug Administration on 8 November 2023, for adult patients with mCRC who had previously received 5-fluorouracil, oxaliplatin and irinotecan-based chemotherapy, anti-VEGF therapy, and anti-EGFR therapy (if the tumour was RAS-wild type).[11]

 

The FRESCO trial recruited 416 Chinese patients from Mainland China, where fruquintinib was developed.[8] On the other hand, the FRESCO-2 trial included patients from North America, Europe, Australia and Japan, but Japanese patients comprised <10% of the trial population.[10] The FRESCO trial excluded patients who had been previously exposed to regorafenib,[8] while patients who progressed on or were intolerant to trifluridine-tipiracil or regorafenib could enter the FRESCO-2 trial.[10] Hong Kong was not a study site in either trial, and local experience in the use of fruquintinib was scarce.

 

This study aimed to analyse the safety and efficacy of fruquintinib in mCRC patients. To the best of our knowledge, this is the first retrospective study of fruquintinib in public healthcare setting in the local population.

 

Clinical data from 26 patients who received fruquintinib between 31 December 2021 and 22 July 2023 were retrospectively reviewed and collected from the institutional databases of two tertiary centres in Hong Kong, namely, Princess Margaret Hospital and Tuen Mun Hospital. The inclusion criteria for fruquintinib use were modified from the FRESCO[8] and FRESCO-2[10] trials, which were as follows: (1) age ≥18 years; (2) an Eastern Cooperative Oncology Group (ECOG) performance status score of 0 to 1; (3) histologically confirmed mCRC; (4) failure (progressive disease or intolerance) on at least two standard chemotherapy regimens using fluoropyrimidine, irinotecan, oxaliplatin, anti-VEGF antibodies (bevacizumab and aflibercept), or anti-EGFR antibodies (cetuximab or panitumumab); (5) measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1; (6) adequate bone marrow reserve (absolute neutrophil count ≥1.5 × 10⁹/L, platelet count ≥100 × 10⁹/L, and haemoglobin level ≥9.0 g/dL); (7) renal function (serum creatinine level ≤1.5 × upper limit of normal [ULN] or creatinine clearance ≥60 mL/min; urine dipstick protein of ≤1+ or 24-hour urine protein level <1.0 g/24 h); and (8) liver function (serum total bilirubin level ≤1.5 × ULN; alanine aminotransferase and aspartate aminotransferase level ≤2.5 × ULN in subjects without hepatic metastases; and alanine aminotransferase and aspartate aminotransferase level ≤5 × ULN in subjects with hepatic metastases). There were no exclusion criteria involving prior use of trifluridine-tipiracil or regorafenib.

 

This was a local, single-arm, retrospective analysis of patients with mCRC conducted at two tertiary centres in Hong Kong. These patients had either progressed or shown intolerance after receiving at least two lines of chemotherapy. The included patients underwent repeated 28-day treatment cycles of fruquintinib, with a schedule of 3 weeks on the medication (5 mg oral daily) followed by a 1-week break. This treatment cycle was continued until disease progression, death, occurrence of unacceptable toxicity, or discontinuation by the physician. Dose reduction was allowed to manage treatment-related adverse effects and followed the protocol of the FRESCO trial.[8]

 

The primary endpoint was OS, defined as the time from the start of treatment using fruquintinib to death from any cause. Tumour response assessment was performed at intervals subject to the availability of imaging and physician discretion, and response was defined by RECIST version 1.1. The secondary endpoints were event-free survival (EFS) [defined as the time from starting treatment to an event, which could be disease progression defined as the first documentation of disease progression assessed by the investigator according to RECIST version 1.1, discontinuation of treatment for any reason, or death], duration of treatment (defined as the time from starting treatment to last study treatment dose), objective response rate (defined as confirmed complete or partial response), disease control rate (defined as the sum of the complete response, partial response and stable disease rates), and carcinoembryonic antigen (CEA) response. EFS was selected instead of progression-free survival because the imaging intervals in real-world settings vary. In heavily pretreated patients, quality of life (QoL) is important, and discontinuation of treatment for any reason can also indicate the tolerability of a drug. For CEA response, a definition modified from the RECIST criteria was used to evaluate treatment response, and responses were classified into three groups, namely, CEA-RD (responsive disease), CEA-SD (stable disease), and CEA-PD (progressive disease).[12] [13] CEA-RD was defined as a decrease of >30% from the original level; CEA-PD was defined as an increase of >20% from the original level.[12] [13] A change in the CEA level that did not meet the criteria for CEA-RD and CEA-PD was defined as CEA-SD.[12] [13]

 

Adverse events (AEs) were recorded throughout the study from the start of treatment to the end of the study period or the start of the next line of treatment. They were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0.[14]

 

For OS and EFS, the Kaplan-Meier method was used to estimate the median survival time and 95% CI. Relationships between individual patient characteristics and OS or EFS were analysed using the Cox proportional hazards model to estimate hazard ratios (HRs) and 95% CIs. All analyses were performed using commercial software SPSS (Windows version 28.0; IBM Corp, Armonk [NY], US). A p value of < 0.05 was considered statistically significant.

 

The baseline demographics and disease characteristics of the patients are shown in Table 1.

 

Table 1. Baseline characteristics of the study population (n = 26).

 

The median duration of treatment was 4.3 months (range, 0.6-15.4) and the median number of treatment cycles was 3 (range, 1-17). The median follow-up time was 7.3 months. The mOS was 8.9 months (95% CI = 4.5-13.3). The Kaplan-Meier plot for OS is shown in Figure 1. The proportion of patients still alive at 6 months was 78.7% and that at 12 months was 41.2%.

 

Figure 1. Kaplan-Meier estimates for overall survival in patients with metastatic colorectal cancer receiving fruquintinib.

 

The median EFS was 4.2 months (95% CI = 2.5-5.9). Among the 22 of 26 patients who experienced an event, 15 (57.7%) had disease progression, six (23.1%) discontinued treatment for any reason, and one (3.8%) died. The Kaplan-Meier plot for EFS is shown in Figure 2.

 

Figure 2. Kaplan-Meier estimates for event-free survival in patients with metastatic colorectal cancer receiving fruquintinib.

 

Subgroup analyses of OS and EFS were carried out with a Cox proportional hazards model (simple and multivariable), but only a few clinical, tumour, or treatment factors exhibited a statistically significant correlation (Tables 2, 3 and 4). Simple analysis also revealed that OS was worse for patients with liver metastasis and with multiple sites of metastasis (Table 2). Patients with an ECOG performance status score of 0 had better EFS (HR = 0.34; 95% CI = 0.14-0.85) [Table 4 and Figure 3]. Previous use of trifluridine-tipiracil, regorafenib, or both did not significantly affect OS or EFS (Tables 2, 3 and 4).

 

Table 2. Simple analysis of risk factors associated with overall survival.

 

Table 3. Multivariable analysis of risk factors associated with overall survival.

 

Table 4. Simple analysis of risk factors associated with event-free survival.

 

Figure 3. Kaplan-Meier estimates for event-free survival in patients with metastatic colorectal cancer receiving fruquintinib (with Eastern Cooperative Oncology Group performance status score of 0 and 1).

 

The starting dose of fruquintinib was 5 mg daily (3 weeks on, 1 week off). 11 patients had their dose reduced, with 5 patients (19.2%) being reduced to 4 mg dailiy and 6 patients (23.1%) being reduced to 3 mg dailiy. Dose reduction of fruquintinib was associated with better OS (HR = 0.19, 95% CI = 0.05-0.72; p = 0.014) [Table 2 and Figure 4], but not in EFS (HR = 0.52, 95% CI = 0.22-1.21; p = 0.129) [Table 4].

 

Figure 4. Kaplan-Meier estimates for overall survival in patients with metastatic colorectal cancer receiving fruquintinib (with or without dose reduction).

 

In patients treated with fruquintinib, the disease control rate was 38.5% (10 of 26 patients), which included two (7.7%) patients with partial response and eight patients (30.8%) with stable disease. There was no patient with complete response.

 

Regarding serum CEA responses, the differences in OS and EFS were not statistically significant between patients with CEA-RD, CEA-SD and CEA-PD. Numerically, patients with CEA-RD had better OS and EFS than patients with CEA-PD (Tables 2, 3 and 4).

 

Twenty-five of 26 patients (96.2%) had at least one AE of any grade (Table 5). The most frequently reported AEs of any grade were hypertension (84.6%), proteinuria (57.7%), hand-foot syndrome (HFS) [50%], and hypothyroidism (50%). Severe AEs (grade ≥3) occurred in 18 patients (69.2%), with the most common being hypertension (53.8%), HFS (19.2%), and diarrhoea (11.5%) [Table 5]. There were no treatment-related deaths in the study population.

 

Table 5. Adverse events of the study population (n = 26).

 

Six of 26 patients (23.1%) discontinued fruquintinib due to treatment-related AEs. The most frequent AE that led to treatment discontinuation was HFS in two patients (7.7%). Treatment interruption due to AEs occurred in five patients (19.2%), and the most common AE associated with treatment interruption was hypertension in two patients (7.7%). Dose reduction due to AEs occurred in 11 patients (42.3%). The most frequent AEs leading to dose reductions were HFS (11.5%), proteinuria (11.5%), and diarrhoea (7.7%).

 

This retrospective study investigated the local population treated with fruquintinib at two tertiary institutions in Hong Kong, which included patients who had experienced disease progression following at least two lines of chemotherapy. This study did not have a placebo arm; the analysis of the results focuses on early experience of safety and efficacy in our locality.

 

In this study, the mOS was 8.9 months and the median EFS was 4.2 months, with a disease control rate of 38.5%. In Hong Kong, third-line or beyond monotherapy options for mCRC include trifluridine-tipiracil and regorafenib. In the RECOURSE trial (trifluridine-tipiracil vs. placebo in patients with previously treated mCRC), the treatment group had an mOS of 7.1 months and a disease control rate of 44%.[5] In the CONCUR trial (regorafenib vs. placebo in Asian patients with previously treated mCRC), the treatment group had an mOS of 8.8 months and a disease control rate of 51%.[6] Our data suggest that fruquintinib is a feasible monotherapy option in the third line and beyond setting for mCRC patients in Hong Kong.

 

OS and EFS analyses did not reveal any statistically significant differences in most of the subgroups (Tables 2, 3 and 4), although OS was shown to worsen when patients had liver metastasis or more than one site of metastasis (Table 2). EFS was shown to be related to ECOG performance status score (Table 4). There was no statistically significant correlation between CEA response and OS or EFS (Tables 2, 3 and 4), although OS tended to improve in patients with CEA-RD and tended to worsen in patients with CEA-PD.

 

In terms of the radiological and CEA (tumour marker) response, there were more patients with CEA-RD than there were with an objective response. This could be due to less intensive imaging schedules in public hospital settings, such that metabolic or relatively short-lived treatment responses could not be captured radiologically. Further study is needed to confirm the correlation between CEA response and survival, and studying the CEA response could help determine whether it can supplement the suboptimal scanning schedule in assessing the treatment response.

 

The incidence of AEs and serious AEs was considerably high in the study population. The most frequently reported grade ≥3 AEs were hypertension, HFS, and diarrhoea (Table 5). These AEs were manageable by supportive measures and dose modification. The discontinuation of fruquintinib in this study was 26.9%, whereas the rate in FRESCO and FRESCO-2 were 15.1%[8] and 20%,[10] respectively. Further QoL analysis would be valuable to correlate the relatively high incidence of AEs and their impact on patient’s QoL.

 

Baseline hypertension was a strong risk factor for high-grade hypertensive toxicity. Among the 14 patients who experienced grade ≥3 hypertension, all had preexisting hypertension at baseline. The baseline hypertension rate (88.4%, n = 23) was relatively high when compared to that of the general population (57.4% in the 65-84 age-group).[15] The odds ratio associated with grade ≥3 hypertension was 7.00 for patients with baseline hypertension of any grade (95% CI = 0.34-144.06; p = 0.20). Of those patients with baseline hypertension, only eight (34.8%) received intervention. Home blood pressure monitoring was started or ensured in seven patients, while antihypertensive therapy was started or titrated only in one patient. Of the eight patients who underwent intervention, seven (87.5%) still developed grade ≥3 hypertension. These findings suggested that more aggressive intervention by managing oncologists is needed for patients with baseline hypertension.

 

According to the evidence from regorafenib, which is also a VEGFR inhibitor, when encountering grade 2 hypertension, treating physicians can consider starting a single antihypertensive agent (such as an angiotensin-converting enzyme inhibitor).[16] For grade 3 hypertension, an additional agent (such as a beta blocker) should be considered, and if it remains refractory, a third agent (such as a calcium channel blocker) may be added. Diuretics should be avoided because diarrhoea is also a common side-effect of fruquintinib, which may cause dehydration.

 

Another important adverse reaction was HFS. In HFS management, preventive measures include reducing skin friction, reducing exposure to heat, using skin barriers and early identification of skin abrasions.[17] The use of urea-based cream in combination with sorafenib (also a VEGFR inhibitor) has been shown to reduce the incidence of HFS.[18] Other commonly used measures include analgesics, topical anaesthetics, topical high-potency corticosteroids, keratolytic, and emollients.[17] If the above supportive measures are not able to improve tolerance, physicians can consider reducing the dose according to the drug’s prescription information.

 

A total of 99% of the patients experienced any grade of AE in the fruquintinib (FRESCO-2) trial,[10] 97% in the regorafenib (CONCUR) trial[6] and 98% in the trifluridinetipiracil (RECOURSE) trial,[5] with 63%, 54%, and 69% of patients experiencing grade ≥3 AEs, respectively. For specific grade ≥3 AEs, we compared the same class of drugs (i.e., fruquintinib vs. regorafenib), and the two drugs had similar severe AE profiles. Compared with drugs of a different class (i.e., fruquintinib vs. trifluridine-tipiracil), the toxicity profiles of these agents clearly differed, with the chemotherapy class (trifluridine-tipiracil) having more haematological toxicity, as one would expect. The most common severe AEs associated with trifluridine-tipiracil were neutropenia (38%), leukopenia (21%), and anaemia (18%).[5]

 

Patients in whom the dose was reduced had better OS and tended to improve EFS. As the dose reduction was mainly in response to toxicity, toxicity may be a predictor of the VEGFR inhibitor treatment response. A similar phenomenon was observed with anti-EGFR therapy, and a worse skin reaction was proven to be associated with a better response. In the OPUS study (untreated EGFR-expressing advanced colorectal cancer, FOLFOX4 vs. FOLFOX plus cetuximab),19 patients with grade 3 to 4 skin toxicity had a 66.7% response rate, while grade 1 patients and grade 0 patients had response rates of 42.2% and 13%, respectively. In the EPIC study (The European Prospective Investigation into Cancer and Nutrition, second-line treatment after oxaliplatin-based therapy, cetuximab plus irinotecan versus irinotecan),20 the median survival was 5.8 months for grade 0 toxicities, 11.7 months for grade 1 to 2 toxicities, and 15.6 months for grade 3 to 4 toxicities. However, further studies are needed to confirm this hypothesis in fruquintinib therapy.

 

This study has several limitations. First, this was a retrospective study based only on data from two public tertiary centres in Hong Kong. Second, the sample size was small, and some subgroup analyses did not show statistical significance. Third, QoL data were not collected in this study.

 

Fruquintinib demonstrated reasonable clinical efficacy and a manageable safety profile and is a valid option for later-line mCRC patients. Hypertension is the most common high-grade toxicity, and preexisting hypertension is a strong risk factor. Proactive management of hypertension is strongly advocated. Prompt AE management can optimise its clinical utility, and dose reduction did not compromise efficacy. Further study of treatment sequence and patient QoL among the approved third-line or beyond options is needed.