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Abstract

Background:

Colorectal cancer (CRC) is increasingly prevalent among young adults (<50 years) in China, a demographic that has been historically underrepresented in clinical studies. While most patients with CRC are aged ⩾65 years, this age group is also underrepresented in trials, highlighting the need for a better understanding of treatment outcomes in both younger and older populations. A recent phase IV trial evaluating the safety of fruquintinib in Chinese patients with metastatic CRC (mCRC) showed a manageable profile.

Objectives:

This subgroup analysis of the phase IV study primarily aims to evaluate the safety of fruquintinib in different age groups.

Design:

Prospective real-world study.

Methods:

The data of patients with CRC from the phase IV fruquintinib trial (NCT04005066) were collected for the young (<50 years) and the late elderly (⩾75 years) patients with CRC who were enrolled between April 24, 2019, and September 27, 2022. The safety outcomes, including treatment-emergent adverse events (TEAEs) and treatment-related adverse events (TRAEs), were recorded.

Results:

A total of 2798 patients with CRC enrolled in the phase IV study were categorized into two subgroups: 512 were young (age <50), and 239 were late elderly (age ⩾75). The young CRC subgroup received more intense treatment with a median treatment duration of 2.75 months, and the late elderly received a median treatment duration of 2.40 months. Combination therapy duration was longer than that of monotherapy in young (4.10 vs 2.40 months) and late elderly patients (3.90 vs 2.10 months). The incidence of TEAE was comparable across the young (78.71%) and the late elderly groups (77.41%). In the young CRC subgroup, the most common TRAEs were palmar-plantar erythrodysesthesia ((PPES) 20.31%) and hypertension (14.06%), whereas in the late elderly, they were hypertension (20.50%) and PPES (14.23%).

Conclusion:

The safety profile of fruquintinib was comparable across age subgroups. Young CRC patients tend to receive more intensive fruquintinib treatment. For the late elderly, who are more susceptible to TRAEs due to underlying health conditions, fruquintinib also offers a safe treatment option. Combination therapy duration was longer than monotherapy in both subgroups, suggesting its promising approach for optimizing treatment outcomes in both age subgroups.

Keywords

Introduction

Colorectal cancer (CRC) represents a significant health burden as it is the world’s third most commonly diagnosed cancer and the second leading cause of cancer-related mortality.¹ Since 2020, it has emerged as one of the five leading causes of cancer-related mortality in China.² According to the recent GLOBOCAN 2022 report, China reported 517,106 new cases of CRC (10.7% of all new cases) and 240,010 CRC-led deaths, ranking it the fourth leading cause of cancer mortality in the country.³ The 5-year prevalence of CRC in China was reported to be 1,477,561 cases, corresponding to a proportion of 13.5 per 100,000 individuals.³ The mean age at CRC diagnosis in China has been reported as 61.3 years, which is comparable to the declining trend observed in the United States, where the average age at diagnosis decreased from 67.0 to 61.2 years between 1992 and 2017.^4,5

Approximately 20% of patients have metastatic CRC (mCRC) at diagnosis, whereas up to 50% of patients with initially localized disease develop metastases.⁶ The most common metastatic sites are the liver, lungs, and peritoneum.⁷ Evaluating treatment options for CRC is difficult because the patient population is heterogeneous, consisting of different molecular subtypes. The prognosis of patients with mCRC has improved significantly with a multidisciplinary approach based on traditional treatments, including surgery, radiotherapy, and chemotherapy combined with novel anti-cancer drugs. Fluoropyrimidine-based chemotherapy in combination with anti-vascular endothelial growth factor (VEGF) and/or anti-epidermal growth factor receptor (EGFR) agents is considered the mainstay for the treatment of mCRC.⁸

In recent years, anti-angiogenic therapy has emerged as a potential adjuvant to conventional chemotherapy by enhancing its anti-tumor effect and thus achieving better treatment outcomes.⁹ Fruquintinib is a highly selective oral tyrosine kinase inhibitor for all three VEGFRs (VEGFR-1, -2, and -3), which play a key role in tumor angiogenesis. Fruquintinib was approved in China in 2018 by the National Medical Products Administration of China,¹⁰ the US Food and Drug Administration in 2023,¹¹ the European Commission in June 2024,¹² and most recently by the Japan’s Ministry of Health, Labour and Welfare in September 2024¹³ as a treatment for patients with mCRC who have received fluoropyrimidine, oxaliplatin, and irinotecan-based chemotherapy, received or are unsuitable to receive anti-VEGF therapy, and if RAS wild type and medically appropriate, an anti-EGFR therapy.¹⁴ This approval is based on the favorable results from the FRESCO and FRESCO-2 trials, where both studies showed an increase in overall survival.^15,16

A prospective, phase IV, real-world study of fruquintinib,¹⁷ which included 3005 patients, showed that the safety profile of fruquintinib was consistent with that of previous clinical trials,^18
–20 and the incidence of adverse events (AEs) was numerically lower than those known to be associated with VEGF/VEGFR inhibitors.²¹ Combination therapy with fruquintinib did not result in unexpected toxicities, and the longer duration of treatment observed in this group may be indicative of improved clinical efficacy and better patient tolerance, suggesting a favorable safety profile for extended use in real-world settings. However, elderly patients merit special attention due to age-related physiological changes, comorbidities, and altered drug metabolism, which may affect the tolerability and safety of cancer therapies.²² While fruquintinib has shown promising safety and efficacy in clinical trials, data specifically addressing the safety profile in younger and older patients with CRC are limited, as they are often underrepresented in clinical trials.

The incidence of CRC in young patients (<50 years), referred to as “Young-onset CRC” (YOCRC), has steadily increased each year.^23,24 Alarmingly, the YOCRC is not detected by routine CRC screening, as the usual recommendation is to start CRC screening at the age of 50 years. Furthermore, the YOCRC often experiences rapid disease progression and has a relatively poorer prognosis.²⁵ Considering their suitability for intensive treatment, clinicians increasingly prefer combination therapies. Therefore, the safety of combination regimens containing fruquintinib is worth exploring in this population. In addition, the risk of CRC increases with age, and the proportion of late elderly patients with CRC (⩾75 years) is increasing. There are no prospective data to guide the treatment of late elderly patients (⩾75 years), as they are recruited less frequently to clinical trials than younger patients.^26,27 The treatment regimen and safety profiles of elderly patients require meticulous consideration, as elderly patients frequently exhibit distinct physiological responses and tolerance levels to therapeutic interventions compared with their younger counterparts. Thus, focusing specifically on these two underrepresented age groups would offer a distinct and meaningful contribution, unlike the broader classification of <65 and ⩾65 used previously.¹⁷ These two age groups have unique clinical characteristics and treatment considerations that differ significantly from the general <65 and ⩾65 categorization. Notably, YOCRC is associated with more aggressive disease biology and is increasingly prevalent, while late elderly patients present challenges related to comorbidities, frailty, and treatment tolerance. Analysis of safety profiles, treatment intensity, and AE patterns specifically within these two distinct and clinically relevant subgroups will guide individualized treatment strategies and optimized monitoring practices for these often-overlooked age groups in real-world clinical settings.

Hence, this subgroup analysis of the phase IV fruquintinib trial aims to evaluate the safety of fruquintinib in young (<50 years) and late elderly patients with CRC (⩾75 years), considering factors such as initial dose and usage as monotherapy or combination with other therapies. We hypothesized that elderly patients may experience different safety profiles compared to younger patients.

Methods

Study design and participants

We performed a subgroup analysis of the phase IV study of fruquintinib (NCT04005066), a prospective, multicenter, post-marketing study across 96 clinical sites to evaluate the safety of fruquintinib in Chinese patients with mCRC.¹⁷ Eligibility criteria for the phase IV study have been previously reported.¹⁷ Briefly, mCRC patients who were either receiving their initial cycle of fruquintinib or anticipated to begin within a week and who were eligible for fruquintinib treatment at the physicians’ discretion were enrolled. All enrolled patients who had received at least one dose of fruquintinib treatment were included in the safety analysis set (SS). The reporting of this study conforms to the STROBE statement (Supplemental Table 1).²⁸ The list of the 96 participating clinical sites is provided in Supplemental Table 2.

All patients with CRC included in this study have been categorized into young patients with CRC, also called YOCRC, consisting of patients aged <50 years²⁹; and late elderly patients with CRC, consisting of patients aged ⩾75 years.³⁰ As defined in previous studies, the traditional definition of “elderly” as ⩾65 years—subdivided into 65–74 (“early elderly”) and ⩾75 years (“late elderly”)—originates from 19th-century Germany.³¹ In China, the average life expectancy has reached 79 years in 2024.³² We therefore defined “late elderly” as those with ⩾75 years, which may better reflect the current clinical and demographic realities.

Based on whether patients with CRC received combined therapy, they were grouped into the fruquintinib monotherapy group and the combination therapy group. The combination therapy group was further grouped into combination chemotherapy, combination immune checkpoint inhibitors (ICIs), combination chemotherapy or ICI, and combination chemotherapy and ICI, depending on the type of combination therapy received. The ICI combined with fruquintinib included programmed cell death protein 1 inhibitors such as sintilimab, camrelizumab, and tislelizumab, and programmed death ligand 1 inhibitor (PD-L1) inhibitors such as durvalumab and atezolizumab. Chemotherapy administered in combination with fruquintinib included oral medications such as capecitabine, trifluridine/tipiracil, and tegafur/gimeracil/octeracil, and intravenous medications such as oxaliplatin, raltitrexed, fluorouracil, and irinotecan.

Ethics approval and consent to participate

The phase IV study was conducted in accordance with the International Conference on Harmonization Good Clinical Practice guidelines³³ and the principles of the Declaration of Helsinki of China.³⁴ The study protocol was approved by the ethics committee of the respective study centers. All participants gave written informed consent before enrolling in the study.

Treatment

Study participants received fruquintinib orally according to the approved label at a dose of 5 mg once daily for 21 days in a 28-day cycle, followed by a 7-day drug-free period or as per the physicians’ discretion. Dose interruption and treatment discontinuation have been described in detail earlier.¹⁷ Briefly, dose interruption is recommended in cases of grade 2 hemorrhage, hand-foot skin reaction, or recurrent stomatitis; grade 2 thrombocytopenia (platelet count 50–75 × 10⁹/L); urinary protein ⩾2.0 g/24 h; and all grade 3 or 4 AEs not requiring permanent discontinuation. Permanent discontinuation was advised for grade ⩾3 hemorrhage, gastrointestinal perforation, clinically significant open wounds or fistula, nephrotic syndrome, hypertensive crisis, grade 4 liver function abnormalities, intolerance to the minimum dose of 3 mg/day, or if adverse reactions persist above grade 1 for more than 2 weeks following interruption.

Follow-up and safety assessment

Enrolled patients had three follow-up visits: at baseline, 1 month, and 6 months after consent or 30 days after the last dose, whichever occurred first. The primary endpoint of the study was safety assessment, such as treatment-emergent adverse events (TEAEs), treatment-related adverse events (TRAEs), incidence of overall serious AEs (SAE), dose adjustment and discontinuations, and severity of AEs, which was assessed according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.03.

Statistical analysis

Statistical analysis was performed using SAS software version 9.4 or later. A safety analysis was performed on all patients with CRC who received at least one dose of fruquintinib from SS. Subgroup analyses were performed for age (<50 vs ⩾75 years) comparing drug exposure, Eastern Cooperative Oncology Group performance status (ECOG PS) score, fruquintinib exposure (monotherapy or combination therapy), and AE between these subgroups. Categorical variables are expressed as numbers (%), whereas numerical variables are expressed as median and interquartile range (IQR).

Results

Between April 24, 2019, and September 27, 2022, a total of 3005 patients were enrolled in a fruquintinib phase IV study¹⁷; of these, 2798 patients with CRC were included in the subgroup analysis. This included 512 young patients with CRC aged <50 years, 239 late elderly patients with CRC aged ⩾75 years, and 2047 patients aged between 50 and 75 years (⩾50 and <75). The median ages of all patients with CRC were 60 years, whereas those of the young and the late elderly patients were 42 and 78 years, respectively. Among young patients with CRC, the proportion of female patients was higher (51.0% vs 41.0%) compared with the late elderly patients with CRC. The proportion of patients with both liver and lung metastases was comparable across groups, with 25.5% in young patients, 27.3% in late elderly patients, and 25.8% in the overall CRC population (Table 1). Moreover, the proportion of patients with CRC with high ECOG PS score (⩾2) was consistent across the groups at 4.9% in all CRC groups, 4.8% in the young patients, and 4.5% in the late elderly patients (Table 2). Demographic and other baseline characteristics of the study population are shown in Table 1.

Table 1.

Demographic and baseline characteristics of the study population stratified by different age groups.

Characteristics	Age <50N = 512	Age ⩾75N = 239	All CRCN = 2798
Age (years)
Median (IQR)	42.0 (36.5, 47.0)	78.0 (76.0, 80.0)	60.0 (52.0, 67.0)
Gender, n (%)
Male	251 (49.0)	141 (59.0)	1658 (59.3)
Female	261 (51.0)	98 (41.0)	1140 (40.7)
BMI (kg/m²)
Median (IQR)	22.040 (19.810, 24.510)	21.915 (20.010, 24.155)	22.640 (20.310, 24.880)
Metastatic lesions, n (%)
n (missing)	364 (148)	198 (41)	2259 (539)
With liver metastasis	271 (74.5)	139 (70.2)	1733 (73.4)
With lung metastasis	186 (51.1)	113 (57.1)	1238 (52.4)
With liver and lung metastases	93 (25.5)	54 (27.3)	609 (25.8)
Time interval from first diagnosis to first medication (months)
n (missing)	511 (1)	236 (3)	2783 (15)
Median (IQR)	18.960 (13.080, 31.840)	23.015 (14.130, 39.560)	21.360 (13.110, 36.240)
Treatment, n (%)
Fruquintinib monotherapy	314 (61.3)	173 (72.4)	1888 (67.5)
Fruquintinib + chemotherapy or ICI	174 (33.9)	52 (21.8)	775 (27.7)
Fruquintinib + chemotherapy	74 (14.5)	29 (12.1)	359 (12.8)
Fruquintinib + ICI	120 (23.4)	29 (12.13)	493 (17.6)
Fruquintinib + chemotherapy + ICI^a	20 (3.9)	6 (2.5)	77 (2.8)

A total of 77 patients are included in both the “fruquintinib + chemotherapy” and “fruquintinib + ICI” groups because of overlapping treatment regimens.

BMI, body mass index; CRC, colorectal cancer; ICI, immune checkpoint inhibitor; IQR, interquartile range.

Table 2.

ECOG PS.

ECOG score, n (%)N = 681^a	Age <50N = 104	Age ⩾75N = 66	All CRCN = 615
0	14 (13.5)	3 (4.5)	55 (8.9)
1	8 (7.7)	9 (13.6)	83 (13.5)
2	5 (4.8)	3 (4.5)	30 (4.9)
3	0	0	2 (0.3)
4	0	0	1 (0.2)
5	0	0	0

The number of patients with ECOG score n (681 cases) is the number of patients who signed the ICF according to the version 2.0 protocol and were enrolled.

CRC, colorectal cancer; ECOG PS, Eastern Cooperative Oncology Group performance status.

Exposure to fruquintinib and dose intensity

The median time from the first diagnosis to the first fruquintinib medication was 21.36 months for all patients with CRC. A shorter median time was observed in young patients with CRC (18.96 months), whereas for the late elderly patients with CRC, it was 23.02 months. A higher proportion of young patients started with an initial dose of 5 mg (72.7%) compared to the late elderly group (46.0%), indicating greater initial treatment intensity in the younger cohort. The durations of median treatment exposure for the young and late elderly groups were 2.75 and 2.40 months, respectively. The proportion of patients who underwent dose reduction was lower in young patients (10.9%) than in overall patients with CRC (15.7%). Among the late elderly patients with CRC, 16.3% underwent dose reduction. The relative dose intensity was lower in the late elderly group (72.00%) compared to the young group (90.70%), suggesting reduced tolerability among late elderly patients, highlighting the need for individualized dose planning in elderly patients (Table 3).

Table 3.

Drug exposure and dose adjustment of fruquintinib in different age groups.

Characteristics	Age <50N = 512	Age ⩾75N = 239	All CRCN = 2798
Total exposure time (months)
Median (IQR)	2.75 (1.40, 5.70)	2.40 (1.10, 5.20)	2.70 (1.40, 5.70)
<6 months	408 (79.7)	199 (83.3)	2207 (78.9)
⩾6 months	104 (20.3)	40 (16.7)	591 (21.1)
Relative dose intensity (%)
Overall, median (IQR)	90.70 (72.00, 101.30)	72.00 (56.00, 96.00)	85.30 (61.30, 101.30)
Mono, median (IQR)	N = 314	N = 173	N = 1888
	93.30 (72.00, 101.30)	72.00 (56.00, 98.70)	85.30 (64.00, 101.30)
Combo, median (IQR)	N = 174	N = 52	N = 775
	88.00 (72.00, 101.30)	61.30 (50.70, 82.70)	82.70 (61.30, 98.70)
First dose N (n%)
5 mg	372 (72.7)	110 (46.0)	1850 (66.1)
4 mg	54 (10.5)	35 (14.6)	288 (10.3)
3 mg	82 (16.0)	83 (34.7)	620 (22.2)
⩽2 mg	4 (0.8)	11 (4.6)	40 (1.4)
Dose adjustment category, n (%)
Dose reduction	56 (10.9)	39 (16.3)	439 (15.7)
Dose interruption	105 (20.5)	41 (17.2)	522 (18.7)
Dose increased	29 (5.7)	16 (6.7)	166 (5.9)
Reasons for dose adjustment, n (%)
Adverse events	95 (18.6)	56 (23.4)	619 (22.1)
Others	88 (17.2)	31 (13.0)	434 (15.5)

Combo, combination therapy: (fruquintinib + chemotherapy or ICI); CRC, colorectal cancer; ICI, immune checkpoint inhibitors; IQR, interquartile range; Mono, monotherapy.

Duration of treatment with fruquintinib alone or in combination therapy

Of all patients with CRC, 1888 (67.48%) received fruquintinib monotherapy. In the subgroups, 61.33% of young and 72.38% of late elderly patients with CRC received fruquintinib monotherapy. The median exposure time of fruquintinib monotherapy was 2.50, 2.40, and 2.10 months for all patients with CRC, young patients, and the late elderly patients, respectively. Notably, the longest exposure time was observed in the fruquintinib + chemotherapy + ICI group in young (5.9 months), late elderly (5.7 months), and all CRC (4.7 months) groups, as shown in Table 4. This suggests that combination therapy may be more favorable in selected patients, particularly the younger ones.

Table 4.

Exposure of patients in subgroups to fruquintinib monotherapy or combination therapy in different age groups.

Exposure duration (months)median (IQR)	Age <50N = 512	Age ⩾75N = 239	All CRCN = 2798
Fruquintinib monotherapy	N = 314	N = 173	N = 1888
	2.40 (1.20, 5.30)	2.10 (1.00, 4.30)	2.50 (1.20, 5.50)
Combination therapy^a	N = 174	N = 52	N = 775
	4.10 (1.90, 6.10)	3.90 (2.00, 5.80)	3.60 (1.80, 6.00)
Fruquintinib + chemotherapy	N = 74	N = 29	N = 359
	5.20 (1.90, 6.10)	3.40 (1.00, 6.10)	3.80 (1.80, 6.00)
Fruquintinib + ICI	N = 120	N = 29	N = 493
	3.75 (1.95, 6.10)	4.60 (2.80, 5.60)	3.60 (1.80, 6.00)
Fruquintinib + chemotherapy + ICI	N = 20	N = 6	N = 77
	5.90 (3.15, 6.30)	5.70 (4.20, 6.40)	4.70 (2.40, 6.20)

Fruquintinib + chemotherapy or ICI.

CRC, colorectal cancer; ICI, immune checkpoint inhibitor; IQR, interquartile range.

Safety

In this study, 77.52% of patients with CRC experienced TEAE, including 78.71% in the young CRC group and 77.41% in the late elderly CRC group. Grade ⩾3 TEAEs were reported in 24.66% of all patients with CRC and 24.22% and 26.78% in young and late elderly patients with CRC, respectively.

The TRAEs of any grade were reported in 64.76% of all patients with CRC, 64.65% of young patients with CRC, and 64.44% of late elderly patients with CRC. However, TRAEs of grade ⩾3 were higher in the late elderly group (16.74%) compared to the young group (9.96%), highlighting potential increased susceptibility to SAEs in older patients (Table 5).

Table 5.

Adverse events summary in different age groups.

Adverse event n (%)	Age <50N = 512	Age ⩾75N = 239	All CRCN = 2798
TEAE	403 (78.71)	185 (77.41)	2169 (77.52)
⩾Grade 3 TEAE	124 (24.22)	64 (26.78)	690 (24.66)
SAE	65 (12.70)	36 (15.06)	317 (11.33)
TEAE to death	41 (8.01)	17 (7.11)	162 (5.79)
TEAE leading to dose modification	91 (17.77)	54 (22.59)	608 (21.73)
TEAE leading to dose discontinuation	76 (14.84)	56 (23.43)	448 (16.01)
TRAE	331 (64.65)	154 (64.44)	1812 (64.76)
⩾Grade 3 TRAE	51 (9.96)	40 (16.74)	407 (14.55)
Serious TRAE	12 (2.34)	13 (5.44)	84 (3.00)
TRAE leading to death	1 (0.20)	2 (0.84)	8 (0.29)
TRAE leading to dose modification	74 (14.45)	50 (20.92)	546 (19.51)
TRAE leading to dose discontinuation	53 (10.35)	43 (17.99)	347 (12.40)

CRC, colorectal cancer; SAE, serious adverse event; TEAE, treatment-emergent adverse event; TRAE, treatment-related adverse event.

The most common TRAEs (⩾10%) in the overall CRC population were palmar-plantar erythrodysesthesia ((PPES) 20.34%), hypertension (16.55%), and fatigue (10.44%). In both age groups, PPES was one of the most common TRAEs, occurring more frequently in the young patients (20.31%) than the late elderly patients (14.23%). However, the proportion grade ⩾3 PPES remained low across groups, with slightly higher rates in young patients (1.17% vs 0.42%), suggesting that while PPES are common, their severity remains manageable across age groups.

By contrast, hypertension showed an age-related difference, with a higher proportion of patients with hypertension in the late elderly CRC group (20.50%) than the young CRC group (14.06%). The grade ⩾3 hypertension was nearly three times higher in the late elderly (11.72%) than in younger patients (3.91%), underscoring the need for close blood pressure monitoring in late elderly patients. Other common TRAEs in young patients included dysphonia (10.16%), fatigue (8.59%), and diarrhea (8.40%), while the late elderly group had higher rates of fatigue (12.97%) and decreased appetite (12.55%). The summaries of common TRAEs and grade ⩾3 TRAEs by subgroups are presented in Table 6.

Table 6.

The most common TRAEs in different age groups.

No.	PT, n (%)	Age <50N = 512		Age ⩾75N = 239		All CRCN = 2798
No.	PT, n (%)	Any grade	⩾Grade 3	Any grade	⩾Grade 3	Any grade	⩾Grade 3
1	PPES	104 (20.31)	6 (1.17)	34 (14.23)	1 (0.42)	569 (20.34)	67 (2.39)
2	Hypertension	72 (14.06)	20 (3.91)	49 (20.50)	28 (11.72)	463 (16.55)	192 (6.86)
3	Fatigue	44 (8.59)	1 (0.20)	31 (12.97)	1 (0.42)	292 (10.44)	14 (0.50)
4	Decreased appetite	28 (5.47)	1 (0.20)	30 (12.55)	1 (0.42)	237 (8.47)	11 (0.39)
5	Dysphonia	52 (10.16)	0	22 (9.21)	0	232 (8.29)	1 (0.04)
6	Diarrhea	43 (8.40)	4 (0.78)	13 (5.44)	0	218 (7.79)	21 (0.75)
7	Proteinuria	30 (5.86)	1 (0.20)	19 (7.95)	3 (1.26)	177 (6.33)	21 (0.75)
8	Platelet count decreased	21 (4.10)	4 (0.78)	9 (3.77)	2 (0.84)	120 (4.29)	17 (0.61)
9	Abdominal pain	19 (3.71)	1 (0.20)	4 (1.67)	0	83 (2.97)	8 (0.29)
10	Vomiting	13 (2.54)	0	7 (2.93)	0	65 (2.32)	3 (0.11)

CRC, colorectal cancer; PPES, Palmar-plantar erythrodysesthesia syndrome; PT, primary term; TRAE, treatment-related adverse event.

Discussion

Randomized controlled trials set the standard for the efficacy and safety of cancer treatments. However, due to strict enrollment limitations and age-related disparities, they lack the representation of diverse participants, which may limit the use in a broader population,^35,36 including the young (<50) and late elderly patients (⩾75 years). Nevertheless, understanding the treatment patterns and outcomes is crucial for developing new treatment strategies for these age groups.^37,38

Baseline characteristics

With China’s aging population, leading to a rise in elderly patients with cancer,³⁹ this study provides a large elderly sample size (n = 239) with a median age of 78 years to evaluate the safety of treatment regimens containing fruquintinib in the real world, providing data reference for future treatment of such patients.

Data from the last decade show that the incidence of YOCRC in adults (<50 years) is increasing.^40,41 Our study, which includes 512 young CRC patients (18.3%), met the YOCRC criteria at the initial diagnosis, with a median age of 42 years and a median time to diagnosis of 18.96 months. This subgroup analysis offers valuable insights into treatment patterns and safety of fruquintinib as both monotherapy and in combination with other interventions in young CRC patients.

In this study, there was a notable difference between the young and the late elderly patients with CRC. Despite CRC being more prevalent in men, the proportion of women was higher in the young (51%) compared to late elderly patients (41%). Similar findings were observed in the study by Vuik et al.,⁴² where a higher proportion of early-onset colorectal cancer (EOCRCs) were diagnosed in women under 30 years of age.⁴² This could be attributed to several factors, such as family history of CRC, differences in dietary intake, inflammatory bowel disease, sedentary lifestyle, diabetes, and obesity—all of which are risk factors for CRC.^43
–45 In addition, other contributing factors may include limited routine screening, particularly among women, who are generally less likely to participate in routine screening programs, inadequate access to healthcare services, and cultural and social barriers affecting their ability to obtain care.⁴⁶ This delayed detection may explain the higher incidence of more severe cases in young women.

The median time from initial diagnosis of CRC to fruquintinib treatment was relatively shorter in young patients (18.96 months) compared with that of late elderly patients (23.02 months) and overall CRC patients (21.36 months). EOCRC patients usually exhibit more aggressive tumor biology characterized by a higher risk of lymph node metastases, frequent presence of signet-ring cells, and poorly differentiated tumors.⁴² Therefore, these patients are often presented with symptoms at an advanced stage of the disease, resulting in a shorter time from initial diagnosis to treatment compared with the late elderly group.

Treatment patterns

The median duration of treatment across age subgroups was comparable (young, 2.75 vs overall, 2.70 vs late elderly, 2.40), indicating that both subgroups could benefit from this treatment. However, the relative dose intensity was higher in young patients with CRC than in the late elderly patients and all patients with CRC, with a higher proportion of young patients starting with the first dose of 5 mg and a lower frequency of dose reductions, indicating that young patients tend to receive more intensive treatment and tolerate a higher dose of fruquintinib. A recent systematic review and meta-analysis found a significantly higher risk of mortality in cancer patients receiving carboplatin-based, FOLFOX-, or FOLFIRI-based regimens at an RDI of less than 80% or 85%, compared to those treated at an RDI of 80% or 85% or higher.⁴⁷ These findings are in line with those reported by Havrilesky,⁴⁸ who observed improved survival outcomes in patients with advanced or metastatic lung, breast, or ovarian cancer receiving chemotherapy at a relative RDI of ⩾85%. Given the higher RDI observed in younger patients in this study, they may be more likely to achieve better treatment outcomes, highlighting the potential benefit of maintaining dose intensity in this subgroup. Identifying patient subgroups that would benefit the most from combination therapy and optimizing treatment regimens are essential for effective CRC management.

In the current study, 33.98% of the young patients received combination therapy. The median relative dose intensity of combination therapy in young patients was lower compared with that of monotherapy (88.00% vs 93.3%), but remained above the 85% threshold associated with improved outcomes, as highlighted in the study by Havrilesky.⁴⁸ The median duration of combination therapy in young patients was longer than that of monotherapy (4.10 vs 2.40), especially when fruquintinib was combined with chemotherapy (median duration of treatment: 5.20 months). The treatment time of the drug might correlate with the survival benefit, which also suggests that the use of appropriate combination therapy in young patients may result in improved survival.

Among the late elderly group, 21.76% of the patients received combination therapy. The median relative dose intensity in this subgroup was also lower for the combination therapy as compared with monotherapy (61.30% vs 72.00%). Elderly patients face a higher risk of chemotherapy-related toxicities, such as febrile neutropenia and asthenia, which frequently result in reduced relative dose intensity and may compromise treatment efficacy.⁴⁹ The duration of combination therapy in the late elderly patients was also longer than that of monotherapy (3.90 vs 2.10 months), especially in fruquintinib combined with ICI (median duration of treatment: 4.60 months), suggesting that combined treatment also improves the outcomes in the late elderly patients. Therefore, the late elderly patients should receive an individualized treatment plan considering their overall health condition, choosing an appropriate individual starting dose, and actively adjusting it, to optimize the treatment benefits. Combination therapy, particularly when fruquintinib is combined with chemotherapy or ICIs, may not only improve treatment duration but also enhance tumor response, providing a more robust strategy for managing both young and elderly patients with CRC. This study suggests that combination therapy could prolong treatment duration across both age groups, potentially leading to improved survival outcomes.

Safety

In the FRESCO trial, 98.6% of patients experienced ⩾1 TEAE and 95.7% experienced ⩾1 TRAE.¹⁶ Similar safety findings have been reported with other VEGF/VEGFR-targeted therapies.^50,51 For instance, the findings from the AVEX phase III trial,⁵¹ which evaluated bevacizumab plus capecitabine combination therapy in elderly patients with mCRC, reported that 96% of patients experienced an AE of any cause, with 84% being TRAE. Grade ⩾3 AEs and SAEs occurred in 60% and 30% of patients in the bevacizumab combination therapy group. Likewise, in the RAISE trial,⁵⁰ which evaluated ramucirumab plus FOLFIRI versus placebo in second-line mCRC patients who had progressed after first-line bevacizumab-based therapy, grade ⩾3 AEs were observed in 79% of patients in the ramucirumab group. In the CORRECT trial, TRAEs occurred in 93% patients, and grade 3 or 4 TRAEs occurred in 54% patients assigned regorafenib.⁵²

In comparison, the present study demonstrated a more favorable safety profile across all age groups. The incidence of TEAEs in all patients with CRC, young patients, and late elderly patients with CRC was 77.52%, 78.71%, and 77.41%, respectively, which was lower than the TEAE rates reported in FRESCO, AVEX, and RAISE trials.^16,50,51 AE-related dose adjustment was less frequent in the present study, occurring in 17.77% of young patients, 22.59% of late elderly patients, and 21.73% of all CRC. This contrasts with higher dose adjustment rates reported in FRESCO (47.1%), AVEX (55%), RAISE (83%), and CORRECT (76%) trials.^16,50
–52 Permanent discontinuation due to AE in the current study was higher in late elderly patients (23.43%) as compared to young patients (14.84%) and all CRC (16.01%). These rates were relatively lower compared to AVEX (25%), FRESCO (15.1%), and RAISE (11%) trials.^51,16,50 The slightly elevated discontinuation rate among late elderly patients in our cohort highlights the need for an individualized treatment approach in the older population, considering their overall condition.

The common TRAEs in the overall population, young, and late elderly patients with CRC were relatively consistent, but the order of incidence varied, reflecting age-related characteristics. Notably, the overall incidence of TRAEs was lower compared to those reported in the CORRECT and CONCUR studies.^52,53

The incidence of PPES in late elderly patients (14.23%) ranked only second, whereas in young patients (20.31%), it remained the most common AE. The low rates of grade ⩾3 events suggest that PPES is generally manageable with supportive care. The incidence of hypertension in late elderly patients was numerically higher (20.50%) than in all patients with CRC (16.55%) and young patients (14.06%). Hypertension, a common TRAE in our study, is a particular concern in older populations due to its potential to exacerbate underlying cardiovascular conditions, which may limit treatment options or necessitate dose adjustments. Overall, treatment-related deaths occurred in 0.29% of the population in our study, which is numerically lower than those reported in the AVEX study (4%).⁵¹

Conclusion

Fruquintinib showed a manageable safety profile across the different age groups, including young CRC patients undergoing more intensive treatment and the late elderly patients. The late elderly subgroup demonstrated a higher incidence of clinically relevant AEs, particularly hypertension and treatment discontinuation, underscoring the importance of proactive blood pressure management, regular cardiovascular monitoring, and timely dose adjustments as part of individualized treatment planning in this population. This study found that combination therapy could prolong the treatment duration in patients of different age groups, which is associated with enhanced survival benefits. Young patients tend to receive more intensive treatment in the real world, and the dose intensity of fruquintinib administered is relatively high; however, the late elderly patients can also fully benefit from optimized individual treatment.

Supplemental Material

sj-docx-1-tam-10.1177_17588359251363537 – Supplemental material for Safety of fruquintinib in Chinese patients with colorectal cancer: an age subgroup analysis from a phase IV real-world clinical practice study

Supplemental material, sj-docx-1-tam-10.1177_17588359251363537 for Safety of fruquintinib in Chinese patients with colorectal cancer: an age subgroup analysis from a phase IV real-world clinical practice study by Yi Wang, Yifu He, Zhiqiang Wang, Haijun Zhong, Zuoxing Niu, Shujun Yang, Tao Zhang, Liangjun Zhu, Yongqian Shu, Jianjun Peng, Yan Song, Jian Li, Ying Yuan, Haibo Zhang, Gengsheng Yu, Yunqi Hua, Jianjun Xiao, Jianfei Fu, Yulong Zheng, Jingyu Zhu, Hua Xue, Xian Luo, Michael Shi, Weiguo Su, Jin Li and Shukui Qin in Therapeutic Advances in Medical Oncology

Footnotes

Acknowledgements

We thank patients and their families who participated in the study, as well as the physicians and site staff who supported data collection and patient care. Medical writing support for the development of this manuscript was provided by Krithishree S. and Roopashree Subbaiah, PhD, of Indegene Limited, Bangalore, India, under the direction of the authors.

Declarations

ORCID iDs

Zhiqiang Wang

Ying Yuan

Shukui Qin

Supplemental material

Supplemental material for this article is available online.

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