TAS-102 Plus Bevacizumab as an Effective and Well Tolerated Regimen in Chemotherapy-Refractory Advanced Colorectal Cancers – A Single Institution Retrospective Analysis

Abstract

Ritam Joarder

Objective There are limited data on the utility of TAS-102 plus bevacizumab in patients with chemotherapy-refractory metastatic colorectal cancer (mCRC) treated in India.

Methods Patients diagnosed with chemotherapy-refractory mCRC, defined as having received at least prior oxaliplatin and irinotecan–based chemotherapy between January 2017 and January 2022, and who began treatment with a combination of TAS-102 and bevacizumab were retrospectively analyzed for demographic variables, survivals, and prognostic parameters. The primary endpoint of the study was estimation of the median overall survival (OS) by the Kaplan–Meier method.

Results The data of 143 patients satisfied the prespecified inclusion criteria and were included for analysis. There was a predominance of left-sided CRCs (78%) and patients having greater than two sites of distant metastases (87%), with 41% of patients with at least two lines of prior therapy. With a median follow-up of 11.6 months, the median OS of the entire cohort was 10.9 months, while the median progression-free survival was 4.4 months. The combination was well tolerated, with the most common grade 3/4 side effects being neutropenia (25%), anemia (6%), and thrombocytopenia (4%). Dose modifications in TAS-102 were required in 20% of patients, though this did not entail permanent cessation of TAS-102 in any patient. The presence of a resected primary was prognostic for improved OS (p < 0.001), while signet ring histology predicted inferior OS (p < 0.001).

Conclusion The combination of TAS-102 and bevacizumab is an efficacious and safe therapeutic option in patients with mCRC who have received at least two lines of prior systemic therapy. There were no requirements for cessation of the combination in the current study, underlying the well-tolerated nature of the combination.

Keywords

bevacizumab - chemotherapy-refractory colorectal cancer - TAS-102 - tipiracil - trifluridine

Introduction

Colorectal cancer (CRC) is one of the leading causes of cancer-related morbidity and mortality across the world.[1] In India, CRCs accounts for approximately 4.9% of all new cancer patients and is responsible for about 4.5% of all cancer-related deaths in the country.[2] [3] Limited evidence suggests that a greater proportion of CRCs present as advanced or metastatic CRCs (mCRC; 28%) in India as compared to the United States and Europe (15–20%).[4]

The backbone of the management of advanced or mCRC is chemotherapy (predominantly 5-fluorouracil [5-FU] or oral analogues of 5-FU, irinotecan, and oxaliplatin), anti-vascular endothelial growth factor (anti-VEGF) inhibitors, and epidermal growth factor receptor (EGFR) inhibitors where indicated.[5] [6] [7] A small proportion of patients (5%) are treated with immune checkpoint inhibitors (ICIs) for microsatellite instability (MSI) mCRC.[8] [9]

However, a majority of patients with mCRC eventually have disease progression or loss of response to oxaliplatin and irinotecan–based therapies and are labeled as “chemotherapy-refractory” mCRC. Well-validated options in this scenario include TAS-102 (trifluridine–tipiracil) alone or with bevacizumab, regorafenib, and fruiquitinib.[10] [11] [12] [13] [14] TAS-102 is an orally active drug composed of a thymidine analog (trifluridine) and a thymidine phosphorylase inhibitor (tipiracil). In this study, we evaluated the efficacy and safety of TAS plus bevacizumab in patients with mCRC refractory to oxaliplatin and irinotecan–based chemotherapy.

Methods

Patient Selection

The current retrospective study aimed to evaluate the survivals of patients with mCRC who were considered chemotherapy refractory. The investigators evaluated data from a prospectively maintained CRC database at the Tata Memorial Hospital (TMH) and included patients who had been treated between January 2017 and January 2022. Patients included in the study satisfied the following criteria: histologically confirmed adenocarcinoma; radiologically confirmed unresectable or metastatic cancer; prior receipt of oxaliplatin- and irinotecan-based chemotherapy (irrespective of use of targeted therapeutic agents) at least (prior receipt of regorafenib, monotherapy with anti-EGFR-directed therapy as monotherapy was allowed); started on TAS-102 plus bevacizumab and had at least one follow-up visit documenting response postadministration, and had documented dates of starting and cessation of TAS-102 plus bevacizumab.

Clinical Data Collection

Data collected were demographic and clinical variables, disease-specific data including the RAS status, BRAF status, MSI, details of TAS-102 plus bevacizumab administration, adverse events, and oncologic outcomes. The primary endpoint of the study was estimation of the median overall survival (OS), while the secondary endpoints were was estimation of progression-free survival (PFS), overall response rates (ORR), and adverse event rates.

Ethics and Consent

The approval for the study was obtained from the Institutional Ethics Committee at the TMH (IEC418). The approval included the requirement of a short telephonic consent for patient data accrued at the TMH as part of ethics committee requirements. Data collection and handling were conducted as per the ethical guidelines of the declaration of Helsinki.

Statistics

Data were analyzed using IBM SPSS version 20 (Armonk, NY, United States). Descriptive statistics such as median, frequency, and percentage were used to summarize the categorical variables. The primary endpoint of the study was estimation of the median OS, which was calculated from the date of starting TAS-102 and bevacizumab to the date of death or loss of follow-up, whichever was earlier. Secondary endpoints were PFS, which was calculated from the date of diagnosis of starting TAS-102 and bevacizumab to the date of progression, loss to follow-up, or death, whichever was earlier, and overall response rates (ORR), which were calculated by combining the complete response (CR) and partial response (PR) rates, while the clinical benefit rate (CBR) was reported as a summation of the CR, PR, and stable disease (SD) rates. Grade 3 and 4 toxicities were recovered from medical records and reported as per the National Cancer Institute (NCI) common terminology criteria for adverse events (CTCAE) version 5.0. Survival analysis was performed using the Kaplan–Meier estimates, and the log-rank test was used for bivariate comparisons. Select prognostic factors were evaluated and those with a p-value of ≤0.05 on univariate analysis were considered significant.

Result

Baseline characteristics

A total of 143 patients satisfying the inclusion criteria were included in the study. Briefly, the median age of the patients was 52 years (range: 14–77 years); the majority of patients were Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) 0 or 1 (92%) and had left-sided primary CRC (78%) and 17% of the patients had signet ring histology. A detailed representation of the baseline characteristics is presented in [Table 1].

Table 1 Baseline demographic and preclinical characteristics

Characteristics	Number (%)
Median age (y)	52 (range: 14–77)
Sex  Male  Female	106 (74) 37 (26)
ECOG performance status  0–1  2  3	132 (92) 10 (7) 1 (1)
Primary tumor location  Right side colon  Left side colon  Rectum	31 (22) 35 (24) 77 (54)
Histology  MDAC  PDAC  None	82 (58) 40 (28) 21 (15)
Signet histology  Yes  No	24 (17) 119 (83)
No. of metastatic sites   < 2  ≥2	19 (13) 124 (87)
Site of metastatic disease  Liver  Lung  Lymph nodes  Peritoneum  Bone	73 (51) 23 (16) 8 (6) 37 (26) 2 (1)
RAS mutation status  Wild type  Mutant  Unknown	59 (41) 37 (26) 47 (33)
BRAF mutation status  Wild type  Mutant  Unknown	96 (77) 0 (0) 47 (33)
MMR status  Deficient  Proficient  Not available	0 (0) 113 (79) 40 (21)
Previous lines of therapy  ≤2   > 2	84 (59) 59 (41)
Resection of primary  Yes  No	81 (57) 62 (43)
Previous bevacizumab treatment  No  Yes	48 (33) 95 (67)
Previous regorafenib treatment  No  Yes	125 (87) 18 (13)

Abbreviations: ECOG, eastern cooperative oncology group; MDAC, moderately differentiated adenocarcinoma; MMR, Mismatch repair; PDAC, poorly differentiated adenocarcinoma; RAS, rat sarcoma virus.

Delivery of TAS-102 and Bevacizumab and Treatment-Related Adverse Events

Most patients (92%) were started on full dose of TAS-102 and bevacizumab. Dose modifications in TAS-102 were required in 29 patients (20%), with the most reasons for dose modifications being grade 3 and 4 hematological toxicities. No dose reductions in bevacizumab were required or made. Overall, the most common grade 3 and 4 treatment-related adverse events (TRAEs) were neutropenia (25%), thrombocytopenia (11%), and anemia (10%; [Table 2]).

Table 2 Treatment-related adverse events (TRAE)

TRAE	Grade 1–2	Grade 3-4
Anemia	92 (64)	14 (10)
Neutropenia	62 (43)	35 (25)
Thrombocytopenia	53 (37)	16 (11)
CINV	47 (33)	2 (1)
Diarrhea	34 (24)	5 (4)
Fatigue	48 (34)	–
Mucositis	11(8)	–
Hypertension	4 (3)	–
Bleeding	1 (1)	–

Response Rates, Survival, and Prognostic Factors

All patients had data available for response rates. Ten patients had a PR (7%), while 68 patients (48%) had SD as the best response to treatment. CBR for the overall cohort was 55%.

With a median follow-up of 11.6 months (95% confidence interval [CI]: 9.66–13.54), the median OS of the entire was 10.9 months (95% CI: 8.9–12.8) in the current study ([Fig. 1]). At the time of data analysis, 108 patients had disease progression (75%) and the median PFS for the entire cohort was 4.4 months (95% CI: 3.1–5.7). Of the factors evaluated as prognostic for OS, the presence of prior resection of the primary tumor predicted for improved OS, while signet ring histology predicted for inferior OS with TAS-102 and bevacizumab ([Supplementary Table S1], available online only).

Fig. 1 Overall survival. mOS, median overall survival.

Discussion

The current study highlights the clinical utility and safety of the combination of TAS-102 and bevacizumab in chemotherapy-refractory advanced CRC and is the first report on this combination from the Indian scenario.

There are limited efficacious treatment options for patients refractory to oxaliplatin and irinotecan–based therapy. The RECOURSE trial (comparing TAS-102 with placebo), the SUNLIGHT trial (comparing TAS-102 plus bevacizumab with TAS-102 alone), and other studies have clearly showed that TAS-102 with or without bevacizumab showed modest but relevant improvements in OS.[10] [12] [15] [16] The clinical profile of patients in this study has certain notable characteristics—17% of patients had signet ring histology, almost 60% of patients had greater than two sites of metastases, more than 40% of patients had received more than two lines of prior therapy, and a minority of patients had received prior regorafenib as well (13%). Despite these characteristics, the response rates and survivals of patients in this study is encouraging and on par with published trials and real-world evidence from other countries.[17] [18] As expected, most patients had disease stabilization as their best response to therapy. A majority of studies have shown median survivals upward of 10 months and the current study has shown similar outcomes. More importantly, it was a well-tolerated regimen with no requirements for drug cessation due to TRAEs. The well-tolerated nature of this regimen has led to its use in potentially frail patients with advanced CRC unsuitable for intensive systemic therapy.[19]

Two important points were noted in this study—the negative prognosis associated with signet ring histology and the improved outcomes in patients with resected tumors. Multiple previous datasets from India have shown that signet ring histology is a negative prognostic factor and further research is needed to delve into the biology of these aggressive tumors.[5] [20] [21] With regard to resection of the primary tumor conferring a survival advantage, a phase 3 trial from Japan has clearly shown the futility of primary tumor resections in patients with advanced mCRC.[22] [23]

The current study has caveats that need to be acknowledged. It evaluates a small cohort of patients retrospectively from a single institution and this limits the generalizability of the results. We have limited data on further treatment options offered to patients who had disease progression on TAS-102 plus bevacizumab.

In conclusion, the combination of TAS-102 and bevacizumab is an efficacious and safe therapeutic option in patients who have received at least two lines of prior systemic therapy (chemotherapy refractory). There were no requirements for cessation of the combination in the current study, underlying the well-tolerated nature of the combination.

Conflict of Interest

None declared.

• References

• 1 Sung H, Ferlay J, Siegel RL. et al. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 2021; 71 (03) 209-249
• 2 Asthana S, Khenchi R, Labani S. Incidence of colorectal cancers in India: A review from population-based cancer registries. Curr Med Res Pract 2021; 11 (02) 91
• 3 Mathew Thomas V, Baby B, Wang K. et al. Trends in colorectal cancer incidence in India. J Clin Oncol 2020; 38 (15) e16084-e16084
• 4 Patil PS, Saklani A, Gambhire P. et al. Colorectal cancer in India: an audit from a tertiary center in a low prevalence area. Indian J Surg Oncol 2017; 8 (04) 484-490
• 5 Ramaswamy A, Babu V, Kothari R. et al. Treatment of metastatic colorectal cancers in resource-constrained low- and middle-income countries (LMICS) scenario-outcomes, practice patterns, and commentary on treatment costs. South Asian J Cancer 2022; 11 (04) 293-298
• 6 Cervantes A, Adam R, Roselló S. et al; ESMO Guidelines Committee. Electronic address: [e-mail]. Metastatic colorectal cancer: ESMO Clinical Practice Guideline for diagnosis, treatment and follow-up. Ann Oncol 2023; 34 (01) 10-32
• 7 Sharma V, Sharma A, Raina V. et al. Metastatic colo-rectal cancer: real life experience from an Indian tertiary care center. BMC Cancer 2021; 21 (01) 630
• 8 André T, Shiu KK, Kim TW. et al; KEYNOTE-177 Investigators. Pembrolizumab in microsatellite-instability-high advanced colorectal cancer. N Engl J Med 2020; 383 (23) 2207-2218
• 9 Trikha M, Sarkar L, Dhanawat A. et al. Performance of low-dose immunotherapy and standard-dose immunotherapy in microsatellite instability-high metastatic colorectal cancer: real-world data (CLouD-high study). JCO Glob Oncol 2024; 10 (10) e2400141
• 10 Mayer RJ, Van Cutsem E, Falcone A. et al; RECOURSE Study Group. Randomized trial of TAS-102 for refractory metastatic colorectal cancer. N Engl J Med 2015; 372 (20) 1909-1919
• 11 Li J, Qin S, Xu R. et al; CONCUR Investigators. Regorafenib plus best supportive care versus placebo plus best supportive care in Asian patients with previously treated metastatic colorectal cancer (CONCUR): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol 2015; 16 (06) 619-629
• 12 Prager GW, Taieb J, Fakih M. et al; SUNLIGHT Investigators. Trifluridine-tipiracil and bevacizumab in refractory metastatic colorectal cancer. N Engl J Med 2023; 388 (18) 1657-1667
• 13 Dasari A, Lonardi S, Garcia-Carbonero R. et al; FRESCO-2 Study Investigators. Fruquintinib versus placebo in patients with refractory metastatic colorectal cancer (FRESCO-2): an international, multicentre, randomised, double-blind, phase 3 study. Lancet 2023; 402 (10395): 41-53
• 14 Ramaswamy A, Ostwal V, Pande N. et al. Practice patterns and outcomes with the use of regorafenib in metastatic colorectal cancer: results from the regorafenib in metastatic colorectal cancer: an Indian exploratory analysis study. South Asian J Cancer 2020; 08: 22-26
• 15 Su GL, Wang YY, Wang JC, Liu H. A meta-analysis comparing regorafenib with TAS-102 for treating refractory metastatic colorectal cancer. J Int Med Res 2020; 48 (07) 300060520926408
• 16 Abrahao ABK, Ko YJ, Berry S, Chan KKW. A comparison of regorafenib and TAS-102 for metastatic colorectal cancer: a systematic review and network meta-analysis. Clin Colorectal Cancer 2018; 17 (02) 113-120
• 17 Fujii H, Matsuhashi N, Kitahora M. et al. Bevacizumab in combination with TAS-102 improves clinical outcomes in patients with refractory metastatic colorectal cancer: a retrospective study. Oncologist 2020; 25 (03) e469-e476
• 18 Kagawa Y, Shinozaki E, Okude R, Tone T, Kunitomi Y, Nakashima M. Real-world evidence of trifluridine/tipiracil plus bevacizumab in metastatic colorectal cancer using an administrative claims database in Japan. ESMO Open 2023; 8 (04) 101614
• 19 Van Cutsem E, Danielewicz I, Saunders MP. et al. Trifluridine/tipiracil plus bevacizumab in patients with untreated metastatic colorectal cancer ineligible for intensive therapy: the randomized TASCO1 study. Ann Oncol 2020; 31 (09) 1160-1168
• 20 Ostwal V, Kapoor A, Engineer R. et al. Systemic chemotherapy and short-course radiation in metastatic rectal cancers: a feasible paradigm in unresectable and potentially resectable cancers. South Asian J Cancer 2019; 8 (02) 92-97
• 21 Ostwal V, Pande NS, Engineer R. et al. Low prevalence of deficient mismatch repair (dMMR) protein in locally advanced rectal cancers (LARC) and treatment outcomes. J Gastrointest Oncol 2019; 10 (01) 19-29
• 22 Huang Y, Ge K, Fu G, Chu J, Wei W. Efficacy of primary tumor resection in metastatic colorectal cancer. Med Sci Monit 2020; 26: e923501
• 23 Kanemitsu Y, Shitara K, Mizusawa J. et al; JCOG Colorectal Cancer Study Group. Primary tumor resection plus chemotherapy versus chemotherapy alone for colorectal cancer patients with asymptomatic, synchronous unresectable metastases (JCOG1007; iPACS): a randomized clinical trial. J Clin Oncol 2021; 39 (10) 1098-1107

Publication History

Received: 25 August 2024

Accepted: 28 November 2024

Article published online:
07 January 2025