Later lines of systemic therapy in patients with metastatic colorectal cancer: real-world data from a setting with barriers to access cancer therapies

Introduction

Colorectal cancer (CRC) is the third most diagnosed cancer and the second most lethal amongst both men and women, with more than 1.88 million cases and 915,000 deaths annually worldwide (1). Of newly diagnosed patients with CRC, approximately 20% have metastatic disease at presentation (2) and 40% of patients present with recurrence after previously treated localized disease (3). In general, the prognosis of metastatic CRC (mCRC) is poor, with a 5-year survival rate of less than 15% (4).

The cornerstone of the systemic therapy of mCRC is fluoropyrimidine-based chemotherapy, which may be offered in doublets or triplets with oxaliplatin and/or irinotecan, with or without monoclonal antibodies targeting vascular endothelial growth factor (VEGF). In patients with RAS wild-type mCRC, monoclonal antibodies targeting epidermal growth factor receptor (EGFR) may also be used. However, the most appropriate way to combine and sequence these agents is continuing to evolve. Furthermore, patients who progress despite being exposed to standard therapies may still maintain good performance status and be eligible for further treatment. Approved oral agents for third-line and beyond are regorafenib and trifluridine/tipiracil (TFD/TPI).

Systemic therapy for chemorefractory mCRC is an unmet clinical need. Immune checkpoint inhibitors and BRAF inhibitors may be used in subgroups of patients who harbor high-frequency microsatellite instability (MSI-H) and BRAF V600 mutations, respectively, but regorafenib and TFD/TPI ± bevacizumab are the only available therapies with demonstrated survival benefit in an unselected population of microsatellite stable (MSS) chemorefractory mCRC patients, which compose the vast majority of the population. However, these two oral drugs are not widely accessible worldwide (5-10).

Despite the remarkable recent progress in cancer therapy, access to the standard of care remains highly unequal, and disparities in cancer treatments are a major health issue globally, mainly in low- and middle-income countries (LMIC) (11,12). Regorafenib and TFD/TPI have not yet been approved by many national agencies worldwide or they have not been regularly covered by health insurances. The treatment patterns and clinical outcomes of patients with chemorefractory mCRC with limited access to those drugs is unknown. The knowledge of the real-world data (RWD) is imperative to characterize cancer disparities in global population and will contribute to the development of solutions to achieve health equity (13,14).

In Brazil, CRC is the second most diagnosed cancer and the third most lethal in both men and women (15). Regorafenib and TFD/TPI were approved for clinical use in the country only in 2016 and 2020, respectively, but they were not covered by health agencies in the interval time in which the data was collected. In this retrospective multicentric study, we aimed to describe the treatment patterns and clinical outcomes of patients with chemorefractory mCRC treated in a setting with limited access to drugs indicated for later lines of therapy. We present this article in accordance with the STROBE reporting checklist (available at https://jgo.amegroups.com/article/view/10.21037/jgo-24-524/rc).

Methods

We conducted a retrospective study evaluating 510 patients with mCRC who were treated at Oncoclinicas, in five different centers (Salvador, Rio de Janeiro, São Paulo, Belo Horizonte, and Porto Alegre), from January 2011 to December 2019. Throughout this period, we assume that patients were treated in a setting with limited resources, since they had barriers to access the standard of care of chemorefractory mCRC. Demographic and clinical data were retrieved from randomly selected electronic medical records and inserted in the case report form of RedCap by medical oncologists in each center. In order to have higher availability of molecular and clinical data, we started from 2019 and tried to reach at least 100 patients from each center. From the aforementioned population of patients, we focused our analysis on the characteristics and the clinical outcomes of the patients who were exposed to third-line and beyond systemic therapy.

Those tumors located from the cecum to the splenic flexure were deemed as right-sided. RAS (KRAS and NRAS) and BRAF V600E mutations were evaluated in tumor tissue by polymerase chain reaction (PCR) method. Mismatch repair (MMR) status was evaluated by immunohistochemistry for MLH1, MSH2, MSH6, and PMS2 proteins.

The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). The study was approved by the institutional review board of the Faculdade de Ciências Médicas de Minas Gerais (FCM-MG) (No. CAAE: 38435820.1.0000.5134) and individual consent for this retrospective analysis was waived.

Statistical analysis

Overall survival (OS) was defined as the time, in months, elapsed from the date of initiation of third-line therapy to the date of death from any cause. The patients lost to follow-up were censored on the date of last contact with the center. The median OS was assessed via Kaplan-Meier (KM) method along with 95% confidence interval (CI). Median follow-up was evaluated by KM reverse. The prognostic factors associated with survival were evaluated via multivariable Cox regression, calculating the hazard ratio (HR) and the 95% CI. A final model was developed using a stepwise backward selection strategy. The analyses were performed using the SPSS software, version 29.0.0.0.

Results

Among the 510 patients with mCRC, 82 were excluded from the analysis due to missing data regarding systemic therapy and/or survival (flow diagram in Figure 1). From the 428 patients eligible for survival analysis, 148 (35%) and 65 (15%) received third- and fourth-line systemic therapy, respectively.

Figure 1 Flow diagram. mCRC, metastatic colorectal cancer.

Focusing on the population of patients who received third-line and beyond systemic therapy (N=148), RAS mutations were found in 48% of patients, and BRAF V600 mutations and dMMR phenotype in 6% each. The majority of this population also presented with liver and lung metastases (76% and 64%, respectively), and most patients (87%) had been submitted to a primary tumor resection (Table 1).

The median number of lines of therapy was 3, and metastasectomy was performed in 62% of the patients. From the initiation of third-line therapy, the median follow-up was 17.8 months, with 58% of deaths, and a median OS of 13.1 months (95% CI: 8.1–18.0) (Figure 2).

Figure 2 Overall survival of the population of patients who were submitted to third-line and beyond systemic therapies (time elapsed from the beginning of third-line to the last date).

The most adopted regimens in third- and fourth-line settings were re-exposure to previous regimens followed by regorafenib and TFD/TPI (Table 2). Despite not being covered by health insurances during the period of this study, some patients had access to those oral drugs by legal prosecutions or international imports.

Variables were chosen for the univariate analysis based on the number of events (86 deaths) in this population (N=148) and on the sample size of each variable of the patient characteristics (Table 1). Therefore, we chose six variables, excluding age, BRAF V600 and dMMR (small sample size), and from the five metastatic sites, we chose peritoneal metastases since it is a well-recognized prognostic factor in mCRC. In a multivariable model (N=148), male patients (HR: 1.98, 95% CI: 1.05–3.74, P=0.03) and right-sided tumors (HR: 2.74, 95% CI: 1.18–6.35, P=0.01) were significant prognostic factors for OS (Table 3).

In Table S1, we listed the treatments used in first-line and subsequent therapies of the 499 patients who had availability of these data.

Discussion

Systemic therapy in patients with mCRC exposed to fluoropyrimidines, oxaliplatin, irinotecan, anti-VEGF, and anti-EGFR monoclonal antibodies is an unmet clinical need and these patients have dismal prognosis. In a real-world setting with limited access to later-line therapies with demonstrated benefit in OS, re-exposure to chemotherapy was the main therapeutic strategy in the treatment of patients with chemorefractory mCRC, with potential negative influence on OS. Nevertheless, this population presented with a meaningful OS of 13.1 months, which could be further improved if the patients received the standard of care (regorafenib and TFD/TPI) in later lines.

The largest placebo-controlled randomized clinical trials (RCTs) of later-line therapeutic strategies with oral agents alone (TFD/TPI and regorafenib) report a median OS of 7.1 and 7.8 months with TFD/TPI in the RECOURSE (6) and the TERRA (16) trials, respectively, and a median OS of 6.4 and 8.8 months with regorafenib in the CORRECT (5) and the CONCUR (17) trials, respectively. In light of these results, both therapies were approved by the United States Food and Drug Administration (FDA) for use in later-line indications. RWD studies corroborate those phase III data. The prospective, multicenter, single-arm CONSIGN study, showed a median duration of treatment with regorafenib of 2.5 months and a median progression-free survival (PFS) of 2.7 months (18). Seventy-four percent of the patients had received at least three prior regimens for mCRC. Additionally, in the CORRELATE study, a prospective observational cohort conducted in 126 centers evaluating regorafenib for mCRC in real-world practice (19), the investigators reported median duration of treatment of 2.5 months, median PFS of 2.9 months, and median OS of 7.7 months. Real-life data show similar outcomes for TFD/TPI, as shown in a study with 341 patients with mCRC, who presented 6-month PFS rate of 19% and median OS of 6.2 months (20). In parallel, results from expanded access use in the United States, Spain and United Kingdom reported similar results to the RECOURSE original study (6,21-23). Nowadays, ideally, TFD/TPI should be offered in combination with bevacizumab according to the SUNLIGHT study (24). The addition of the anti-angiogenic significantly increased the median PFS (5.6 vs. 2.4 months, HR: 0.44, 95% CI: 0.36–0.54) and the OS (10.8 vs. 7.5 months, HR: 0.61, 95% CI: 0.49–0.77), and it has become the standard of care of chemorefractory mCRC. Nevertheless, the combination of TFD/TPI plus bevacizumab has not yet been universally approved worldwide, so that the discussion of the sequencing of systemic therapy in chemorefractory setting remains clinically relevant.

The longer OS (13.1 months) observed in this study population compared to the previous studies may be due to the characteristics of the patients selected. The patients in this study presented with a higher-than-expected percentage of left-sided tumors (80%) and metastasectomy (62%), and with a low rate of RAS mutations (48%). These favorable prognostic factors in a small sample size, associated with other variables not analyzed in this study, probably explain the superior OS. Generalizability of these results should be seen with caution and might need to be externally validated in other data sets and populations of different characteristics.

The low number of patients exposed to both oral drugs in this study do not allow an adequate comparison with previous studies. The optimal sequencing of these oral treatment strategies has not yet been established and can be considered relevant to clinical practice since both agents are indicated in the same setting and share the same administration route. But the available data suggest that trying to expose patients to both drugs is more important than the sequence of them, which reinforces the core principle of the systemic therapy of mCRC, that is optimizing the continuum of care, exposing the patient to all the available cytotoxics with minimal toxicity burden (25). To date, no RCTs comparing TFD/TPI and regorafenib have been conducted and indirect comparisons have been made, reporting no differences in efficacy between the two drugs (20,26-28).

Both regorafenib and TFD/TPI were not obligatorily covered by Brazilian health agencies in the interval in which the data was collected (as of December 2019). The limited access to those drugs is the main reason for the low rates of their use in later lines of therapy in the studied population. Regorafenib and TFD/TPI were used by only 13% and 2% of the patients in third-line, respectively, and by 25% and 4% in fourth-line. Despite novel diagnostics and therapeutics, cancer disparities persist across many countries worldwide (29). RWD studies are paramount to identify patterns of care in clinical practice, outside of the controlled environments of clinical trials. These data produce insights to help improve clinical decision-making and, ultimately, lead to better therapeutic options to the patients. RWD studies in patient populations with restricted or no access to the standard of care, as demonstrated in our study, evidence the persistence of cancer health disparities.

Therefore, in clinical settings characterized by limited therapeutic access, even in the absence of robust randomized data, re-exposure to previously used lines of chemotherapy, as well as anti-EGFR or anti-VEGF drugs, is commonly used as shown in the present study. Oxaliplatin is one of the main backbones of chemotherapy and a pooled analysis of the OPTIMOX trials shows that re-exposing sensitive patients after an oxaliplatin-free interval of at least 6 months is a reasonable strategy. Thus, oxaliplatin reintroduction is an important option to be considered in third-line settings (30,31). In the present study, 39% and 26% of the patients were submitted to a rechallenge strategy with oxaliplatin in the third- and fourth-line settings, respectively.

Previous studies aimed at evaluating retreating patients with oxaliplatin-based regimens after disease progression to oxaliplatin in previous lines showed modest results (32-34). Studies evaluating re-exposure to irinotecan-based regimens are even more limited. Recent studies have explored the promising and evolving strategy of rechallenge with anti-EGFR monoclonal antibodies in RAS/BRAF wild-type patients. Both CRICKET (35) and CHRONUS (36) trials have demonstrated that previously sensitive patients may derive clinical benefit from rechallenge with anti-EGFR, mainly if ctDNA-guided.

This study has several limitations, such as its retrospective design, small sample size, and the aforementioned selection bias. In addition, our study reports data only from private health system in Brazil. Reporting additional data from public health system might contribute to a better analysis of cancer health disparities. Nevertheless, our study originally demonstrates RWD of patterns of mCRC in the private health system in five cities in Brazil, which harbor the largest population of cancer patients in Latin America.

Conclusions

In summary, this study reports that reexposure to previous regimens of chemotherapy was the most adopted therapeutic option in third-line and beyond systemic therapy of mCRC in Brazil, demonstrating limited access to the standard of care, with potential negative impact on the quality of life and survival of these patients. Ultimately, it demonstrates how access barriers hamper the achievement of health equity in cancer care and increases the awareness of patients and stakeholders, contributing to engaging them in ensuring equitable access to high-quality cancer care.

Acknowledgments

Funding: The present study was funded by Bayer (No. 21712 IIR), which had no role in the study design, data collection, analyses, and manuscript writing.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://jgo.amegroups.com/article/view/10.21037/jgo-24-524/rc

Data Sharing Statement: Available at https://jgo.amegroups.com/article/view/10.21037/jgo-24-524/dss

Peer Review File: Available at https://jgo.amegroups.com/article/view/10.21037/jgo-24-524/prf

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jgo.amegroups.com/article/view/10.21037/jgo-24-524/coif). All authors are current Oncoclinicas affiliates. A.A.J. reports funding for the present study from Bayer; consulting fees from Bayer, Servier, MSD, Takeda; payment or honoraria for lectures, presentations, speakers’ bureaus, manuscript writing or educational events from Roche, Amgen, Servier, MSD; and support for attending meetings and/or travel from Servier and Daiichi-Sankyo. Rafael D. Paes reports payment or honoraria for lectures, presentations, speakers’ bureaus, manuscript writing or educational events from Teva and Libbs. Renata D’Alpino Peixoto reports payment or honoraria for lectures, presentations, speakers’ bureaus, manuscript writing or educational events from Bayer, Servier, AstraZeneca, Roche, Lilly, BMS, MSD; support for attending meetings and/or travel from AstraZeneca, Roche; Participation on a Data Safety Monitoring Board or Advisory Board from AstraZeneca, Astellas, Bayer; Leadership or fiduciary role in other board, society, committee or advocacy group, paid or unpaid as Scientific Director of the Grupo Brasileiro de Tumores Gastrointestinais. The authors have no other conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). The study was approved by the institutional review board of the Faculdade de Ciências Médicas de Minas Gerais (FCM-MG) (No. CAAE: 38435820.1.0000.5134) and individual consent for this retrospective analysis was waived.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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