Secondary Logo

Increasing Effectiveness of Chemo for Metastatic Colorectal Cancer

Tabernero, Josep, MD, PhD, MSc

doi: 10.1097/01.COT.0000557845.45857.a7

Colorectal cancer (CRC) is the third most common cancer in men (10% of the total) and the second in women (9.2%), with more than 1.8 million new cases identified every year globally accounting for about one in 10 cancer cases and deaths (CA Cancer J Clin 2011;61(2):69-90, CA Cancer J Clin 2018;68(6):394-424). Approximately 40-50 percent of the affected patients develop metastatic colorectal cancer (mCRC) and more than half a million deaths are reported annually worldwide as a consequence of CRC (CA Cancer J Clin 2011;61(2):69-90). Patients with mCRC (stage IV) are seldom curable, with a 5-year survival rate of less than 10 percent (Eur J Cancer 2013;49:(11)2476-2485). This creates a great need for advancements in the standard of care (SoC) for patients and families affected by mCRC.

Early-stage CRC patients are treated surgically with the intent of curing the condition by removing all cancerous tissue. As the stage of the tumor advances, in terms of depth of penetration and lymph node involvement, the chance of cure with surgery alone diminishes and the rate of local recurrence increases.

More advanced CRC is treated using standard first-line systemic therapy in accordance with current European Society for Medical Oncology (ESMO) guidelines: chemotherapy with 5-fluorouracil (5-FU) + leucovorin + oxaliplatin/irinotecan ± bevacizumab or cetuximab/panitumumab, depending on clinical factors and RAS mutation status (Ann Oncol 2016;27:1386-1422).

One of the oldest and most widely used chemotherapy agents, 5-FU, was first identified in 1957 as a potent inhibitor of DNA synthesis and has been given to cancer patients for over 50 years (Nature 1957;179(4561):663-666). In 1978, leucovorin was found to greatly increase the efficacy of 5-FU and fast became adopted as an integral component of palliative chemotherapy regimens for cancers, including CRC (NCI Monogr 1987:165-170, Cancer Res 1981;41:3288-3295). However, even with the addition of leucovorin, only about 20 percent of mCRC patients respond to treatment, compared to approximately 10 percent response to 5-FU alone (J Clin Oncol 1989;7:1419-1426) (Figure 1).

Figure 1

Figure 1

Figure 2

Figure 2

Figure 3

Figure 3

More recently, oxaliplatin was found to have synergistic effects when combined with 5-FU + leucovorin therapy, called FOLFOX therapy, raising the response rate in mCRC patients to approximately 38-45 percent (Semin Oncol 1999;26(6):647-662, J Clin Oncol 2008;26:2013-2019) (Figure 1). With the exception of biologic agents that can help increase overall survival when paired with FOLFOX treatment (Oncology 2008;75(3-4):215-223), there have been no significant advances to therapies for mCRC for decades.

Back to Top | Article Outline

Rationale for Arfolitixorin

Arfolitixorin is a new drug that has the potential to increase the efficacy of first-line standard of care treatment for mCRC (FOLFOX therapy). The hypothesis for arfolitixorin is well-supported by preclinical models and research on the mechanism of 5-FU-based inhibition of the normal cellular process of DNA synthesis.

In normal cells, deoxythymidine monophosphate (dTMP) is a critical substrate necessary for DNA synthesis (Figure 2, left). To produce dTMP, a ternary complex is formed between enzyme thymidylate synthase, and its substrates deoxyuridine monophosphate (dUMP) and methylene-tetrahydrofolic acid (MTHF). When administered, 5-FU metabolite 5-FdUMP competes with dUMP while forming the ternary complex. Incorporation of 5-FdUMP to the ternary complex blocks the formation of dTMP, effectively inhibiting DNA synthesis required for cancer cell replication (Figure 2, right).

Leucovorin, which can be converted to MTHF through a complex set of metabolic steps, helps stabilize 5-FdUMP-containing ternary complexes, thereby increasing the effectiveness of 5-FU in blocking DNA synthesis (Figure 2, right). However, only a fraction of CRC patients are able to fully metabolize leucovorin to MTFH, greatly limiting its effectiveness (Cancer Chemother Pharmacol 2014;74:1167). Since maintaining a high concentration of MTHF is key to increasing the effectiveness of 5-FU, patients who are unable to fully metabolize leucovorin will not be able to benefit from it (Crit Rev Oncol Hematol 2016;106:118-131).

Arfolitixorin is the first pure form of MTHF. It does not require complicated metabolic steps to become biologically active and therefore has the potential to fully benefit all patients with mCRC. Early testing has shown that administration of arfolitixorin can lead to higher and, more importantly, more consistent intracellular concentrations of MTHF in tumor tissue and plasma from patients with mCRC (Cancer Chemother Pharmacol 2015;75:37).

In a recently completed cohort of an ongoing phase I/IIa open-label study of patients with mCRC treated with arfolitixorin, 47 percent of patients showed early tumor shrinkage defined as a greater than 20 percent reduction in tumor size from baseline, further supporting the premise that arfolitixorin can improve first-line treatment.

Back to Top | Article Outline

Phase III AGENT Clinical Study

The recently initiated global pivotal phase III AGENT study (NCT03750786) will compare arfolitixorin to leucovorin in the first-line treatment of mCRC patients (i.e., in combination with 5-FU, oxaliplatin, and bevacizumab). The trial is a global, randomized, parallel group study with a primary endpoint of overall response rate (ORR) as measured by changes in tumor size according to RECIST 1.1 criteria (Figure 3). Key secondary endpoints of the study are progression-free survival (PFS) and duration of response.

Approximately 440 patients will be randomized 1:1 to receive either arfolitixorin or leucovorin as a component of standard first-line therapy for mCRC. The study will consist of a screening visit, a randomization visit during which patients will receive their first course of treatment, regular treatment visits every 2 weeks thereafter, and CT/MRI assessments every 8 weeks from baseline. Treatment visits are to continue until disease progression, as identified by the investigator based on locally performed assessment of CT scans/MRIs.

As seen in Figure 1, the ORR for the current standard of care for mCRC (FOLFOX + bevacizumab) is approximately 38-45 percent. The expected ORR for the experimental arm of the AGENT study has been set at 60 percent. These assumptions were used to help determine the sample size for the study—440 patients. However, an adaptive design allows for a re-estimation of the sample size based on interim results.

For the planned interim analysis, a minimum of 330 patients with events (based on RECIST criteria) will be evaluated with the objective of calculating whether increasing the sample size is necessary for accurate assessment of ORR and PFS. An additional 220 patients can be added, if the analysis meets prespecified specifications. The interim analysis for the AGENT study is expected to happen in the first half of 2020.

In addition, randomization of patients into experimental groups will be stratified to help minimize potential bias. The three prespecified stratification factors are geography (Europe vs. North America), primary tumor location (left colon vs. right colon vs. rectum), and previous neoadjuvant/adjuvant CRC treatment (yes or no).

Geography can be a source of potential bias due to small differences in chemotherapy administration schedules. In the U.S., patients are often treated until progression of disease whereas in Europe patients are more likely to be treated for 4-6 months before being moved to maintenance therapy, a difference which can affect measures such as PFS.

Primary tumor location is strongly correlated with how aggressive the cancer is with right-side tumors being less frequent yet often more aggressive (J Clin Oncol 2016;34(no. 15_suppl):3504-3504). Balancing patients with previous adjuvant/neoadjuvant treatment between experimental groups will also help minimize bias that could affect accurate measurement of study endpoints.

Metastatic colorectal cancer is a devastating disease with limited treatment options. Due to lack of recent innovation in the field, it has been over a decade since an advancement to the first-line treatment of mCRC has significantly increased patient response.

Arfolitixorin represents a promising new drug and has the potential to benefit all patients with mCRC. The ongoing global pivotal phase III AGENT study will help evaluate arfolitixorin's potential to improve the effectiveness of first-line mCRC treatment. With a trial readout expected in 2021, arfolitixorin is rapidly advancing to the pivotal assessment of its potential clinical benefits to mCRC patients.

JOSEP TABERNERO, MD, PHD, MSC, is Head of the Medical Oncology Department of Vall d'Hebron University Hospital, Barcelona, Spain, and Global Coordinating Investigator of the global pivotal phase III AGENT study.

Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.
Home  Clinical Resource Center
Current Issue       Search OT
Archives Get OT Enews
Blogs Email us!