Background

One of the goals in chemotherapy for unresectable/metastatic colorectal cancer (mCRC) is to prolong survival and maintain quality of life by controlling the disease through exposure to all active agents in an appropriate sequence of administration. Nine different classes of drugs have shown antitumor activity in mCRC: fluoropyrimidines, irinotecan, oxaliplatin, anti-epidermal growth factor receptor (EGFR) antibodies, anti-vascular endothelial growth factor (VEGF) drugs, regorafenib, trifluridine/tipiracil (FTD/TPI, TAS-102), encorafenib for BRAF V600E mutant mCRC, and immunotherapy for microsatellite instability-high/deficient mismatch repair (MSI-H/dMMR) mCRC. Chemotherapy is usually performed with a combination of cytotoxic drugs and a molecular target drug such as anti-VEGF drug or anti-EGFR antibody. A cytotoxic DOUBLET combination of fluorouracil (5-FU) plus levofolinate (l-LV) and either oxaliplatin (FOLFOX) or irinotecan (FOLFIRI) with a molecular target drug is generally proposed as initial systemic chemotherapy; recently, however, a TRIPLET combination of fluorouracil plus levofolinate, oxaliplatin and irinotecan (FOLFOXIRI) showed superior efficacy in terms of tumor shrinkage and survival benefit compared with the DOUBLET combination.

The TRIBE study showed that FOLFOXIRI plus bevacizumab (BEV) is a promising regimen in first–line therapy for patients with mCRC [1], and this regimen is now regarded as a recommended first-line therapy for patients whose treatment goal is tumor shrinkage and in patients with BRAF mutant tumors. However, a second-line therapy after FOLFOXIRI plus BEV treatment has not been well established. The TRIBE2 study showed that after maintenance treatment with 5-FU/ l-LV plus BEV, re-introduction of FOLFOXIRI plus BEV offered the most favorable survival benefit [2]. However, most patients who receive an oxaliplatin-based regimen experience peripheral sensory neuropathy. Therefore, FOLFIRI plus BEV appears to be the most commonly used regimen for second-line therapy after FOLFOXIRI plus BEV [1]. Although FOLFIRI plus BEV may be suitable as a standard regimen for second-line therapy, all of the drugs in this regimen are included in first-line FOLFOXIRI plus BEV; accordingly, a response to FOLFIRI plus BEV would not be expected following the failure of first-line FOLFOXIRI plus BEV. Recently, two new anti-VEGF drugs - aflibercept [3] and ramucirumab [4] - showed promising anti-tumor effects as second-line treatment when combined with a FOLFIRI-based regimen for patients with mCRC. FOLFOXIRI plus BEV, or its maintenance phase - 5-FU/ l-LV plus BEV, does not include aflibercept, and thus this drug might provide additional benefit to patients who have progressed after FOLFOXIRI plus BEV.

To investigate this possibility, we planned a phase II EFFORT study to investigate whether FOLFIRI plus aflibercept has efficacy following FOLFOXIRI plus BEV treatment. Here, we describe the protocol for the phase II EFFORT study.

Methods/design

Study design and treatment

The EFFORT study is an open-label, multicenter, single arm phase II study to evaluate whether FOLFIRI plus aflibercept has efficacy following FOLFOXIRI plus BEV for mCRC in patients with unresectable or metastatic colorectal cancer. The study has been approved by a central review board and is currently ongoing at 47 medical facilities in Japan. The main inclusion criteria are histologically confirmed advanced mCRC, known RAS mutation status (known BRAF mutation status also, if possible), mCRC treated with FOLFOXIRI plus BEV as first-line therapy for at least two courses, adjuvant chemotherapy and FOLFOXIRI plus BEV treatment for recurrence, age ≥ 20 years, ECOG PS 0 or 1, measurable lesions based on the Response Evaluation Criteria in Solid Tumors (RECIST) guidelines version 1.1, adequate organ function, and sufficient oral ingestion function. Complete inclusion and exclusion criteria are shown in Table 1. RAS and BRAF testing are performed locally.

Table 1 Patient inclusion and exclusion criteria
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Patients receive aflibercept and FOLFIRI (aflibercept 4 mg/kg, irinotecan 150 mg/m2 IV over 90 min, with l-LV 200 mg/m2 IV over 2 h, followed by 5-FU 400 mg/m2 bolus and 5-FU 2400 mg/m2 continuous infusion over 46 h) every 2 weeks on day 1 of each cycle. Patients receive premedication with antiemetic agents according to institutional guidelines. Treatment continues until disease progression, unacceptable toxicity, death, patient refusal, or investigator decision. When irinotecan is stopped due to severe diarrhea or other adverse events, irinotecan can be skipped, in which case 5-FU/l-LV plus aflibercept or aflibercept alone can be administered. When aflibercept is missed due to an adverse event, FOLFIRI, irinotecan alone, or 5-FU/l-LV can be administered, and such treatments are also within the protocol treatment. There is no prescribed treatment following completion or discontinuation of protocol treatment. Planned enrollment period is 2019 April to 2021 March, and the observation period will include a 2-year follow-up period from the time the last patient is enrolled. No interim analysis of this study will be performed.

Endpoints and assessments

The primary objective of this trial is to determine whether the FOLFIRI plus aflibercept regimen has efficacy following FOLFOXIRI plus BEV in patients with mCRC in terms of progression-free survival (PFS). Secondary endpoints are overall response rate (ORR), overall survival (OS) and safety.

Disease assessment is performed every 6 weeks by computed tomography (CT). Response is determined by CT scanning based on Response Evaluation Criteria in Solid Tumors version 1.1. PFS is defined as the time from study enrollment to first disease progression or death, whichever occurs first; OS is defined as the time from study enrollment to the date of death due to any cause; and ORR is defined as the percentage of patients relative to the total of enrolled subjects who achieve a complete response (CR) or partial response (PR) based on CT scan images.

All adverse events (AEs) observed during the study treatment period are appropriately registered in the subjects’ medical records and in electronic case reports forms. All serious adverse events (SAEs), namely fatal or life-threatening adverse events or those requiring hospitalization or resulting in persistence or significant disability/incapacity, are required to be disclosed by the investigator to the KSCC (Kyushu Study group of Clinical Cancer) Study Office/Enrollment and Data Analysis Center within 24 h. AEs will be assessed according to the Common Terminology Criteria for Adverse Events version 5.0.

Plasma levels of placental growth factor (PlGF), vascular endothelial growth factor-A (VEGF-A), vascular endothelial growth factor-B (VEGF-B), vascular endothelial growth factor-C (VEGF-C), vascular endothelial growth factor-D (VEGF-D), and interleukin-8 (IL-8) are assessed in blood samples collected from each patient before the protocol treatment, prior to first imaging evaluation, and within 30 days after treatment discontinuation to identify biomarkers that predict the efficacy of aflibercept. This analysis aims to identify a potential predictive biomarker for the efficacy of FOLFIRI plus aflibercept treatment.

Target sample size and statistical analyses

The primary endpoint of this study is PFS. Second-line PFS with a FOLFIRI-based regimen after FOLFOXIRI/BEV is considered to be shorter than second-line PFS after FOLFOX/BEV due to treatment resistance to irinotecan. According to the TRIBE-2 trial, the second-line PFS of FOLFIRI/BEV after FOLFOX/BEV was 5.6 months [2]. Furthermore, a phase 2 trial of FOLFIRI plus aflibercept conducted in Japan showed its PFS as 5.4 months (95% CI, 4.14–6.70) [5]. Based on these results, the expected PFS value in this study was set at 5.4 months. To achieve 80% power to show a significant response benefit with a one-sided alpha level of 0.10, and assuming a threshold PFS of 3 months, we estimated that 32 patients would be necessary. Considering dropouts, a total of 35 patients would need to be enrolled.

The following hypothesis will be tested using the confidence intervals for median survival time as defined by Brookmeyer and Crowley. Sample size calculation was performed using SAS ver.9.4 (Cary, NC, USA).

Discussion

A survival benefit for anti-EGFR antibody in 2nd-line chemotherapy has not been shown even in the case of RAS wild-type mCRC [6,7,8,9]. In contrast, the combination of an anti-VEGF drug and doublet combination has shown a survival effect [3, 4, 10, 11], and an anti-VEGF drug is therefore usually selected in combination with second-line chemotherapy for mCRC. While bevacizumab, aflibercept and ramucirumab are currently used as anti-VEGF drugs [3, 4, 12], no biomarker or definite criteria for selection of these drugs is available, and no data for second-line therapy after FOLFOXIRI plus BEV as pretreatment have been reported.

Attempts to discover a molecular predictive biomarker for anti-VEGF drugs have not led to clinically useful findings, although several studies are currently underway. The acquisition of resistance to BEV in patients with mCRC may involve BEV-induced cytokine changes and high VEGF-A, −D and placental growth factor (PlGF) serum levels [13,14,15,16]. Following biomarker analysis of the RAISE trial (NCT01183780), ramucirumab is likely to be added to second-line FOLFIRI for patients with high VEGF-D levels. However, ramucirumab has been reported to show negative effects when administered to patients with low VEGF-D levels equivalent to the one-third of normal levels seen after first-line treatment with a bevacizumab-containing oxaliplatin-based regimen for mCRC [17]. In contrast, a biomarker post hoc analysis of the VELOUR trial (NCT00561470) reported that aflibercept retains its activity regardless of baseline VEGF-A and PlGF levels [18]. The GI-SCREEN CRC-Ukit study, a prospective longitudinal study to investigate an association between plasma angiogenesis-related mediators and clinical outcomes in mCRC, suggested that changes in VEGF-D and PlGF occurred independently, and it may be possible to select drugs by assessing these alterations [19].

Furthermore, regarding the effects of these anti-VEGF drugs, the usefulness of second-line treatment after administration of FOLFOXIRI plus BEV as pretreatment has not been reported. Moreover, the desirability of switching to a different type of anti-VEGF drug in subsequent treatment following BEV as pretreatment remains unclear.

FOLFOXIRI plus BEV showed significant superiority to DOUBLET plus BEV as initial systemic chemotherapy for patients with mCRC in terms of survival benefit and tumor shrinkage [1, 2, 20]. Subgroup analyses also indicated that FOLFOXIRI plus BEV is remarkably effective in patients with poor prognosis, such as those with BRAF mutations, extrahepatic metastases or a right-sided primary [1, 20]. Patients with mCRC who receive FOLFOXRI plus BEV as initial systemic chemotherapy may therefore expect an aggressive therapeutic combination as a subsequent regimen. Aflibercept uniquely targets both VEGF-A and PlGF, with higher affinity for both than other anti-angiogenic therapies, and VEGF-A and PlGF bind aflibercept with higher affinity than their native receptor [21]. These findings suggest that tumors progressing under blockade of a single anti-angiogenic therapy, such as BEV, most likely use numerous non-VEGF-A mechanisms to sustain their growth. Switching to a different therapy to target these alternative mechanisms, such as aflibercept, may be beneficial. Although differences in study design and patient characteristics hamper decision-making from cross-trial comparisons, aflibercept plus FOLFIRI combination showed an attractive ORR and survival benefit for patients with mCRC compared to BEV and ramucirumab as second-line therapy (Table 2). This study uses comparison with historical controls to investigate biomarkers able to predict the effects of aflibercept, and to determine the desirability of switching to a different type of anti-VEGF drug for second-line therapy following FOLFOXIRI therapy as pretreatment.

Table 2 Background of second-line anti-VEGF drug trials
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