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Effect of Reduced-Dose Capecitabine Plus Cetuximab as Maintenance Therapy for RAS Wild-Type Metastatic Colorectal Cancer

This phase 2 clinical trial evaluates the biological activity and safety of capecitabine plus cetuximab as a novel maintenance therapy for RAS wild-type metastatic colorectal cancer.


Introduction
Colorectal cancer is the third most common and the second most lethal cancer in the United States. 1,2 Fluorouracil-based chemotherapy (combined with oxaliplatin or irinotecan) plus anti-epidermal growth factor receptor/vascular endothelial growth factor (anti-EGFR/VEGF) therapy is the standard first-line treatment for metastatic colorectal cancer, with an overall median survival of 29 to 30 months. [3][4][5][6][7] After stable disease status or better is achieved, switching to a low-intensity or low-toxicity maintenance therapy could balance the clinical efficacy and adverse effects (AEs). [8][9][10][11][12][13] In the OPTIMOX1 and OPTIMOX2 trials, 8,9 fluorouracil as maintenance therapy after leucovorin calcium and fluorouracil with oxaliplatin 4 (FOLFOX4) induction therapy vs continuous FOLFOX4 showed a similar effectiveness, fewer AEs, and better progression-free survival (PFS) and overall survival (OS) compared with an observation group. The results of those trials suggested that the use of a single cytotoxic agent could be valuable after intensive therapy. The MACRO, MACRO-2, and NORDIC-VII trials 11,13,14 also concluded that single-agent bevacizumab or cetuximab maintenance therapy was more tolerable than continued induction therapy. In addition, the CAIRO3 trial 12 found that bevacizumab combined with capecitabine for maintenance therapy obtained better results compared with an observation group, suggesting that the combination could achieve maximal clinical efficacy. Moreover, the MACBETH trial 15 tested maintenance therapy with cetuximab or bevacizumab after induction therapy with chemotherapy combined with cetuximab. The results showed that the group treated with cetuximab achieved better clinical efficacy than the group treated with bevacizumab, although the difference was not statistically significant. For patients with wild-type RAS (OMIM 190070 for KRAS and 164790 for NRAS) or BRAF (OMIM 164757) metastatic colorectal cancer (mCRC), the findings of previous trials 14,16 suggested that an EGFR-targeted drug may be the optimal maintenance therapy after induction chemotherapy in combination with the EGFR-targeted drug. Consistent with this notion, in the VALENTINO trial, 17 maintenance therapy with the EGFR-targeted drug panitumumab combined with fluorouracil achieved higher PFS and OS than panitumumab alone. However, this regimen is not the most convenient strategy because fluorouracil is an injectable drug.
Therefore, oral administration of capecitabine combined with the EGFR-targeted drug cetuximab as maintenance therapy could be an alternative choice after induction chemotherapy combined with cetuximab for patients with RAS or BRAF wild-type mCRC. However, there have been concerns about the safety of this approach after studies 4,18,19 reported AEs, including diarrhea, rash acneiform, and hand-foot syndrome. To evaluate the biological activity and safety of capecitabine plus cetuximab as a novel maintenance therapy for RAS wild-type mCRC, we performed a phase 2 prospective clinical trial. We aimed to test whether this maintenance therapy combination would result in expected outcomes, have only tolerable nonserious AEs, and provide evidence for future phase 3 clinical trials.

Study Design and Participants
This investigation was a multicenter, single-arm, phase 2 prospective clinical trial to evaluate the biological activity and safety of capecitabine plus cetuximab as a novel maintenance therapy after induction therapy consisting of fluorouracil-based chemotherapy combined with cetuximab. The trial protocol is available in the eAppendix in the Supplement. According to work by Simon, 20

Investigational Treatment
Investigational treatment began with a chemotherapy regimen of fluorouracil plus oxaliplatin or irinotecan combined with cetuximab in 8 to 12 cycles of induction therapy. After stable disease status or better was achieved, patients entered the maintenance therapy phase, receiving a combination of reduced-dose capecitabine (1000 mg/m 2 orally twice a day on days 1-14 every 3 weeks) and cetuximab (400 mg/m 2 orally on day 1 of the first week and then 250 mg/m 2 on day 1 every week or 500 mg/m 2 on day 1 every 2 weeks.). Treatment continued until disease progression, intolerable AEs, or death occurred.

Outcomes
The primary end point of the study was mPFS with reduced-dose capecitabine plus cetuximab. The secondary end points were total PFS, OS, quality of life, safety, and toxicity of treatment.

Study Assessments
To evaluate the response to metastatic lesions after treatment, magnetic resonance imaging or computed tomography was performed every 6 weeks until disease progression. Disease was assessed radiographically according to the Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1. 23 The mPFS was defined as the time from the beginning of maintenance therapy to first disease progression or death. The total OS was defined as the time from follow-up to withdrawal from the trial or death, and the OS from maintenance started at the time of the maintenance stage.
The PFS was defined as the time from induction therapy to first disease progression or death. activity analyses were evaluated in the intent-to-treat population receiving at least 1 cycle of maintenance therapy. Safety data described the rate of AEs with grade and the grade 3 to 4 AEs during maintenance therapy as well as the entire treatment for the intent-to-treat population. For the final analysis, the data cutoff date was December 15, 2019, with 47 patients enrolled in maintenance therapy assessed with survival curves. SAS (version 9.4; SAS Institute Inc) and GraphPad Prism 6 (GraphPad Software Inc) were used for statistical analysis and survival curves.

Results
Sixty-one patients with RAS wild-type mCRC were enrolled in induction therapy from April 29, 2016, to April 29, 2019, at 5 centers in China. They received 8 to 12 cycles of fluorouracil-based chemotherapy combined with cetuximab. The patients entered into maintenance therapy after reaching stable disease status or better. Fourteen patients were excluded, including 9 patients with disease progression, 4 patients with intolerable AEs, and 1 patient who died.
Forty-seven patients entered this phase 2 prospective clinical trial and were enrolled in maintenance therapy consisting of capecitabine plus cetuximab (Figure 1). The characteristics and disease status of patients are listed in Table 1    pharmacokinetic parameters and metabolic conversion could be detected. Therefore, the coadministration of capecitabine plus cetuximab seems to be safe, without altering the plasma concentration-time profiles. 26

JAMA Network Open | Gastroenterology and Hepatology
Our median PFS was 12.7 months, which was better than the 10.2 months achieved by the VALENTINO trial 17 with the EGFR-targeted drug panitumumab combined with fluorouracil. The MACRO2 trial 13 explored the efficacy of maintenance with either cetuximab only or chemotherapy plus cetuximab. For the cetuximab-only approach, the results showed a median PFS of 9 months and a median OS of 25 months, which was comparable to the modified FOLFOX6 (fluorouracil, leucovorin, and oxaliplatin) combined with cetuximab approach. The study confirmed that cetuximab alone can achieve a similar effect as 3 drugs plus cetuximab. Similarly, in the NORDIC-VII trial, 14 maintenance therapy with cetuximab alone, with a median PFS of 7.5 months and a median OS Dashed lines represent 95% CIs. Short vertical lines represent censored patients.

JAMA Network Open | Gastroenterology and Hepatology
Maintenance Therapy for RAS Wild-Type Metastatic Colorectal Cancer of 21.4 months, was more clinically effective than FLOX (fluorouracil/leucovorin and oxalipatin) combined with cetuximab. Other trials that explored the effect of single agents, chemotherapy drugs, or their combination for maintenance therapy were OPTIMOX, 8,9,27 CAIRO3, 12 28 Nordic ACT2, 18 MACRO, 11 MACRO2, 13 AOI0207, 29 and MACBETH, 15 as well as other studies. 15,27,29,30 The results of the OPTIMOX1 trial 8 suggested a stop-and-go strategy for mCRC treatment (eFigure in the Supplement). In that trial measuring the duration of disease control as the primary end point, disease control lasted 9.0 months for the FOLFOX7-treated group and 10.6 months for the maintenance group. In another phase 2 trial, 31 6 cycles of XELOX (capecitabine and oxaliplatin) induction therapy followed by capecitabine maintenance achieved a PFS of 8.0 months and an OS of 20.0 months. Compared with OPTIMOX1, the findings of the OPTIMOX2 trial 9 suggested that patients can still benefit from fluorouracil-based maintenance therapy after intensive treatment.
Therefore, according to that study, fluorouracil-based agents were the backbone for maintenance therapy. In the analysis of the maintenance efficacy, the duration of 2 stages (induction therapy and maintenance therapy) could influence the total PFS together. Longer fluorouracil-based induction therapy could increase PFS.
In the present trial, AEs and toxic effects were observed most often in maintenance therapy. The MACRO2 trial 13 reported differences between cetuximab only vs modified FOLFOX6 combined with cetuximab in the frequency of grade 3 to 4 AEs (15% vs 24% for rash acneiform and 7% vs 8% diarrhea). The use of capecitabine after XELOX induction therapy 31 resulted in grade 3 to 4 AEs, including diarrhea (2.4%) and hand-foot syndrome (2.4%). In a trial 30 administering CAPIRI (capecitabine and irinotecan) vs CAPOX (capecitabine and oxaliplatin) combined with cetuximab, rash acneiform was observed in 12.4% vs 20.5%, hand-foot syndrome in 12.4% vs 22.7%, and diarrhea in 15.7% vs 9.3%. In our trial, it should be noted that the final dosage of capecitabine was 900 mg/m 2 to avoid AEs. The maintenance therapy in our study was safer than CAPIRI vs CAPOX combined with cetuximab, and the incidence of rash acneiform in maintenance therapy was lower than that in induction therapy. During maintenance therapy, we observed grade 3 to 4 rash acneiform in 8 patients (17%), hand-foot syndrome in 5 patients (11%), and diarrhea in 2 patients (4%). It should be pointed out that 47 patients (60%) had grade 1 to 2 skin toxic effects, and more AEs were observed in our trial compared with previous research in patients treated with cetuximab only. 13 However, no patients experienced serious AEs in the present study.

Limitations
A limitation of this multicenter, single-arm, phase 2 prospective clinical trial is that control groups were lacking. A future phase 3 clinical trial 33 will compare cetuximab plus capecitabine vs cetuximab alone as a control group.