The present single-arm phase 2 study showed favorable efficacy and acceptable safety profiles of the alternating schedule of mCAPOX/mCAPIRI plus bevacizumab for unresectable mCRC patients with no prior systemic treatment.

The combination regimen of alternating mCAPOX/mCAPIRI plus bevacizumab resulted in a median PFS of 11.0 months (95% CI 9.0–12.4) and a median OS of 28.1 months (95% CI 18.4–34.0). In previous studies of alternating schedules of doublet chemotherapy without bevacizumab for unresectable mCRC in the first-line setting, the median PFS or time to progression (TTP) ranged from 8.8 to 13 months, and the median OS ranged from 17.3 to 26.1 months.7,8,9 For the first-line triplet chemotherapy (FOLFOXIRI) without bevacizumab in patients with no prior systemic treatment, the median PFS or TTP was 8.4 to 10.8 months, and the median OS was 21.5 to 28.4 months.11,12,13 A meta-analysis involved studies of first-line triplet chemotherapy (FOLFOXIRI) in combination with bevacizumab and doublet chemotherapy (FOLFOX or FOLFIRI) in combination with bevacizumab.6 Compared with the pooled data in the meta-analysis, the present study included a higher proportion of patients with BRAF mutations (19% vs 8%), which may result in worse prognosis. The pooled median PFS in the meta-analysis was 12.2 months for triplet chemotherapy plus bevacizumab and 9.9 months for doublet chemotherapy plus bevacizumab. The meta-analysis also provided a pooled median OS of 28.9 months for triplet chemotherapy combined with bevacizumab and 24.5 months for doublet chemotherapy combined with bevacizumab. Additionally, in the present study, patients who received the alternating schedule of mCAPOX/mCAPIRI combined with bevacizumab reached an ORR of 73% (95% CI 59–84%) and a DpR of 46.0% ± 26.3%. While ORR was 64.5% for triplet chemotherapy plus bevacizumab and 53.6% for doublet chemotherapy plus bevacizumab, and DpR were 43.4% for triplet chemotherapy combined with bevacizumab and 37.8% for doublet chemotherapy combined with bevacizumab.6,14 Thus, it is suggested that the alternating schedule of mCAPOX/mCAPIRI plus bevacizumab may have promising anti-tumor activity comparable with triplet FOLFOXIRI plus bevacizumab. We speculate that the alternating nature of chemotherapy may be less likely to lead to drug resistance, compared with conventional doublet chemotherapy regimens. Of note, due to a lack of head-to-head randomized controlled trials, the results of each study should be interpreted with caution.

Subgroup analyses for PFS indicated that the alternating schedule of chemotherapy in combination with bevacizumab brought better benefits in mCRC patients with NLR < 5 or RAS wild-type diseases. As a systemic inflammation indicator, increased NLR was found associated with poorer prognosis in CRC, irrespective of tumor in early stage or advanced stage.15,16,17 The role of systemic inflammation in tumor progression is well-established,18 and the interaction between alternating schedules of chemotherapy and inflammation is worthy to be further investigated. In previous studies, it was found patients with RAS wild-type mCRC had better outcome than those with RAS mutation,19,20 which was consistent with the findings in the present study. Chemotherapy in combination with anti-epidermal growth factor receptor (EGFR) antibody (e.g., panitumumab) may be more effective than chemotherapy plus bevacizumab for patients with unresectable RAS wild-type mCRC.21,22 Further studies should evaluate the efficacy and safety of alternating chemotherapy plus bevacizumab vs (alternating or conventional) chemotherapy plus anti-EGFR antibody. In treatment-naïve mCRC patients with RAS mutation, median PFS for alternating schedules of chemotherapy plus bevacizumab, triplet chemotherapy plus bevacizumab, and doublet chemotherapy plus bevacizumab were 9.8, 11.5 to 12.5, and 8.1 to 9.7 months, respectively.19,20,23,24,25 In addition, the alternating regimen in combination with bevacizumab had encouraging efficacy in mCRC patients with BRAFV600E mutation. Median PFS for the regimen reached 11.6 months, which is better than triplet chemotherapy plus bevacizumab and doublet chemotherapy plus bevacizumab (median PFS 7.5 to 10.7 and 5.5 to 6.6 months, respectively).19,25,26,27 The mechanisms of alternating schedule of chemotherapy treating RAS- or BRAF-mutant tumors are also a direction for future research.

In terms of safety, although the incidence rate of any grade TRAE was 96%, only 33% of patients suffered grade 3 to 4 TRAE. The most frequent grade 3 to 4 TRAE included hypertension, neutrophil count decreased, and hand-foot syndrome, all of which were manageable. Further, no patient died due to TRAE. There was no unexpected TRAE reported, either. In detail, compared with regimens consisting of fluorouracil, capecitabine-based chemotherapy had a higher incidence rate of hand-foot syndrome.28,29 The present study had a similar result. Further, it was noteworthy that the alternating chemotherapy schedule regimen may have obviously lower risks of neutrophil count decreased, peripheral neuropathy, and diarrhea than triplet and doublet chemotherapy.6 The reason was considered that the dose intensity of each oxaliplatin and irinotecan in the alternating regimen was half of that in conventional chemotherapies. With regard to capecitabine, the dose in the alternating chemotherapy (1000 mg/m2 twice daily for a total of 14 days in a 28-day cycle) was also lower than that in the conventional chemotherapy regimen (1000 mg/m2 twice daily for a total of 14 days in a 21-day cycle).

As an alternating schedule, the doses of oxaliplatin and irinotecan in mCAPOX/mCAPIRI plus bevacizumab regimen were half of those in triplet chemotherapy plus bevacizumab, which means the regimen may cost less than triplets and reduce the disease burden. Additionally, capecitabine is administered orally, while fluorouracil needs to be given using a peripherally inserted central catheter or implanted port. Thus, the administration of capecitabine is more convenient with less expense.

Indeed, there are several limitations in the present study. First, the efficacy in subgroups should be interpreted with caution because that the sample sizes are small. Then, head-to-head comparison of alternating mCAPOX/mCAPIRI chemotherapy combined with bevacizumab and triplet chemotherapy combined with bevacizumab in the first-line setting was not conducted in this study. The regimen of mCAPOX/mCAPIRI plus bevacizumab needs to be evaluated in randomized controlled trials in future.

In conclusion, the alternating schedule of mCAPOX/mCAPIRI chemotherapy in combination with bevacizumab had promising efficacy in unresectable mCRC patients with no prior systemic treatment. The toxicities were acceptable and manageable, with no new safety signal found. The regimen may be a novel option for unresectable mCRC in the first-line setting. International randomized controlled trials are warranted.