SAPPHIRE: A randomized phase II study of oxaliplatin discontinuation after 6 cycles of mFOLFOX6 + panitumumab therapy in patients with colorectal cancer: Final analysis of efficacy and safety results
Authors: M. Takahashi, Y. Munemoto, M. Nakamura, M. Kotaka, H. Kuroda, T. Kato, N. Minagawa, S. Noura, M. Fukunaga, H. Kuramochi, T. Touyama, T. Takahashi, Y. Akagi, H. Satake, S. Kurosawa, T. Miura, H. Mishima, J. Sakamoto, K. Oba, N. Nagata
Journal: Annals of Oncology (2018)

Introduction: mFOLFOX6 is a common first-line chemotherapy regimen for patients with unresectable, advanced or recurrent colorectal cancer (CRC). However, the long-term administration of oxaliplatin is associated with peripheral neuropathy (PN). Recently, we reported that 5-fluorouracil (5-FU)/leucovorin (LV) + panitumumab therapy after 6 fixed cycles of mFOLFOX6 + panitumumab therapy maintained efficacy with reduced incidence of PN, compared with continued treatment with mFOLFOX6 + panitumumab. Here, we report results from the final analysis of efficacy and safety endpoints (data cut-off: 31 Aug 2017), and from subgroup analyses according to tumor location and early tumor shrinkage (ETS). Methods: Chemotherapy-naïve patients, aged ≥20 years with RAS wild-type advanced or recurrent CRC were enrolled to receive 6 cycles of panitumumab + mFOLFOX6 once every 2 weeks. Patients who completed 6 cycles of panitumumab + mFOLFOX6 and confirmed no progressive disease were randomized 1:1 to continue receiving mFOLFOX6 + panitumumab (Group A) or 5-FU/LV + panitumumab (Group B). Allocation factors included study site, age, number of liver metastases at enrolment, and response at randomization. Efficacy endpoints included progression-free survival (PFS), depth of response (DpR) and overall survival (OS) after randomization. Primary tumor was classified as right-sided if located in the cecum, ascending and proximal two-thirds of transverse colons; and otherwise as left-sided. ETS was defined as > 20% decrease of tumor load within 8 weeks from enrolment. Results: 164 patients were enrolled to receive initial mFOLFOX6 + panitumumab treatment, of which 56 were randomized to Group A and 57 to Group B. Median follow-up was 20 months. Median PFS and DpR were: Group A, 9.1 months (95% confidence interval [CI]: 8.6–11.1) and –65.4%, respectively; Group B, 9.3 months (95% CI: 6.0–13.0) and –64.3%, respectively. Median OS was not reached in either group. In patients with right-sided tumors, median PFS and DpR were: Group A (n = 9), 3.8 months (95% CI: 0.8–10.5) and –46.2%, respectively; and Group B (n = 14), 8.0 months (95% CI: 4.3–13.0) and –68.1%, respectively. In patients with left-sided tumors, median PFS and DpR were comparable between Group A (n = 47) (10.5 months and –69.9%, respectively) and Group B (n = 42) (11.5 months and –63.1%, respectively). Median PFS in patients who achieved ETS was 10.5 months in Group A and 11.5 months in Group B. In patients who did not achieve ETS, median PFS was 6.8 months in Group A and 7.8 months in Group B. Grade ≥2 PN occurred in 13.5% and 1.9%, and serious adverse events in 14 (25.0%) and 11 (20.4%) of patients in Groups A and B, respectively. Conclusion: Results from this final analysis support the use of 5-FU/LV + panitumumab after 6 fixed-cycles of mFOLFOX6 + panitumumab as a suitable treatment option for patients with RAS wild-type, chemotherapy-naïve, advanced or recurrent CRC. PFS was numerically lower in patients with right-sided tumors compared to those with left-sided tumors. Tumor location was not only a prognostic factor, but might be a predictive factor for these regimens. Primary tumor location may need to be considered as a stratification factor in future trials. Clinical trial identification: NCT02337946