Abstract
PurposeNK012 is a polymeric micelle formulation of SN-38, the active metabolite of irinotecan. We evaluated the efficacy and safety of NK012 in Japanese patients with unresectable metastatic colorectal cancer.MethodsWe conducted a multicenter open-label phase II trial of NK012 monotherapy in 58 patients who had been treated with an oxaliplatin-based chemotherapy regimen (group A: 53 patients with UGT1A1 genotype –/–, *6/–, or *28/–; group B: 5 patients with UGT1A1 genotype *6/*28 or *6/*6). The primary endpoint was the response rate (RR). Initial doses of 28 and 18 mg/m2 for group A and group B, respectively, were administered intravenously over 30 min, and these doses were subsequently administered every 3 weeks. Group A was evaluated as the primary efficacy population, while group B was evaluated for reference.ResultsIn group A, the RR was 3.8%, and the median progression-free survival and overall survival were 3.30 months and 15.03 months, respectively. In both groups, the most common grade ≥ 3 adverse drug reaction (ADR) was neutropenia and the incidence of grade ≥ 3 diarrhea was low or zero. In group A, 17 serious ADRs were observed in 10 patients (17%); all improved or recovered. In group B, no serious ADRs were observed. No treatment-related deaths were reported in either group.ConclusionsNK012 monotherapy yielded an RR similar to the RR of irinotecan monotherapy that was reported in the phase III EPIC trial (4.2%), and the incidence of grade ≥ 3 diarrhea was low. Based on the incidence and severity of febrile neutropenia and grade ≥ 3 neutropenia, the initial dose of NK012 28 mg/m2 may be too high for colorectal cancer patients who have previously been treated with an oxaliplatin-based chemotherapy regimen.
Highlights
The number of patients with colorectal cancer has been rapidly increasing worldwide in recent decades
For the treatment of unresectable metastatic colorectal cancer, the National Comprehensive Cancer Network (NCCN) guidelines recommend the use of fluorinated pyrimidines (+ folinate), oxaliplatin, and irinotecan hydrochloride (CPT-11), either as monotherapy or in combination, as well as add-on bevacizumab, aflibercept and ramucirumab therapies
CPT-11 is a key drug in various chemotherapy regimens for unresectable metastatic colorectal cancer, such as FOLFIRI combination chemotherapy, add-on therapy with cetuximab or panitumumab, or monotherapy
Summary
The number of patients with colorectal cancer has been rapidly increasing worldwide in recent decades. Since the approval of bevacizumab by the FDA in 2004, remarkable progress has been made in chemotherapy for unresectable metastatic colorectal cancer: the median survival time has exceeded 30 months in the latest clinical. The importance of the “continuum of care,” characterized by the strategic and continued use of effective drugs, is widely accepted for the treatment of colorectal cancer. For the treatment of unresectable metastatic colorectal cancer, the National Comprehensive Cancer Network (NCCN) guidelines recommend the use of fluorinated pyrimidines (+ folinate), oxaliplatin, and irinotecan hydrochloride (CPT-11), either as monotherapy or in combination, as well as add-on bevacizumab, aflibercept and ramucirumab therapies. When patients have received an oxaliplatin-based combination therapy (e.g., FOLFOX) as their initial therapy, the recommended second-line therapy is a CPT-11-based combination therapy (e.g., FOLFIRI) or CPT-11 monotherapy. By contrast, when patients have received a CPT-11-based
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