PURPOSE: The purpose of this study was to compare the rate of grade 3-4 immune related adverse events (irAEs) in patients with advanced metastatic melanoma treated with the combined anti-CTLA-4 and anti-PD-immune-therapy at the Dana Farber Cancer Institute(DFCI), to that of the published rate of grade 3-4 irAEs among patients treated with the same combination of check-point therapy in the pivotal phase II and phase III trials that led to the FDA approval of the combination regimen. This study also measures the tumor response with the Ipi-Nivo combination therapy and overall-survival of patients in the study cohort at DFCI. METHODS/PROCEDURES: This is a retrospective cohort study conducted at DFCI during 2014 to 2016 among stage III/IV melanoma patients treated outside of the clinical trials with the Ipi-Nivo combination therapy. Chart review of the electronic medical record(EMR) was conducted to abstract the data for this study. irAEs were graded and classified as per the NCI-CTCAE v.4.0 guidelines. The comparison of the rate of grade 3 4 toxicity in the clinical settings at DFCI and the clinical trials was performed using a one sample proportion hypothesis test. For efficacy assessment of tumor response, RECIST1.1 criterion was used to ascertain the best clinical response. RESULTS: During an overall follow-up period of 600 days, 52 patients were treated on expanded access protocol (EAP) and commercial Ipi-Nivo combination therapy at DFCI. The rate of grade 3-4 immune mediated toxicity for this cohort of patients treated outside of clinical trials was 32.6%. The average rate of grade 3-4 irAEs reported in phase II/III clinical trials was approximately 55%. The results from the one-proportion hypothesis test [(P-value: 0.002) (95% C.I: 19.14-46.23)], prove that patients in the “real world” clinical settings have a different safety profile than patients treated in the clinical trials. The rate of grade 3-4 irAEs was found to be lower (19.14% to 46.23%) in the population treated with Ipi/Nivo combination therapy at the DFCI, compared to the check-mate clinical trials (approximately 55%) CONCLUSION: The results from the study indicate a lower rate of grade 3-4 irAEs in patients treated at DFCI, in comparison with the patients treated in the clinical trials for the Ipi-Nivo combination group. The results support the need for preemptive safety signal detection of symptoms of irAEs to improve patient’s safety. However, larger database studies are required for the generalizability of this results to a wider patient population treated outside of DFCI.

京都大学 / 新制・課程博士 / 博士(医学) / 甲第23105号 / 医博第4732号 / 新制||医||1050(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 竹内 理, 教授 上野 英樹, 教授 椛島 健治 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM