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Background: The association between objective imaging response and first line immune checkpoint inhibitor (ICI) therapy regimes in advanced melanoma remains uncharacterized in routine practice. Methods: We conducted a multi-center retrospective cohort analysis of advanced melanoma patients receiving first line ICI therapy from August 2013-May 2020 in Alberta, Canada. The primary outcome was likelihood of RECIST v1.1 assessed objective imaging response between patients receiving anti-programmed cell death protein 1 (anti-PD1) monotherapy and those receiving combination ipilimumab-nivolumab. Secondary outcomes were identification of baseline characteristics associated with non-response and the association of imaging response with overall survival (OS) and time to next treatment (TTNT). Results: 198 patients were included, 41/198 (20.7%) had complete response, 86/198 (43.4%) had partial response, 23/198 (11.6%) had stable disease, and 48/198 (24.2%) had progressive disease. Median OS was not reached (NR) (95% CI 49.0-NR) months for complete responders, NR (95%CI 52.9-NR) months for partial responders, 33.7 (95%CI 15.8-NR) months for stable disease, and 6.4 (95%CI 5.2–10.1) months for progressive disease (log-rank p<0.001). Likelihood of objective imaging response remained similar between anti-PD1 monotherapy and ipilimumab-nivolumab groups (OR 1.95 95%CI 0.85–4.63, p=0.121). Elevated LDH level (OR 0.46; 95%CI 0.21–0.98, p=0.043), mucosal primary site (OR 0.14; 95%CI 0.03–0.48, p=0.003), and BRAF V600E mutation status (OR 0.31; 95%CI 0.13–0.72, p=0.007) were associated with decreased likelihood of response. Conclusion: No significant difference in likelihood of imaging response between anti-PD1 monotherapy and combination ipilimumab-nivolumab was observed. Elevated LDH level, mucosal primary site, and BRAF V600E mutation status were associated with decreased likelihood of response. Given that pivotal clinical trials of ipilimumab-nivolumab did not formally compare ipilimumab-nivolumab with nivolumab monotherapy, this work adds context to differences in outcomes when these agents are used. These results may inform treatment selection, and aid in counseling of patients treated with first-line ICI therapy in routine clinical practice settings. [ABSTRACT FROM AUTHOR]

Introduction: Objective response rates (ORR) appear to be higher in melanoma patients who develop immune‐related adverse events (irAEs), but whether there is a similar association between irAEs and survival remains unknown. Materials and Methods: Patients with advanced melanoma treated with single‐agent pembrolizumab or nivolumab in the province of Alberta from June 2014 to May 2017 were identified through the provincial pharmacy database. Chart review identified and categorized all irAEs that occurred while on anti–programmed cell death protein 1 (PD‐1) checkpoint inhibitors. The primary objective was to compare overall survival (OS) with patients who developed any irAEs versus those who did not. Secondary outcomes included progression‐free survival (PFS) and ORR. Results: Among 186 patients, any‐grade and grade ≥3 irAEs occurred in 88 (47%) and 27 (15%) patients, respectively; one patient died of pneumonitis. In a landmark analysis excluding patients who died within the first 12 weeks, the median follow‐up was 24 months, 20 months in patients without any irAEs and 26 months in patients with irAEs (p =.006). Median OS was 39 versus 23 months (hazard ratio [HR], 0.46; p =.001) for any irAE and no irAE, respectively, and median OS not reached versus 29 months for grade ≥3 irAEs and no grade ≥3 irAEs, respectively. In multivariate analysis, elevated lactate dehydrogenase correlated with reduced OS (HR, 2.34; p =.001), whereas each additional cycle of treatment received (HR, 0.94; p <.001) and development of grade ≥3 irAEs (HR, 0.29, p =.024) were significantly associated with longer OS. Conclusion: Anti‐PD‐1–associated grade ≥3 irAEs in patients with advanced melanoma is associated with better patient outcomes, including overall survival. Implications for Practice: Previous prospective randomized clinical trials demonstrate improved response rates in patients with melanoma who develop select adverse events. The current population‐based real‐world study in advanced melanoma reports an association with anti–programmed cell death protein 1 (PD‐1)–induced grade ≥3 immune‐related adverse events (irAEs) and better patient outcomes, including overall survival. These results suggest that irAEs may be a manifestation of a patient's ability to mount a systemic immune response from PD‐1–directed therapies, which may be associated with therapeutic benefit. The finding of irAEs coinciding with clinical benefit from these therapies supposes that these events are, by and large, unavoidable, and the critical management of irAEs remains essential for optimizing patient outcomes. Real world patient data on efficacy, side‐effects, and clinical predictors of outcomes are lacking for immune checkpoint inhibitors. This multicenter population‐based study investigated the incidence of immune‐related adverse events and how the adverse events related to patient outcomes. [ABSTRACT FROM AUTHOR]

Purpose Chemotherapy remains the primary treatment for metastatic gastric/GEJ cancer but optimal agents and schedule remain controversial. This study examined the safety and efficacy of first-line Irinotecan, capecitabine (Xeloda®), and Oxaliplatin (IXO). Patients and Methods Eligible patients with HER2-unamplified/unknown, metastatic gastric/GEJ adenocarcinoma were treated with 21-day cycle IXO at dose level 1 (DL1: Day 1 O-100 mg/m2 & I-160 mg/m2 IV, Day 2-15 X-1900 mg/m2/day PO divided doses) or modified IXO (mIXO): Day 1 O-85 mg/m2 & I-120 mg/m2 IV, Day 2-15 X-1425 mg/m2/day PO divided doses). This Bryant and Day two-stage designed study had dual primary endpoints of objective response rate (ORR) and toxicity. Secondary endpoints were overall survival (OS) and progression-free survival (PFS). Results Fifty patients were enrolled and received a median of 7 cycles. After accrual of 9 patients at DL1, evaluable RR was 88% however dose limiting toxicity (DLT) rate was 56% thus doses were adjusted to mIXO. Fifteen patients accrued at mIXO had a RR of 60% and DLT rate of 13% allowing continuation to stage 2. Overall, 48 and 49 patients were evaluable for efficacy and safety, respectively, with ORR of 54% and DLTs in 24% of patients (DL1 = 56%; mIXO = 18%). Disease control rate was 85%. The most frequent grade 3/4 adverse events were diarrhea, neutropenia, fatigue, hypokalemia, and nausea. Median PFS and OS were 7.5 and 13.0 months, respectively, with a median follow-up of 9.7 months. Conclusion mIXO demonstrates promising ORR, PFS, OS, and acceptable toxicity compared to standard triplet regimens. IXO should be evaluated in phase III trials. [ABSTRACT FROM AUTHOR]

Simple Summary: Immune checkpoint inhibitor-induced insulin-dependent diabetes mellitus (ICI-induced IDDM) is an emerging form of autoimmune diabetes. We describe the characteristics of 34 patients who developed ICI-induced IDDM across five Canadian cancer centres. We observed that presentation with hyperglycemic crisis is common and that patients treated with combination immunotherapy regimens develop ICI-induced IDDM earlier than those treated with monotherapy. Our results suggest that ICI-induced IDDM is irreversible but is associated with high tumor response rates and prolonged survival. The data generated by this study may help clinicians manage ICI-induced IDDM. Immune checkpoint inhibitor (ICI)-induced insulin-dependent diabetes mellitus (IDDM) is a rare but potentially fatal immune-related adverse event (irAE). In this multicentre retrospective cohort study, we describe the characteristics of ICI-induced IDDM in patients treated across five Canadian cancer centres, as well as their tumor response rates and survival. In 34 patients identified, 25 (74%) were male and 19 (56%) had melanoma. All patients received anti-programed death 1 (anti-PD1) or anti-programmed death ligand-1 (anti-PD-L1)-based therapy. From ICI initiation, median time to onset of IDDM was 2.4 months (95% CI 1.1–3.6). Patients treated with anti-PD1/PD-L1 in combination with an anti-cytotoxic T lymphocyte antigen 4 antibody developed IDDM earlier compared with patients on monotherapy (1.4 vs. 3.9 months, p = 0.05). Diabetic ketoacidosis occurred in 21 (62%) patients. Amongst 30 patients evaluable for response, 10 (33%) had a complete response and another 10 (33%) had a partial response. Median overall survival was not reached (95% CI NE; median follow-up 31.7 months). All patients remained insulin-dependent at the end of follow-up. We observed that ICI-induced IDDM is an irreversible irAE and may be associated with a high response rate and prolonged survival. [ABSTRACT FROM AUTHOR]