Safety and Efficacy of Ipilimumab plus Nivolumab and Sequential Selective Internal Radiation Therapy in Hepatic and Extrahepatic Metastatic Uveal Melanoma.

To assess the safety and efficacy of ipilimumab plus nivolumab around selective internal radiation therapy (SIRT) in patients with metastatic uveal melanoma (mUM). We present a retrospective, single center study of 32 patients with mUM divided into two groups based on the treatment received between April 2013 and April 2021. The SIRT_IpiNivo cohort was treated with Yttrium-90 microspheres and ipilimumab plus nivolumab before or after the SIRT (n = 18). The SIRT cohort underwent SIRT but did not receive combined immunotherapy with ipilimumab plus nivolumab (n = 14). Twelve patients (66.7%) of the SIRT_IpiNivo arm received SIRT as first-line treatment and six patients (33.3%) received ipilimumab plus nivolumab prior to SIRT. In the SIRT group, seven patients (50.0%) received single-agent immunotherapy. One patient treated with combined immunotherapy 68 months after the SIRT was included in this group. At the start of ipilimumab plus nivolumab, 94.4% (n = 17) presented hepatic metastases and 72.2% (n = 13) had extra liver disease. Eight patients (44.4%) of the SIRT_IpiNivo group experienced grade 3 or 4 immune related adverse events, mainly colitis and hepatitis. Median overall survival from the diagnosis of metastases was 49.6 months (95% confidence interval (CI); 24.1-not available (NA)) in the SIRT_IpiNivo group compared with 13.6 months (95% CI; 11.5-NA) in the SIRT group (log-rank p-value 0.027). The presence of extra liver metastases at the time of SIRT, largest liver lesion more than 8 cm (M1c) and liver tumor volume negatively impacted the survival. This real-world cohort suggests that a sequential treatment of ipilimumab plus nivolumab and SIRT is a well-tolerated therapeutic approach with promising survival rates

Estimated Costs of the Ipilimumab-Nivolumab Therapy and Related Adverse Events in Metastatic Melanoma.

Combined ipilimumab and nivolumab significantly improve outcomes in metastatic melanoma patients but bear an important financial impact on the healthcare system. Here, we analyze the treatment costs, focusing on irAE. We conducted a retrospective analysis of 62 melanoma patients treated with ipilimumab-nivolumab at the Lausanne University Hospital between 1 June 2016 and 31 August 2019. The frequency of irAEs and outcomes were evaluated. All melanoma-specific costs were analyzed from the first ipilimumab-nivolumab dose until the therapy given subsequently or death. A total of 54/62 (87%) patients presented at least one irAE, and 31/62 (50%) presented a grade 3-4 irAE. The majority of patients who had a complete response 12/14 (86%) and 21/28 (75%) of overall responders presented a grade 3-4 toxicity, and there were no responses in patients without toxicity. Toxicity costs represented only 3% of the total expenses per patient. The most significant contributions were medication costs (44%) and disease costs (39%), mainly disease-related hospitalization costs, not toxicity-related. Patients with a complete response had the lowest global median cost per week of follow up (EUR 2425) and patients who had progressive disease (PD), the highest one (EUR 8325). Except for one patient who had a Grade 5 toxicity (EUR 6043/week), we observe that less severe toxicity grades (EUR 9383/week for Grade 1), or even the absence of toxicity (EUR 9922/week), are associated with higher median costs per week (vs. EUR 3266/week for Grade 4 and EUR 2850/week for Grade 3). The cost of toxicities was unexpectedly low compared to the total costs, especially medication costs. Patients with higher toxicity grades had better outcomes and lower total costs due to treatment discontinuation

The combination of stereotactic radiosurgery with immune checkpoint inhibition or targeted therapy in melanoma patients with brain metastases: a retrospective study.

Evidence pointing to a synergistic effect of stereotactic radiosurgery (SRS) with concurrent immunotherapy or targeted therapy in patients with melanoma brain metastases (BM) is increasing. We aimed to analyze the effect on overall survival (OS) of immune checkpoint inhibitors (ICI) or BRAF/MEK inhibitors initiated during the 9 weeks before or after SRS. We also evaluated the prognostic value of patients' and disease characteristics as predictors of OS in patients treated with SRS. We identified patients with BM from cutaneous or unknown primary origin melanoma treated with SRS between 2011 and 2018. We included 84 patients. The median OS was 12 months (95% CI 9-20 months). The median follow-up was 30 months (95% CI 28-49). Twenty-eight patients with newly diagnosed BM initiated anti-PD-1 +/-CTLA-4 therapy (n = 18), ipilimumab monotherapy (n = 10) or BRAF+/- MEK inhibitors (n = 11), during the 9 weeks before or after SRS. Patients who received anti-PD-1 +/-CTLA-4 mAb showed an improved survival in comparison to ipilimumab monotherapy (OS 24 vs. 7.5 months; HR 0.32, 95% 0.12-0.83, p = 0.02) and BRAF +/-MEK inhibitors (OS 24 vs. 7 months, respectively; HR 0.11, 95% 0.04-0.34, p = 0.0001). This benefit remained significant when compared to the subgroup of patients treated with dual BRAF/MEK inhibition (BMi) (n = 5). In a multivariate Cox regression analysis an age > 65, synchronous BM, > 2 metastatic sites, > 4 BM, and an ECOG > 1 were correlated with poorer prognosis. A treatment with anti-PD-1+/-CTLA-4 mAbs within 9 weeks of SRS was associated with better outcomes. The presence of serum lactate dehydrogenase (LDH) levels ≥ 2xULN at BM diagnosis was associated with lower OS (HR 1.60, 95% CI 1.03-2.50; p = 0.04). The concurrent administration of anti-PD-1+/-CTLA-4 mAbs with SRS was associated with improved survival in melanoma patients with newly diagnosed BM. In addition to CNS tumor burden, the extension of systemic disease retains its prognostic value in patients treated with SRS. Elevated serum LDH levels are predictors of poor outcome in these patients

Late-onset and long-lasting immune-related adverse events from immune checkpoint-inhibitors: An overlooked aspect in immunotherapy.

Immune checkpoint inhibitors (ICIs) have revolutionised cancer therapy but frequently cause immune-related adverse events (irAEs). Description of late-onset and duration of irAEs in the literature is often incomplete. To investigate reporting and incidence of late-onset and long-lasting irAEs, we reviewed all registration trials leading to ICI's approval by the US FDA and/or EMA up to December 2019. We analysed real-world data from all lung cancer (LC) and melanoma (Mel) patients treated with approved ICIs at the University Hospital of Lausanne (CHUV) from 2011 to 2019. To account for the immortal time bias, we used a time-dependent analysis to assess the potential association between irAEs and overall survival (OS). Duration of irAEs and proportion of patients with ongoing toxicities at data cut-off were not specified in 56/62 (90%) publications of ICIs registration trials. In our real-world analysis, including 437 patients (217 LC, 220 Mel), 229 (52.4%) experienced at least one grade ≥2 toxicity, for a total of 318 reported irAEs, of which 112 (35.2%) were long-lasting (≥6 months) and about 40% were ongoing at a median follow-up of 369 days [194-695] or patient death. The cumulative probability of irAE onset from treatment initiation was 42.8%, 51.0% and 57.3% at 6, 12 and 24 months, respectively. The rate of ongoing toxicity from the time of first toxicity onset was 42.8%, 38.4% and 35.7% at 6, 12 and 24 months. Time-dependent analysis showed no significant association between the incidence of irAEs and OS in both cohorts (log Rank p = 0.67 and 0.19 for LC and Mel, respectively). Late-onset and long-lasting irAEs are underreported but common events during ICIs therapy. Time-dependent survival analysis is advocated to assess their impact on OS. Real-world evidence is warranted to fully capture and characterise late-onset and long-lasting irAEs in order to implement appropriate strategies for patient surveillance and follow-up