Nivolumab plus ipilimumab in melanoma patients with asymptomatic brain metastases: 7-year outcomes and quality of life from the multicenter phase III NIBIT-M2 trial.

BACKGROUND: The primary analysis of the phase III NIBIT-M2 study showed a 41% 4-year overall survival (OS) of melanoma patients with asymptomatic brain metastases treated with ipilimumab plus nivolumab. METHODS: Here, we report the 7-year efficacy outcomes and the Health-Related Quality of Life (HRQoL) analyses of the NIBIT-M2 study. RESULTS: As of May 1, 2023, at a median follow-up of 67 months (mo), the median OS was 8.5 (95% CI: 6.6-10.3), 8.2 (95% CI: 2.1-14.3) and 29.2 (95% CI: 0-69.9) mo for the fotemustine (F) Arm A, ipilimumab plus fotemustine Arm B, and ipilimumab plus nivolumab Arm C, respectively. The 7-year OS rate was 10.0% (95% CI: 0-22.5) in Arm A, 10.3% (95% CI: 0-22.6) in Arm B, and 42.8% (95% CI: 23.4-62.2) in Arm C. HRQoL was preserved in all treatment arms. Most functional scales evaluated from baseline to W12 were preserved, with a lower mean score decrease for EORTC Quality of Life Questionnaire (QLQ)-C30 and an increase for EORTC QLQ-Brain neoplasm (BN20) in patients receiving ipilimumab plus nivolumab. CONCLUSIONS: With the longest follow-up available to date in melanoma patients with asymptomatic brain metastases, the NIBIT-M2 study continues to show persistent therapeutic efficacy of I ipilimumab plus nivolumab while preserving HRQoL.

Guadecitabine plus ipilimumab in unresectable melanoma: five-year follow-up and integrated multi-omic analysis in the phase 1b NIBIT-M4 trial.

Association with hypomethylating agents is a promising strategy to improve the efficacy of immune checkpoint inhibitors-based therapy. The NIBIT-M4 was a phase Ib, dose-escalation trial in patients with advanced melanoma of the hypomethylating agent guadecitabine combined with the anti-CTLA-4 antibody ipilimumab that followed a traditional 3 + 3 design (NCT02608437). Patients received guadecitabine 30, 45 or 60 mg/m2/day subcutaneously on days 1 to 5 every 3 weeks starting on week 0 for a total of four cycles, and ipilimumab 3 mg/kg intravenously starting on day 1 of week 1 every 3 weeks for a total of four cycles. Primary outcomes of safety, tolerability, and maximum tolerated dose of treatment were previously reported. Here we report the 5-year clinical outcome for the secondary endpoints of overall survival, progression free survival, and duration of response, and an exploratory integrated multi-omics analysis on pre- and on-treatment tumor biopsies. With a minimum follow-up of 45 months, the 5-year overall survival rate was 28.9% and the median duration of response was 20.6 months. Re-expression of immuno-modulatory endogenous retroviruses and of other repetitive elements, and a mechanistic signature of guadecitabine are associated with response. Integration of a genetic immunoediting index with an adaptive immunity signature stratifies patients/lesions into four distinct subsets and discriminates 5-year overall survival and progression free survival. These results suggest that coupling genetic immunoediting with activation of adaptive immunity is a relevant requisite for achieving long term clinical benefit by epigenetic immunomodulation in advanced melanoma patients.

From Co-Stimulation to Co-Inhibition: A Continuum of Immunotherapy Care Toward Long-Term Survival in Melanoma.

Harnessing the immune system with immune-checkpoint(s) blockade (ICB) has dramatically changed the treatment landscape of advanced melanoma patients in the last decade. Indeed, durable clinical responses and long-term survival can be achieved with anti-Cytotoxic T-Lymphocyte Antigen-4 (CTLA-4) and anti-Programmed cell Death-1 (PD-1) monoclonal antibodies (mAb) either alone or in combination. Despite these unprecedented results, due to intrinsic or acquired resistance to ICB-based immunotherapy, about half of metastatic melanoma (MM) patients neither respond to therapy nor experience durable clinical benefit or long-term survival. To improve the efficacy of ICB therapy among a larger proportion of MM patients, in addition to the targeting of immune-checkpoint(s) inhibitors (ICI) such as CTLA-4 or PD-1, several co-stimulatory molecules, such as Inducible T-cell COStimulator (ICOS), CD137 and OX40, have been investigated in MM, with initial signs of activity. Thus, a number of MM patients have been exposed to co-inhibitory and co-stimulatory mAb in the course of their disease. Being aware of the clinical outcome of such patients may pave the way to novel and more effective clinical approaches and therapeutic sequences for MM patients. Here we report a paradigmatic clinical case of a cutaneous MM patient who achieved multiple and durable complete responses, leading to an extraordinary long-term survival with sequential ICB therapies, suggesting the possibility to build a highly effective continuum of care with co-inhibitory and co-stimulatory therapeutic mAb.