Discussion
cancers, melanoma, toxicity, cancer, Breast cancer, anti-PD1-refractory, toxicities
DISEASE PROGRESSION, CANCERS, MELANOMA, CANCER, DISEASE, BREAST CANCER, MUTANT, SECONDARY
To our knowledge, this trial represents the largest prospective clinical trial of IT immunotherapy in any cancer type and the first to systematically evaluate IT administration of anti-PD1 antibodiesThese initial results of our concurrent IT/IV nivolumab trial can be viewed in light of three recently published trials that assessed the efficacy of systemically (IV) administered CPI in patients with LMD, namely pembrolizumab (For the secondary endpoint of OS, the median OS with IT/IV nivolumab was 25 weeks, which is numerically similar to the results observed with IV pembrolizumab (median OS 3.6–4.9 months) and with IV ipilimumab plus nivolumab (median OS 2.9 months). However, a key difference is that, whereas the three previous studies of IV CPI for LMD excluded previous anti-PD1 treatment, the majority (88%) of our cohort had previous exposure to and progression on systemic anti-PD1 (with or without anti-CTLA4). We included anti-PD1-refractory patients in our study because LMD typically represents a late manifestation of disease progression in melanoma, a disease in which CPI is standard frontline therapy. Perhaps consistent with this, the other immune checkpoint inhibitor trials for LMD included very few melanoma patients (two treated with ipilimumab and nivolumab; none treated with pembrolizumab). Breast cancer was the most common diagnosis in those studies (total 22 of 33 patients treated with pembrolizumab; 8 of 18 with ipilimumab and nivolumab), and in retrospective studies has been associated with better outcomes than melanoma in patients with LMDWe did not conclusively observe a clear IT dose–response relationship with either toxicity or efficacy. However, longer follow-up for patients treated with either 20 mg or 50 mg of IT nivolumab is ongoing and we will continue to evaluate a potential relationship between IT dose and clinical benefit, as well as continue monitoring for any long-term toxicity. Planned exploratory analysis of longitudinal CSF samples collected in this study, including cytokine, cell-free DNA and single-cell RNA sequencing analysis, will also assess for dose-dependent effects of IT nivolumab, and/or factors that correlate with clinical outcomes.As described earlier, concurrent targeted therapy with BRAF or BRAF/MEK inhibitor was initially not permitted. However, after observing several patients with rapid disease progression and clinical deterioration upon targeted therapy discontinuation, an amendment to the protocol allowed continued/concurrent therapy with BRAF/MEK inhibitors, without any dose adjustments. Because concurrent treatment with targeted therapy was not associated with a significant difference in OS when compared with either the entire study population or within the group of BRAF mutant patients, we believe that the promising OS results are still attributable to the IT + IV immunotherapy treatment, but larger patient numbers are needed to confirm this. Reassuringly, among the 11 patients receiving concurrent targeted therapy, none experienced grade ≥3 toxicity with IT nivolumab alone, and only one with concurrent IT/IV nivolumab therapy. Although safety data will continue to be collected in the dose expansion cohort, our current safety results support the feasibility of combining anti-PD1 with targeted therapy in patients with LMD, consistent with the recent approval of vemurafenib, cobimetinib and atezolizumab, as well as ongoing investigations of triplet combination regimensIn summary, our preliminary analysis demonstrates that concurrent IT and IV administration of nivolumab was safe in melanoma patients with LMD up to the highest planned dose level, with no new or unexpected toxicities, and established the recommended IT nivolumab dose at 50 mg. In this heavily pretreated cohort, there was preliminary evidence of clinical benefit in a subset of patients, including in patients previously treated with systemic anti-PD1. Importantly, our study demonstrates the feasibility of prospective clinical trials for melanoma patients with LMD. These initial results support the rationale for further evaluation of IT anti-PD1 in patients with LMD from melanoma and other cancers.