This month's featured editor is a JITC Social Media Editor, Dr. Praveen K. Bommareddy.
“Combination dabrafenib and trametinib versus combination nivolumab and ipilimumab for patients with advanced BRAF-mutant melanoma: The DREAMseq Trial – ECOG-ACRIN EA6134” by Michael B. Atkins et al
J Clin Oncol (2022)
Two highly effective first-line combination therapies are available for patients with BRAFV600-mutated melanoma: targeted therapy with BRAF/MEK-inhibition and immunotherapy with PD-1/CTLA-4 checkpoint blockade, however, no prospective data were available to inform optimal sequencing of these regimens. In the open-label, two-step, phase III DREAMseq study, Michael B. Atkins et al randomized 265 patients with treatment-naïve, unresectable stage III or IV BRAFV600-mutated melanoma 1:1 to receive first-line treatment with nivolumab (1mg/kg)/ipilimumab (3mg/kg) (Arm A, with nivolumab 3mg/kg plus ipilimumab 1mg/kg dosing later allowed) dabrafenib (150mg BID)/trametinib (2mg daily) in step 2 (Arm C). Patients in Arm B received dabrafenib (150mg BID)/trametinib (2mg daily) in step 1 followed by treatment with nivolumab (1mg/kg)/ipilimumab (3mg/kg) in step 2 (Arm D). Randomization was stratified by ECOG PS and LDH level. At the time of disease progression, patients received the second-line alternative treatment in Step 2 with either dabrafenib/trametinib (Arm C) or nivolumab/ipilimumab (Arm D). The 2-year landmark OS rates (the study’s primary endpoint) were 71.8% versus 51.5% for the patients randomized to the immunotherapy-first arm versus the targeted therapy-first arms (Arm A vs Arm B, respectively, log-rank p=0.010). Median PFS (a secondary endpoint) were 11.8 months and 8.5 months for immunotherapy versus targeted therapy first, respectively (log-rank p=0.054). Importantly, objective response rate for immunotherapy was lower following progression of disease on targeted therapy (29.6% [95% CI 12.7% to 47.2%]) versus in the frontline (46.0% [36.6% to 55.6%]). The ORR for dabrafenib/trametinib, on the other hand, was similar regardless of sequence (47.8% in Arm C and 43.0% in Arm B). There were no significant differences in grade ≥3 toxicities between treatment arms.
Why this matters: DREAMseq prospectively demonstrated improved survival and response rates when sequencing dual immune checkpoint blockade before BRAF/MEK inhibition, setting a new practice-changing standard of care for patients with advanced BRAFV600-mutated melanoma.
“Neoadjuvant Cemiplimab for Stage II to IV Cutaneous Squamous-Cell Carcinoma” by Neil D. Gross et al
Anti-PD-1 immune checkpoint inhibitors (ICIs) have become the standard of care for patients with unresectable cutaneous squamous cell carcinoma (CSCC), however, the limited data are available on the efficacy of ICIs in the perioperative setting for this common skin cancer. Previously, a pilot study reported encouraging data with two cycles of neoadjuvant cemiplimab in patients with locoregionally advanced cutaneous squamous cell carcinoma of the head and neck (Ferrarotto R, et al. Clin Cancer Res. 2021), and Neil D. Gross and colleagues describe a confirmatory phase II non-randomized trial assessing neoadjuvant cemiplimab (anti-PD-1 monoclonal antibody) in patients with resectable stage II, III, or IV (M0) CSCC. The primary endpoint was pathological complete response (pCR), and key secondary endpoints were pathological major response rate (≤ 10% viable tumor cells) and objective response rate (ORR). Of the 79 patients that were enrolled, 40 (51%) had a pCR and 10 (13%) had a pathologic major response. The ORR was 68%, and, interestingly, the complete response rate on imaging was significantly lower than the pathologic response assessment at only 6%. Patients with PD-L1-positive tumors (defined as ≥ 1% tumor cells expressing) had a higher pCR rate than the group with PD-L1-negative tumors, however, responses were seen in both groups. No new safety signals were observed. Taken together, these promising results further support the use of cemiplimab in the neoadjuvant setting for CSCC
Why this matters: While long-term outcomes data in this setting are not yet available, pCR after neoadjuvant ICI treatment has been associated with reduced risk of recurrence for other cancer types. For some patients with resectable CSCC, ICIs may be preferable over adjuvant radiation therapy, which is the current standard of care. In some patients, neoadjuvant therapy can also be beneficial to treat tumors that are unresectable by achieving a complete response or making the tumors amenable to subsequent surgical resection.
“Oncometabolite D-2HG alters T cell metabolism to impair CD8+ T cell function” by Giulia Notarangelo et al
Altered metabolism in tumor cells supports tumor growth in a variety of environments, but the effects of these adaptations on other cells in the tumor microenvironment, including immune cells, is not fully known. Immunosuppression arising from increased D-2-hydroxyglutarate (D-2HG) secretion due to a mutation in isocitrate dehydrogenase (IDH) is described by Giulia Notarangelo and colleagues. In vitro, CD8+ T cells exposed to D-2HG had reduced proliferation, degranulation, interferon gamma (IFNy) secretion, and cytotoxic capabilities. Mechanistically, D-2HG-treated CD8+ T cells had significant metabolic changes, notably, a shift from glycolysis to electron transport chain-mediated for ATP production via inhibition of lactate dehydrogenase (LDH). In human tumor samples from patients with IDH-wild-type and IDH-mutant gliomas, D-2HG was restricted to tumor area and the number of CD8+ T cells was reduced in the vicinity of increased secretion the metabolite, supporting the in vitro finding of repressed proliferation. Additionally, CD8+ T cells from IDH-mutant tumors had impaired cytotoxicity and IFNy activity. These data for the first time link IDH mutations to impaired anti-tumor immunity mediated by suppressing the CD8+ T cell function.
Why this matters: This mechanistic insight into pathways of immunosuppression in cold tumors such as IDH-mutant gliomas and glioblastomas may pave the way toward finding effective combination strategies for immunotherapy in these challenging-to-treat disease settings.
“Hormonal therapies up-regulate MANF and overcome female susceptibility to immune checkpoint inhibitor myocarditis” by Yaohua Zhang et al
Sci Transl Med (2022)
Immune checkpoint inhibitor (ICI)-related myocarditis disproportionately affects females and the underlying mechanisms of toxicity are not well understood. Yaohua Zhang et al identify a hormone-regulated cardioprotective pathway underlying sex-specific discrepancies in ICI-related myocarditis, with potential therapeutic implications. In murine models, clinical and histologic features of myocarditis (ie, CD8+ T cell and macrophage infiltration) were observed in hearts of both tumor and matched non-tumor bearing mice treated with anti-PD-1 plus anti-CTLA-4, preferentially afflicting female mice. Cardiac Manf and Hspa5 expression (genes that encode for a cardiomyokine and an endoplasmic reticulum chaperone, respectively) were differentially decreased in ICI-treated female mice, with Manf down-regulation more pronounced in female mice. Immunohistochemical staining confirmed decreased MANF and HSPA5 protein expression in ICI-treated mouse and human myocarditis-affected cardiac tissue. Manf-deficient mouse hearts had more pronounced CD8+ tissue staining and clinical manifestations of myocarditis following ICI treatment. Coadministration of recombinant MANF and HSPA5 decreased cardiac macrophage manifestations of myocarditis without affecting tumor-infiltrating CD8+ T cells or the anti-tumor effect of ICI therapy. Interestingly, the promoter sequences for MANF and HSPA5 contain hormone receptor binding elements and ICIs reduced serum 17 beta-estradiol concentrations in female mice. In vitro, estrogen receptor beta-specific agonism or androgen receptor deprivation increased MANF and HSPA5 expression. Simultaneous treatment with ICIs in addition to an estrogen receptor beta-specific agonist in female EO771 TNBC-bearing mice (or androgen deprivation in male RM1 prostate cancer-bearing mice) increased cardiac MANV/HSPA5 expression, reduced cardiac CD8+ T cell infiltration, and improved cardiac function.
Why this matters: These data establish a hormone-regulated cardiac protection pathway that is perturbed by ICI therapy and can be restored with hormone modulation. Exogenous hormone administration, a treatment that is already widely-available, may offer a potential strategy to mitigate immune-mediated myocarditis.
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