When the cyclin kinase 4/6 inhibitor abemaciclib was sequenced with PD-1 blockade in mostly immunologically "cold" murine models, enhanced immune-mediated antitumor effects-including increased ...lifespan, recruitment of CD8 cells to tumor, reduction of regulatory T-cell and immunosuppressive cytokines in tumor, increased tumor antigen presentation, and broadening of the T-cell receptor repertoire-were achieved in both cutaneous and brain metastases. See related article by Nayyar et al., p. 420.
Opinion Statement
Advanced melanoma, rarely diagnosed at the time of primary melanoma excision but most often occurring later via lymphatic or hematogenous dissemination, is the cause of death for ...approximately 10,000 people in the USA each year, with the rate of incidence and death increasing yearly. Its causes are multifactorial and depend in large part on solar ultraviolet damage to DNA as well as underlying genetic predisposition. Cutaneous melanoma is the most common, but other subsets of importance are mucosal and uveal primaries, with different biology and treatment considerations. Mutational oncogenic “drivers” may be targeted with chronically administered, oral kinase inhibitors, currently consisting of the mitogen-activated protein kinase (MAPK) inhibitor combinations of BRAF plus MEK-targeted drugs. These agents work quickly to relieve symptoms and induce remissions but generally have limited durations of disease control. Immunotherapies include the immune checkpoint inhibitors that block CTLA4 or PD-1-negative immune signaling as well as interleukin-2, a cytokine that stimulates T lymphocytes and natural killer cells. A combination of CTLA4 plus PD-1 blockade has the highest activity ever reported for metastatic melanoma, at the cost of high autoimmune-like toxicities. However, immunotherapies of this type may provide durable responses and even cure a subset of patients. Thus, these immunotherapeutic agents are recommended as first-line therapy for most patients with advanced melanoma. Patients with rapidly progressive, symptomatic melanoma whose tumor carries a BRAF mutation may benefit more from initial therapy with combined MAPK inhibitors.
Cytokines are molecular messengers that allow the cells of the immune system to communicate with one another to generate a coordinated, robust, but self-limited response to a target antigen. The ...growing interest over the past two decades in harnessing the immune system to eradicate cancer has been accompanied by heightened efforts to characterize cytokines and exploit their vast signaling networks to develop cancer treatments. The goal of this paper is to review the major cytokines involved in cancer immunotherapy and discuss their basic biology and clinical applications. The paper will also describe new cytokines in pre-clinical development, combinations of biological agents, novel delivery mechanisms, and potential directions for future investigation using cytokines.
Nivolumab is a fully human immunoglobulin G4 programmed death-1 immune checkpoint inhibitor antibody that restores T-cell immune activity. This phase II trial assessed the antitumor activity, ...dose-response relationship, and safety of nivolumab in patients with metastatic renal cell carcinoma (mRCC).
Patients with clear-cell mRCC previously treated with agents targeting the vascular endothelial growth factor pathway were randomly assigned (blinded ratio of 1:1:1) to nivolumab 0.3, 2, or 10 mg/kg intravenously once every 3 weeks. The primary objective was to evaluate the dose-response relationship as measured by progression-free survival (PFS); secondary end points included objective response rate (ORR), overall survival (OS), and safety.
A total of 168 patients were randomly assigned to the nivolumab 0.3- (n = 60), 2- (n = 54), and 10-mg/kg (n = 54) cohorts. One hundred eighteen patients (70%) had received more than one prior systemic regimen. Median PFS was 2.7, 4.0, and 4.2 months, respectively (P = .9). Respective ORRs were 20%, 22%, and 20%. Median OS was 18.2 months (80% CI, 16.2 to 24.0 months), 25.5 months (80% CI, 19.8 to 28.8 months), and 24.7 months (80% CI, 15.3 to 26.0 months), respectively. The most common treatment-related adverse event (AE) was fatigue (24%, 22%, and 35%, respectively). Nineteen patients (11%) experienced grade 3 to 4 treatment-related AEs.
Nivolumab demonstrated antitumor activity with a manageable safety profile across the three doses studied in mRCC. No dose-response relationship was detected as measured by PFS. These efficacy and safety results in mRCC support study in the phase III setting.
To provide a more precise estimate of long-term survival observed for ipilimumab-treated patients with advanced melanoma, we performed a pooled analysis of overall survival (OS) data from multiple ...studies.
The primary analysis pooled OS data for 1,861 patients from 10 prospective and two retrospective studies of ipilimumab, including two phase III trials. Patients were previously treated (n = 1,257) or treatment naive (n = 604), and the majority of patients received ipilimumab 3 mg/kg (n = 965) or 10 mg/kg (n = 706). We also conducted a secondary analysis of OS data (n = 4,846) with an additional 2,985 patients from an expanded access program. OS rates were estimated using the Kaplan-Meier method.
Among 1,861 patients, median OS was 11.4 months (95% CI, 10.7 to 12.1 months), which included 254 patients with at least 3 years of survival follow-up. The survival curve began to plateau around year 3, with follow-up of up to 10 years. Three-year survival rates were 22%, 26%, and 20% for all patients, treatment-naive patients, and previously treated patients, respectively. Including data from the expanded access program, median OS was 9.5 months (95% CI, 9.0 to 10.0 months), with a plateau at 21% in the survival curve beginning around year 3.
To our knowledge, this is the largest analysis of OS to date for ipilimumab-treated patients with advanced melanoma. We observed a plateau in the survival curve, beginning at approximately 3 years, which was independent of prior therapy or ipilimumab dose. These data add to the evidence supporting the durability of long-term survival in ipilimumab-treated patients with advanced melanoma.
In a Phase II clinical study enrolling individuals with melanoma brain metastases, 51 asymptomatic patients (cohort A) and 21 on a stable steroid dose (cohort B) received 4 courses of 10 mg/kg ...intravenous ipilimumab (induction), then (at 24 weeks) maintenance therapy with the same dose of ipilimumab every 12 weeks. Disease control rate at 12 weeks was 18% (according to the modified WHO criteria) and 26% (according to the immune-related response criteria) in cohort A (median survival = 7 mo) and 5% and 10% in cohort B (median survival = 4 mo). Toxicities were as previously reported for ipilimumab patients without brain metastases.
Combination nivolumab plus ipilimumab was efficacious in patients with asymptomatic melanoma brain metastases (MBM) in CheckMate 204, but showed low efficacy in patients with symptomatic MBM. Here, ...we provide final 3-year follow-up data from the trial.
This open-label, multicentre, phase 2 study (CheckMate 204) included adults (aged ≥18 years) with measurable MBM (0·5–3·0 cm in diameter). Asymptomatic patients (cohort A) had an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 and no neurological symptoms or baseline corticosteroid use; symptomatic patients (cohort B) had an ECOG performance status of 0–2 with stable neurological symptoms and could be receiving low-dose dexamethasone. Nivolumab 1 mg/kg plus ipilimumab 3 mg/kg was given intravenously every 3 weeks for four doses, followed by nivolumab 3 mg/kg every 2 weeks for up to 2 years, until disease progression or unacceptable toxicity. The primary endpoint was intracranial clinical benefit rate (complete responses, partial responses, or stable disease lasting ≥6 months) assessed in all treated patients. Intracranial progression-free survival and overall survival were key secondary endpoints. This study is registered with ClinicalTrials.gov, NCT02320058.
Between Feb 19, 2015, and Nov 1, 2017, 119 (72%) of 165 screened patients were enrolled and treated: 101 patients were asymptomatic (cohort A; median follow-up 34·3 months IQR 14·7–36·4) and 18 were symptomatic (cohort B; median follow-up 7·5 months 1·2–35·2). Investigator-assessed intracranial clinical benefit was observed in 58 (57·4% 95% CI 47·2–67·2) of 101 patients in cohort A and three (16·7% 3·6–41·4) of 18 patients in cohort B; investigator-assessed objective response was observed in 54 (53·5% 43·3–63·5) patients in cohort A and three (16·7% 3·6–41·4) patients in cohort B. 33 (33%) patients in cohort A and three (17%) patients in cohort B had an investigator-assessed intracranial complete response. For patients in cohort A, 36-month intracranial progression-free survival was 54·1% (95% CI 42·7–64·1) and overall survival was 71·9% (61·8–79·8). For patients in cohort B, 36-month intracranial progression-free survival was 18·9% (95% CI 4·6–40·5) and overall survival was 36·6% (14·0–59·8). The most common grade 3–4 treatment-related adverse events (TRAEs) were increased alanine aminotransferase and aspartate aminotransferase (15 15% of 101 patients each) in cohort A; no grade 3 TRAEs occurred in more than one patient each in cohort B, and no grade 4 events occurred. The most common serious TRAEs were colitis, diarrhoea, hypophysitis, and increased alanine aminotransferase (five 5% of each among the 101 patients in cohort A); no serious TRAE occurred in more than one patient each in cohort B. There was one treatment-related death (myocarditis in cohort A).
The durable 3-year response, overall survival, and progression-free survival rates for asymptomatic patients support first-line use of nivolumab plus ipilimumab. Symptomatic disease in patients with MBM remains difficult to treat, but some patients achieve a long-term response with the combination.
Bristol Myers Squibb.
Patients who received 3 doses of pembrolizumab before surgery and 15 doses after surgery had significantly longer event-free survival than those who received adjuvant-only therapy with 18 doses after ...surgery.
A combination of nivolumab and ipilimumab produced complete responses in 26% and partial responses in 30% of patients with previously untreated brain metastases from melanoma.
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