Retrospective study of advanced melanoma patients treated with ipilimumab after nivolumab: Analysis of 60 Japanese patients

Background

Due to resistance and immune-related adverse events (irAE) some melanoma patients require ipilimumab after nivolumab therapy. However, little is known about the result of this switching.

Cutaneous T-cell lymphomas: Focusing on novel agents in relapsed and refractory disease

Patients with relapsed or refractory cutaneous T-cell lymphoma (CTCL) display a dismal prognosis and their therapy represents an unmet medical need, as the best treatment strategy is yet to be determined. Exciting data on novel targeted agents are now emerging from recently concluded and ongoing clinical trials in patients with relapsed and refractory CTCL. Three FDA approved compounds are used as single agents including the oral retinoid bexarotene and histone deacetylase inhibitors romidepsin and vorinostat. Brentuximab vedotin, an anti-CD30 drug-conjugated monoclonal antibody, has received from European Commission the orphan designation but has not been approved by EMA yet. Several other molecules have demonstrated their activity in the same context and combination strategies are being explored. Participation in a well designed clinical trial is encouraged, as the introduction of novel agents will continue to expand the therapeutics options available in the management of CTCL.     

Endocrine-related adverse events associated with immune checkpoint blockade and expert insights on their management

Agents that modulate immune checkpoint proteins, such as cytotoxic T-lymphocyte antigen-4 (CTLA-4) and programmed death receptor-1 (PD-1), have become a mainstay in cancer treatment. The clinical benefit afforded by immune checkpoint inhibitors can be accompanied by immune-related adverse events (irAE) that affect the skin, gastrointestinal tract, liver, and endocrine system. The types of irAEs associated with immune checkpoint inhibitors are generally consistent across tumor types. Immune-related endocrine events can affect the pituitary, thyroid, and adrenal glands, as well as other downstream target organs. These events are unique when compared with other irAEs because the manifestations are often irreversible. Immune-related endocrine events are typically grade 1/2 in severity and often present with non-specific symptoms, making them difficult to diagnose. The mechanisms underlying immune-related target organ damage in select individuals remain mostly undefined. Management includes close patient monitoring, appropriate laboratory testing for endocrine function, replacement of hormones, and consultation with an endocrinologist when appropriate. An awareness of the symptoms and management of immune-related endocrine events may aid in the safe and appropriate use of immune checkpoint inhibitors in clinical practice.     

Peripheral CD8 effector-memory type 1 T-cells correlate with outcome in ipilimumab-treated stage IV melanoma patients

The role of the assessment of peripheral T-cell phenotypes in predicting overall survival (OS) after ipilimumab treatment is unclear. Here, we analysed mononuclear cells in the blood before and at different time points during treatment with ipilimumab in 137 late-stage melanoma patients. The proportions of baseline naïve and memory T-cells were measured by flow cytometry and correlated with OS, with an emphasis on PD-1 expression. High frequencies (>13%) of CD8 effector-memory type 1 (EM1) T-cells at baseline correlated with longer OS (p = 0.029) and higher clinical response rates (p = 0.01). The frequency of these EM1 cells and the M category had independent impacts on OS (hazard ratio = 1.5, p = 0.033; and hazard ratio = 1.9, p = 0.007). In contrast, high baseline frequencies of late stage-differentiated effector memory CD8 cells (>23.8%) were negatively associated with OS (p = 0.034) but did not correlate with clinical response. Following treatment, a decrease of CD8 cells from baseline to the time of the second drug dose and at later time points was strongly and consistently correlated with a high clinical response rate. Our observations thus suggest an important predictive role of baseline CD8 EM1 cells and changes in CD8 cells for clinical response of ipilimumab. Further validation of these biomarker candidates is warranted.     

Meta-analysis of randomized controlled trials for the incidence and risk of fatal adverse events in cancer patients treated with ipilimumab

Background: Ipilimumab is a fully human immunoglobulin G1 monoclonal antibody that increases antitumor T-cell responses. We conducted a meta-analysis of randomized controlled trials (RCTs) to evaluate the risk of FAEs associated with ipilimumab.

Methods: We searched PubMed, EMBASE, and ASCO meeting abstract up to September 2016 for RCT comparing ipilimumab with no ipilimumab on cancer patients. Incidence rates, relative risk ratios (RRs), and 95% confidence intervals (CIs) were calculated using fixed- or random effects models. The primary end point was the association of ipilimumab with FAEs. Subgroup analyses were performed according to tumor type, concurrent therapy, and dose of ipilimumab.

Results: A total of 5,466 patients from 10 RCTs were included. For patients receiving ipilimumab, the overall incidences of FAEs was 0.99% (95% CI: 0.48%-1.69%). Allocation to ipilimumab therapy increased the risk of FAEs (RR = 2.16, 95% CI, 1.03–4.54) significantly. Subgroup analyses reached statistical significance for prostate cancer, high dose of ipilimumab, and placebo as a control group. No evidence of publication bias was observed.

Conclusions: Compared with control or placebo, ipilimumab was associated with an increased risk of FAEs in cancer patients. As ipilimumab gains greater clinical use, practitioners must be aware of the risks associated with its use.     

A Phase 1 Trial of Concurrent or Sequential Ipilimumab,Nivolumab, and Stereotactic Body Radiotherapy in Patients With Stage IV NSCLC Study

IntroductionPrevious studies have evaluated stereotactic body radiotherapy (SBRT) in oligometastatic patients with NSCLC, including multimodality treatment with anti–programmed cell death protein-1 monotherapy. Questions remain regarding the timing of SBRT and immunotherapy, safety with dual checkpoint blockade, and the utility in widely metastatic patients. This randomized phase 1 trial combined nivolumab and ipilimumab with sequential or concurrent multisite SBRT in patients with stage IV NSCLC to evaluate safety and obtain preliminary activity data.MethodsTreatment-naive patients with metastatic NSCLC were randomized to concurrent (SBRT with immunotherapy) or sequential (SBRT followed by immunotherapy) treatment. A maximum of four treatment fields received SBRT. Nivolumab and ipilimumab were continued until clinical progression, development of toxicity, or after 2 years. Dose-limiting toxicity was defined as greater than or equal to grade 3 toxicity to the relevant organ system attributed to SBRT and immunotherapy occuring within 3 months.ResultsA total of 37 patients were assessable. No dose-limiting toxicity occurred in the concurrent cohort (n = 18). The sequential cohort required a dose reduction in the central lung group owing to two grade 4 pneumonitis events (2 of 19). Overall best response was as follows: 5.4% (2 of 37) complete response, 40.5% (15 of 37) partial response, 16.2% (6 of 37) stable disease, and 37.8% (14 of 37) progressive disease. Median progression-free survival was 5.8 months (95% confidence interval: 3.6–11.4 mo), with median follow-up of 17.0 months. Median overall survival was not reached.ConclusionsConcurrent nivolumab, ipilimumab, and SBRT were not more toxic than sequential therapy, and multisite SBRT was well tolerated in widely metastatic patients. Multimodality therapy resulted in durable metastasis control and encouraging early overall survival.     

Current and future adjuvant immunotherapies for melanoma: Blockade of cytotoxic T-lymphocyte antigen-4 as a novel approach

The current treatment for melanoma with nodal involvement, but without distant metastasis, is surgical excision and lymph node dissection followed by adjuvant therapy. A number of systemic regimens have been evaluated for melanoma patients with a medium or high risk of disease recurrence following surgery. The only agent approved for the adjuvant therapy of melanoma is high-dose interferon (IFN)-α2b, which prolongs relapse-free survival, but its effects on overall survival remain controversial. Its use is also accompanied by significant toxicity. Thus, despite its approval, high-dose IFN-α2b is not always used for the adjuvant therapy of melanoma, particularly in countries other than the United States. Studies aimed at identifying subgroups of patients that have the greatest benefit-to-risk ratio with this regimen are ongoing. Several vaccines have been studied in the adjuvant setting for melanoma, but none has shown superiority to IFN-containing regimens. The GMK ganglioside vaccine, for instance, has actually been shown to be inferior to high-dose IFN-α2b. Therefore, a therapeutic regimen which improves overall survival with a favorable safety profile would be a major advance in the adjuvant therapy of melanoma. One approach that is currently being investigated is the potentiation of antitumour immune responses through blockade of cytotoxic T-lymphocyte antigen-4 (CTLA-4). Here, we provide an overview of the current unmet needs in the adjuvant therapy of melanoma and evaluate the potential of CTLA-4 blockade as a future therapeutic option in this setting.     

Clinical experience with ipilimumab 10?mg/kg in patients with melanoma treated at Italian centres as part of a European expanded access programme

Background

Patients with advanced melanoma are faced with a poor prognosis and, until recently, limited treatment options. Ipilimumab, a novel immunotherapy that blocks cytotoxic T-lymphocyte-associated antigen-4, was the first agent to improve survival of patients with advanced melanoma in a randomised, controlled phase 3 trial. We used data from an expanded access programme (EAP) at Italian centres to evaluate the clinical activity and safety profile of ipilimumab 10 mg/kg in patients with advanced melanoma in a setting more similar to that of daily practice.

Methods

Data were collected from patients enrolled in an ipilimumab EAP across eight participating Italian centres. As per the EAP protocol, patients had life-threatening, unresectable stage III/IV melanoma, had failed or did not tolerate previous treatments and had no other therapeutic option available. Treatment comprised ipilimumab 10 mg/kg every 3 weeks for a total of four doses. If physicians believed patients would continue to derive benefit from ipilimumab treatment, maintenance therapy with ipilimumab 10 mg/kg was provided every 12 weeks. Tumour responses were assessed every 12 weeks using modified World Health Organization criteria and safety continuously monitored.

Results

Seventy-four pretreated patients with advanced melanoma were treated with ipilimumab 10 mg/kg. Of these, 9 (13.0%) had an objective response, comprising 3 patients with a complete response and 6 with a partial response. Median overall survival was 7.0 months (95% confidence interval, 5.3–8.7) and 16.6% of patients were alive after 3 years. Forty-five patients (60.8%) reported treatment-related adverse events of any grade, which were most commonly low-grade pruritus, pain, fever and diarrhoea. Grade 3 or 4 treatment-related AEs were reported in 8 patients (10.8%).

Conclusions

The clinical activity and safety profile of ipilimumab 10 mg/kg in the EAP was similar to that seen in previous clinical trials of ipilimumab in pretreated patient populations.     

Systematic Review and Network Meta‐Analysis of Overall Survival Comparing 3 mg/kg Ipilimumab With Alternative Therapies in the Management of Pretreated Patients With Unresectable Stage III or IV Melanoma

Objective.

To compare the overall survival (OS) of patients treated with 3 mg/kg ipilimumab versus alternative systemic therapies in pretreated unresectable stage III or IV melanoma patients.

Methods.

A systematic literature search was performed to identify relevant randomized clinical trials. From these trials, Kaplan–Meier survival curves for each intervention were digitized and combined by means of a Bayesian network meta-analysis (NMA) to compare different drug classes.

Results.

Of 38 trials identified, 15 formed one interlinked network by drug class to allow for an NMA. Ipilimumab, at a dose of 3 mg/kg, was associated with a greater mean OS time (18.8 months; 95% credible interval [CrI], 15.5–23.0 months) than single-agent chemotherapy (12.3 months; 95% CrI, 6.3–28.0 months), chemotherapy combinations (12.2 months; 95% CrI, 7.1–23.3 months), biochemotherapies (11.9 months; 95% CrI, 7.0–22.0 months), single-agent immunotherapy (11.1 months; 95% CrI, 8.5–16.2 months), and immunotherapy combinations (14.1 months; 95% CrI, 9.0–23.8 months).

Conclusion.

Results of this NMA were in line with previous findings and suggest that OS with ipilimumab is expected to be greater than with alternative systemic therapies, alone or in combination, for the management of pretreated patients with unresectable stage III or IV melanoma.