65 research outputs found
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Antitumour activity of pembrolizumab in advanced mucosal melanoma: a post-hoc analysis of KEYNOTE-001, 002, 006.
BackgroundMucosal melanoma is an aggressive melanoma with poor prognosis. We assessed efficacy of pembrolizumab in patients with advanced mucosal melanoma in KEYNOTE-001 (NCT01295827), -002 (NCT01704287), and -006 (NCT01866319).MethodsPatients received pembrolizumab 2 mg/kg every 3 weeks (Q3W) or 10 mg/kg Q2W or Q3W. Response was assessed by independent central review per RECIST v1.1.Results1567 patients were treated and 84 (5%) had mucosal melanoma. Fifty-one of 84 were ipilimumab-naive. In patients with mucosal melanoma, the objective response rate (ORR) was 19% (95% CI 11-29%), with median duration of response (DOR) of 27.6 months (range 1.1 + to 27.6). Median progression-free survival (PFS) was 2.8 months (95% CI 2.7-2.8), with median overall survival (OS) of 11.3 months (7.7-16.6). ORR was 22% (95% CI 11-35%) and 15% (95% CI 5-32%) in ipilimumab-naive and ipilimumab-treated patients.ConclusionPembrolizumab provides durable antitumour activity in patients with advanced mucosal melanoma regardless of prior ipilimumab
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Phase I dose-escalation trial of the oral AKT inhibitor uprosertib in combination with the oral MEK1/MEK2 inhibitor trametinib in patients with solid tumors.
PurposeThis study aimed to determine the safety, tolerability, and recommended phase II doses of trametinib plus uprosertib (GSK2141795) in patients with solid tumors likely to be sensitive to MEK and/or AKT inhibition.MethodsThis was a phase I, open-label, dose-escalation, and dose-expansion study in patients with triple-negative breast cancer or BRAF-wild type advanced melanoma. The primary outcome of the expansion study was investigator-assessed response. Among 126 enrolled patients, 63 received continuous oral daily dosing of trametinib and uprosertib, 29 received various alternative dosing schedules, and 34 were enrolled into expansion cohorts. Doses tested in the expansion cohort were trametinib 1.5 mg once daily (QD) + uprosertib 50 mg QD.ResultsAdverse events (AEs) were consistent with those reported in monotherapy studies but occurred at lower doses and with greater severity. Diarrhea was the most common dose-limiting toxicity; diarrhea and rash were particularly difficult to tolerate. Overall, 59% and 6% of patients reported AEs with a maximum severity of grade 3 and 4, respectively. Poor tolerability prevented adequate delivery of uprosertib with trametinib at a concentration predicted to have clinical activity. The study was terminated early based on futility in the continuous-dosing expansion cohorts and a lack of pharmacological or therapeutic advantage with intermittent dosing. The objective response rate was < 5% (1 complete response, 5 partial responses).ConclusionsContinuous and intermittent dosing of trametinib in combination with uprosertib was not tolerated, and minimal clinical activity was observed in all schedules tested
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Ipilimumab administration for advanced melanoma in patients with pre-existing Hepatitis B or C infection: a multicenter, retrospective case series
Ipilimumab is a fully human, monoclonal antibody directed against Cytotoxic T Lymphocyte Antigen-4 (CTLA-4) that has demonstrated a survival benefit and durable disease control in patients with advanced melanoma. Ipilimumab is associated with potentially serious immune-related adverse events, including autoimmune hepatitis. Because clinical trials of ipilimumab excluded patients with pre-existing hepatitis B or C infection, there is a paucity of data on the safety of ipilimumab administration to that patient population. Here, we report the largest case series to date of patients with hepatitis B or C who received ipilimumab for advanced melanoma. Two of the nine patients described in this case series experienced fluctuations in their liver function tests (LFTs) and were subsequently treated with corticosteroids. Although this is a small series, the rate of hepatotoxicity appears similar to what has been seen in the general population treated with ipilimumab, and the ability to administer ipilimumab did not appear to be affected by concomitant hepatitis B or C infection. The use of ipilimumab in patients with metastatic melanoma who have pre-existing hepatitis can be considered among other therapeutic options
The role of whole brain radiation therapy in the management of melanoma brain metastases
Background: Brain metastases are common in patients with melanoma, and optimal management is not well defined. As melanoma has traditionally been thought of as “radioresistant,” the role of whole brain radiation therapy (WBRT) in particular is unclear. We conducted this retrospective study to identify prognostic factors for patients treated with stereotactic radiosurgery (SRS) for melanoma brain metastases and to investigate the role of additional up-front treatment with whole brain radiation therapy (WBRT). Methods: We reviewed records of 147 patients who received SRS as part of initial management of their melanoma brain metastases from January 2000 through June 2010. Overall survival (OS) and time to distant intracranial progression were calculated using the Kaplan-Meier method. Prognostic factors were evaluated using the Cox proportional hazards model. Results: WBRT was employed with SRS in 27% of patients and as salvage in an additional 22%. Age at SRS > 60 years (hazard ratio [HR] 0.64, p = 0.05), multiple brain metastases (HR 1.90, p = 0.008), and omission of up-front WBRT (HR 2.24, p = 0.005) were associated with distant intracranial progression on multivariate analysis. Extensive extracranial metastases (HR 1.86, p = 0.0006), Karnofsky Performance Status (KPS) ≤ 80% (HR 1.58, p = 0.01), and multiple brain metastases (HR 1.40, p = 0.06) were associated with worse OS on univariate analysis. Extensive extracranial metastases (HR 1.78, p = 0.001) and KPS (HR 1.52, p = 0.02) remained significantly associated with OS on multivariate analysis. In patients with absent or stable extracranial disease, multiple brain metastases were associated with worse OS (multivariate HR 5.89, p = 0.004), and there was a trend toward an association with worse OS when up-front WBRT was omitted (multivariate HR 2.56, p = 0.08). Conclusions: Multiple brain metastases and omission of up-front WBRT (particularly in combination) are associated with distant intracranial progression. Improvement in intracranial disease control may be especially important in the subset of patients with absent or stable extracranial disease, where the competing risk of death from extracranial disease is low. These results are hypothesis generating and require confirmation from ongoing randomized trials
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Long-term safety of pembrolizumab monotherapy and relationship with clinical outcome: A landmark analysis in patients with advanced melanoma
Objective
Long-term safety of pembrolizumab in melanoma was analyzed in KEYNOTE-001, KEYNOTE-002, and KEYNOTE-006.
Patients and methods
Analysis involved patients who received ≥1 pembrolizumab dose. Lead-time bias was addressed via landmark analyses in patients who were progression-free before day 147.
Results
Adverse events (AEs) were analyzed for 1567 patients (median follow-up, 42.4 months). Most AEs were mild/moderate; grade 3/4 treatment-related AEs occurred in 17.7% of patients. Two pembrolizumab-related deaths occurred. Any-grade immune-mediated AEs (imAEs) occurred in 23.0%, most commonly hypothyroidism (9.1%), pneumonitis (3.3%), and hyperthyroidism (3.0%); grade 3/4 imAEs occurred in 6.9% of patients. Most imAEs occurred within 16 weeks of treatment. In landmark analysis, patients who did (n = 79) versus did not (n = 384) develop imAEs had similar objective response rates (ORRs) (64.6% versus 63.0%); median time to response (TTR), 5.6 months for both; median duration of response (DOR), 20.0 versus 25.3 months; median progression-free survival (PFS), 17.0 versus 17.7 months; median overall survival (OS), not reached (NR) versus 43 months (p = 0.1104). Patients who did (n = 17) versus did not (n = 62) receive systemic corticosteroids had similar ORRs (70.6% vs. 62.9%) and median TTR (6.4 vs. 5.6 months) but numerically shorter median PFS (9.9 vs. 17.0 months); median DOR, 14.2 months versus NR; median OS, NR for both.
Conclusions
These results enhance the knowledge base for pembrolizumab in advanced melanoma, with no new toxicity signals after lengthy follow-up of a large population. In landmark analyses, pembrolizumab efficacy was similar regardless of imAEs or systemic corticosteroid use.
Clinical trial registry
NCT01295827, NCT01704287, NCT01866319
KEYNOTE-716: Phase III study of adjuvant pembrolizumab versus placebo in resected high-risk stage II melanoma.
Patients with high-risk stage II melanoma are at significant risk for recurrence after surgical resection. Adjuvant treatment options to lower the risk for distant metastases are limited. Although adjuvant IFN-α2b is associated with improved relapse-free survival in patients with high-risk melanoma, toxicity and limited overall survival benefits limit its use. Adjuvant treatment with the PD-1 inhibitor pembrolizumab significantly improved recurrence-free survival, compared with placebo, in patients with resected stage III melanoma in the Phase III KEYNOTE-054 trial; efficacy in patients with stage II disease has not been established. This article describes the design and rationale of KEYNOTE-716 (NCT03553836), a two-part, randomized, placebo-controlled, multicenter Phase III study of adjuvant pembrolizumab in patients with surgically resected high-risk stage II melanoma. Clinical trial registry & ID: ClinicalTrials.gov, NCT0355383
Adjuvant Pembrolizumab versus Placebo in Resected Stage III Melanoma
BACKGROUND The programmed death 1 (PD-1) inhibitor pembrolizumab has been found to prolong progression-free and overall survival among patients with advanced melanoma. We conducted a phase 3 double-blind trial to evaluate pembrolizumab as adjuvant therapy in patients with resected, high-risk stage III melanoma. METHODS Patients with completely resected stage III melanoma were randomly assigned (with stratification according to cancer stage and geographic region) to receive 200 mg of pembrolizumab (514 patients) or placebo (505 patients) intravenously every 3 weeks for a total of 18 doses (approximately 1 year) or until disease recurrence or unacceptable toxic effects occurred. Recurrence-free survival in the overall intention-to-treat population and in the subgroup of patients with cancer that was positive for the PD-1 ligand (PD-L1) were the primary end points. Safety was also evaluated. RESULTS At a median follow-up of 15 months, pembrolizumab was associated with significantly longer recurrence-free survival than placebo in the overall intention-to-treat population (1-year rate of recurrence-free survival, 75.4% [95% confidence interval {CI}, 71.3 to 78.9] vs. 61.0% [95% CI, 56.5 to 65.1]; hazard ratio for recurrence or death, 0.57; 98.4% CI, 0.43 to 0.74; P<0.001) and in the subgroup of 853 patients with PD-L1-positive tumors (1-year rate of recurrence-free survival, 77.1% [95% CI, 72.7 to 80.9] in the pembrolizumab group and 62.6% [95% CI, 57.7 to 67.0] in the placebo group; hazard ratio, 0.54; 95% CI, 0.42 to 0.69; P<0.001). Adverse events of grades 3 to 5 that were related to the trial regimen were reported in 14.7% of the patients in the pembrolizumab group and in 3.4% of patients in the placebo group. There was one treatment-related death due to myositis in the pembrolizumab group. CONCLUSIONS As adjuvant therapy for high-risk stage III melanoma, 200 mg of pembrolizumab administered every 3 weeks for up to 1 year resulted in significantly longer recurrencefree survival than placebo, with no new toxic effects identified.
Longer follow-up confirms recurrence-free survival benefit of adjuvant pembrolizumab in high-risk stage III melanoma: Updated results from the EORTC 1325-MG/KEYNOTE-054 trial
PURPOSE: We conducted the phase III double-blind European Organisation for Research and Treatment of Cancer (EORTC) 1325/KEYNOTE-054 trial to evaluate pembrolizumab versus placebo in patients with resected high-risk stage III melanoma. On the basis of 351 recurrence-free survival (RFS) events at a 1.25-year median follow-up, pembrolizumab prolonged RFS (hazard ratio [HR], 0.57; P \u3c .0001) compared with placebo. This led to the approval of pembrolizumab adjuvant treatment by the European Medicines Agency and US Food and Drug Administration. Here, we report an updated RFS analysis at the 3.05-year median follow-up. PATIENTS AND METHODS: A total of 1,019 patients with complete lymph node dissection of American Joint Committee on Cancer Staging Manual (seventh edition; AJCC-7), stage IIIA (at least one lymph node metastasis \u3e 1 mm), IIIB, or IIIC (without in-transit metastasis) cutaneous melanoma were randomly assigned to receive pembrolizumab at a flat dose of 200 mg (n = 514) or placebo (n = 505) every 3 weeks for 1 year or until disease recurrence or unacceptable toxicity. The two coprimary end points were RFS in the overall population and in those with programmed death-ligand 1 (PD-L1)-positive tumors. RESULTS: Pembrolizumab (190 RFS events) compared with placebo (283 RFS events) resulted in prolonged RFS in the overall population (3-year RFS rate, 63.7% v 44.1% for pembrolizumab v placebo, respectively; HR, 0.56; 95% CI, 0.47 to 0.68) and in the PD-L1-positive tumor subgroup (HR, 0.57; 99% CI, 0.43 to 0.74). The impact of pembrolizumab on RFS was similar in subgroups, in particular according to AJCC-7 and AJCC-8 staging, and BRAF mutation status (HR, 0.51 [99% CI, 0.36 to 0.73] v 0.66 [99% CI, 0.46 to 0.95] for V600E/Kv wild type). CONCLUSION: In resected high-risk stage III melanoma, pembrolizumab adjuvant therapy provided a sustained and clinically meaningful improvement in RFS at 3-year median follow-up. This improvement was consistent across subgroups
Adjuvant pembrolizumab versus placebo in resected stage III melanoma
The programmed death 1 (PD-1) inhibitor pembrolizumab has been found to prolong progression-free and overall survival among patients with advanced melanoma. We conducted a phase 3 double-blind trial to evaluate pembrolizumab as adjuvant therapy in patients with resected, high-risk stage III melanoma.Patients with completely resected stage III melanoma were randomly assigned (with stratification according to cancer stage and geographic region) to receive 200 mg of pembrolizumab (514 patients) or placebo (505 patients) intravenously every 3 weeks for a total of 18 doses (approximately 1 year) or until disease recurrence or unacceptable toxic effects occurred. Recurrence-free survival in the overall intention-to-treat population and in the subgroup of patients with cancer that was positive for the PD-1 ligand (PD-L1) were the primary end points. Safety was also evaluated.At a median follow-up of 15 months, pembrolizumab was associated with significantly longer recurrence-free survival than placebo in the overall intention-to-treat population (1-year rate of recurrence-free survival, 75.4% [95% confidence interval {CI}, 71.3 to 78.9] vs. 61.0% [95% CI, 56.5 to 65.1]; hazard ratio for recurrence or death, 0.57; 98.4% CI, 0.43 to 0.74;
31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2016) : part two
Background
The immunological escape of tumors represents one of the main ob- stacles to the treatment of malignancies. The blockade of PD-1 or CTLA-4 receptors represented a milestone in the history of immunotherapy. However, immune checkpoint inhibitors seem to be effective in specific cohorts of patients. It has been proposed that their efficacy relies on the presence of an immunological response. Thus, we hypothesized that disruption of the PD-L1/PD-1 axis would synergize with our oncolytic vaccine platform PeptiCRAd.
Methods
We used murine B16OVA in vivo tumor models and flow cytometry analysis to investigate the immunological background.
Results
First, we found that high-burden B16OVA tumors were refractory to combination immunotherapy. However, with a more aggressive schedule, tumors with a lower burden were more susceptible to the combination of PeptiCRAd and PD-L1 blockade. The therapy signifi- cantly increased the median survival of mice (Fig. 7). Interestingly, the reduced growth of contralaterally injected B16F10 cells sug- gested the presence of a long lasting immunological memory also against non-targeted antigens. Concerning the functional state of tumor infiltrating lymphocytes (TILs), we found that all the immune therapies would enhance the percentage of activated (PD-1pos TIM- 3neg) T lymphocytes and reduce the amount of exhausted (PD-1pos TIM-3pos) cells compared to placebo. As expected, we found that PeptiCRAd monotherapy could increase the number of antigen spe- cific CD8+ T cells compared to other treatments. However, only the combination with PD-L1 blockade could significantly increase the ra- tio between activated and exhausted pentamer positive cells (p= 0.0058), suggesting that by disrupting the PD-1/PD-L1 axis we could decrease the amount of dysfunctional antigen specific T cells. We ob- served that the anatomical location deeply influenced the state of CD4+ and CD8+ T lymphocytes. In fact, TIM-3 expression was in- creased by 2 fold on TILs compared to splenic and lymphoid T cells. In the CD8+ compartment, the expression of PD-1 on the surface seemed to be restricted to the tumor micro-environment, while CD4 + T cells had a high expression of PD-1 also in lymphoid organs. Interestingly, we found that the levels of PD-1 were significantly higher on CD8+ T cells than on CD4+ T cells into the tumor micro- environment (p < 0.0001).
Conclusions
In conclusion, we demonstrated that the efficacy of immune check- point inhibitors might be strongly enhanced by their combination with cancer vaccines. PeptiCRAd was able to increase the number of antigen-specific T cells and PD-L1 blockade prevented their exhaus- tion, resulting in long-lasting immunological memory and increased median survival
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