Outcomes of patients with non‐melanoma solid tumours receiving self‐funded pembrolizumab at Chris O'Brien Lifehouse
Anna J. LomaxJane BeithVivek A. BhadriMichael BoyerPeter GrimisonLisa G. HorvathSteven KaoMartin TattersallDavid M. ThomasCatriona M. McNeil
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Immunotherapy agents show anti-cancer activity in several solid cancers. Efficacy in non-melanoma solid tumours for non-approved indications is unknown.To evaluate patient and disease characteristics, rate and duration of response, and toxicity of self-funded pembrolizumab in patients with non-melanoma solid cancers.Retrospective review describing outcomes and toxicity of self-funded pembrolizumab in patients with non-melanoma solid cancers treated at Chris O'Brien Lifehouse.From April 2015 to December 2015, 21 patients received or were planned to receive self-funded pembrolizumab. The median age was 50 years (16-76), 28 and 10% had an Eastern Cooperative Oncology Group performance status of 2, and 3-4 respectively. Sixty-two percent received at least two to four lines of prior drug treatment. Median follow-up was 3.0 months (range, 0.4-9.6). Fourteen (67%) patients requested pembrolizumab. Pembrolizumab was clinician offered for 7 (33%) patients. Patients who requested pembrolizumab had worse outcomes. Three patients died before receiving pembrolizumab. Of the 18 patients that received at least one dose, a partial response was observed in 3 (17%). Progressive disease occurred in 83%. Four patients received only one cycle of pembrolizumab and died after a median of 27 days (range 13-43). Immune-related adverse events of any grade occurred in 33%. No grade 3-4 events were observed.Pembrolizumab was well tolerated. Meaningful responses were observed in 17% of treated patients. Response continues after 5-6.5 months follow-up in 11% and >8 months of follow-up for the other responding patient. Financial impact to the patient can be substantial. Outcomes for 33% were poor with three patients dying prior to receiving therapy and four dying within weeks of receiving one dose. This highlights issues regarding the careful selection of patients, futility of anti-cancer therapy at the end-of-life and patients' perceived benefit of receiving this therapy.advanced melanoma: advanced melanomaCHICAGO—New data on long-term disease control and extended survival continue to prove the success of immunotherapy and targeted therapy for the treatment of advanced melanoma, according to two new studies presented at the 2017 ASCO Annual Meeting, held June 2-6. Immunotherapy Long-term outcomes show pembrolizumab treatment provides durable efficacy after stopping the protocol-specified duration of treatment in patients with ipilimumab-näive advanced melanoma, reported lead author Caroline Robert, MD, of Gustave Roussy, Villejuif, France (Abstract 9504). Earlier results of the KEYNOTE-006 trial showed that pembrolizumab provided superior progression-free survival (PFS) and overall survival (OS) and improved overall response rate versus ipilimumab, with a lower rate of grade 3-5 treatment-related adverse events despite longer exposure. The 834 patients, median age 62 years, were randomized to pembrolizumab 10 mg/kg every 2 weeks, pembrolizumab 10 mg/kg every 3 weeks, or ipilimumab 3 mg/kg every 3 weeks for four doses. Treatment was continued for 2 years in the pembrolizumab arm or until disease progression, intolerable toxicity, or the patient or investigator decided to discontinue therapy. Tumor imaging was performed at week 12, then every 6 weeks up to week 48 and every 12 weeks thereafter. Robert reported that after a median follow-up of nearly 3 years, pembrolizumab superiority over ipilimumab was confirmed, with nearly a doubling of median OS (32.3 vs. 15.9 months). Median PFS was higher with pembrolizumab (8.3 months) than with ipilimumab (3.3 months). Virtually all (98%) of the 104 patients who completed 2 years of pembrolizumab treatment are alive after a median follow-up of 9.7 months, noted Robert. Responses were durable in patients who completed pembrolizumab; the estimated PFS was 91 percent. The safety profile with pembrolizumab continued to be favorable. In conclusion, Robert said “the estimated risk for progression or death nearly 10 months after completing pembrolizumab is 9 percent and does not appear to differ by best response to pembrolizumab. The data further support the use of pembrolizumab as standard of care for patients with advanced melanoma.” Targeted Therapy The longest follow-up for any randomized trial evaluating a BRAF inhibitor combined with a MEK inhibitor found that long-term survival is achievable with dabrafenib plus trametinib in patients with BRAF V600-mutant metastatic melanoma, particularly those with favorable baseline factors (Abstract 9505). The combination of dabrafenib plus trametinib has been shown to improve outcomes versus a BRAF inhibitor alone in this patient population after 3 years of follow-up. Specific baseline factors, such as LDH level and number of organ sites with metastases, have been associated with long-term OS. Study co-author Jeffery Weber, MD, of NYU Langone Medical Center, New York, N.Y., presented an updated 5-year landmark analysis to further characterize the impact of dabrafenib and trametinib in 162 patients with BRAF V600–mutant unresectable or metastatic melanoma. The patients were equally divided in three cohorts of dabrafenib 150 mg plus trametinib 2 mg, dabrafenib 150 mg plus trametinib 1 mg, or dabrafenib monotherapy 150 mg twice daily. After a median follow-up of 66.5 months, the 5-year OS with the higher dose combination was 28 percent; for those with normal baseline LDH and less than three organ sites with metastasis, the OS was 51 percent. No new safety signals were identified with the long-term combined therapy. “These results demonstrate that some patients with metastatic melanoma can achieve durable benefit with dabrafenib plus trametinib therapy. These data support the use of the combination as a treatment option that can achieve long-term survival in BRAF V600E/K-mutated melanoma,” said Weber. ASCO discussant Alexander Menzies, MD, of Melanoma Institute Australia, The University of Sydney in Sydney, commented: “The introduction of ipilimumab changed the game for advanced melanoma. It cured patients, but most still do not respond.” The 20 percent survival rate with ipilimumab is 10 percent higher than historical rates. Now phase III studies show 5-year survival rates of 44 percent with dabrafenib plus trametinib, 37 percent with another targeted therapy combination, vemurafenib plus cobimetinib, and 35 percent with the checkpoint inhibitor nivolumab. As for the pembrolizumab trial presented by Robert, “these are the most mature phase III PD-1 trial data to date, and is the first trial to end treatment at 2 years,” stated Menzies. He noted the difference in PFS rates were similar for patients with primary resistance, but for acquired resistance PFS was higher for those in the pembrolizumab group (31%) as compared to those in the ipilimumab group (14%). The 2-year duration of response was 71 percent in both groups. Similarly, the data Weber presented are the most mature for a combination of a BRAF inhibitor and a MEK inhibitor to date, Menzies said. He noted the survival curve appears to plateau at about 3 years, adding that in the highest dose group, which is the commonly used dose, the PFS was 13 percent at 5 years even though only 4 percent of patients were still on treatment. Menzies pointed out that none of patients with high LDH levels were progression-free at 2 years as compared to one-quarter of those with normal LDH levels. Among advanced melanoma patients, “who are the survivors?” asked Menzies. Clinical features among survivors include normal LDH, less disease or volume of disease, ECOG 0 status, and complete response. Biomarkers in the tumor, blood, and imaging may help, but “no biomarkers are sufficiently robust to accurately predict outcome,” he said. In conclusion, Menzies noted: “Current drugs provide long-term survival for a subset of patients, but most progress and die. We need better treatments to raise the bar. We need better biomarkers to predict the clinical outcomes.” The goal, he said, “should not simply be to improved overall survival, but improved long-term control, preferably off therapy, and not just in melanoma but across cancer.” Mark L. Fuerst is a contributing writer.
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<div>Abstract<p>Patients with metastatic melanoma whose disease progresses on ipilimumab can clearly derive benefit from subsequent anti–programmed death-1 (PD-1). However, patients experience heterogeneous outcomes with ipilimumab, including rapid or delayed progression, and it is unclear whether patterns of ipilimumab progression influence subsequent clinical responses to anti–PD-1. We retrospectively reviewed data from 116 patients with metastatic melanoma who progressed on ipilimumab and were subsequently treated with pembrolizumab. The study objectives were to determine whether progression-free survival (PFS) with ipilimumab was associated with PFS, objective response rate (ORR), and clinical benefit rate (CBR; ORR + stable disease) with pembrolizumab. Patients with PFS ≥90 days after treatment with ipilimumab generally had superior outcomes with subsequent pembrolizumab treatment compared with patients with PFS <90 days (ORR, 49% vs. 35%, <i>P</i> = 0.12; CBR, 66% vs. 46%, <i>P</i> = 0.03). Patients with prolonged ipilimumab benefit (PFS ≥ 180 days) had excellent outcomes with pembrolizumab compared with rapid progressors (PFS < 45 days; ORR, 55% vs. 25%; CBR, 80% vs. 25%; median PFS, 249 vs. 50 days). Using logistic regression models, PFS with ipilimumab was independently correlated with response to pembrolizumab (odds ratio, 1.22; 95% CI, 1.02–1.51). This study shows that prolonged PFS with ipilimumab predicts excellent outcomes with subsequent pembrolizumab treatment, offering valuable prognostic information for clinicians. <i>Cancer Immunol Res; 4(7); 569–73. ©2016 AACR</i>.</p></div>
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Pembrolizumab (Keytruda®) is an anti-PD-1 antibody, indicated as monotherapy for the treatment of adult patients with advanced (unresectable or metastatic) melanoma. For this indication, the EMA granted marketing authorisation in July 2015. The FDA approved pembrolizumab under accelerated approval in June 2015 for patients with unresectable or metastatic melanoma and disease progression following ipilimumab and, if BRAF V600 mutation-positive, a BRAF (proto-oncogene B-Raf) inhibitor. KEYNOTE-006, a randomised, open-label, phase III study, was conducted to compare two different dosage regimens of pembrolizumab with ipilimumab in patients with advanced melanoma. A total of 834 patients received pembrolizumab at a dose of 10 mg/kg either every two weeks or every three weeks, or four cycles of ipilimumab at a dose of 3 mg/kg every three weeks. Enrolled patients had received no more than one previous systemic therapy for advanced disease. Results showed a significant increase in progression-free survival (PFS) in patients who received pembrolizumab; This group achieved a gain of 2.7 months and 1.3 months in median PFS receiving pembrolizumab every 2 weeks and every 3 weeks compared to the ipilimumab group. 12-month overall survival (OS) was also improved among patients who received pembrolizumab: 74.1% (pembrolizumab every 2 weeks) and 68.4% (pembrolizumab every 3 weeks) compared to 58.2% of patients in the ipilimumab group. Response rates were also higher among patients who received pembrolizumab: 33.7 (pembrolizumab every 2 weeks) and 32.9% (pembrolizumab every 3 weeks) versus 11.9% in ipilimumab-group patients. However, it is notable that efficacy results of the KEYNOTE-006 trial are based on interim analysis. Treatment-related adverse events (AEs) of grade 3–5 were more frequent in ipilimumab-group patients compared to patients in the pembrolizumab groups. In terms of AEs of special interest (autoimmune and immune-related), hypothyroidism and hyperthyroidism were most frequent in the pembrolizumab groups. Due to the superior OS results of the two pembrolizumab groups over the ipilimumab group results, the data and safety monitoring committee recommended to stop the study early and give patients of the ipilimumab group the option to receive pembrolizumab. Pembrolizumab provides a new option for the treatment of patients with advanced melanoma, showing a significant increase in PFS, an improved 12-month OS and higher response rates compared to ipilimumab. In patients who are refractory to ipilimumab, pembrolizumab offers a new therapeutic option based on phase II studies. For these patients, chemotherapy is the only currently available treatment option and fewer AEs were observed with pembrolizumab by comparison with chemotherapy. In contrast, the situation for patients who were previously untreated is less clear. Furthermore, the role of pembrolizumab for the treatment of patients with/without BRAF mutation is not fully elucidated. Not least, the optimal dosage and schedule of pembrolizumab administration remain unclear. However, phase III long-term data is required to confirm the effectiveness and safety of pembrolizumab. Furthermore, biomarkers must be identified to define the appropriate patient population, not least in light of the high costs of pembrolizumab therapy.
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What is this summary about? In this article, we discuss the results of our clinical study that looked at the use of two immunotherapy drugs for the treatment of advanced melanoma. Melanoma is considered advanced when it is no longer curable with surgery. What happened in the study? The two-drug combination, pembrolizumab and ipilimumab, was given to people with melanoma who's cancer had progressed. This study looked at how effective these two drugs were in terms of controlling the melanoma, as well their safety. These results from the study were then compared to the results from previous studies looking at melanoma treatment with ipilimumab on its own, which previously had been the most commonly used drug. What were the results? The study, originally published in the Journal of Clinical Oncology, showed that combination treatment with pembrolizumab and ipilimumab was more likely to be effective than ipilimumab on its own. Not all of the study participants benefited, but many of those who did benefit experienced long-term remission from their melanoma without needing more treatment. Around 1/3 of the participants in the study had their tumors shrink compared to previous studies, which showed that ipilimumab was expected to shrink 1 in 8 tumors. The rates of side effects were similar with the pembrolizumab and ipilimumab combination compared to ipilimumab alone.
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Report results of patient-reported health-related quality of life (HRQoL) and symptoms from phase III KEYNOTE-006 study of pembrolizumab versus ipilimumab in patients with ipilimumab-naive advanced melanoma.Patients received pembrolizumab 10 mg/kg every 2 (Q2W) or every 3 weeks (Q3W) for up to 2 years, or four cycles of ipilimumab 3 mg/kg Q3W. The European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire C30 (EORTC QLQ-C30) was administered at baseline and throughout the study. Patient-reported outcome (PRO) analyses were pre-specified exploratory endpoints; the primary PRO assessment was the score change from baseline to week 12 in EORTC QLQ-C30 global health status (GHS)/HRQoL score between the arms using constrained longitudinal data analysis.The PRO analysis population included 776 patients: pembrolizumab Q2W (n = 270); pembrolizumab Q3W (n = 266); ipilimumab (n = 240). Baseline GHS was similar across arms. QLQ-C30 compliance rates at week 12 were 87% (n = 214), 97% (n = 226), and 96% (n = 178), for the pembrolizumab Q2W, pembrolizumab Q3W, and ipilimumab arms, respectively. From baseline to week 12, GHS/HRQoL scores were better maintained with pembrolizumab than with ipilimumab (decrease of -1.9 and -2.5 for pembrolizumab versus -10.0 for ipilimumab; p < 0.001 for each pembrolizumab arm versus ipilimumab). Fewer patients treated with pembrolizumab experienced deterioration in GHS at week 12 (31% for pembrolizumab Q2W; 29% for Q3W and 44% for ipilimumab), with similar trends observed for individual functioning and symptoms scales.HRQoL was better maintained with pembrolizumab than with ipilimumab in patients with ipilimumab-naive advanced melanoma. CLINICALTRIALS.NCT01866319.
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Currently, limited data exist on the safety of pembrolizumab in patients with metastatic melanoma who have developed severe immune-related adverse events following treatment with ipilimumab. We report a 45-year-old male patient with BRAF-mutant metastatic melanoma who discontinued treatment with ipilimumab due to treatment-related grade 3 colitis and was subsequently treated with the anti-programmed cell death 1 protein (PD-1) antibody pembrolizumab. He has been on treatment with pembrolizumab for more than 20 months with no major toxicities and has achieved an objective partial response, which is ongoing.
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Patients with metastatic melanoma whose disease progresses on ipilimumab can clearly derive benefit from subsequent anti-programmed death-1 (PD-1). However, patients experience heterogeneous outcomes with ipilimumab, including rapid or delayed progression, and it is unclear whether patterns of ipilimumab progression influence subsequent clinical responses to anti-PD-1. We retrospectively reviewed data from 116 patients with metastatic melanoma who progressed on ipilimumab and were subsequently treated with pembrolizumab. The study objectives were to determine whether progression-free survival (PFS) with ipilimumab was associated with PFS, objective response rate (ORR), and clinical benefit rate (CBR; ORR + stable disease) with pembrolizumab. Patients with PFS ≥90 days after treatment with ipilimumab generally had superior outcomes with subsequent pembrolizumab treatment compared with patients with PFS <90 days (ORR, 49% vs. 35%, P = 0.12; CBR, 66% vs. 46%, P = 0.03). Patients with prolonged ipilimumab benefit (PFS ≥ 180 days) had excellent outcomes with pembrolizumab compared with rapid progressors (PFS < 45 days; ORR, 55% vs. 25%; CBR, 80% vs. 25%; median PFS, 249 vs. 50 days). Using logistic regression models, PFS with ipilimumab was independently correlated with response to pembrolizumab (odds ratio, 1.22; 95% CI, 1.02-1.51). This study shows that prolonged PFS with ipilimumab predicts excellent outcomes with subsequent pembrolizumab treatment, offering valuable prognostic information for clinicians. Cancer Immunol Res; 4(7); 569-73. ©2016 AACR.
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Introduction: Until recently, overall long term survival in patients with stage IV melanoma was lower than 10%. However, the treatment of melanoma has evolved rapidly over the last few years, with the advent of inhibitors of BRAF and MEK and of immunotherapeutic agents including ipilimumab, nivolumab, and pembrolizumab.Areas covered: This is a comprehensive review of the literature on the role of pembrolizumab in melanoma. Pembrolizumab is a Programmed Death Receptor 1 (PD-1) directed monoclonal antibody which is approved by FDA and EMA for the treatment of patients with metastatic melanoma.Expert opinion: Phase II and III trials demonstrated that pembrolizumab is superior to ipilimumab in previously untreated patients and to chemotherapy in ipilimumab pre-treated patients. Unfortunately, prospectively validated predictive markers are lacking. Immune-related adverse events are particularly interesting and should be managed per the published guidelines. There are still many issues that remain unresolved including: when to stop treatment, biomarkers for choosing a single agent or combination therapy, the optimal schedule of ipilimumab in combination with anti-PD1 monoclonal antibodies, optimal management of adverse events, the role of immunotherapy in specific populations, the optimal sequence of immunotherapy and the BRAF/MEK inhibitor combination in patients.
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