Author
Scot Ebbinghaus
Bio: Scot Ebbinghaus is an academic researcher from Merck & Co.. The author has contributed to research in topics: Pembrolizumab & Ridaforolimus. The author has an hindex of 37, co-authored 90 publications receiving 12801 citations.
Topics: Pembrolizumab, Ridaforolimus, Ipilimumab, Population, Melanoma
Papers
More filters
Institut Gustave Roussy1, University of California, San Francisco2, Harvard University3, University of Sydney4, Memorial Sloan Kettering Cancer Center5, Kolling Institute of Medical Research6, Mayo Clinic7, University of South Florida8, University of Pennsylvania9, University of Pittsburgh10, Princess Margaret Cancer Centre11, Merck & Co.12, University of California, Los Angeles13
TL;DR: In patients with advanced melanoma, including those who had had disease progression while they had been receiving ipilimumab, treatment with lambrolizumab resulted in a high rate of sustained tumor regression, with mainly grade 1 or 2 toxic effects.
Abstract: A b s t r ac t Background The programmed death 1 (PD-1) receptor is a negative regulator of T-cell effector mechanisms that limits immune responses against cancer. We tested the anti–PD-1 antibody lambrolizumab (previously known as MK-3475) in patients with advanced melanoma. Methods We administered lambrolizumab intravenously at a dose of 10 mg per kilogram of body weight every 2 or 3 weeks or 2 mg per kilogram every 3 weeks in patients with advanced melanoma, both those who had received prior treatment with the immune checkpoint inhibitor ipilimumab and those who had not. Tumor responses were assessed every 12 weeks. Results A total of 135 patients with advanced melanoma were treated. Common adverse events attributed to treatment were fatigue, rash, pruritus, and diarrhea; most of the adverse events were low grade. The confirmed response rate across all dose cohorts, evaluated by central radiologic review according to the Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1, was 38% (95% confidence interval [CI], 25 to 44), with the highest confirmed response rate observed in the cohort that received 10 mg per kilogram every 2 weeks (52%; 95% CI, 38 to 66). The response rate did not differ significantly between patients who had received prior ipilimumab treatment and those who had not (confirmed response rate, 38% [95% CI, 23 to 55] and 37% [95% CI, 26 to 49], respectively). Responses were durable in the majority of patients (median follow-up, 11 months among patients who had a response); 81% of the patients who had a response (42 of 52) were still receiving treatment at the time of analysis in March 2013. The overall median progression-free survival among the 135 patients was longer than 7 months. Conclusions In patients with advanced melanoma, including those who had had disease progression while they had been receiving ipilimumab, treatment with lambrolizumab resulted in a high rate of sustained tumor regression, with mainly grade 1 or 2 toxic effects. (Funded by Merck Sharp and Dohme; ClinicalTrials.gov number, NCT01295827.)
3,195 citations
Harvard University1, University of California, Los Angeles2, Chiba University3, University of Liverpool4, Katholieke Universiteit Leuven5, Hochschule Hannover6, University of Cambridge7, The Chinese University of Hong Kong8, Princess Margaret Cancer Centre9, Merck & Co.10, National Taiwan University11, Kindai University12
TL;DR: Pembrolizumab was effective and tolerable in patients with advanced hepatocellular carcinoma who had previously been treated with sorafenib and is undergoing further assessment in two phase 3, randomised trials as a second-line treatment.
Abstract: Summary Background Immune checkpoint blockade therapy has shown promising results in patients with advanced hepatocellular carcinoma. We aimed to assess the efficacy and safety of pembrolizumab in this patient population. Methods KEYNOTE-224 is a non-randomised, multicentre, open-label, phase 2 trial that is set in 47 medical centres and hospitals across ten countries. Eligible patients had pathologically confirmed hepatocellular carcinoma; had previously been treated with sorafenib and were either intolerant to this treatment or showed radiographic progression of their disease after treatment; an Eastern Cooperative Oncology Group performance status of 0–1; adequate organ function, and were Child-Pugh class A. Participants received 200 mg pembrolizumab intravenously every 3 weeks for about 2 years or until disease progression, unacceptable toxicity, patient withdrawal, or investigator decision. The primary endpoint was objective response, defined as the proportion of patients with complete or partial response in all patients who received at least one dose of pembrolizumab, which was radiologically confirmed by use of the Response Evaluation Criteria in Solid Tumors version 1.1 by central review. Safety was also assessed in all treated patients. This trial is ongoing but closed to enrolment and is registered with ClinicalTrials.gov number NCT02702414. Findings Between June 7, 2016, and Feb 9, 2017, we screened 169 patients with advanced hepatocellular carcinoma, of whom 104 eligible patients were enrolled and treated. As of data cutoff on Feb 13, 2018, 17 (16%) patients were still receiving pembrolizumab. We recorded an objective response in 18 (17%; 95% CI 11–26) of 104 patients. The best overall responses were one (1%) complete and 17 (16%) partial responses; meanwhile, 46 (44%) patients had stable disease, 34 (33%) had progressive disease, and six (6%) patients who did not have a post-baseline assessment on the cutoff date were considered not to be assessable. Treatment-related adverse events occurred in 76 (73%) of 104 patients, which were serious in 16 (15%) patients. Grade 3 treatment-related events were reported in 25 (24%) of the 104 patients; the most common were increased aspartate aminotransferase concentration in seven (7%) patients, increased alanine aminotransferase concentration in four (4%) patients, and fatigue in four (4%) patients. One (1%) grade 4 treatment-related event of hyperbilirubinaemia occurred. One death associated with ulcerative oesophagitis was attributed to treatment. Immune-mediated hepatitis occurred in three (3%) patients, but there were no reported cases of viral flares. Interpretation Pembrolizumab was effective and tolerable in patients with advanced hepatocellular carcinoma who had previously been treated with sorafenib. These results indicate that pembrolizumab might be a treatment option for these patients. This drug is undergoing further assessment in two phase 3, randomised trials as a second-line treatment in patients with hepatocellular carcinoma. Funding Merck & Co, Inc.
1,630 citations
Institut Gustave Roussy1, University of California, Los Angeles2, Memorial Sloan Kettering Cancer Center3, Harvard University4, University of Sydney5, Westmead Hospital6, Princess Margaret Cancer Centre7, University of Texas MD Anderson Cancer Center8, University of Pennsylvania9, Mayo Clinic10, University of Pittsburgh11, Merck & Co.12, University of California, San Francisco13
TL;DR: The results suggest that pembrolizumab at a dose of 2mg/kg or 10 mg/kg every 3 weeks might be an effective treatment in patients for whom there are few effective treatment options.
1,569 citations
University of California, Los Angeles1, Vanderbilt University2, University of Zurich3, University of Duisburg-Essen4, University of Paris-Sud5, Harvard University6, Sheba Medical Center7, New York University8, University of Colorado Denver9, University of Arizona10, Netherlands Cancer Institute11, Durham University12, Seattle Cancer Care Alliance13, University of Tübingen14, University of Pennsylvania15, Temple University16, University of North Carolina at Chapel Hill17, University of Pittsburgh18, Memorial Sloan Kettering Cancer Center19, Merck & Co.20, University of California, San Francisco21
TL;DR: In this article, the efficacy and safety of two pembrolizumab doses versus investigator-choice chemotherapy in patients with ipilimumab-refractory melanoma were compared.
Abstract: Summary Background Patients with melanoma that progresses on ipilimumab and, if BRAF V600 mutant-positive, a BRAF or MEK inhibitor or both, have few treatment options. We assessed the efficacy and safety of two pembrolizumab doses versus investigator-choice chemotherapy in patients with ipilimumab-refractory melanoma. Methods We carried out a randomised phase 2 trial of patients aged 18 years or older from 73 hospitals, clinics, and academic medical centres in 12 countries who had confirmed progressive disease within 24 weeks after two or more ipilimumab doses and, if BRAF V600 mutant-positive, previous treatment with a BRAF or MEK inhibitor or both. Patients had to have resolution of all ipilimumab-related adverse events to grade 0–1 and prednisone 10 mg/day or less for at least 2 weeks, an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, and at least one measurable lesion to be eligible. Using a centralised interactive voice response system, we randomly assigned (1:1:1) patients in a block size of six to receive intravenous pembrolizumab 2 mg/kg or 10 mg/kg every 3 weeks or investigator-choice chemotherapy (paclitaxel plus carboplatin, paclitaxel, carboplatin, dacarbazine, or oral temozolomide). Randomisation was stratified by ECOG performance status, lactate dehydrogenase concentration, and BRAF V600 mutation status. Individual treatment assignment between pembrolizumab and chemotherapy was open label, but investigators and patients were masked to assignment of the dose of pembrolizumab. We present the primary endpoint at the prespecified second interim analysis of progression-free survival in the intention-to-treat population. This study is registered with ClinicalTrials.gov, number NCT01704287. The study is closed to enrolment but continues to follow up and treat patients. Findings Between Nov 30, 2012, and Nov 13, 2013, we enrolled 540 patients: 180 patients were randomly assigned to receive pembrolizumab 2 mg/kg, 181 to receive pembrolizumab 10 mg/kg, and 179 to receive chemotherapy. Based on 410 progression-free survival events, progression-free survival was improved in patients assigned to pembrolizumab 2 mg/kg (HR 0·57, 95% CI 0·45–0·73; p Interpretation These findings establish pembrolizumab as a new standard of care for the treatment of ipilimumab-refractory melanoma. Funding Merck Sharp & Dohme.
1,333 citations
University of California, Los Angeles1, University of Ulsan2, Kindai University3, Samsung Medical Center4, Taipei Veterans General Hospital5, Chiba University6, Pontifical Catholic University of Chile7, The Chinese University of Hong Kong8, Princess Margaret Cancer Centre9, Merck & Co.10, Harvard University11, National Taiwan University12
TL;DR: The results are consistent with those of KEYNOTE-224, supporting a favorable risk-to-benefit ratio for pembrolizumab in this population, and one-sided significance thresholds for OS and PFS did not reach statistical significance per specified criteria.
Abstract: PURPOSEPembrolizumab demonstrated antitumor activity and safety in the phase II KEYNOTE-224 trial in previously treated patients with advanced hepatocellular carcinoma (HCC). KEYNOTE-240 evaluated ...
1,056 citations
Cited by
More filters
TL;DR: The following Clinical Practice Guidelines will give up-to-date advice for the clinical management of patients with hepatocellular carcinoma, as well as providing an in-depth review of all the relevant data leading to the conclusions herein.
7,851 citations
TL;DR: Pembrolizumab is a humanized monoclonal antibody against programmed death 1 (PD-1) that has antitumor activity in advanced non-small-cell lung cancer (NSCLC), with increased activity in tumors that express PD-L1 as mentioned in this paper.
Abstract: BackgroundPembrolizumab is a humanized monoclonal antibody against programmed death 1 (PD-1) that has antitumor activity in advanced non–small-cell lung cancer (NSCLC), with increased activity in tumors that express programmed death ligand 1 (PD-L1). MethodsIn this open-label, phase 3 trial, we randomly assigned 305 patients who had previously untreated advanced NSCLC with PD-L1 expression on at least 50% of tumor cells and no sensitizing mutation of the epidermal growth factor receptor gene or translocation of the anaplastic lymphoma kinase gene to receive either pembrolizumab (at a fixed dose of 200 mg every 3 weeks) or the investigator’s choice of platinum-based chemotherapy. Crossover from the chemotherapy group to the pembrolizumab group was permitted in the event of disease progression. The primary end point, progression-free survival, was assessed by means of blinded, independent, central radiologic review. Secondary end points were overall survival, objective response rate, and safety. ResultsMedi...
7,053 citations
TL;DR: This study showed that mismatch-repair status predicted clinical benefit of immune checkpoint blockade with pembrolizumab, and high somatic mutation loads were associated with prolonged progression-free survival.
Abstract: BackgroundSomatic mutations have the potential to encode “non-self” immunogenic antigens. We hypothesized that tumors with a large number of somatic mutations due to mismatch-repair defects may be susceptible to immune checkpoint blockade. MethodsWe conducted a phase 2 study to evaluate the clinical activity of pembrolizumab, an anti–programmed death 1 immune checkpoint inhibitor, in 41 patients with progressive metastatic carcinoma with or without mismatch-repair deficiency. Pembrolizumab was administered intravenously at a dose of 10 mg per kilogram of body weight every 14 days in patients with mismatch repair–deficient colorectal cancers, patients with mismatch repair–proficient colorectal cancers, and patients with mismatch repair–deficient cancers that were not colorectal. The coprimary end points were the immune-related objective response rate and the 20-week immune-related progression-free survival rate. ResultsThe immune-related objective response rate and immune-related progression-free survival ...
6,835 citations
The Royal Marsden NHS Foundation Trust1, European Institute of Oncology2, University of Colorado Denver3, Aix-Marseille University4, Baylor University5, University of Michigan6, University of Zurich7, Cross Cancer Institute8, Peter MacCallum Cancer Centre9, Netherlands Cancer Institute10, Hospital General Universitario Gregorio Marañón11, Memorial Sloan Kettering Cancer Center12, Huntsman Cancer Institute13, Yale University14, University of Melbourne15, University of Sydney16, Cornell University17, Ludwig Institute for Cancer Research18, University of Utah19, Yale Cancer Center20, Odense University Hospital21, Bristol-Myers Squibb22, Harvard University23
TL;DR: Among previously untreated patients with metastatic melanoma, nivolumab alone or combined with ipilimumab resulted in significantly longer progression-free survival than ipILimumab alone, and in patients with PD-L1-negative tumors, the combination of PD-1 and CTLA-4 blockade was more effective than either agent alone.
Abstract: The median progression-free survival was 11.5 months (95% confidence interval [CI], 8.9 to 16.7) with nivolumab plus ipilimumab, as compared with 2.9 months (95% CI, 2.8 to 3.4) with ipilimumab (hazard ratio for death or disease progression, 0.42; 99.5% CI, 0.31 to 0.57; P<0.001), and 6.9 months (95% CI, 4.3 to 9.5) with nivolumab (hazard ratio for the comparison with ipilimumab, 0.57; 99.5% CI, 0.43 to 0.76; P<0.001). In patients with tumors positive for the PD-1 ligand (PD-L1), the median progression-free survival was 14.0 months in the nivolumab-plus-ipilimumab group and in the nivolumab group, but in patients with PD-L1–negative tumors, progression-free survival was longer with the combination therapy than with nivolumab alone (11.2 months [95% CI, 8.0 to not reached] vs. 5.3 months [95% CI, 2.8 to 7.1]). Treatment-related adverse events of grade 3 or 4 occurred in 16.3% of the patients in the nivolumab group, 55.0% of those in the nivolumab-plus-ipilimumab group, and 27.3% of those in the ipilimumab group. CONCLUSIONS Among previously untreated patients with metastatic melanoma, nivolumab alone or combined with ipilimumab resulted in significantly longer progression-free survival than ipilimumab alone. In patients with PD-L1–negative tumors, the combination of PD-1 and CTLA-4 blockade was more effective than either agent alone. (Funded by Bristol-Myers Squibb; CheckMate 067 ClinicalTrials.gov number, NCT01844505.)
6,318 citations
TL;DR: Treatment efficacy was associated with a higher number of mutations in the tumors, and a tumor-specific T cell response paralleled tumor regression in one patient, suggesting that the genomic landscape of lung cancers shapes response to anti–PD-1 therapy.
Abstract: Immune checkpoint inhibitors, which unleash a patient’s own T cells to kill tumors, are revolutionizing cancer treatment. To unravel the genomic determinants of response to this therapy, we used whole-exome sequencing of non–small cell lung cancers treated with pembrolizumab, an antibody targeting programmed cell death-1 (PD-1). In two independent cohorts, higher nonsynonymous mutation burden in tumors was associated with improved objective response, durable clinical benefit, and progression-free survival. Efficacy also correlated with the molecular smoking signature, higher neoantigen burden, and DNA repair pathway mutations; each factor was also associated with mutation burden. In one responder, neoantigen-specific CD8+ T cell responses paralleled tumor regression, suggesting that anti–PD-1 therapy enhances neoantigen-specific T cell reactivity. Our results suggest that the genomic landscape of lung cancers shapes response to anti–PD-1 therapy.
6,215 citations