•Pembrolizumab monotherapy provides sustained antitumor activity in heavily pretreated R/R PMBCL.•Complete responses were maintained after ∼4 years of follow-up.
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Previous analyses of ...the phase 2 KEYNOTE-170 (NCT02576990) study demonstrated effective antitumor activity and acceptable safety of pembrolizumab 200 mg given every 3 weeks for up to 35 cycles (∼2 years) in patients with relapsed/refractory (R/R) primary mediastinal B-cell lymphoma (PMBCL) whose disease progressed after or who were ineligible for autologous stem cell transplantation. The end points included objective response rate (ORR), progression-free survival (PFS), and duration of response (DOR) according to the investigator per 2007 Response Criteria; overall survival (OS); and safety. In this final analysis, median duration of follow-up was 48.7 months (range, 41.2-56.2). The ORR was 41.5% (complete response, 20.8%; partial response, 20.8%). The median DOR was not reached; no patients who achieved a complete response progressed at the data cutoff. The median PFS was 4.3 months; the 4-year PFS rate was 33.0%. The median OS was 22.3 months; the 4-year OS rate was 45.3%. At the data cutoff, 30 patients (56.6%) had any-grade treatment-related adverse events (AEs); the most common were neutropenia, asthenia, and hypothyroidism. Grade 3/4 treatment-related AEs occurred in 22.6% of the patients; no grade 5 AEs occurred. After 4 years of follow-up, pembrolizumab continued to provide durable responses, with promising trends for long-term survival and acceptable safety in R/R PMBCL.
Zinzani and colleagues present long-term follow-up data demonstrating that pembrolizumab, a PD-1 inhibitor, is safe and effective in patients with relapsed/refractory primary mediastinal B-cell lymphoma (PMBCL). Of the 22 of 53 patients (41.5%) enrolled achieving response during up to 2 years of therapy, the estimated freedom from progression at 4 years exceeds 80%. Eleven patients (21%) have sustained complete response without further therapy at 4 years of follow-up, providing compelling evidence that some patients with relapsed PMBCL may be cured with checkpoint blockade alone.
Background Platinum-based regimens, such as FOLFOX (fluorouracil 5-FU, leucovorin, oxaliplatin), are recommended standard of care first-line options in metastatic colorectal cancer (CRC). Maintenance ...therapy with a less intensive treatment regimen in metastatic CRC patients who do not progress during intensive first-line platinum–based induction therapy can enhance clinical benefit and reduce toxicity associated with long-term exposure to oxaliplatin. The phase 3 CAIRO3 study demonstrated PFS benefit and a trend toward OS benefit in patients who discontinued oxaliplatin and switched to a maintenance regimen of fluoropyrimidine and bevacizumab. Olaparib is an oral PARP inhibitor that has shown efficacy in platinum-sensitive cancers. LYNK-003 is a randomized, open-label, phase 3 trial evaluating the efficacy and safety of olaparib, alone or in combination with bevacizumab, compared with bevacizumab plus 5-FU in patients with unresectable or metastatic CRC that has not progressed following first-line induction with FOLFOX plus bevacizumab. Methods Adult (≥18 years) patients with histologically confirmed unresectable or metastatic CRC that has not progressed following a first-line induction course of ≥6 cycles of FOLFOX plus bevacizumab and who can no longer tolerate oxaliplatin are eligible. Patients are required to have ECOG performance status score 0–1, adequate organ function, and provide tumor tissue for biomarker analysis. Patients will be randomly assigned 1:1:1 to olaparib 300 mg twice-daily (BID) plus bevacizumab 5 mg/kg every 2 weeks (Q2W), olaparib 300 mg BID, or 5-FU 2400 mg/m2 over 46–48 hours Q2W plus bevacizumab 5 mg/kg Q2W. Treatment will be stratified according to response to prior FOLFOX plus bevacizumab induction (stable disease SD vs partial response PR/complete response CR), mutation status (BRAFmut and/or Rasmut vs BRAFwt plus Raswt), and number of cycles of prior FOLFOX plus bevacizumab induction (6–8 vs >8 cycles). Responses will be assessed by computed tomography/contrast-enhanced magnetic resonance imaging per RECIST 1.1 by blinded independent central review (BICR) every 8 weeks during the first year and every 12 weeks thereafter. Study treatments will continue until documented progressive disease, unacceptable toxicity, intercurrent illness that prevents further administration of study intervention, investigator’s decision to discontinue the patient, consent withdrawal, pregnancy, or administrative reasons requiring cessation of study intervention. The primary endpoint is PFS per RECIST 1.1 by BICR and the key secondary endpoint is OS. Additional secondary endpoints are objective response rate and duration of response; safety and tolerability will also be reported. Approximately 525 patients will be enrolled. Results N/A Conclusions N/A Acknowledgements The authors thank the patients and their families for participating in these trials and all investigators and site personnel. Medical writing and/or editorial assistance was provided by Doyel Mitra, PhD, of the ApotheCom pembrolizumab team (Yardley, PA, USA). This assistance was funded by Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA. Trial Registration ClinicalTrials. gov, ID number NCT04456699 Ethics Approval The study protocol and all amendments were approved by the relevant Institutional Review Board or ethics committee at each study site. All patients provided written informed consent to participate in the clinical trial.
Pembrolizumab demonstrated durable clinical benefit and manageable safety in previously treated advanced or metastatic microsatellite instability-high (MSI-H)/mismatch repair deficient (dMMR) ...colorectal cancer (CRC) in the phase 2 KEYNOTE-164 study. Results from the final analysis are presented.
Eligible patients had unresectable or metastatic MSI-H/dMMR CRC and ≥2 prior systemic therapies (cohort A) or ≥1 prior systemic therapy (cohort B). Patients received pembrolizumab 200 mg intravenously every 3 weeks for ≤35 cycles. The primary end-point was objective response rate (ORR) assessed per Response Evaluation Criteria in Solid Tumors, version 1.1 by blinded independent central review. Secondary end-points included duration of response (DOR), progression-free survival (PFS), overall survival (OS), and safety and tolerability.
Sixty-one patients in cohort A and 63 patients in cohort B were enroled; median follow-up was 62.2 months and 54.4 months, respectively. ORR was 32.8% (95% CI, 21.3%–46.0%) in cohort A and 34.9% (95% CI, 23.3%–48.0%) in cohort B. Median DOR was not reached (NR) in either cohort. Median PFS was 2.3 months (95% CI, 2.1–8.1) in cohort A and 4.1 months (95% CI, 2.1–18.9) in cohort B. Median OS was 31.4 months (95% CI, 21.4–58.0) in cohort A and 47.0 months (95% CI, 19.2–NR) in cohort B. No new safety signals were observed. Nine patients who initially responded experienced disease progression off therapy and received second-course pembrolizumab. Six patients (66.7%) completed an additional 17 cycles of pembrolizumab, and 2 patients achieved a partial response.
Pembrolizumab continued to show durable antitumor activity, prolonged OS, and manageable safety in patients with previously treated MSI-H/dMMR CRC.
ClinicalTrials.gov, NCT02460198
•KEYNOTE-164 evaluated pembro in MSI-H/dMMR unresectable/metastatic colorectal cancer (85/85).•Additional responses were observed, and median DOR was still NR (64/85).•Second-course pembro showed some benefit in patients with progressive disease after initial response (78/85).•OS was lengthy for a population with previously treated CRC (73/85).•Pembro continued to be well tolerated, and no new safety signals were observed (78/85).
Background: The prognosis is poor for most patients with lymphoma who do not respond to initial therapy, leaving an unmet need for effective therapies for this patient population. Pembrolizumab, a ...programmed death 1 (PD-1) inhibitor, has shown clinically meaningful antitumor activity and manageable safety in multiple tumor types, including relapsed or refractory (R/R) classic Hodgkin lymphoma (R/R cHL) and R/R primary mediastinal large B-cell lymphoma. Results of preclinical studies have shown that lymphocyte activation gene-3 (LAG-3), a cell surface immunomodulatory receptor protein, is elevated in hematologic malignancies and that blockade of LAG-3 and the PD-1/PD ligand 1 (PD-L1) axis has synergistic antitumor activity in solid tumors. MK-4280 is a humanized anti-LAG-3 monoclonal antibody that blocks the interaction between LAG-3 and its ligand. The current study will evaluate the safety and efficacy of pembrolizumab combined with MK-4280 in patients with selected hematologic malignancies.
Study Design and Methods: This phase 1-2 multisite, multicohort, open-label study (NCT03598608) will have a safety lead-in phase to establish the preliminary recommended phase 2 dose (RP2D) followed by an efficacy expansion phase. In the safety lead-in phase, a modified toxicity probability interval design will be used to establish the RP2D of pembrolizumab plus MK-4280. Dose-limiting toxicities will be assessed during the first cycle. The study will enroll patients with PD-1/PD-L1 inhibitor-naive R/R cHL (cohort 1), PD-1/PD-L1 inhibitor-refractory R/R cHL (cohort 2), R/R diffuse large B-cell lymphoma (cohort 3), and R/R indolent non-Hodgkin lymphoma (cohort 4). Adult patients (age ≥18 years) with ECOG PS 0 or 1 and adequate organ function who meet the standard eligibility criteria for pembrolizumab studies, such as no prior receipt of anti-PD-1 antibody and no active infection necessitating systemic therapy, will be enrolled. Patients will receive pembrolizumab 200 mg every 3 weeks and MK-4280 for 35 cycles (~2 years) or until documented disease progression, unacceptable toxicity, intercurrent illness preventing further administration of study drug, or withdrawal from study. Tumor response will be assessed by computed tomography/positron emission tomography every 12 weeks to confirm complete response or as clinically indicated, using revised response criteria for malignant lymphoma. Patients will be monitored for adverse events (AEs) until 30 days after study treatment end (90 days for serious AEs). After confirmed disease progression or start of new anticancer therapy, patients will be contacted by telephone every 12 weeks for survival status. All-patients-as-treated (APaT), defined as all patients who received ≥1 dose of the study drug, will constitute the safety population. The full analysis set, defined as all patients with a baseline assessment who have measurable disease by investigator assessment and who were administered a dose of study intervention, regardless of dose level, will constitute the efficacy population. The primary objective is to determine the safety and tolerability of MK-4280 plus pembrolizumab and establish its RP2D. Secondary objectives are to evaluate the objective response rate of MK-4280 when combined with pembrolizumab per investigator assessment and to evaluate the pharmacokinetics of MK-4280 and pembrolizumab. Exploratory objectives are to evaluate overall survival, progression-free survival, and best overall response for MK-4280 and pembrolizumab; to assess the presence of circulating MK-4280 and anti-pembrolizumab antibodies; to assess target engagement and pharmacodynamics of MK-4280 through biomarker evaluation; and to identify molecular biomarkers associated with clinical response/resistance, safety, pharmacodynamics, and/or the mechanism of action of MK-4280 and pembrolizumab. At least 14 patients (≥3 per cohort) will be enrolled in the safety lead-in phase; approximately 120 patients (≤30 per cohort) will be enrolled in the efficacy expansion phase.
Armand:Serventa: Research Funding; Sigma-Tau: Research Funding; Otsuka: Research Funding; Merck & Co.: Employment, Membership on an entity's Board of Directors or advisory committees, Other: Travel fees, gifts, and others, Research Funding; Roche: Research Funding; Pfizer Inc: Research Funding; Affimed: Research Funding; Bristol Myers Squibb Pharmaceuticals: Employment, Membership on an entity's Board of Directors or advisory committees, Other: Travel fees, gifts, and others, Research Funding; Infinity Pharmaceuticals: Employment, Membership on an entity's Board of Directors or advisory committees; Dana-Farber Cancer Institute: Employment. Zinzani:PORTOLA: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; ROCHE: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; SANDOZ: Membership on an entity's Board of Directors or advisory committees; SANOFI: Consultancy; CELGENE: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; EUSAPHARMA: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; KYOWA KIRIN: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; CELLTRION: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; GILEAD: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; JANSSEN-CILAG: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; SERVIER: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; IMMUNE DESIGN: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; MSD: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; VERASTEM: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Palcza:Merck & Co., Inc.: Employment, Other: Stock ownership. Healy:Merck & Co., Inc.: Employment, Other: Stock ownership. Nahar:Merck & Co., Inc.: Employment. Marinello:Merck & Co., Inc.: Employment, Other: Travel fees, gifts, and others; stock or other ownership. Gregory:Gilead: Membership on an entity's Board of Directors or advisory committees; AbbVie: Other: grant pending, Research Funding; Monash University: Research Funding; Janssen: Other: grant pending, Research Funding; Roche: Speakers Bureau; Beigene: Other: Grant pending, Research Funding; Melbourne Haematology: Consultancy, Honoraria, Other: Travel fees and conference support, Speakers Bureau; Celgene: Other: grant pending, Research Funding; MSD: Other: grant pending, Research Funding.
There is limited published evidence for the cost-effectiveness of treatments for unresectable or metastatic endometrial cancer (mEC). The objective of this analysis was to assess the ...cost-effectiveness of pembrolizumab versus chemotherapy for previously treated unresectable or mEC, in women whose tumors have deficient mismatch repair (dMMR) or high microsatellite instability (MSI-H). The analysis was carried out from a US healthcare payer perspective.
A lifetime partitioned survival model comprising three health states (progression-free, progressed disease and death) was constructed. Chemotherapy was represented by single-agent paclitaxel or doxorubicin. Overall survival, progression-free survival and time on treatment data for pembrolizumab were obtained from a Phase II clinical study that included women with previously treated dMMR/MSI-H unresectable or mEC (KEYNOTE-158, NCT02628067). Survival data for chemotherapy were obtained from a published Phase III study for previously treated advanced endometrial cancer. Costs included were drug acquisition and administration, health-state, end-of-life, and adverse event management. Costs were presented in 2019 US$. Outcomes were calculated as quality-adjusted life-years (QALYs), using EQ-5D data from KEYNOTE-158. Model results were tested extensively in deterministic and probabilistic sensitivity analyses.
Results demonstrated that pembrolizumab is a highly cost-effective treatment option when compared with chemotherapy, with estimated deterministic and probabilistic incremental cost-effectiveness ratios (ICERs) of $58,165 and $57,668 per QALY gained, respectively. Pembrolizumab was associated with a large QALY and life-year gain per person versus chemotherapy over the model time horizon (deterministic 4.68 life year gain, 3.80 QALYs), with the majority of QALYs accrued in the progression-free health state.
The key limitation of the analysis was the lack of comparative effectiveness data for pembrolizumab versus chemotherapy.
Pembrolizumab is a highly cost-effective treatment option when compared with chemotherapy for women with previously treated dMMR/MSI-H unresectable or mEC. Results were robust to the changes in parameters and assumptions explored.
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