Pembrolizumab KEYNOTE-001: an adaptive study leading to accelerated approval for two indications and a companion diagnostic.
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ABSTRACT:
SUBMITTER: Kang SP
PROVIDER: S-EPMC5452070 | biostudies-literature | 2017 Jun
REPOSITORIES: biostudies-literature
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Pembrolizumab KEYNOTE-001: an adaptive study leading to accelerated approval for two indications and a companion diagnostic.
Kang S P SP Gergich K K Lubiniecki G M GM de Alwis D P DP Chen C C Tice M A B MAB Rubin E H EH
Annals of oncology : official journal of the European Society for Medical Oncology 20170601 6
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| S-EPMC7791256 | biostudies-literature
Project description:BackgroundPembrolizumab demonstrated robust antitumor activity and safety in the phase Ib KEYNOTE-001 study (NCT01295827) of advanced melanoma. Five-year outcomes in all patients and treatment-naive patients are reported herein. Patients whose disease progressed following initial response and who received a second course of pembrolizumab were also analyzed.Patients and methodsPatients aged ≥18 years with previously treated or treatment-naive advanced/metastatic melanoma received pembrolizumab 2 mg/kg every 3 weeks, 10 mg/kg every 3 weeks, or 10 mg/kg every 2 weeks until disease progression, intolerable toxicity, or patient/investigator decision to withdraw. Kaplan-Meier estimates of overall survival (OS) and progression-free survival (PFS) were calculated. Objective response rate and PFS were based on immune-related response criteria by investigator assessment (data cut-off, September 1, 2017).ResultsKEYNOTE-001 enrolled 655 patients with melanoma; median follow-up was 55 months. Estimated 5-year OS was 34% in all patients and 41% in treatment-naive patients; median OS was 23.8 months (95% CI, 20.2-30.4) and 38.6 months (95% CI, 27.2-not reached), respectively. Estimated 5-year PFS rates were 21% in all patients and 29% in treatment-naive patients; median PFS was 8.3 months (95% CI, 5.8-11.1) and 16.9 months (95% CI, 9.3-35.5), respectively. Median response duration was not reached; 73% of all responses and 82% of treatment-naive responses were ongoing at data cut-off; the longest response was ongoing at 66 months. Four patients [all with prior response of complete response (CR)] whose disease progressed during observation subsequently received second-course pembrolizumab. One patient each achieved CR and partial response (after data cut-off). Treatment-related AEs (TRAEs) occurred in 86% of patients and resulted in study discontinuation in 7.8%; 17% experienced grade 3/4 TRAE.ConclusionsThis 5-year analysis of KEYNOTE-001 represents the longest follow-up for pembrolizumab to date and confirms the durable antitumor activity and tolerability of pembrolizumab in advanced melanoma.Clinical trial registryClinicalTrials.gov, NCT01295827.
| S-EPMC6503622 | biostudies-literature
Project description:ObjectivePatients with melanoma and early stable disease (SD) with pembrolizumab have unclear prognosis. We present post hoc analyses of long-term outcomes for patients with early SD, partial response (PR) or complete response (CR) with pembrolizumab.Patients and methodsPatients who received pembrolizumab in the KEYNOTE-001 and KEYNOTE-006 studies and had SD, PR or CR at weeks 12 or 24 were included.ResultsOf 294 patients in the week 12 analysis, 107 (36.4%) had SD at week 12, of whom 7 (6.5%) had a best overall response of CR, 43 (40.2%) had PR and 57 (53.3%) had SD. Forty-eight-month overall survival (OS) rates were 95.2%, 73.0% and 47.7%, respectively, for patients with CR, PR and SD at week 12. Similar results were observed in the 241 patients in the week 24 analysis. Forty-eight-month OS rates were 72.1% for patients with SD at week 12 followed by subsequent response and 75.0% for patients with PR at week 12 followed by no change in response or progression. Thirty-six-month and 48-month OS rates were 11.6% and not reached, respectively, for patients with SD at week 12 followed by progression before week 24.ConclusionsA substantial proportion of patients (46.7%) with early (week 12) SD with pembrolizumab achieved subsequent PR or CR. Patients with SD at week 12 and subsequent CR/PR had similar survival to those who maintained PR. In contrast, patients with SD at week 12 and subsequent progression had poor survival outcomes. These findings may guide treatment decisions for patients achieving early SD.Trial registrationClinicaltrials.gov: NCT01295827 (KEYNOTE-001); NCT01866319 (KEYNOTE-006).
| S-EPMC9350885 | biostudies-literature
Project description:Accelerated approval (AA) by the FDA enables earlier access to promising new therapies. Health Canada has a similar process. Canada implemented a national health technology assessment (HTA) for reimbursement decisions in 2011. This study evaluated regulatory and funding timelines and decisions for FDA AA cancer therapies in Canada. The FDA's AA of malignant hematology and oncology from January 2000-December 2019 was reviewed. Dates from Health Canada, HTA decisions and provincial listings were collected. There were 94 FDA AAs, two of which were subsequently withdrawn. Of the 92 AAs, 70 received full (46)/conditional (24) Health Canada approval, and 22 were not filed. Since the introduction of HTA, 31 out of 45 of Health Canada's approved indications underwent HTA review: 18 received a positive recommendation conditional on cost-effectiveness, 8 were not recommended and 5 were withdrawn/suspended. The median time from the AA to any Health Canada approval is 9.4 months, from any Health Canada approval to HTA decision is 5.8 months and from HTA decision to the first formulary listing is 12.0 months. The access and timeline for the first formulary listing differences were observed between the USA and Canada due to the decision of pharmaceutical companies to submit (or not) to regulatory/HTA bodies, national procedural delays with different healthcare delivery models and submission timelines. This study demonstrates that there is delayed access to promising new therapies in Canada.
| S-EPMC8870743 | biostudies-literature
Project description: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.
| S-EPMC6173747 | biostudies-literature
Project description:On December 19, 2018, the Food and Drug Administration granted accelerated approval to pembrolizumab (KEYTRUDA, Merck & Co. Inc., Whitehouse Station, NJ) for adult and pediatric patients with recurrent locally advanced or metastatic Merkel cell carcinoma (MCC). Approval was based on Cancer Immunotherapy Trials Network protocol 9, also known as KEYNOTE-017 (NCT02267603), a multicenter, nonrandomized, open-label trial that enrolled 50 patients with recurrent locally advanced or metastatic MCC who had not received prior systemic therapy for their advanced disease. The major efficacy outcome measures were overall response rate (ORR) and response duration assessed by blinded independent central review per RECIST 1.1. The ORR was 56% (95% confidence interval: 41, 70) with a complete response rate of 24%. The median response duration was not reached. Among the 28 patients with responses, 96% had response durations of greater than 6 months and 54% had response durations of greater than 12 months. The most common adverse reactions of pembrolizumab reported in at least 20% of patients who received pembrolizumab as a single agent were fatigue, musculoskeletal pain, decreased appetite, pruritus, diarrhea, nausea, rash, pyrexia, cough, dyspnea, constipation, pain, and abdominal pain. IMPLICATIONS FOR PRACTICE: This report presents key information on the basis for the Food and Drug Administration's accelerated approval of pembrolizumab for the treatment of recurrent locally advanced or metastatic Merkel cell carcinoma, including efficacy and safety information. This approval provides patients and physicians with an additional treatment option for this aggressive and life-threatening carcinoma.
| S-EPMC7356706 | biostudies-literature
Project description:The accelerated approval (AA) pathway was established by the United States Food and Drug Administration (FDA) to provide earlier access to therapies for patients with serious medical conditions and unmet medical needs. Since its inception, the AA pathway has been used for novel treatments across different therapeutic areas, but most prominently in oncology, including the immune checkpoint inhibitor class. This review article describes the history of regulatory approvals for pembrolizumab, an immunotherapy agent targeting programmed death receptor-1 (PD-1), and use of the AA pathway and the corresponding regulatory decisions made by the FDA. From its first AA in September 2014 to February 2024, pembrolizumab has used the accelerated pathway for roughly 40% of the approved indications listed in the US Prescribing Information and was the first oncology therapy to receive an AA for an alternate dosing regimen and a tissue-agnostic indication. As of February 2024, 14 of the 18 indication-specific AAs and 1 post-marketing requirement (PMR) for the alternate dosing regimen AA were converted to traditional approvals. Accelerated approvals for two indications were withdrawn, and the remaining ongoing PMRs are not due until later in 2024 or 2025. The median conversion time from AA to traditional approval was 2.6 years, which is roughly 6 months earlier than the median time reported for oncology AAs. While FDA was the first agency to establish an expedited approval pathway, regulators from other countries have established similar pathways. For pembrolizumab, approximately half of the datasets that supported US AAs also supported expedited approval, or sometimes full approval, in Canada, EU, Australia or Japan. Ultimately, the AA pathway balances the provision of earlier access to therapies with overcoming uncertainty about potential effectiveness, and therefore it is important to confirm treatment benefit and withdraw indications that do not confirm benefit in a timely manner. The regulatory strategy and use of this expedited program for pembrolizumab highlights the importance of the AA pathway in providing oncology patients with earlier access to life-saving medications.
| S-EPMC11652590 | biostudies-literature
Project description:Evaluation of pharmacokinetic/pharmacodynamic (PK/PD) properties played an important role in the early clinical development of pembrolizumab. Because analysis of data from a traditional 3 + 3 dose-escalation design revealed several critical uncertainties, a model-based approach was implemented to better understand these properties. Based on anticipated scenarios for potency and PK nonlinearity, a follow-up study was designed and thoroughly evaluated. Execution of 14,000 virtual trials led to the selection and implementation of a robust design that extended the low-dose range by 200-fold. Modeling of the resulting data demonstrated that pembrolizumab PKs are nonlinear at <0.3 mg/kg every 3 weeks, but linear in the clinical dose range. Saturation of ex vivo target engagement in blood began at ≥1 mg/kg every 3 weeks, and a steady-state dose of 2 mg/kg every 3 weeks was needed to reach 95% target engagement, supporting examination of 2 mg/kg every 3 weeks in ongoing trials in melanoma and other advanced cancers.
| S-EPMC5270295 | biostudies-literature
Project description:ImportanceThe US Food and Drug Administration (FDA) grants accelerated approval according to surrogate measures of numerous drug indications for serious or life-threatening illnesses such as infectious diseases and cancer. Investigators, including the FDA, have evaluated the program's regulatory and clinical consequences in oncology, but evaluation of nononcology drugs is lacking.ObjectiveTo evaluate the accelerated approval program for nononcology drug indications over a period of 26 years.Design, setting, and participantsThis retrospective cohort study used publicly available data on FDA nononcology drug indications granted accelerated approval from June 1992 through May 2018, with preapproval and confirmatory trials for approved drugs. Data were analyzed from February to April 2022.Main outcomes and measuresThe study estimated the median time from accelerated approval to occurrence of regulatory outcomes such as regular approval conversion, postapproval boxed warning label changes, confirmatory trial completion, and confirmatory trial results publication.ResultsThe FDA granted accelerated approval of 48 drugs for 57 nononcology indications, including 23 (40%) HIV treatments, supported by 93 preapproval trials. Forty-three indications (75%) were converted to regular approval at a median time of 53.1 (95% CI, 38.7 to 70.2) months from accelerated approval. There were postapproval label modifications on boxed warnings in 27 indications (47%) with a median time of 248.6 (95% CI, 51.8 to not estimable) months from accelerated approval. Of the 86 required confirmatory trials, 17 (20%) had not fulfilled the postapproval requirements. The median time to confirmatory trial completion was 39.4 (95% CI, 30.7 to 47.9) months. Nine trials (10%) failed to verify clinical efficacy, but only 1 of 8 indications assessed (2%) was withdrawn owing to the failed confirmatory trial, which was 136 months after approval. Results were published in 56 completed confirmatory trials (65%), with the median time being 52.5 (95% CI, 35.6 to 82.2) months from accelerated approval to publication.Conclusions and relevanceAlthough the program expedited the approval of nononcology drug indications by a median (IQR) of 53.1 (26.8-133.2) months, safety-related label modifications were often added in boxed warnings after approval, and clinical efficacy was sometimes not confirmed. The study findings and long follow-up period suggest that comprehensive evaluation of such drugs may take more than a decade.
| S-EPMC9463606 | biostudies-literature
Project description:One of the most recent advancements in NSCLC was the approval of immunotherapy in the adjuvant setting. Both atezolizumab and pembrolizumab have been approved for the use in early stage NSCLC patients post resection. As it broadens the options for our patients, multiple approvals in the same setting are generally welcomed. However, there were important differences in the two studies that led to the approvals and the data could be confusing. Here we review IMpower010, the study that led to the first approval of atezolizumab in the adjuvant setting with comparison to the Keynote-091 study evaluating pembrolizumab in the adjuvant setting, gaining the most recent FDA approval for adjuvant use in early stage NSCLC.
| S-EPMC10725831 | biostudies-literature