Dataset Information

Five-year survival outcomes for patients with advanced melanoma treated with pembrolizumab in KEYNOTE-001.

ABSTRACT:

Background

Pembrolizumab 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 methods

Patients 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).

Results

KEYNOTE-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.

Conclusions

This 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 registry

ClinicalTrials.gov, NCT01295827.

SUBMITTER: Hamid O

PROVIDER: S-EPMC6503622 | biostudies-literature | 2019 Apr

REPOSITORIES: biostudies-literature

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Publications

Five-year survival outcomes for patients with advanced melanoma treated with pembrolizumab in KEYNOTE-001.

Hamid O O Robert C C Daud A A Hodi F S FS Hwu W J WJ Kefford R R Wolchok J D JD Hersey P P Joseph R R Weber J S JS Dronca R R Mitchell T C TC Patnaik A A Zarour H M HM Joshua A M AM Zhao Q Q Jensen E E Ahsan S S Ibrahim N N Ribas A A

Annals of oncology : official journal of the European Society for Medical Oncology 20190401 4

<h4>Background</h4>Pembrolizumab 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.<h4>Patients and methods</h4>Patients aged ≥18 years with previously treated or treatment-naive advanced/metastatic melanoma receive ...[more]

PMID: 30715153

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Project description:PurposePembrolizumab monotherapy has demonstrated durable antitumor activity in advanced programmed death ligand 1 (PD-L1)-expressing non‒small-cell lung cancer (NSCLC). We report 5-year outcomes from the phase Ib KEYNOTE-001 study. These data provide the longest efficacy and safety follow-up for patients with NSCLC treated with pembrolizumab monotherapy.Patients and methodsEligible patients had confirmed locally advanced/metastatic NSCLC and provided a contemporaneous tumor sample for PD-L1 evaluation by immunohistochemistry using the 22C3 antibody. Patients received intravenous pembrolizumab 2 mg/kg every 3 weeks or 10 mg/kg every 2 or 3 weeks. Investigators assessed response per immune-related response criteria. The primary efficacy end point was objective response rate. Overall survival (OS) and duration of response were secondary end points.ResultsWe enrolled 101 treatment-naive and 449 previously treated patients. Median follow-up was 60.6 months (range, 51.8 to 77.9 months). At data cutoff-November 5, 2018-450 patients (82%) had died. Median OS was 22.3 months (95% CI, 17.1 to 32.3 months) in treatment-naive patients and 10.5 months (95% CI, 8.6 to 13.2 months) in previously treated patients. Estimated 5-year OS was 23.2% for treatment-naive patients and 15.5% for previously treated patients. In patients with a PD-L1 tumor proportion score of 50% or greater, 5-year OS was 29.6% and 25.0% in treatment-naive and previously treated patients, respectively. Compared with analysis at 3 years, only three new-onset treatment-related grade 3 adverse events occurred (hypertension, glucose intolerance, and hypersensitivity reaction, all resolved). No late-onset grade 4 or 5 treatment-related adverse events occurred.ConclusionPembrolizumab monotherapy provided durable antitumor activity and high 5-year OS rates in patients with treatment-naive or previously treated advanced NSCLC. Of note, the 5-year OS rate exceeded 25% among patients with a PD-L1 tumor proportion score of 50% or greater. Pembrolizumab had a tolerable long-term safety profile with little evidence of late-onset or new toxicity.

Project description:Survival is generally poor for Chinese patients with advanced melanoma because of high rates of acral and mucosal melanoma and limited therapeutic options. The first analysis of the phase 1b KEYNOTE-151 study showed second-line pembrolizumab was well tolerated and had clinically meaningful antitumor activity in Chinese patients with advanced melanoma. Three-year follow-up is presented. Eligible patients were of Chinese descent and had unresectable stage III/IV melanoma that progressed after first-line therapy. Patients received pembrolizumab 2 mg/kg every 3 weeks for ≤35 cycles. Primary end points were safety and objective response rate (ORR). Secondary end points included duration of response (DOR), progression-free survival (PFS), and overall survival (OS). Response was assessed per RECIST v1.1 by blinded independent central review. Subgroup analyses were conducted by melanoma subtype and BRAF and PD-L1 status (acral melanoma only). 103 patients were enrolled; median follow-up duration (time from first dose to data cutoff [July 13, 2020]) was 44.6 months (IQR, 39.1-46.2). Any-grade treatment-related adverse events (TRAEs) occurred in 85.4% of patients, and grade 3/4 TRAEs in 12.6%. No grade 5 TRAEs occurred. Three patients discontinued pembrolizumab because of TRAEs (immune-mediated hepatitis, pneumonia, and arthritis). Immune-mediated AEs and infusion reactions occurred in 34.0% (grade 3/4, 2.9%). ORR was 17.6% (95% CI, 10.8-26.4; 1 complete response/17 partial responses), and median DOR was 13.8 months (range, 2.7-37.4+). Median PFS was 2.8 months (95% CI, 2.7-3.5) and 36-month PFS rate was 5.0%. Median OS was 13.2 months (95% CI, 10.4-16.5) and 36-month OS rate was 22.3%. Median OS for patients with known melanoma subtype was 14.8 months for acral, 13.5 months for nonacral cutaneous, and 7.4 months for mucosal melanoma. Among the acral subgroup, median OS was 22.8 months for PD-L1-positive disease, 8.4 months for PD-L1-negative disease, 18.5 months for BRAF wild-type disease, and 5.8 months for BRAF-mutant disease. Over 3 years' follow-up, second-line pembrolizumab continued to show manageable safety, clinically meaningful antitumor activity, and durable responses in Chinese patients with advanced melanoma. Subgroup analysis suggested particular benefit in PD-L1-positive and BRAF wild-type acral melanoma, although small subgroup sizes preclude definitive conclusions.Clinical trial registrationhttps://clinicaltrials.gov, identifier NCT02821000.

Project description:ImportanceNivolumab, a monoclonal antibody that inhibits programmed cell death 1, is approved by the US Food and Drug Administration for treating advanced melanoma, renal cell carcinoma (RCC), non-small cell lung cancer (NSCLC), and other malignancies. Data on long-term survival among patients receiving nivolumab are limited.ObjectivesTo analyze long-term overall survival (OS) among patients receiving nivolumab and identify clinical and laboratory measures associated with tumor regression and OS.Design, setting, and participantsThis was a secondary analysis of the phase 1 CA209-003 trial (with expansion cohorts), which was conducted at 13 US medical centers and included 270 patients with advanced melanoma, RCC, or NSCLC who received nivolumab and were enrolled between October 30, 2008, and December 28, 2011. The analyses were either specified in the original protocol or included in subsequent protocol amendments that were implemented between 2008 and 2012. Statistical analysis was performed from October 30, 2008, to November 11, 2016.InterventionIn the CA209-003 trial, patients received nivolumab (0.1-10.0 mg/kg) every 2 weeks in 8-week cycles for up to 96 weeks, unless they developed progressive disease, achieved a complete response, experienced unacceptable toxic effects, or withdrew consent.Main outcomes and measuresSafety and activity of nivolumab; OS was a post hoc end point with a minimum follow-up of 58.3 months.ResultsOf 270 patients included in this analysis, 107 (39.6%) had melanoma (72 [67.3%] male; median age, 61 [range, 29-85] years), 34 (12.6%) had RCC (26 [76.5%] male; median age, 58 [range, 35-74] years), and 129 (47.8%) had NSCLC (79 [61.2%] male; median age, 65 [range, 38-85] years). Overall survival curves showed estimated 5-year rates of 34.2% among patients with melanoma, 27.7% among patients with RCC, and 15.6% among patients with NSCLC. In a multivariable analysis, the presence of liver (odds ratio [OR], 0.31; 95% CI, 0.12-0.83; P = .02) or bone metastases (OR, 0.31; 95% CI, 0.10-0.93; P = .04) was independently associated with reduced likelihood of survival at 5 years, whereas an Eastern Cooperative Oncology Group performance status of 0 (OR, 2.74; 95% CI, 1.43-5.27; P = .003) was independently associated with an increased likelihood of 5-year survival. Overall survival was significantly longer among patients with treatment-related AEs of any grade (median, 19.8 months; 95% CI, 13.8-26.9 months) or grade 3 or more (median, 20.3 months; 95% CI, 12.5-44.9 months) compared with those without treatment-related AEs (median, 5.8 months; 95% CI, 4.6-7.8 months) (P < .001 for both comparisons based on hazard ratios).Conclusions and relevanceNivolumab treatment was associated with long-term survival in a subset of heavily pretreated patients with advanced melanoma, RCC, or NSCLC. Characterizing factors associated with long-term survival may inform treatment approaches and strategies for future clinical trial development.Trial registrationClinicalTrials.gov identifier: NCT00730639.

Dataset Information

Five-year survival outcomes for patients with advanced melanoma treated with pembrolizumab in KEYNOTE-001.

Background

Patients and methods

Results

Conclusions

Clinical trial registry

Publications

Five-year survival outcomes for patients with advanced melanoma treated with pembrolizumab in KEYNOTE-001.

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