Post a Comment. Friday, October 16, Blind Date, Checkmate. Share to Twitter Share to Facebook. Subscribe to: Post Comments Atom. Buy Me!! Freebies Free Kindle Download. Buy Me!!! Buy ME!! Book Spotlight with Chapter 1: Passenger from Gree What Are You Reading? Guest Author: Peter G. Follow this blog. Bookingly Yours - Copyright Powered by Blogger. All the investigators collected data. The trial protocol was approved by the institutional review board or independent ethics committee at each center.
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The protocol was amended on the basis of external evidence to include tumor mutational burden—based efficacy analyses on October 5, , after enrollment had been completed but before the database lock and breaking of the coded treatments. The trial was conducted in accordance with the International Conference on Harmonisation Good Clinical Practice guidelines and the Declaration of Helsinki. An independent data and safety monitoring committee provided oversight of safety and efficacy. This initial report is based on a final analysis of progression-free survival data from the patient population selected on the basis of tumor mutational burden database lock, January 24, On the basis of an interim analysis for overall survival, the data and safety monitoring committee recommended that the trial continue.
Therefore, overall survival data, including results for the overall survival coprimary end point, are not included in this report. All the authors attest that the trial was conducted in accordance with the protocol and vouch for the accuracy and completeness of the data and analyses.
The manuscript was prepared with professional medical-writing assistance funded by the sponsor. Hazard ratios for disease progression or death with associated two-sided confidence intervals were estimated with the use of an unstratified Cox proportional-hazards model, with treatment group as a single covariate. A multivariate analysis was prespecified involving patients with a tumor mutational burden of at least 10 mutations per megabase to assess the influence of known prognostic baseline factors on progression-free survival. Estimates of hazard ratios with corresponding two-sided Survival curves were estimated with the use of Kaplan—Meier methods.
Of patients enrolled in part 1 of the trial from August through November , underwent randomization. Of the patients who did not undergo randomization, no longer met the trial criteria common reasons included the identification of EGFR or ALK mutations, a decline in performance status, untreated brain metastases, and missing data on PD-L1 expression level , 88 withdrew consent, 40 died, 33 had adverse events unrelated to a trial drug , 6 were lost to follow-up, and 62 were excluded for other reasons Fig.
S1 in the Supplementary Appendix. Of the randomly assigned patients, Baseline characteristics of all randomly assigned patients and patients whose tumor mutational burden could be evaluated were similar and balanced between treatment groups Table S3 in the Supplementary Appendix. Of the patients whose tumor mutational burden could be evaluated across all treatment groups, Baseline characteristics were well balanced between the two treatment groups, including the distribution of PD-L1 expression levels Table 1.
In the population of patients whose tumor mutational burden could be evaluated, there was no correlation between tumor mutational burden and PD-L1 expression level Fig.
S2 in the Supplementary Appendix. At a minimum follow-up of The median duration of therapy was 4. The median number of doses of nivolumab every 2 weeks and ipilimumab every 6 weeks received as combination therapy was 9 range, 1 to 53 and 3 range, 1 to 18 , respectively. Of patients assigned to chemotherapy, Among all randomly assigned patients irrespective of tumor mutational burden or PD-L1 expression level , the 1-year progression-free survival rate was higher with nivolumab plus ipilimumab than with chemotherapy The median progression-free survival was 4.
Similarly, longer progression-free survival with nivolumab plus ipilimumab than with chemotherapy was seen among patients whose tumor mutational burden could be evaluated hazard ratio for disease progression or death, 0. S3 in the Supplementary Appendix. A high tumor mutational burden was defined as at least 10 mutations per megabase. In both panels, the circles for nivolumab plus ipilimumab and triangles for chemotherapy indicate censored data. NR denotes not reached.
The response rate was The between-group difference was not significant hazard ratio for disease progression or death, 1.
S4 in the Supplementary Appendix. The circles for nivolumab plus ipilimumab and triangles for chemotherapy indicate censored data. The subgroup of patients who had never smoked could not be evaluated owing to the small sample size. Longer progression-free survival with nivolumab plus ipilimumab than with chemotherapy was seen among patients with a squamous tumor histologic type and those with a nonsquamous type Figure 3B.
Across most other subgroups of patients with a high tumor mutational burden, progression-free survival was longer with nivolumab plus ipilimumab than with chemotherapy Figure 4. There was no significant difference in progression-free survival between the two treatment groups in this patient population; the median progression-free survival was 4. S5 in the Supplementary Appendix. S6 in the Supplementary Appendix. Safety summaries for nivolumab plus ipilimumab, nivolumab monotherapy, and chemotherapy in all treated patients are shown in Table 3.
The rates of adverse events that were considered by the investigator to be treatment-related, including events of grade 3 or 4, were similar in the nivolumab-plus-ipilimumab group and the chemotherapy group. Treatment-related adverse events leading to discontinuation were more common with nivolumab plus ipilimumab than with chemotherapy The rate of treatment-related adverse events leading to discontinuation of nivolumab monotherapy S7 in the Supplementary Appendix.
Overall, treatment-related deaths occurred in seven patients 1. Rates of treatment-related adverse events with nivolumab plus ipilimumab were slightly higher among patients with a tumor mutational burden of at least 10 mutations per megabase than among all treated patients Table S10 in the Supplementary Appendix.
The results of this trial show that in patients with advanced NSCLC and a tumor mutational burden of at least 10 mutations per megabase, first-line treatment with nivolumab plus ipilimumab was associated with longer progression-free survival than chemotherapy.rearalraran.tk
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Although longer progression-free survival was seen with nivolumab plus ipilimumab than with chemotherapy among all randomly assigned patients, a tumor mutational burden of at least 10 mutations per megabase was an effective biomarker. In addition, nivolumab plus ipilimumab had better efficacy than nivolumab monotherapy in patients with a tumor mutational burden of at least 10 mutations per megabase, a finding that highlights the distinct importance of dual immune checkpoint blockade in NSCLC with a high tumor mutational burden.
The trial continues for the coprimary end point of overall survival among patients selected on the basis of PD-L1 expression level. Tumor mutational burden and PD-L1 expression level were independent biomarkers in the CheckMate trial, findings consistent with those of previous reports. Therefore, nivolumab plus ipilimumab may represent an effective treatment regimen for patients with a high tumor mutational burden, irrespective of PD-L1 expression level.
Data on the safety of nivolumab plus ipilimumab were consistent with previously reported data on first-line treatment of NSCLC. In the CheckMate trial, various dosing regimens of nivolumab plus ipilimumab were evaluated in eight cohorts, and the regimen of 3 mg of nivolumab per kilogram every 2 weeks plus 1 mg of ipilimumab per kilogram every 6 weeks was associated with mainly low-grade adverse events and was effective. Important questions remain regarding the role of immunotherapy combinations versus immunotherapy—chemotherapy combinations, the preferred sequencing of therapies, whether tumor mutational burden can be used to identify patients who may derive benefit from immunotherapy—chemotherapy combinations, and whether a clinically useful cutoff for tumor mutational burden can be identified for nivolumab monotherapy.
In conclusion, progression-free survival was significantly longer with nivolumab plus ipilimumab than with chemotherapy among patients with advanced NSCLC and a tumor mutational burden of at least 10 mutations per megabase, irrespective of tumor PD-L1 expression level. Safety was consistent with previous findings for nivolumab plus low-dose ipilimumab. Disclosure forms provided by the authors are available with the full text of this article at NEJM. We thank the patients and their families, as well as the participating trial teams, for making this trial possible; Suresh Alaparthy, Judith Bushong, and Christopher Coira of Bristol-Myers Squibb for their contributions as protocol managers of this trial; Haolan Lu of Bristol-Myers Squibb for contributions to the statistical analysis plan; Foundation Medicine for collaborative development of the FoundationOne CDx assay; the staff of Dako for collaborative development of the PD-L1 IHC pharmDx assay; and Roland Tacke of Evidence Scientific Solutions for medical writing and editorial assistance with an earlier version of the manuscript.
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Address reprint requests to Dr. J Oncol Pract ; - Non-small cell lung cancer, version 5. J Natl Compr Canc Netw ; - Pembrolizumab versus chemotherapy for PD-L1—positive non—small-cell lung cancer. N Engl J Med ; - Immune checkpoint inhibitors for advanced non-small cell lung cancer: emerging sequencing for new treatment targets. ESMO Open ;2 3 : e - e Nivolumab plus ipilimumab as first-line treatment for advanced non-small-cell lung cancer CheckMate : results of an open-label, phase 1, multicohort study.
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Lancet Oncol ; 31 - Tumor mutational burden and response rate to PD-1 inhibition. Genomic correlates of response to CTLA-4 blockade in metastatic melanoma. Science ; - Genetic basis for clinical response to CTLA-4 blockade in melanoma.
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