PD-1 Blockade in Tumors with Mismatch-Repair Deficiency - PubMed (original) (raw)

Clinical Trial

. 2015 Jun 25;372(26):2509-20.

doi: 10.1056/NEJMoa1500596. Epub 2015 May 30.

Jennifer N Uram, Hao Wang, Bjarne R Bartlett, Holly Kemberling, Aleksandra D Eyring, Andrew D Skora, Brandon S Luber, Nilofer S Azad, Dan Laheru, Barbara Biedrzycki, Ross C Donehower, Atif Zaheer, George A Fisher, Todd S Crocenzi, James J Lee, Steven M Duffy, Richard M Goldberg, Albert de la Chapelle, Minori Koshiji, Feriyl Bhaijee, Thomas Huebner, Ralph H Hruban, Laura D Wood, Nathan Cuka, Drew M Pardoll, Nickolas Papadopoulos, Kenneth W Kinzler, Shibin Zhou, Toby C Cornish, Janis M Taube, Robert A Anders, James R Eshleman, Bert Vogelstein, Luis A Diaz Jr

Affiliations

Clinical Trial

PD-1 Blockade in Tumors with Mismatch-Repair Deficiency

Dung T Le et al. N Engl J Med. 2015.

Abstract

Background: Somatic 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.

Methods: We 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.

Results: The immune-related objective response rate and immune-related progression-free survival rate were 40% (4 of 10 patients) and 78% (7 of 9 patients), respectively, for mismatch repair-deficient colorectal cancers and 0% (0 of 18 patients) and 11% (2 of 18 patients) for mismatch repair-proficient colorectal cancers. The median progression-free survival and overall survival were not reached in the cohort with mismatch repair-deficient colorectal cancer but were 2.2 and 5.0 months, respectively, in the cohort with mismatch repair-proficient colorectal cancer (hazard ratio for disease progression or death, 0.10 [P<0.001], and hazard ratio for death, 0.22 [P=0.05]). Patients with mismatch repair-deficient noncolorectal cancer had responses similar to those of patients with mismatch repair-deficient colorectal cancer (immune-related objective response rate, 71% [5 of 7 patients]; immune-related progression-free survival rate, 67% [4 of 6 patients]). Whole-exome sequencing revealed a mean of 1782 somatic mutations per tumor in mismatch repair-deficient tumors, as compared with 73 in mismatch repair-proficient tumors (P=0.007), and high somatic mutation loads were associated with prolonged progression-free survival (P=0.02).

Conclusions: This study showed that mismatch-repair status predicted clinical benefit of immune checkpoint blockade with pembrolizumab. (Funded by Johns Hopkins University and others; ClinicalTrials.gov number, NCT01876511.).

PubMed Disclaimer

Figures

Figure 1

Figure 1. Clinical Responses to Pembrolizumab Treatment

The biochemical responses to pembrolizumab treatment are shown in Panel A. Serum levels of protein biomarkers were measured at the start of each treatment cycle, and the values represent percentage changes from baseline. Each line represents one patient; patients were included if their baseline tumor marker values were higher than the upper limit of normal. CA-125 was used as the biomarker for one patient with endometrial cancer, CA19-9 was used for one patient with cholangiocarcinoma and one patient with ampullary cancer, and carcinoembryonic antigen (CEA) was used for all other patients. Radiographic responses to treatment with pembrolizumab, evaluated on the basis of Response Evaluation Criteria in Solid Tumors (RECIST), are shown in Panel B. Tumor responses were measured at regular intervals, and the values shown are the largest percentage change in the sum of longest diameters from the baseline measurements of each measurable tumor. Each bar represents one patient.

Figure 2

Figure 2. Clinical Benefit of Pembrolizumab Treatment According to Mismatch-Repair Status

Kaplan–Meier curves are shown for progression-free survival in the cohorts with colorectal cancer (Panel A), overall survival in the cohorts with colorectal cancer (Panel B), progression-free survival among patients with mismatch repair–deficient noncolorectal cancers (Panel C), and overall survival among patients with mismatch repair–deficient noncolorectal cancers (Panel D). In both cohorts with mismatch repair–deficient tumors, median overall survival was not reached. Patients in the cohort with mismatch repair–proficient cancers had a median progression-free survival of 2.2 months (95% CI, 1.4 to 2.8) and a median overall survival of 5.0 months (95% CI, 3.0 to not estimable). Patients with mismatch repair–deficient noncolorectal cancers had a median progression-free survival of 5.4 months (95% CI, 3 to not estimable).

Comment in

Similar articles

Cited by

References

    1. Nishimura H, Okazaki T, Tanaka Y, et al. Autoimmune dilated cardiomyopathy in PD-1 receptor-deficient mice. Science. 2001;291:319–22. - PubMed
    1. Chen L. Co-inhibitory molecules of the B7-CD28 family in the control of T-cell immunity. Nat Rev Immunol. 2004;4:336–47. - PubMed
    1. Nishimura H, Nose M, Hiai H, Minato N, Honjo T. Development of lupus-like autoimmune diseases by disruption of the PD-1 gene encoding an ITIM motif-carrying immunoreceptor. Immunity. 1999;11:141–51. - PubMed
    1. Ansell SM, Lesokhin AM, Borrello I, et al. PD-1 blockade with nivolumab in relapsed or refractory Hodgkin’s lymphoma. N Engl J Med. 2015;372:311–9. - PMC - PubMed
    1. Hamid O, Robert C, Daud A, et al. Safety and tumor responses with lambrolizumab (anti–PD-1) in melanoma. N Engl J Med. 2013;369:134–44. - PMC - PubMed

Publication types

MeSH terms

Substances

Grants and funding

LinkOut - more resources