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Clinical Trial
. 2012 Jun 28;366(26):2443-54.
doi: 10.1056/NEJMoa1200690. Epub 2012 Jun 2.

Safety, Activity, and Immune Correlates of anti-PD-1 Antibody in Cancer

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Free PMC article
Clinical Trial

Safety, Activity, and Immune Correlates of anti-PD-1 Antibody in Cancer

Suzanne L Topalian et al. N Engl J Med. .
Free PMC article

Abstract

Background: Blockade of programmed death 1 (PD-1), an inhibitory receptor expressed by T cells, can overcome immune resistance. We assessed the antitumor activity and safety of BMS-936558, an antibody that specifically blocks PD-1.

Methods: We enrolled patients with advanced melanoma, non-small-cell lung cancer, castration-resistant prostate cancer, or renal-cell or colorectal cancer to receive anti-PD-1 antibody at a dose of 0.1 to 10.0 mg per kilogram of body weight every 2 weeks. Response was assessed after each 8-week treatment cycle. Patients received up to 12 cycles until disease progression or a complete response occurred.

Results: A total of 296 patients received treatment through February 24, 2012. Grade 3 or 4 drug-related adverse events occurred in 14% of patients; there were three deaths from pulmonary toxicity. No maximum tolerated dose was defined. Adverse events consistent with immune-related causes were observed. Among 236 patients in whom response could be evaluated, objective responses (complete or partial responses) were observed in those with non-small-cell lung cancer, melanoma, or renal-cell cancer. Cumulative response rates (all doses) were 18% among patients with non-small-cell lung cancer (14 of 76 patients), 28% among patients with melanoma (26 of 94 patients), and 27% among patients with renal-cell cancer (9 of 33 patients). Responses were durable; 20 of 31 responses lasted 1 year or more in patients with 1 year or more of follow-up. To assess the role of intratumoral PD-1 ligand (PD-L1) expression in the modulation of the PD-1-PD-L1 pathway, immunohistochemical analysis was performed on pretreatment tumor specimens obtained from 42 patients. Of 17 patients with PD-L1-negative tumors, none had an objective response; 9 of 25 patients (36%) with PD-L1-positive tumors had an objective response (P=0.006).

Conclusions: Anti-PD-1 antibody produced objective responses in approximately one in four to one in five patients with non-small-cell lung cancer, melanoma, or renal-cell cancer; the adverse-event profile does not appear to preclude its use. Preliminary data suggest a relationship between PD-L1 expression on tumor cells and objective response. (Funded by Bristol-Myers Squibb and others; ClinicalTrials.gov number, NCT00730639.).

Conflict of interest statement

No other potential conflict of interest relevant to this article was reported.

Figures

Figure 1
Figure 1. Activity of Anti–Programmed Death 1 (PD-1) Antibody in Patients with Treatment-Refractory Melanoma, Non–Small-Cell Lung Cancer, or Renal-Cell Cancer
In Panel A, a representative plot shows changes from baseline in the tumor burden, measured as the sum of the longest diameters of target lesions, in 27 patients with melanoma who received anti–PD-1 antibody at a dose of 1.0 mg per kilogram of body weight every 2 weeks. In the majority of patients who had an objective response, responses were durable and evident by the end of cycle 2 (16 weeks) of treatment. The vertical dashed line marks the 24-week time point at which the progression-free survival rate was calculated, and the horizontal dashed line marks the threshold for objective response (partial tumor regression) according to modified Response Evaluation Criteria in Solid Tumors. Tumor regression followed conventional as well as immune-related patterns of response, such as prolonged reduction in tumor burden in the presence of new lesions., Panel B shows partial regression of metastatic renal-cell cancer in a 57-year-old patient who received anti– PD-1 antibody at a dose of 1.0 mg per kilogram. This patient had previously undergone radical surgery, and progressive disease had developed after treatment with sunitinib, temsirolimus, sorafenib, and pazopanib. The arrowheads show regression of recurrent tumor in the operative field. Panel C shows a complete response in a 62-year-old patient with metastatic melanoma who received anti–PD-1 antibody at a dose of 3.0 mg per kilogram. Pretreatment computed tomographic scanning (i) revealed inguinal-lymph-node metastasis (arrowhead), which regressed completely after 13 months of treatment (ii). Numerous metastases in the subcutaneous tissue and retroperitoneum also regressed completely (not shown). Vitiligo, which developed after 6 months of treatment, is evident in photographs taken at 9 months under visible light (iii) and ultraviolet light (iv). Skin-biopsy specimens with immunohistochemical staining for micro-ophthalmia–associated transcription factor show that melanocytes (arrows) are abundant at the epidermal–dermal junction in normal skin (v), scarce in skin partially affected by vitiligo (vi), and absent in skin fully affected by vitiligo (vii). Panel D shows a partial response in a patient with metastatic non–small-cell lung cancer (nonsquamous histologic type) who received anti–PD-1 antibody at a dose of 10.0 mg per kilogram. The arrowheads show initial progression in pulmonary lesions, followed by regression (an immune-related pattern of response)
Figure 2
Figure 2. Pharmacodynamic and Molecular-Marker Assessments
Panel A shows PD-1–receptor occupancy by anti–PD-1 antibody. The graph at the left shows PD-1–receptor occupancy on circulating T cells in 65 patients with melanoma after one cycle (8 weeks) of treatment at a dose of 0.1 to 10.0 mg per kilogram every 2 weeks. Bars indicate median values. The graphs at the right show PD-1–receptor occupancy on CD3-gated peripheral-blood mononuclear cells from a patient with melanoma who received 0.1 mg per kilogram, before treatment (top) and after one treatment cycle (bottom). Cells were stained with biotinylated antihuman IgG4 to detect infused anti–PD-1 antibody bound to PD-1 molecules on the cell surface. Detection was accomplished with the use of streptavidin–phycoerythrin, followed by flow-cytometric analysis. Dashed lines indicate isotype staining controls, and solid lines antihuman IgG4. Panel B shows the correlation of pretreatment tumor cell-surface expression of PD-1 ligand (PD-L1), as determined with immunohistochemical analysis of formalin-fixed, paraffin-embedded specimens, with an objective response to PD-1 blockade in 42 patients with advanced cancers: 18 with melanoma, 10 with non–small-cell lung cancer, 7 with colorectal cancer, 5 with renal-cell cancer, and 2 with castration-resistant prostate cancer. Tumor cell-surface expression of PD-L1 was significantly correlated with an objective clinical response (graph at the left). No patients with PD-L1–negative tumors had an objective response. Of the 25 patients with PD-L1–positive tumors, 2 who were categorized as not having had a response at the time of data analysis are still under evaluation. Shown at the right are immunohistochemical analysis with the anti–PD-L1 monoclonal antibody 5H1 in a specimen of a lymph-node metastasis from a patient with melanoma (top), a nephrectomy specimen from a patient with renal-cell cancer (RCC) (middle), and a specimen of a brain metastasis from a patient with lung adenocarcinoma (bottom). The arrow in each specimen indicates one of many tumor cells with surface-membrane staining for PD-L1. The asterisk indicates a normal glomerulus in the nephrectomy specimen, which was negative for PD-L1 staining.

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