Uncloaking Tumor Cells With Programmed-Death Receptor-1 Inhibitors

Scientists are using monoclonal antibodies to help the body fight off tumors in the same way that the body fights off infections. Monoclonal antibodies that target the interaction of programmed-death receptor-1 (PD-1) on T cells and its ligand (PD-L1) on tumor cells. Merck’s MK-3475 prevents the interaction of PD-1 and PD-L1, thereby inhibiting a mechanism by which some tumors avoid immune detection.

At least 2 anti—programmed-death receptor-1 (PD-1) medications, including nivolumab and MK-3475, are in development. Three more medications that work on a similar pathway—programmed-death receptor ligand-1 (PD-L1) inhibitors—are also in development, including BMS-936559, RG7446, and MEDI4736.¹

Under normal conditions, active T cells bind to the cell surface ligands on normal body tissues, PD-L1 and PD-L2. The PD-1 surface molecule on active T cells interacts with the PD-L1 receptors on epithelial cells. The interaction of these 2 proteins delivers signals that inhibit the destructive capacity of active T cells. This inhibitory signal protects healthy epithelial cells from T cell—mediated destruction of healthy tissue. PD-L1 is found in several body tissues, including hematopoietic cells, pancreatic islets, cardiac tissue, the endothelium, the small intestine, and the placenta, whereas PD-L2 is only found in macrophages and dendritic cells.¹

In patients with high levels of PD-L1 expressed by tumors of the lung, CD8+ cytotoxic T cells do not act against tumor cells due to the interaction of the PD-1 receptors located on T cells with abundant PD-L1 on tumor cells. The interaction of PD-1 receptors on active T cells with the PD-L1 receptors on tumor cells prevents the immune system from destroying tumor cells.²

In some cancers of epithelial cells, high levels of PD-L1 correlate with poor outcomes. Depending on how the measurement is made, PD-L1 is expressed at abnormal levels in 19% to 100% of non—small-cell lung cancer (NSCLC) tumors.² However, unlike other mutations that either exist or do not exist in tumor cells, PD-L1 expression in tumor cells may change over time.¹

Topalian et al treated 296 patients withvarious types of cancers using varying doses and regimens of the anti-PD-1 antibody nivolumab. Complete- or partial-responses occurred in 28% in patients with melanoma, 27% of patients with renal-cell cancer, and 18% of patients with NSCLC. In the same trial, of 25 patients with a PD-L1—positive test result, 9 patients experienced a complete or partial response to therapy, for an objective response rate of 36%. Zero of 17 patients with a PD-L1–negative result of biopsied tumor samples benefitted from therapy. The difference was statistically significant (P = .006).³

On October 29, 2013, at the World Conference on Lung Cancer in Sydney, Australia, it was reported that of patients with NSCLC receiving nivolumab at a range of dosages, 42% of patients survived 1 year and 24% of patients survived 2 years, with a median overall 9.9-month survival time. At the same conference, investigators from Merck presented data from a phase-Ib trial in 38 patients with NSCLC who had received MK-3475. Almost one-fourth (24%) of treated patients experienced an immune response, as judged by investigators, and just over one-fifth (21%) of patients responded to medication, as measured by Response Evaluation Criteria in Solid Tumors (RECIST) response criteria.⁴ Merck will begin a phase 2/3 trial comparing docetaxel therapy, which is the standard in patients with NSCLC lung cancer, against 2 different dosage regimens of MK-3475. Merck also plans to conduct trials of MK-3475, both as monotherapy, and as part of combination treatment for NSCLC.⁵

Of 38 patients with NSCLC treated with the humanized IgG4 anti—PD-1 antibody MK-3475, just over half of patients (53%) experienced an adverse event, including 3 of the most common adverse events: fatigue, rash, and pruritus. One case of grade-3 pulmonary edema did occur with MK-3475 treatment. Cases of pulmonary edema have also occurred in trials of nivolumab.⁵

In addition to investigations in NSCLC, Merck scientists are testing the efficacy of MK-3475 in 13 clinical trials and 30 types of cancer, including bladder cancer, colorectal cancer, gastric cancer, head and neck cancer, hematologic malignancies, and triple-negative breast cancer.⁵

Trials in progress (NCT01905657 and NCT01840579) are evaluating the effectiveness of MK-3475 in patients with relapsed or refractory NSCLC, and as part of an early combination treatment with chemotherapy. Both studies are currently recruiting participants.^6,7

References

• Ascierto PA, Kalos M, Schaer DA, Callahan MK, Wolchok JD. Biomarkers for immunostimulatory monoclonal antibodies in combination strategies for melanoma and other tumor types. Clin Cancer Res. 2013;19(5):1009-1020.
• Creelan BC. Update on immune checkpoint inhibitors in lung cancer. Cancer Control. 2014;21(1):80-89.
• Topalian SL, Hodi FS, Brahmer JR, et al. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med. 2012;366(26):2443-2454.
• National Cancer Institute. Imaging Response Criteria. imaging.cancer.gov/clinicaltrials/imaging. Accessed February 2014.
• PD-1 Inhibitors raise survival in NSCLC. Cancer Discov. 2013;4(1):6.
• Study of two doses of MK-3475 versus docetaxel in previously-treated participants with non-small cell lung cancer (MK-3475-010). http://clinicaltrials.gov/show/NCT01905657. Accessed February 2014.
• Study of MK-3475 monotherapy in participants with advanced solid tumors and MK-3475 combination therapy in participants with advanced non-small cell lung cancer (MK-3475-011 AM2). http://clinicaltrials.gov/show/NCT01840579. Accessed February 2014.