Keytruda® (pembrolizumab) was approved on September 4, 2014, for the treatment of patients with advanced, unresectable, or metastatic melanoma whose disease has progressed despite prior treatment with ipilimumab and (in those who have tested positive for a BRAF V600 mutation) a BRAF inhibitor. Melanoma accounts for about 5% of all cases of cancer in the United States. The National Cancer Institute estimates that in 2014 76,100 Americans will be diagnosed with melanoma and 9,710 will die of the disease.
The term melanoma refers to cancer that arises in melanocytes, the pigment cells of the skin. Skin, the largest organ of the body and our first line of defense against invasion by pathogens, is protected, not surprisingly, by multifactorial immune mechanisms that play a major role in the immune response to cancer. Many genetic mutations that characterize some cancers lead to the expression of new antigens, which may be recognized as foreign by the immune system. T lymphocytes play a central role in this immune process, as they are able to recognize and to attack specific cancer cells. However, cancer can often successfully disguise itself, and T cells can also be down-regulated to fail to recognize and attack cancer cells, depending on the balance of stimulatory versus inhibitory signals that they receive. Older immunotherapies such as vaccines, interferon-α, and interleukin (IL)-2 have demonstrated only moderate efficacy against most cancers and are associated with significant toxicities. Recently, however, through better understanding of T-lymphocyte co-stimulatory and co-inhibitory molecular signaling interactions, an immunotherapeutic approach to controlling cancer is becoming a reality.
CTLA-4 and PD-1 surface receptors on T cells represent the first two such immuno-therapeutic molecular checkpoints studied in cancer research. Preventing these receptors from binding with their ligands prevents inhibition of their respective T cells, allowing these T cells to attack cancer cells. In 2011, ipilimumab became the first CTLA-4 inhibitor approved to treat melanoma. It was the first agent to ever demonstrate a survival benefit in metastatic melanoma. Patients with melanoma who achieved durable responses in ipilimumab clinical trials survived 1.5 to 2 years and 18% had longer survival, with some patients surviving for many years. However, CTLA-4 blockade works at only one level: it promotes initial T-cell activation. PD-1 activity likely plays immunoregulatory roles at multiple levels.
Predominantly, PD-1 regulates T-lymphocyte effector killer activity distally as opposed to centrally in tissues and tumors, but PD-1 is also expressed on other activated immune cells such as B lymphocytes and natural killer cells. PD-1 ligands are expressed on numerous types of tumors, most commonly on solid tumors, including those associated with melanoma and ovarian, lung, and renal cancers. PD-1 ligands have also been reported to be upregulated in various lymphomas. Thus, the 2 components of the PD-1 signaling pathway hold significant therapeutic target potential.
The Food and Drug Administration (FDA) granted Keytruda priority review, breakthrough therapy, and orphan product designations as the first PD-1 blocker. The month following the approval of Keytruda for the treatment of melanoma, Merck announced that Keytruda had also been granted a breakthrough therapy designation for the treatment of patients with epidermal growth factor receptor (EGFR) mutation–negative, anaplastic lymphoma kinases (ALK) rearrangement–negative non–small cell lung cancer with disease progression following platinum-based chemotherapy. Keytruda is being studied across more than 30 cancer types, both as monotherapy and in combination with other agents. In advanced lung cancer, Merck is conducting clinical studies in several tumor types of various histologies and examining tumor characteristics, such as expression of PD-1 ligand as predictors of responsiveness.
Contributed by William Yarnall, RPh, CCP
Medical Writer, Connexion Healthcare