Keytruda® PD-1 Immunotherapy Treatment Improves Survival in Advanced Melanoma
by Dr. C.H. Weaver M.D. updated 8/2019
Keytruda (pembrolizumab) immunotherapy works by blocking the action of a protein called PD-1. Because PD-1 inhibits certain types of immune responses, drugs that block it may enhance the ability of the immune system to fight cancer. Keytruda was the first anti-PD-1 "checkpoint inhibitor" drug, aimed at re-energizing a patient’s protective immune response to cancer to receive FDA approval in the U.S.
Keytruda also appears to treat central nervous system disease and may ultimately be most effective when combined with other precision cancer medicines. Keytruda is also FDA approved as adjuvant therapy for earlier stage melanoma.(1-3)
Keytruda Effective Treatment in Advanced Melanoma-Keynote 006
Keytruda® outperformed Yervoy® (ipilimumab) as initial treatment of patients with advanced melanoma. Results of the KEYNOTE 006 trial updated at the 2017 annual meeting of the American Society of Clinical Oncology (ASCO) reported that Keytruda is associated with a 30% improvement in survival when used as initial treatment for advanced melanoma. In August 2019 another update was published in Lancet clearly demonstrated the long term superiority of Keytruda in prolonging survival.
With longer term follow up now beyond 5 years, Keytruda remains associated with a significant improvement in average overall survival doubling that achieved with Yervoy from 16 to 33 months.
The Phase III clinical trial known as KEYNOTE-006 directly compared Keytruda with Yervoy for the initial treatment of patients with advanced melanoma that could not be removed with surgery. Yervoy is a monoclonal antibody approved for the treatment of advanced melanoma that enhances the immune system’s response against tumor cells and was approved in 2011 for the treatment of melanoma. The 834 patients included in KEYNOTE-006 had no more than one previous systemic therapy (such as chemotherapy or biological agents).
Initial results of KEYNOTE 006 published in 2015 demonstrated that Keytruda was significantly more effective than Yervoy in both progression-free and overall survival. With these outcomes, Keytruda became the first anti-PD-1 therapy to demonstrate a survival advantage compared to the standard of care for the first-line treatment of advanced melanoma.
Overall 50% of patients treated with Keytruda were alive nearly three years after starting treatment compared to 39% of patients treated with Yervoy.(9)
Keytruda Active Against Brain Metastases
Brain metastases are a common cause of disabling neurologic complications and death in patients with metastatic melanoma and occur in up to 40% of patients. A recently reported clinical study in 23 patients with melanoma and one or more asymptomatic, untreated 5- to 20-mm brain metastases treated with Keytruda monotherapy found that 26% of the patients treated with Keytruda responded for an average of 24 months.
Cancer in the brain and the rest of the body responded in a similar manner suggesting the brain metastases were of similar biology to the rest of the cancer. The average overall survival was 17 months and ~ 50% of the patients survived 2 years or longer.
Doctors are now evaluating the use of dual immunotherapy as treatment for metastatic melanoma that has spread to the brain. Patients with brain metastases should discuss these options with their treating physician and explore newer combinations of immunotherapy being evaluated in clinical trials.(4)
Keytruda Combination Therapy
Keytruda may ultimately be more effective when used in combination with other precision cancer medicines or immunotherapies.
BRAF V600E mutated advanced melanoma patients survive longer without their cancer progressing when they are treated with a combination of two precision cancer medicines that block the BRAF mutation (dabrafenib and trametinib) and Keytruda.(5)
Keytruda + T-VEC
UCLA scientists have developed a potential new treatment that combines Keytruda with a herpes virus treatment called T-VEC (talimogene laherpareovec).
T-VEC is a genetically modified version of the herpes simplex virus that causes cold sores but is safe to use. T-VEC has already been approved for the treatment of melanoma and it works both by directly killing cancer cells and using a protein that attracts immune cells into the cancers.(6,7)
According to the study people whose melanoma does not respond to keytruda often lack a type of T cell called CD8+ in their tumors; the lack of CD8+ cells seems to prevent immunotherapy drugs from working. But the researchers believe those people might benefit from a combination therapy, because T-VEC attracts CD8+ immune cells to the tumors and keytruda allows them to attack the cancer cells.
The phase 1 clinical trial evaluated 21 people with advanced melanoma. Researchers injected patients’ melanoma tumors with T-VEC for six weeks and then gave them infusions of keytruda. Sixty-two percent of the patients had a partial or complete response, meaning that their tumors either shrank or were no longer detectable.
The combination therapy could provide an alternative treatment for people with melanoma whose tumors don’t respond to other therapies. It also being tested in people with head, neck and colon cancers.
Keytruda + Epacadostat
Epacdostat is a selective IDO1 enzyme inhibitor that when combined with Keytruda® appears promising. Epacadostat is an agent that blocks an enzyme called IDO1, which is implicated in the growth and spread of cancer cells. The immunosuppressive effects of indoleamine 2,3-dioxygenase 1 (IDO1) enzyme activity help cancer cells evade immunosurveillance. In single-arm studies, epacadostat combined with the PD-1 inhibitors Keytruda or Opdivo (nivolumab) improved response rates compared with studies of the immune checkpoint inhibitors alone.(8)
Epacadostat in combination with Keytruda appears well-tolerated in advanced melanoma patients. The average time to cancer progression was 12.4 months, and 70 percent, 54 percent, and 50 percent of individuals survived without evidence of cancer progression at 6 months, 12 months, and 18 months respectively. In patients who had never received treatment for advanced melanoma 52 percent survived without melanoma progression at 18 months from treatment and the average duration of survival had not been reached.
- Merck’s Pivotal KEYNOTE-006 Study in First-Line Treatment for Advanced Melanoma Met Co-Primary Endpoints and Will Be Stopped Early [press release]. Merck website. Available at: . Accessed April 8, 2015.
- Ribas A, Hodi FS, Kefford R, et al. Efficacy and safety of the anti-PD-1 monoclonal antibody MK-3475 in 411 patients (pts) with melanoma (MEL). J Clin Oncol 32:5s, 2014
- Lancet Oncol**. 2019 Jul 22. Epub ahead of print).**
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