Merck & Co.

Hayes Viewpoint

Prognosis for survival in patients with advanced or unresectable melanoma is poor, but is improving due to recent FDA-approved therapies that have transformed treatment approaches. These new therapies include intravenous (IV) immunotherapy with Yervoy (ipilimumab; Bristol-Myers Squibb), Opdivo (nivolumab; Bristol-Myers Squibb), and Keytruda. The new therapies also include the oral targeted agents Zelboraf (vemurafenib; Genentech Inc.), Mekinist (trametinib; GlaxoSmithKline), and Tafinlar (dabrafenib; GlaxoSmithKline).

Zelboraf, Mekinist, and Tafinlar are kinase inhibitors indicated to treat advanced or unresectable melanoma containing specific mutations in the v-raf murine sarcoma viral oncogene homolog B1 (BRAF) gene. Approximately 50% of patients with melanoma have tumors with a BRAF mutation (see links below to product labels). Keytruda and Opdivo are programmed death-1 (PD-1) immune checkpoint inhibitors. They were developed initially to address an unmet treatment need in patients whose disease does not adequately respond to new melanoma therapies. Both Keytruda and Opdivo are indicated to treat unresectable or metastatic melanoma in patients with disease progression after treatment with Yervoy and, if BRAF V600 mutation positive, a BRAF inhibitor. Yervoy is a cytotoxic T-lymphocyte antigen 4 (CTLA-4)-blocking antibody indicated to treat advanced or unresectable melanoma.

Keytruda was the first PD-1 receptor inhibitor approved for U.S. market. The FDA approved Keytruda on September 4, 2014, about 3 months before it approved Opdivo (see links below to product labels). Keytruda received an FDA accelerated approval based on tumor response rates and safety data from the phase I KEYNOTE-001 trial (NCT01295827). This approval is contingent upon phase III trials of Keytruda confirming clinical benefits such as prolonged survival or a delay in disease progression. A survival advantage or improvements in melanoma-related symptoms have not been established for Keytruda to date.

Keytruda and Opdivo are competing in the Yervoy-refractory advanced melanoma setting (see Prognosis Overview on Opdivo for Yervoy-Refractory Advanced Melanoma). It is unclear whether Keytruda offers a clear advantage over rival Opdivo in patients with Yervoy-refractory advance melanoma. A paucity of published evidence is available on the 2 PD-1 inhibitors, and no head-to-head trials have compared them to date. Of note, Opdivo developer Bristol-Myers Squibb filed suit in federal court on the day Keytruda received FDA approval, alleging that the development of Keytruda represents patent infringement by Merck & Co. Litigation is ongoing.

Keytruda is an innovative intravenous agent that stimulates an antitumor immune response by blocking PD-1 receptor activity. PD-1 is an immune checkpoint protein. Immune checkpoints are protective inhibitory pathways that regulate duration and degree of physiological immune responses. Research suggests that some tumors, including malignant melanoma, hijack specific immune checkpoint pathways, causing immune resistance, particularly against the type of immune cell that targets tumor cell antigens.

The FDA recommends that Keytruda be infused over 30 minutes at a dose of 2 mg/kg. Keytruda is given every 3 weeks until disease progression or unacceptable toxicity. Keytruda costs approximately $12,500 per patient monthly, about the same price as rival Opdivo. The cost of both drugs will vary depending upon patient weight and treatment duration.

Keytruda has potential for off-label use in Yervoy-naïve patients with unresectable or metastatic melanoma. The phase III KEYNOTE-006 trial (NCT01866319) evaluating Keytruda in this patient population was stopped early after meeting the 2 primary endpoints of progression-free survival and overall survival (see link below to trial registration). Keytruda may also be used off-label in combination with a kinase inhibitor; a clinical trial (KEYNOTE-022; NCT02130466) evaluating Keytruda, Mekinist, and Tafinlar combination regimens was recently launched in the U.S. Keytruda is also being developed to treat other advanced solid malignancies such as head and neck cancer, bladder cancer, renal cancer, and non-small cell lung cancer.

Approximately 76,100 people in the U.S. will be diagnosed with melanoma and approximately 9710 will die of the disease this year, according to the National Cancer Institute. The annual cost of melanoma treatment in the U.S. is estimated at $3.3 billion, according to a July 2014 report from the U.S. Office of the Surgeon General (see link below). Melanoma incidence in the U.S. increased at an average annual rate of 1.6% in men and 1.5% in women from 2002 to 2011. Incidence is highest among older people, but melanoma is now the third most common cancer in individuals aged 15 to 39 years.

Proposed Use

An intravenous programmed death-1 inhibitor to treat advanced melanoma that has progressed following therapy with Yervoy (ipilimumab).


The best available evidence on Keytruda for the treatment of Yervoy-refractory advanced melanoma is limited to published results of a KEYNOTE-001 trial expansion cohort (Robert et al., 2014; see link below). Also available are unpublished results of the KEYNOTE-002 trial that were presented in an oral presentation during conference proceedings (Dummer et al., 2015; see link below).


KEYNOTE-001 was a phase I dose escalation trial that primarily explored dose-limiting toxicities, adverse events (AEs), and tumor response in different patient populations with progressive locally advanced or metastatic melanoma or non-small cell lung cancer.


The open-label KEYNOTE-001 trial randomized an expansion cohort of adults with progressive unresectable melanoma previously treated with Yervoy to receive either Keytruda 2 mg/kg (n=89) or 10 mg/kg (n=84) every 3 weeks until disease progression or unacceptable toxicity. Patients with BRAF-mutant-positive melanoma were required to have also received prior therapy with an FDA-approved BRAF inhibitor. The primary efficacy endpoint was overall response rate (ORR), defined as the percentage of patients who achieved a complete or partial tumor response. Evaluation Criteria in Solid Tumors (RECIST) was used to measure ORR. At median 8-month follow-up, the ORR did not significantly differ between the 2 Keytruda treatment groups. In the Keytruda 2 mg/kg group (the FDA-approved dose), the ORR was 24% (21 of 89 patients), with 1 patient achieving a complete response. The median duration of response was not yet reached.


The overall safety profile did not statistically differ between the 2 Keytruda dose treatment groups. In the Keytruda 2 mg/kg group, 7% of patients discontinued treatment because of AEs. The most frequent AEs in this group were fatigue (33%), pruritus (23%), and rash (18%).


FDA approved in September 2014.


FDA Label for Yervoy (Revised March 2015)

FDA Label for Opdivo (Revised March 2015)

FDA Label for Keytruda (Revised September 2014)

FDA Label for Tafinlar (Revised January 2014)

FDA Label for Zelboraf (Revised November 2014)

FDA Label for Mekinist (Revised January 2014)

KEYNOTE-006 Trial Information

KEYNOTE-006 Trial Stopped Early (March 2015)

Surgeon General Call to Action to Prevent Skin Cancer (July 2014)

Robert et al. (2014)

Dummer et al. (2015)

KEYNOTE-022 Trial Information

Last Updated

April 2015

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