Pembrolizumab: The First to the FDA Approval Finish Line!

Pembrolizumab (Keytruda) became the leader of the PD-1 and PD-L1 antibody pack by crossing the finish line first, and successfully being granted accelerated FDA approval in September 2014 based on tumor responses and durability of the responses seen in early clinical trials.

Pembrolizumab (Keytruda) became the leader of the PD-1 and PD-L1 antibody pack by crossing the finish line first, and successfully being granted accelerated FDA approval in September 2014 based on tumor responses and durability of the responses seen in early clinical trials. 

The drug was formerly known as MK-3475 or lambrolizumab, and now is approved at a dose of 2 mg/kg given over 30 minutes, every 3 weeks.  This particular drug is approved for use in patients with advanced melanoma who have progressed on ipilimumab and BRAF-directed therapy if the patient is positive for the V600E or V600K mutation.

The role of the immune system, specifically T-cell activation, in the pathophysiology of melanoma has been well known for many years, and is based on reports of spontaneous regression of melanoma lesions as well as long remission periods between initial localized disease resection and appearance of metastatic lesions.  Upregulation of the immune system is the goal of interferon and high-dose IL-2 (HD IL-2) therapy in melanoma.  Even with the serious immune side effects seen with HD IL-2, especially capillary leak syndrome necessitating hospital admission and close blood pressure monitoring, it remains a therapy options for very fit patients because of the rare, but durable responses seen in 5% to 10% of patients.   

Harnessing the immune system in more successful, less toxic ways has been an ongoing goal in melanoma research. This in turn has produced the first-in-class anti-CTLA-4 inhibitor, ipilimumab, which gained FDA approval in 2011 for unresectable or metastatic melanoma, and has produced durable responses in about 20% of patients. 

Cytotoxic T-lymphocyte-associated-antigen-4 (CTLA-4) is a protein on the surface of T-cells that is upregulated after T-cell activation, and negatively regulates the T-cell when bound to the costimulatory molecule, B7.1 In a simple way, activation of CTLA-4 puts the breaks on the T-cell.  By blocking CTLA-4 with ipilimumab, the T-cell remains active.  Because of this immune regulation, immune-related adverse events (irAE) are common.  The toxicity profile is more tolerable than high-dose IL-2, allowing for more patients to be candidates for the treatment; however, 10% to 15% of patients still experience grade 3 or 4 irAE.

In contrast to working at the T-cell level and causing immune-related adverse events system wide, the mechanism of action of PD-1 inhibitors are more focused at the level of the tumor, which also results in a more favorable side effect profile. 

Programmed death receptor-1 (PD-1) is expressed by T-cells after they have been exposed to an antigen for a long period of time.  PD-L1 is expressed on the tumor cell.  Binding of PD-L1 to PD-1 also results in negative regulation of the T-cell and allows the tumor to evade the immune system.  By blocking either PD-1 or PD-L1, the T-cell continues to stay on and can recognize the tumor.1 It's like the tumor putting on an invisibility cloak and hiding from the immune system.  PD-1 or PD-L1 inhibitors remove this invisibility cloak and reveal the tumor to the immune system.   The PD-1 and PD-L1 inhibitors gained excitement following an initial publication in the New England Journal of Medicine in June 2012.  BMS-936558 (now known as nivolumab) is another anti-PD-1 antibody that demonstrated cumulative response rates in 28% of advanced melanoma patients with many responses lasting 1 year or longer. 2

The trial that led to the approval of pemrbolizumab was a randomized dose-comparison cohort of the phase I trial.  One hundred and seventy-three patients with advanced melanoma whose disease had progressed after at least 2 doses of ipilimumab were randomly assigned to either 2 mg/kg or 10 mg/kg, every 3 weeks until disease progression or toxicity.  After a median follow up of 8 months, the primary endpoint of response rate was seen in 26% of patients treated at both dose levels.  The median response duration was not reached in either dosing group, ranging from greater than 6 weeks to greater than 37 weeks.  The safety profile between the two dose levels was also similar with the most common grade toxicities being: fatigue (33% in the 2 mg/kg vs. 37% in the 10 mg/kg), pruritis (26% in the 2 mg/kg  vs. 19% in the 10 mg/kg ) and rash (18% in both groups).3  

More than 40 trials involving different PD-1 inhibitors are currently recruiting, and numerous others have completed accrual with results pending.  Current clinical questions center on optimal combinations of therapy and sequencing of the treatment options available for melanoma, especially for BRAF (V600E) mutation-positive patients. 



  • Ribas A. (2012).Tumor immunotherapy directed at PD-1.  N Engl J Med. Jun 28; 366(26):2517-9.
  • Topalian SL, et al. (2012). Safety, Activity, and Immune Correlates of Anti-PD-1 Antibody in Cancer.  N Eng J Med.  Jun 28; 366:2443-2454.
  • Robert C, et al. (2014). Anti-programmed-death receptor-1 treatment with pembrolizumab in ipilimumab-refractory advanced melanoma: a randomised dose-comparison cohort of a phase I trial.  The Lancet. Sep 20; 384:1109-1117.