The FDA ( U.S. Food and Drug Administration ) has approved Keytruda ( Pembrolizumab ), the anti-PD-1 ( programmed death receptor-1 ) therapy, for the treatment of adult and pediatric patients with refractory classical Hodgkin lymphoma ( cHL ), or who have relapsed after three or more prior lines of therapy.
Under the FDA’s accelerated approval regulations, this indication is approved based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.
In refractory or relapsed classical Hodgkin lymphoma, Keytruda is approved for use in adult patients at a fixed dose of 200 mg and in pediatric patients at a dose of 2 mg/kg ( up to a maximum of 200 mg ).
Keytruda is administered intravenously every three weeks until disease progression or unacceptable toxicity, or up to 24 months in patients without disease progression.
Immune-mediated adverse reactions occurred with Pembrolizumab including pneumonitis, colitis, hepatitis, endocrinopathies, and nephritis.
Based on the severity of the adverse reaction, Pembrolizumab should be withheld or discontinued and corticosteroids administered when appropriate.
Immune-mediated complications, including fatal events, occurred in patients with classical Hodgkin lymphoma who underwent allogeneic hematopoietic stem cell transplantation ( HSCT ) after being treated with Pembrolizumab.
Follow patients closely for early evidence of transplant-related complications, and intervene promptly.
Pembrolizumab can also cause severe or life-threatening infusion-related reactions. Monitor patients for signs and symptoms of infusion-related reactions; for grade 3 or 4 reactions, stop infusion and permanently discontinue Pembrolizumab.
Based on its mechanism of action, Pembrolizumab can cause fetal harm when administered to a pregnant woman. Female patients of reproductive potential should be advised of the potential hazard to a fetus.
The approval is based on data in 210 patients from the KEYNOTE-087 trial, which demonstrated an overall response rate ( ORR ) with Keytruda ( 200 mg every three weeks ) of 69% ( 95% CI: 62, 75 ) with a complete remission rate ( CRR ) of 22% and a partial remission rate ( PRR ) of 47%.
The median follow-up time was 9.4 months.
Among the 145 responding patients, the median duration of response was 11.1 months ( range 0.0+ to 11.1 months ).
The accelerated FDA approval was based on data in 210 patients with relapsed or refractory classical Hodgkin lymphoma enrolled in the multicenter, nonrandomized, open-label KEYNOTE-087 study.
Patients with active, non-infectious pneumonitis, an allogeneic HSCT within the past five years ( or greater than five years but with symptoms of GVHD [ graft-versus-host disease ] ), active autoimmune disease, a medical condition that required immunosuppression, or an active infection requiring systemic therapy were ineligible for the trial.
Patients received Keytruda at a dose of 200 mg every three weeks until unacceptable toxicity or documented disease progression, or for up to 24 months in patients who did not progress.
The major efficacy outcome measures ( ORR, CRR, and duration of response ) were assessed by blinded independent central review according to the 2007 revised International Working Group ( IWG ) criteria.
Fifty-eight percent of patients were refractory to the last prior therapy, including 35% with primary refractory disease and 14% whose disease was chemo-refractory to all prior regimens.
Additionally, 61% of patients had undergone prior auto-HSCT, 17% had no prior Brentuximab use, and 36% had prior radiation therapy.
Keytruda was discontinued due to adverse reactions in 5% of 210 patients with classical Hodgkin lymphoma and treatment was interrupted due to adverse reactions in 26% of patients.
Fifteen percent of patients had an adverse reaction requiring systemic corticosteroid therapy. Serious adverse reactions occurred in 16% of patients.
The most frequent serious adverse reactions ( greater than or equal to 1% ) included pneumonia, pneumonitis, pyrexia, dyspnea, GVHD, and herpes zoster.
Two patients died from causes other than disease progression; one from GVHD after subsequent allogeneic HSCT and one from septic shock.
The most common adverse reactions ( occurring in greater than or equal to 20% of patients ) were fatigue ( 26% ), pyrexia ( 24% ), cough ( 24% ), musculoskeletal pain ( 21% ), diarrhea ( 20% ), and rash ( 20% ).
There is limited experience in pediatric patients. Efficacy for pediatric patients was extrapolated from the results in the adult cHL population.
In a study of 40 pediatric patients with advanced melanoma, PD-L1–positive advanced, relapsed, or refractory solid tumors or lymphoma, patients were treated with Keytruda for a median of 43 days ( range 1-414 days ), with 24 patients ( 60% ) receiving treatment for 42 days or more.
The safety profile in pediatric patients was similar to that seen in adults treated with Keytruda. Toxicities that occurred at a higher rate ( greater than or equal to 15% difference ) in these patients when compared to adults under 65 years of age were fatigue ( 45% ), vomiting ( 38% ), abdominal pain ( 28% ), hypertransaminasemia ( 28% ), and hyponatremia ( 18% ).
Pembrolizumab is a humanized monoclonal antibody that works by increasing the ability of the body’s immune system to help detect and fight tumor cells. It blocks the interaction between PD-1 and its ligands, PD-L1 and PD-L2, thereby activating T lymphocytes which may affect both tumor cells and healthy cells.
Keytruda is administered as an intravenous infusion over 30 minutes every three weeks for the approved indications. Keytruda for injection is supplied in a 100 mg single-dose vial. ( Xagena )
Source: Merck, 2017