Merck issued the following announcement on June 13.
Merck (NYSE:MRK), known as MSD outside the United States and Canada, today announced that the U.S. Food and Drug Administration (FDA) has approved KEYTRUDA®, the company’s anti-PD-1 therapy, for the treatment of adult and pediatric patients with refractory primary mediastinal large B-cell lymphoma (PMBCL), or who have relapsed after two or more prior lines of therapy. This indication is approved under the FDA’s accelerated approval regulations 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 confirmatory trials. KEYTRUDA is not recommended for the treatment of patients with PMBCL who require urgent cytoreductive therapy. With this indication, KEYTRUDA becomes the first anti-PD-1 therapy to be approved for the treatment of PMBCL, a type of non-Hodgkin lymphoma. This is the second indication for KEYTRUDA for the treatment of a hematologic malignancy.
"Relapsed or refractory PMBCL is often a challenging disease to treat, and many affected patients are young adults,” said Philippe Armand, M.D., Ph.D., medical oncologist in the Hematologic Oncology Treatment Center at Dana-Farber Cancer Institute. “In the clinical trial that supported this approval, treatment with KEYTRUDA resulted in meaningful responses, including complete disease remission in some patients. This approval therefore provides another therapeutic option for patients with PMBCL who have progressed on or after prior therapies."
Immune-mediated adverse reactions occurred with KEYTRUDA, including pneumonitis, colitis, hepatitis, endocrinopathies, nephritis, severe skin reactions and solid organ transplant rejection. Based on the severity of the adverse reaction, KEYTRUDA should be withheld or discontinued and corticosteroids administered if appropriate. Immune-mediated complications, including fatal events, occurred in patients with classical Hodgkin lymphoma (cHL) who underwent allogeneic hematopoietic stem cell transplantation (HSCT) after treatment with KEYTRUDA. Follow patients closely for early evidence of transplant-related complications, and intervene promptly. In patients with a history of allogeneic HSCT, acute graft-versus-host disease (GVHD), including fatal GVHD, has been reported after treatment with KEYTRUDA; consider the benefit of KEYTRUDA versus the risk of GVHD. KEYTRUDA 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 KEYTRUDA. Based on its mechanism of action, KEYTRUDA 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. For more information, see “Selected Important Safety Information” below.
“The approval of our anti-PD-1 therapy, KEYTRUDA, for the treatment of refractory or relapsed PMBCL provides an important therapeutic option for patients who have this rare disease,” said Jonathan Cheng, M.D., vice president, oncology clinical research, Merck Research Laboratories. “This approval reinforces Merck’s commitment to helping patients diagnosed with hematologic cancers and marks the second indication for KEYTRUDA in a hematologic malignancy.”
Data Supporting the Approval
The approval was based on data from KEYNOTE-170, a multicenter, open-label, single-arm trial evaluating KEYTRUDA in 53 patients with relapsed or refractory PMBCL. Patients were not eligible for the trial if they had active non-infectious pneumonitis, allogeneic HSCT within the past five years (or greater than 5 years but with symptoms of GVHD), active autoimmune disease, a medical condition that required immunosuppression, or an active infection requiring systemic therapy. Patients received KEYTRUDA 200 mg every three weeks until unacceptable toxicity or documented disease progression, or for up to 24 months for patients who did not progress. Disease assessments were performed every 12 weeks and assessed by blinded independent central review according to the 2007 revised International Working Group criteria. Efficacy was based on overall response rate (ORR) and duration of response (DOR).
Among the 53 patients accrued in KEYNOTE-170, the baseline characteristics were: median age of 33 years (range, 20 to 61 years); 43 percent were male; 92 percent were White; 43 percent had an ECOG performance status (PS) of 0 and 57 percent had an ECOG PS of 1. The median number of prior lines of therapy administered for the treatment of PMBCL was three (range, 2 to 8). Thirty-six percent had primary refractory disease, 49 percent had relapsed disease refractory to the last prior therapy, and 15 percent had untreated relapse. Twenty-six percent of patients had undergone prior autologous HSCT and 32 percent of patients had prior radiation therapy. All patients had received rituximab as part of a prior line of therapy.
In KEYNOTE-170, the ORR was 45 percent (95% CI, 32, 60), with a complete response rate (CRR) of 11 percent and a partial response rate of 34 percent. Median DOR, based on 24 patients who responded, was not reached (range, 1.1+ to 19.2+ months). For the 24 responders, the median time to first objective response (complete or partial response) was 2.8 months (range, 2.1 to 8.5 months). Median follow-up time was 9.7 months.
Among the 53 patients with PMBCL treated in KEYNOTE-170, KEYTRUDA was discontinued due to adverse reactions in eight percent of patients, and treatment was interrupted due to adverse reactions in 15 percent. Twenty-five percent of patients had an adverse reaction requiring systemic corticosteroid therapy. Serious adverse reactions occurred in 26 percent of patients, and included arrhythmia (4%), cardiac tamponade (2%), myocardial infarction (2%), pericardial effusion (2%) and pericarditis (2%). Six (11%) patients died within 30 days of start of treatment. The most common adverse reactions (occurring in ≥20% of patients) were musculoskeletal pain (30%), upper respiratory tract infection and pyrexia (28% each), cough (26%), fatigue (23%) and dyspnea (21%).
There is limited experience with KEYTRUDA in pediatric patients. Efficacy for pediatric patients with PMBCL was extrapolated from the results in the adult PMBCL population. In a study of 40 pediatric patients with advanced melanoma, lymphoma, or PD-L1 positive advanced, relapsed, or refractory solid tumors, patients were administered KEYTRUDA 2 mg/kg every three weeks. Patients received KEYTRUDA for a median of three doses (range, 1-17 doses), with 34 patients (85%) receiving KEYTRUDA for two doses or more. The safety profile in these pediatric patients was similar to that seen in adults treated with KEYTRUDA. Toxicities that occurred at a higher rate (≥15% difference) in pediatric patients when compared to adults under 65 years of age were fatigue (45%), vomiting (38%), abdominal pain (28%), hypertransaminasemia (28%) and hyponatremia (18%).
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