George F. Geils, Jr, MD
The treatment paradigm for patients with classical Hodgkin lymphoma (cHL) continues to evolve as new agents are explored and existing therapies are moved to earlier treatment settings. These adjustments call for renewed focus on existing agents and indications, to fully realize the potential for these medications.
During a lunch session at the 2nd Annual Live Medical Crossfire on Hematologic Malignancies, George F. Geils, Jr, MD, described the clinical efficacy and adverse event management techniques for pembrolizumab (Keytruda) as a treatment for patients with cHL. Of the most important distinctions, Geils noted that pembrolizumab is specifically approved following 3 prior regimens, and that prior stem cell transplant is not a criterion for use.
"It's the 20% of patients who we aren't curing with frontline therapy who are a topic of discussion," said Geils, medical director for the Blood and Marrow Transplant Program for Roper St. Francis Healthcare. "In contrast with the other approved PD-1 inhibitor [nivolumab], Keytruda does not require prior transplantation."
The FDA granted pembrolizumab an accelerated approval in 2017 as a treatment for adult and pediatric patients with cHL who are refractory or have relapsed after 3 or more lines of therapy. The approval was based on findings from the nonrandomized, open-label KEYNOTE-087 trial, which included 210 adult patients with relapsed/refractory cHL.
In the study, the median age was 35 (range, 18-76) and 9% of patients were older than 65. Fifty-four percent of patients were male and 88% were white. The ECOG performance status was 0 for 49% of patients and the remainder had a score of 1. The median number of prior therapies was 4 (range, 1-12). Prior treatment included brentuximab vedotin (Adcetris; 83%), autologous hematopoietic stem cell transplantation (61%), and radiation therapy (36%).
At a median follow-up of 9.4 months, the overall response rate (ORR) with pembrolizumab was 69% (95% CI, 62%-75%). There was a complete response for 22% of patients and a median duration of response of 11.1 months (range, 0+ to 11.1) among the 145 responding patients.
"This drug can work, and work well," Geils said. "I saw a patient who was referred prior to transplantation. Initially, he had a partial response to a gemcitabine regimen. He'd had anthracycline exposure, and then he had brentuximab vedotin with no response. He went on pembrolizumab and had a complete response. This patient is now 11 months into therapy and remains in complete remission."
The most common non-hematologic adverse events with pembrolizumab were fatigue (26%), pyrexia (24%), cough (24%), musculoskeletal pain (21%), diarrhea (20%), and rash (20%). Adverse events occurring in at least 10% of patients included dyspnea, arthralgia, vomiting, nausea, pruritus, hypothyroidism, upper respiratory tract infections, headache, peripheral neuropathy, hyperbilirubinemia and increased creatinine.
Serious adverse reactions occurred in 16% of patients. The most frequent serious adverse events included pneumonia, pneumonitis, pyrexia, dyspnea, GVHD, and herpes zoster. Adverse events requiring corticosteroid therapy occurred in 15% of patients.
"These grade 2 toxicities are real and we need to monitor for them," said Geils. "The issue of course in these toxicities is when a patient with Hodgkin disease, who is already immunocompromised, presents with dry cough and some infiltrates, it could just as well be atypical pneumonitis, infectious viral colitis, or C. diff. There are so many confounding things that can mimic a drug effect."
"What you don't want to do is not consider a drug effect," he added. "Rapidly rule out the other causes, and start steroids until you can rule out these other causes, so that it does not become more severe."
In the study that led to approval, adverse reactions led to discontinuations and treatment interruptions in 5% and 26% of patients, respectively. There were 2 patient deaths that were both unrelated to disease: 1 patient died of septic shock and 1 patient died of GVHD after subsequent allogeneic hematopoietic stem cell transplantation. These deaths were reflected in the warning and precaution section of the medication's label, calling for close monitoring for transplant-related complications.
"It's hard to keep the different drugs and different management techniques straight. With regard to Keytruda, when a patient has a grade 2 reaction or great, hold the drug until it resolves to grade 1 or less, then you can resume Keytruda," Geils said. "If it's grade 3 or 4, then don't resume that drug. That's the bottom line."<<< More Hematologic Malignancies Medical Crossfire News