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FDA approves Keytruda for relapsed, refractory classical Hodgkin lymphoma
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The FDA approved pembrolizumab for adults and children with classical Hodgkin lymphoma who are refractory to treatment or who have relapsed after three or more prior lines of therapy, according to the drug’s manufacturer.
Pembrolizumab (Keytruda, Merck) is the only anti–PD-1 therapy approved for the treatment of classical Hodgkin lymphoma regardless of prior hematopoietic stem cell transplantation or therapy with brentuximab vedotin (Adcetris, Seattle Genetics).
The approval is based, in part, on data from the KEYNOTE-087 trial, which included 210 patients who received 200 mg pembrolizumab every 3 weeks. Fifty-eight percent of patients were refractory to their last therapy, including 35% who had primary refractory disease and 14% whose disease was chemotherapy refractory to all prior regimens. Sixty-one percent of patients had undergone prior HSCT, 17% had no prior brentuximab use and 36% had prior radiation therapy.
Median follow-up was 9.4 months. Results showed an ORR of 69% (95% CI, 62-75), which included a complete remission rate of 22% and a partial remission rate of 47%.
Median duration of response among the 145 responders was 11.1 months (range, 0+ to 11.1).
“The results from KEYNOTE-087 showed that most patients with relapsed or refractory classical Hodgkin lymphoma responded to treatment with Keytruda, and 22% experienced complete remission,” Roger M. Perlmutter, MD, PhD, president of Merck Research Laboratories, said in a company-issued press release. “Today’s approval — the first for Keytruda in a hematologic malignancy — reinforces the hope that immunotherapy will prove useful in a wide variety of cancers.”
Five percent of patients discontinued therapy due to adverse events and 26% experienced treatment interruption. Fifteen percent of patients had an adverse event that required systemic corticosteroid therapy. The most common adverse events included fatigue (26%), pyrexia (24%), cough (24%), musculoskeletal pain (21%), diarrhea (20%) and rash (20%).
Serious adverse events occurred in 16% of patients, the most frequent of which included pneumonia, pneumonitis, pyrexia, dyspnea, graft-versus-hosts disease (GVHD) and herpes zoster. Two patients died of causes other than disease progression: one of GVHD after subsequent allogeneic HSCT and one of septic shock.
Data on pediatric patients are limited and efficacy was extrapolated from the results in the adult trial. In another study, 40 children with advanced melanoma; PD-L1–positive advanced, relapsed or refractory solid tumors; or lymphoma received pembrolizumab for a median of 43 days (range, 1-414 days), with 24 patients (60%) receiving treatment for 42 days or more.
The drug’s safety profile appeared comparable among adults and children. Toxicities that occurred at a 15% or greater rate in children than adults included fatigue (45%), vomiting (38%), abdominal pain (28%), hypertransaminasemia (28%) and hyponatremia (18%).
“For the patients with classical Hodgkin lymphoma who are not cured with existing treatments, there are limited options, and treating their disease becomes more challenging,” Craig H. Moskowitz, MD, clinical director in the division of hematologic oncology at Memorial Sloan Kettering Cancer Center and a HemOnc Today Editorial Board member, said in the release. “This approval is an important step forward in treating these patients, who are generally young and have a particularly poor prognosis, and gives us the opportunity to help patients in their fight against this devastating disease.”
Perspective
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Joshua Brody, MD
Prior to the development of anti–PD-1 antibodies, these patients have had a poor prognosis.
Standard chemotherapy can cure up to 70% of newly diagnosed patients with classical Hodgkin lymphoma, and for those who are not cured, high-dose chemotherapy with stem cell transplant may cure about half. When these therapies did not work in the past, we thought of these patients as having incurable disease. Some of these newer therapies may change that.
Brentuximab vedotin (Adcetris, Seattle Genetics) — approved in 2011 — is helpful, but disease recurs in most patients. The great context is that this cancer — as opposed to most cancers — afflicts young adults in their 20s and 30s. Because of the advances made in the 1980s with chemotherapy, these patients are frequently told, “Don't worry, we'll be able to cure this disease.” Although it is true for many patients, it is especially emotionally terrifying for the remaining patients to then hear, “We told you that we would likely cure you, but now the therapies are failing.” Therefore, new approaches like immune therapy are especially needed for these young patients.
The benefit of anti–PD-1 antibodies is twice as great for Hodgkin lymphoma as for melanoma, and three times better for lung cancer. The reason is somewhat obvious: Hodgkin lymphoma expresses more of the receptor PD-L1 than other cancers.
If PD-1 is a brake pedal on immune cells, the PD-L1 is the “foot” that presses the brakes. Hodgkin lymphoma cells are genetically programmed to express a lot of PD-L1; they have made many photocopies of the PD-L1 gene. So, these tumors rely on being safe from immune cells, because they built it into their DNA. Once we free up the immune cells — or block the foot from hitting the brake — the immune system becomes quite good at killing these tumors cells.
Other types of tumors sometimes express PD-L1, but it’s not usually built into their DNA. Rather, they just learn how to express it over time as they learn to evade the immune system.
This type of immunotherapy is remarkably effective in Hodgkin lymphoma and quite effective in several other cancers but, overall, it only results in long-term benefit in a minority of patients with cancer.
So, the future of this approach is to understand how we can combine this immunotherapy with other immunotherapies or standard therapies, like radiation therapy, targeted therapy or chemotherapy. This is a primary focus of cancer immunotherapy research — in the lab and in patients — as we see that some combinations are synergistic. Even when the two therapies have minimal benefit alone, they can have a drastically increased anticancer effect when combined.
One example of this is some newly developed anticancer vaccines which, in the lab, eliminate a minority of tumors. However, when combined with anti–PD-1 antibodies, they eliminate nearly all tumors. Such combination therapies are coming into clinical trials this year. Unfortunately, only a very small number of cancer patients get enrolled into such trials, primarily because they do not hear about them.
This type of immunotherapy is arguably the greatest recent breakthrough for patients with this type of lymphoma. The therapy allowed more than two-thirds of patients’ immune systems to drastically shrink their tumors and almost one-quarter of patients' tumors disappeared completely on follow-up scans.
Although this type of immunotherapy is helpful in patients with several types of cancer — including lung cancer, kidney cancer and melanoma — the benefit seen in patients with Hodgkin lymphoma is strikingly greater than any of these. This great result is just an early step in learning how to allow patients’ immune systems to completely eliminate cancers of all types.
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