August 2, 2018, by NCI Staff
In June, the Food and Drug Administration (FDA) further expanded the approved uses of the immunotherapy drug pembrolizumab (Keytruda). The two recent approvals cover the use of pembrolizumab for some women with advanced cervical cancer and for adults and children with relapsed or treatment-resistant primary mediastinal large B-cell lymphoma (PMBCL), a rare type of aggressive non-Hodgkin lymphoma.
Both actions by FDA were accelerated approvals, meaning further studies are needed to confirm the drug’s clinical benefit in patients with these cancers.
Pembrolizumab is a type of immunotherapy called an immune checkpoint inhibitor. It works by blocking the binding of PD-1, a protein expressed on cytotoxic T cells, to the PD-L1 protein expressed on some cancer cells, an interaction that acts as a brake on the immune system and prevents T cells from attacking the cancer.
First Approval of a PD-1 Inhibitor for Cervical Cancer
On June 12, FDA approved pembrolizumab to treat women with cervical cancer that has recurred or spread (metastasized) to other parts of the body and gotten worse during or after chemotherapy. The approval makes pembrolizumab the first immune checkpoint inhibitor approved to treat cervical cancer.
Under the approval, patients’ tumors must express PD-L1, as determined by an FDA-approved laboratory test. FDA simultaneously approved the PD-L1 IHC 22C3 pharmDx test (manufactured by Dako North America, Inc.), as a companion diagnostic test for women with cervical cancer.
The accelerated approval was based on results from a single cohort of 98 women with cervical cancer who were enrolled in an ongoing phase 2 clinical trial of pembrolizumab for the treatment of several cancer types. The trial, called Keynote-158, is sponsored by Merck, the drug’s manufacturer.
Of the 98 women, 77 had tumors that expressed PD-L1. Two of these women had their tumors disappear completely (complete responses) and nine had their tumors shrink by 30% or more (partial responses), for an overall response rate of 14.3%. In 10 of the 11 women who responded to pembrolizumab, the responses lasted 6 months or longer, and after nearly 12 months of follow-up, the median duration of response had not been reached. None of the women with PD-L1–negative tumors responded to pembrolizumab.
Nearly 40% of the women experienced serious side effects, including anemia (7%), fistula (4%), infection (4%), or hemorrhage (4%), and 8% of the patients had to stop treatment because of them. The most common side effects included fatigue, pain, nausea and vomiting, and difficulty breathing (dyspnea).
The current standard of care for women with cervical cancer that has recurred or metastasized after previous treatment is chemotherapy in combination with bevacizumab (Avastin). FDA approved the combination regimen in 2014 based on results of an sponsored randomized phase 3 trial showing a 3.7-month improvement in median overall survival with the addition of bevacizumab to chemotherapy.
The clinical trials that led to the approvals of bevacizumab and pembrolizumab for cervical cancer that recurs or spreads and worsens during or after chemotherapy had different designs and goals, so “it’s not possible to compare the two regimens given the data currently available,” said Elise Kohn, M.D., Gynecologic Cancer Therapeutics Lead in NCI’s Cancer Therapy Evaluation Program.
“We now have two very different approved therapeutic options for these patients,” she said, “so patients should discuss the pros and cons of each regimen with their physicians before deciding on their treatment.”
Dr. Kohn stressed that patients and clinicians need to weigh the risks of side effects when considering the treatment options.
“Although the patterns of toxicity are different, they are not insignificant for either option,” she explained.
New Treatment Option for Rare Lymphoma
On June 13, FDA approved pembrolizumab for the treatment of adult and pediatric patients with PMBCL that is resistant to available treatments (refractory) or returned following treatment with two prior therapies.
The accelerated approval was based on results from a multicenter single-arm phase 2 trial called Keynote-170. The trial, sponsored by Merck, included 53 patients between the ages of 20 and 61 with relapsed or refractory PMBCL.
Although there were no children in the trial, “efficacy for pediatric patients with PMBCL was extrapolated from the results in the adult PMBCL population,” according to a Merck news release, and safety was determined based on “a study of 40 pediatric patients with advanced melanoma, lymphoma, or PD-L1–positive advanced, relapsed, or refractory solid tumors” who were treated with pembrolizumab.
The overall response rate in the Keynote-170 trial was 45%, with 11% of patients achieving a complete response and 34% experiencing a partial response. At an average follow-up of nearly 10 months, the median duration of response had not yet been reached.
In its approval notice, FDA stated that pembrolizumab should not be used in patients who have an urgent need for surgery to reduce a PMBCL mass that may be compressing a major blood vessel or other critical structure within the mediastinum.
The most common side effects of pembrolizumab in the Keynote-170 trial included musculoskeletal pain, upper respiratory tract infection, fever, fatigue, and dyspnea. Serious side effects occurred in 26% of patients, causing 15% to interrupt therapy and 8% to discontinue treatment with pembrolizumab entirely. Twenty-five percent of patients had side effects that required treatment with corticosteroids.
“In the short follow-up thus far, there haven’t been signs of increased toxicity compared to other trials of PD-1 inhibitors,” said Mark Roschewski, M.D., of the Lymphoid Malignancies Branch in NCI’s Center for Cancer Research. “But PMBCL patients are often young and female, so longer follow-up will be important for these patients because their lifetime risk of developing autoimmune diseases is much higher” than older patients treated with PD-1 inhibitors, he emphasized.
The distinction between patients with refractory PMBCL after first-line therapy and those who have relapsed or still have refractory disease following two previous lines of therapy is important, said Dr. Roschewski. Patients who have not been cured despite two previous lines of therapy—the patients covered by this approval—have a very poor prognosis.
“These patients need better therapies,” he said. “Now that we have an approved drug in PMBCL, it opens the possibility of combination therapy studies, such as pembrolizumab and CAR T-cell therapy, for example.”