In a head-to-head comparison between the immunotherapy drug pembrolizumab and standard chemotherapy as a first-line therapy for advanced nonsmall cell lung cancer, patients taking pembrolizumab had a 50 percent greater drop in the risk of death or disease progression and a four-month greater increase in progression-free survival compared with those who took chemotherapy.
A report on these findings of an international clinical trial of 305 patients with stage 4 nonsmall cell lung cancer appeared Oct. 9 in The New England Journal of Medicine and is noted in today's Washington Post. What made the trial significant and novel, say the researchers, is that it included only people whose tumor cells were abundantly studded with so-called PD-L1 proteins.
“This is a group of patients we think should get anti-PD-1 therapy first before chemotherapy,” says Julie Brahmer, M.D., director of the Thoracic Oncology Program at the Johns Hopkins Kimmel Cancer Center co-director of the Upper Aerodigestive Program of the Bloomberg~Kimmel Institute for Cancer Immunotherapy. Pembrolizumab and another immunotherapy drug, nivolumab, are approved by the Food and Drug Administration to treat patients with advanced nonsmall cell lung cancer, but only after their cancers have progressed after treatment with chemotherapy.
Pembrolizumab, which is sold under the trade name Keytruda, blocks a molecular “handshake” between immune system T cells and cancer cells carrying PD-L1 proteins on their surface. With no handshake, T cells target the cancer cells for destruction.
Brahmer, who led the trial with a group of international scientists, says that another study showed little difference in progression-free survival of patients with nonsmall cell lung cancer who took a different PD-1 inhibitor compared with chemotherapy. “That study included nonsmall lung cancer patients with any level of PD-L1 protein on their tumors, but this study included only those with high levels of PD-L1 proteins on their tumor cells, whose tumors are more likely to respond,” says Brahmer. Some 23 to 28 percent of patients with advanced nonsmall cell lung cancer have high levels of PD-L1 proteins on their tumor cells. Nonsmall cell lung cancer accounts for more than 80 percent of an estimated 220,000 lung cancers diagnosed annually in the U.S.
For the study, funded by Merck, which makes pembrolizumab, tumor biopsy samples from 1,729 patients from 142 hospitals worldwide were evaluated by the researchers to determine which of them had more than 50 percent of tumor cells marked with PD-L1 proteins. From that group, 305 patients were randomly chosen to receive 35 intravenous doses of pembrolizumab over more than two years versus the standard treatment of four to six cycles over six months of one of five types of chemotherapy.
Among the two groups, 154 patients who received pembrolizumab had a median progression-free survival rate of 10.3 months, compared with six months for 151 patients on chemotherapy. Median follow-up was 11.2 months. The researchers estimated that patients who took pembrolizumab were 50 percent less likely to die from their cancer or have disease progression over the duration of the trial, which began in 2014. “Extending the time we can keep these patients’ cancer under control is an important step in creating more long-term survival,” says Brahmer.
The trial was stopped early because researchers’ interim analysis revealed the pembrolizumab’s benefit on progression-free survival. As a result, 66 patients who had received chemotherapy were switched to pembrolizumab, and more than half of them were still taking the drug at the end of the trial.
During the study, 108 patients died. One of the patients died after taking pembrolizumab potentially associated with that treatment, and three deaths were potentially caused by chemotherapy. The most common side effects in patients taking pembrolizumab were diarrhea, fatigue and fever. In patients taking chemotherapy, common side effects were anemia, nausea and fatigue.
“This study shows that immunotherapy can benefit some patients early on in their treatment, and our hope is that when we determine the best combinations of immunotherapy and targeted anticancer drugs, these patients may never need chemotherapy,” says Brahmer.
In her practice, Brahmer says treatment options for patients whose cancer progresses after taking pembrolizumab include clinical trials using combinations of immunotherapy drugs as well as chemotherapy.
Pembrolizumab’s cost can reach more than $100,000 annually for each patient, and Brahmer says her goal is to determine which groups of patients are more likely to benefit from it by itself. Plans are underway, she says, to study more closely the drug’s effectiveness in lung cancer patients whose cancers have lower levels of PD-L1 proteins.
Funding and materials for the study described in this press release were provided by Merck. Dr. Brahmer is also a paid consultant to Merck. This arrangement has been reviewed and approved by the Johns Hopkins University in accordance with its conflict of interest policies.
Researchers who contributed to the study include Martin Reck from the German Center for Lung Research; Delvys Rodriguez-Abreu from the Hospital Universitario Insular de Gran Canaria; Andrew Robinson from the Cancer Centre of Southeastern Ontario; Rina Hui from Westmead Hospital and the University of Sydney; Tibor Csoszi from the Jasz-Nagykun-Szolnok County Hospital; Andrea Fulop from Orszagos Koraanyi TBC es Pulmonologiai Intezet; Maya Gottfried from the Meir Medical Center; Nir Peled from the Davidoff Cancer Center; Ali Tafreshi from the Southern Medical Day Care Centre; Sinead Cuffe from the St. James’ Hospital and Cancer Trials Ireland; Mary O’Brien from the Royal Marsden Hospital; Suman Rao from MedStar Franklin Square Hospital; Katsuyuki Hotta from Okayama University Hospital; and Melanie Leiby, Gregory Lubiniecki, Yue Shentu and Reshma Rangwala from Merck.