From the Journals

PD-1/PD-L1 treatment linked to hyperprogressive disease in lung cancer patients



Hyperprogressive disease is a new pattern of progression that may be more prevalent in patients with non–small-cell lung cancer receiving treatment with PD-1/PD-L1 inhibitors than in those receiving chemotherapy, results of a multicenter retrospective study suggest.

Nearly 14% of patients treated with PD/1/PD-L1 inhibitors had hyperprogressive disease in the study, compared with about 5% of patients treated with chemotherapy, the investigators reported.

This acceleration of tumor growth during therapy was associated with a high metastatic burden before treatment, and with a poor prognosis after treatment, wrote Benjamin Besse, MD, PhD, of the cancer medicine department at Gustave Roussy, Villejuif, France, and his colleagues.

Based on these findings, disease evolution should be carefully monitored to identify “hyperprogressors” among non–small-cell lung cancer (NSCLC) patients receiving PD-1/PD-L1 inhibitors, Dr. Besse and his colleagues said.

“Because of the poor overall survival associated with hyperprogressive disease, an early switch to salvage chemotherapy in these patients should be considered,” they wrote in JAMA Oncology.

This is believed to be the first study to look at incidence of hyperprogressive disease after PD-1/PD-L1 therapy specifically in NSCLC patients, and the first in any tumor type to include a chemotherapy treatment control group, according to Dr. Besse and his coauthors.

In one other recent report, hyperprogressive disease was seen in 9% of advanced cancers, and in a second recent investigation, it was seen in 29% of head and neck cancer patients, they said.

Although those proportions appear different, that could be due to differing interpretations of hyperprogressive disease, as there is no consensus on the optimal definition, they noted.

In this study, which included 406 patients with advanced NSCLC treated with PD-1/PD-L1 inhibitors and 59 treated with chemotherapy, hyperprogressive disease was defined as progressive disease observed at the first computed tomography scan and an absolute increase in tumor growth rate of 50% or more per month.

A total of 56 patients (13.8%) in the PD-1/PD-L1 treatment group met that definition for hyperprogressive disease, the investigators found. By comparison, three patients (5.1%) in the chemotherapy treatment group had hyperprogressive disease.

With a median follow-up of 12.1 months in the PD-1/PD-L1 group, the median overall survival was 13.4 months. Median overall survival for those with progressive disease was 6.2 months, and significantly lower at 3.4 months for those who had experienced hyperprogressive disease (P = .002), Dr. Besse and his coinvestigators found.

Moreover, 42.6% patients with progressive disease had two or more metastatic sites, compared with 62.5% of patients with hyperprogressive disease (P = .006), they reported.

The phenomenon of hyperprogressive disease might explain the initial excess in deaths seen in some phase 3 trials, Dr. Besse said in an interview posted on the JAMA Oncology website.

“In most of the second-line trials that compared single-agent immunotherapy to single-agent chemotherapy, overall survival curves crossed, meaning that there were an extra number of deaths in the immunotherapy arm,” he said in the interview. “That led us to evaluate the speed of progression.”

Based on the study results, Dr. Besse recommends early assessment by CT scan at 6 or 8 weeks after the start of immunotherapy. “If a patient has hyperprogressive disease, you don’t have much time to react,” he said. “You have to switch to a new treatment quite early.”

Dr. Besse reported receiving research funding from AstraZeneca, Boehringer, Bristol-Myers Squibb, Clovis Oncology, GlaxoSmithKline, Eli Lilly, Inivata, Merck Sharp & Dohme, Onxeo, OSE Pharma, Pfizer, Roche/Genentech, and Servier.

SOURCE: Ferrara R et al. JAMA Oncol. 2018 Sep 6. doi: 10.1001/jamaoncol.2018.3676.

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