Hyperprogression in NSCLC Patients With PD-1/PD-L1 Inhibitors

Hyperprogressive disease (HPD) occurred more commonly among patients with pretreated non-small cell lung cancer (NSCLC) receiving PD-1 (programmed cell death protein 1)/PD-L1 (ligand 1) inhibitors than in patients treated with chemotherapy, according to the results of a study published in JAMA Oncology.

Among those patients with hyperprogressive disease – defined as disease progression at first evaluation with a variation per month exceeding 50% – treated with immunotherapy there was a higher metastatic burden and poorer prognosis, compared with patients without hyperprogressive disease.

According to researchers led by Roberto Ferrara, MD, of the Cancer Medicine Department, Gustave Roussy, Villejuif, France, these data suggest “a detrimental association of immunotherapy in a subset of patients with NSCLC” and hyperprogressive disease could “potentially explain the initial excess death in some phase III trials.”

Ferrara and colleagues undertook this study to explore whether hyperprogressive disease is an unforeseen pattern of progression that occurs in patients with NSCLC who undergo immunotherapy. The retrospective study included 406 patients treated with PD-1/PD-L1 inhibitors from 8 institutions and 59 patients treated with single-agent chemotherapy from 4 institutions. The researchers calculated tumor growth rate both before and during treatment and the variation per month.

Among patients treated with immunotherapy, the median follow-up was 12.1 months. More than 40% of patients had progressive disease as the best response to immunotherapy. The median progression-free survival (PFS) was 2.1 months and the median overall survival (OS) was 13.4 months.

Prior to immunotherapy, 18.5% of patients had a tumor growth rate of 0 or less. During immunotherapy, 65.5% of patients had a stable or decreasing tumor growth rate, and 34.5% had an increasing tumor growth rate. Hyperprogressive disease was found in 13.8% of patients.

Having hyperprogressive disease was associated with more than two metastatic sites prior to immunotherapy compared with non-hyperprogressive disease disease (62.5% vs 42.6%; P = .006). In addition, those patients who had hyperprogressive disease within the first 6 weeks of immunotherapy had a lower OS compared with other patients with progressive disease (median OS 3.4 months vs 6.2 months; P = .003).

In the patients treated with single-agent chemotherapy, the median follow-up was 26.3 months. About one-third (30.5%) of patients had progressive disease as their best response. The median PFS was 3.9 months and the median OS was 8.6 months. In this group, 3 patients had hyperprogressive disease. The median OS was 4.5 months in patients with hyperprogressive disease treated with chemotherapy compared with 3.9 months in patients without hyperprogressive disease treated with chemotherapy.

“Although in some immunotherapy trials the first CT scan was performed at week 9, the fact that HPD drives toward early death (mainly in the first 6 weeks of treatment) prompts discussion over an anticipated first radiological evaluation during PD-1/PD-L1 inhibitor therapy to properly identify hyperprogressors,” the researchers wrote. “Ultimately, because of the poor OS associated with

HPD, an early switch to salvage chemotherapy in these patients should be considered.”