Incidence of PD-1 inhibitor–related pneumonitis highest in NSCLC, renal cell carcinoma

PD-1 inhibitor–related pneumonitis occurred most frequently among patients with non–small cell lung cancer or renal cell carcinoma, according to results of a meta-analysis.

The incidence of this adverse event also appeared greater during treatment with combination therapy.

PD-1 inhibitors — including FDA–approved nivolumab (Opdivo, Bristol-Myers Squibb) and pembrolizumab (Keytruda, Merck) — are associated with unique toxicities known as immune-related adverse events. Pneumonitis is one such adverse event that, although rare, can be serious and life threatening.

Pneumonitis-related deaths have been reported in phase 1 trials, but a meta-analysis across trials of different disease types — representing use of the class of drug as monotherapy or in combinations — had not previously been conducted.

“Because this is a relatively rare adverse event, the knowledge based on the individual cohort data from each trial is limited,” Mizuki Nishino, MD, MPH, associate professor of radiology at Harvard Medical School and physician at Dana-Farber Cancer Institute, and colleagues wrote. “Given the increasing number of published reports of trial results of PD-1 inhibitors, such an investigation may provide important knowledge of this rare but clinically significant and potentially serious immune-related adverse event.”

Nishino and colleagues searched PubMed to identify 26 original articles with PD-1 inhibitor trial results published through Nov. 10, 2015. Twenty studies of melanoma (n = 12), NSCLC (n = 5) and renal cell carcinoma (n = 3) — representing 4,496 unique patients — were included in the analysis.

Incidence of all-grade and grade 3 or worse pneumonitis, as well as pneumonitis-related deaths, served as the main outcome measures.

The overall incidence of PD-1 inhibitor–related all-grade pneumonitis was 2.7% (95% CI, 1.9-3.6) and incidence of grade 3 or worse pneumonitis was 0.8% (95% CI, 0.4-1.2).

A greater proportion of patients with NSCLC than melanoma experienced all-grade (4.1% vs. 1.6%; P = .002) or grade 3 or worse (1.8% vs. 0.2%; P < .001) PD-1 inhibitor–related pneumonitis.

“A higher incidence of pneumonitis among patients with NSCLC may be because these patients are more prone to develop drug-related lung toxic effects because of their exposure to smoking and underlying lung conditions, including chronic obstructive pulmonary disease and pulmonary fibrosis,” the researchers wrote. “Existing tumor burden in the lung may also limit the lung tolerance to exogenous stress and injury.”

All-grade pneumonitis also occurred more frequently among patients with renal cell carcinoma than melanoma (4.1% vs. 1.6%; P < .001).

Researchers only observed pneumonitis-related deaths in four patients with NSCLC (0.4%; 95% CI, 0-0.3), all of whom received monotherapy treatment.

Researchers then evaluated the difference in incidence of pneumonitis with PD-1 inhibitors administered as a monotherapy or in combination with other agents for patients with melanoma; the combination studies were only conducted in the melanoma setting. Combinations evaluated included nivolumab plus ipilimumab (Yervoy, Bristol-Myers Squibb) or nivolumab plus peptide vaccines.

Overall, more patients who received combination therapy than monotherapy experienced all-grade (6.6% vs. 1.6%; P < .001) and grade 3 or worse (1.5% vs. 0.2%; P = .001) pneumonitis.

Results of a multivariable analysis adjusted for correlated incidence data and controlled for agents and trial phases showed that patients with NSCLC were more likely than patients with melanoma to experience any-grade pneumonitis (OR = 1.43; 95% CI, 1.08-1.89) and grade 3 or worse pneumonitis (OR = 2.85; 95% CI, 1.6-5.08). Patients with renal cell carcinoma were significantly more likely to experience any-grade pneumonitis (OR = 1.59; 95% CI, 1.32-1.92), but the risk was not elevated for grade 3 or worse pneumonitis.

Results also showed significantly increased risk with combination therapy compared with monotherapy for pneumonitis of any grade (OR = 2.04; 95% CI, 1.69-2.5) and grade 3 or worse (OR = 2.86; 95% CI, 1.79-4.25).

Limitations of the analysis include the relatively small number of studies available, as well as concerns about meta-analysis techniques regarding missing studies, heterogeneity of studies and use of aggregated patient data. The researchers acknowledged publication bias was present in the monotherapy data included, particularly in the NSCLC studies.

“In addition to the incidence of pneumonitis across a larger variety of immune-checkpoint inhibitors and tumor types, there remains a significant lack of knowledge of this entity in terms of its risk factors, diagnostic workup strategy, and optimal management guidelines,” Nishino and colleagues wrote. “We strongly believe that systematic investigations of a collection of individual cases of PD-1 inhibitor–related pneumonitis from multiple studies across different institutions will significantly contribute to characterize a full spectrum of clinical and radiographic manifestations of this entity and will serve as the first step to address these remaining clinically urgent questions.” – by Alexandra Todak

Disclosure: Nishino reports a research grant from Merck and paid consultant roles with Bristol-Myers Squibb, Toshiba Medical Systems and WorldCare Clinical. Please see the full study for a list of all other researchers’ relevant financial disclosures.