PD-1 Inhibitor-Related Pneumonitis Risk Highest For NSCLC, RCC Patients

Programmed cell death 1 inhibitor-associated pneumonitis patient risk groups identified

medwireNews: Patients with non-small-cell lung cancer (NSCLC) or renal cell carcinoma (RCC) have a higher risk of developing pneumonitis related to programmed cell death 1 (PD-1) inhibition than those with melanoma, a meta-analysis demonstrates.

Patients who receive nivolumab PD-1 inhibitor therapy concurrently or sequentially with the CTLA-4 inhibitor ipilimumab or a peptide vaccine also have an increased risk of the side effect compared with patients given nivolumab monotherapy, the study authors report in JAMA Oncology.

“The underlying reasons for these observations remain to be further investigated; however, the results again demonstrate the different susceptibilities of developing PD-1 inhibitor–related pneumonitis among patients with different tumor types and varying effect on their clinical course and outcome”, they write.

The review included 4496 patients participating in one of five NSCLC studies, three RCC studies or 12 melanoma trials of pembrolizumab or nivolumab, of whom 2.7% developed any grade of pneumonitis and 0.8% grade 3 or more severe pneumonitis.

Both NSCLC patients and RCC patients had significantly higher rates than melanoma patients for all-grade pneumonitis (4.1 and 4.1 vs 1.6%, respectively), while NSCLC patients also had a significantly higher rate of grade 3 or higher pneumonitis than melanoma trial participants (1.8 vs 0.2%).

Patients who received combination therapy also had a significantly increased risk of all-grade and grade 3 or more severe pneumonitis than those given PD-1 inhibitor monotherapy, at 6.6% versus 1.6% and 1.5% versus 0.2%, respectively.

After adjusting for a range of confounding factors, including agents and trial phases, NSCLC was confirmed as a significant and independent predictor of both all-grade and grade 3 and higher pneumonitis (odds ratio [OR]=1.43 and 2.85, respectively), as was RCC diagnosis for all-grade pneumonitis (OR=1.59), compared with melanoma.

In addition, multivariate analysis found no difference in the risk of pneumonitis between use of pembrolizumab and nivolumab, but confirmed that combination therapy was significantly associated with both all-grade and grade 3 or higher events (OR=2.04 and 2.86, respectively).

Subgroup analysis indicated that patients who received nivolumab plus ipilimumab were significantly more likely to develop all-grade and grade 3 or higher pneumonitis than those given ipilimumab alone (OR=2.13 and 2.78, respectively). Nivolumab plus peptide vaccine also significantly predicted an increased risk of all-grade pneumonitis (OR=1.54) but not grade 3 or higher events.
Finally, the team reports four pneumonitis-related deaths in NSCLC patients taking monotherapy and one such death in a melanoma patient taking combination therapy but no mortality in RCC cases.

Mizuki Nishino, from the Dana-Farber Cancer Institute in Boston, Massachusetts, USA, and co-authors note that their research into pneumonitis is focused only on two early PD-1 inhibitors and three key indications and highlights the “significant lack of knowledge of this entity in terms of its risk factors, diagnostic workup strategy, and optimal management guidelines.”

They conclude: “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.”


Nishino M, Giobbie-Hurder A, Hatabu H, et al. Incidence of programmed cell death 1 inhibitor-related pneumonitis in patients with advanced cancer. A systematic review and meta-analysis. JAMA Oncol 2016; Advance online publication 18 August. doi:10.1001/jamaoncol.2016.2453

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