PD-1 Inhibitor-Related Pneumonitis in Advanced Cancer Patients: Radiographic Patterns and Clinical Course

Abstract

Purpose: Investigate the clinical characteristics, radiographic patterns, and treatment course of PD-1 inhibitor-related pneumonitis in advanced cancer patients.

Experimental design: Among patients with advanced melanoma, lung cancer, or lymphoma treated in trials of nivolumab, we identified those who developed pneumonitis. Chest CT scans were reviewed to assess extent, distribution, and radiographic patterns of pneumonitis.

Results: Among 170 patients treated in 10 different trials of nivolumab, 20 patients (10 melanoma, 6 lymphoma, and 4 lung cancer) developed pneumonitis. Five patients received nivolumab monotherapy, and 15 received combination therapy. The median time from therapy initiation to pneumonitis was 2.6 months. Radiographic pattern was cryptogenic organizing pneumonia (COP) in 13, nonspecific interstitial pneumonia (NSIP) in 3, hypersensitivity pneumonitis (HP) in 2, and acute interstitial pneumonia (AIP)/acute respiratory distress syndrome (ARDS) in 2 patients. The AIP/ARDS pattern had the highest grade, followed by COP, whereas NSIP and HP had lower grade (median grade: 3, 2, 1, 1, respectively; P = 0.006). The COP pattern was most common in all tumors and treatment regimens. Most patients (17/20; 85%) received corticosteroids, and 3 (15%) also required infliximab. Seven patients restarted nivolumab therapy; 2 of them developed recurrent pneumonitis and were successfully retreated with corticosteroids. One of the patients experienced a pneumonitis flare after completion of corticosteroid taper without nivolumab retreatment.

Conclusions: PD-1 inhibitor-related pneumonitis showed a spectrum of radiographic patterns, reflecting pneumonitis grades. COP was the most common pattern across tumor types and therapeutic regimens. Most patients were successfully treated with corticosteroids. Recurrent pneumonitis and pneumonitis flare were noted in a few patients. Clin Cancer Res; 22(24); 6051-60. ©2016 AACRSee related commentary by Castanon, p. 5956.

Fig. 1

Spectrum of radiographic manifestations of PD-1 inhibitor-related pneumonitis. A, B. Pneumonitis with a COP pattern in a 30-year-old female with Hodgkin lymphoma treated with nivolumab and ipilimumab combination therapy (Patient 15). CT scan of the chest at 11.5 months of therapy demonstrated a development of ground-glass and reticular opacities and consolidations involving both lungs with a multifocal distribution (arrowheads, A), representing a COP pattern. One of the involved areas in the left lower lobe demonstrated a “reversed halo” sign (arrow, B) with central GGO surrounded by dense air-space consolidation of crescentic shape, which has been reported as a radiographic manifestation of COP. C, D. Pneumonitis with a NSIP pattern in a 58-year-old male with melanoma treated with nivolumab monotherapy (Patient 1). Chest CT scan at 1.7 months of therapy demonstrated new ground glass and reticular opacities and consolidations (arrowheads, C, D) indicative of a NSIP pattern. E, F. Pneumonitis with a HP pattern in a 40-year-old female with lung adenocarcinoma treated with nivolumab monotherapy (Patient 12). Chest CT scan at 1.2 months of therapy demonstrated new diffuse GGOs and centrilobular nodularity in both lungs, indicative of a HP pattern of pneumonitis. Note that the consolidations and interlobular septal thickening in the right lung demonstrate tumor involvement by lung cancer, which were present since the baseline scan. G, H. Pneumonitis with an AIP/ARDS pattern in a 70-year-old man with melanoma treated with sequentially administered nivolumab and ipilimumab combination therapy (Patient 3). Chest CT scan at 5.6 months of therapy demonstrated ground-glass and reticular opacities, consolidations and traction bronchiectasis as well as pleural effusions (asterisks), involving both lungs.

Fig. 2

Pneumonitis with a COP pattern in a 33-year-old female with Hodgkin lymphoma treated with nivolumab and ipilimumab combination therapy (Patient 16), with a recurrence during retreatment and two episodes of pneumonitis flare after completion of corticosteroid taper. A, B. CT scan of the chest at 1.4 months of therapy demonstrated ground-glass and reticular opacities and consolidations with multifocal distribution, indicative of a COP pattern of pneumonitis (arrowheads). Left perihilar opacity and traction bronchiectasis are due to prior radiation therapy (arrows). C, D. The patient was treated with oral prednisone taper, and the findings have resolved on the follow-up scan performed 1.5 month later. E, F. The patient restarted therapy and received 2 doses of nivolumab and ipilimumab and 2 doses of nivolmab monotherapy, then developed recurrent pneumonitis after 2 months since restarting therapy. The scan at the time of recurrent pneumonitis demonstrated similar findings with muitifocal ground-glass and reticular opacities and consolidations, again representing a COP pattern. The findings were more extensive than the first episode. G, H. Nivolumab was held and the patient was treated again with prednisone taper for pneumonitis, with subsequent improvement.

Fig. 3

Pneumonitis with a COP pattern in a 33-year-old female with Hodgkin lymphoma treated with nivolumab and ipilimumab combination therapy (Patient 16), with a recurrence during retreatment and two episodes of pneumonitis flare after completion of corticosteroid taper. A, B. The patient completed 2 months of corticosteroid taper and after one month, she experienced another episode of pneumonitis with a very similar radographic pattern, without nivolumab retreatment or other systemic therapy, indicating a pneumonitis flare. C, D. Another course of corticosteroid taper was given and with subsequent improvement. E, F. The 2.7-month course of corticosteroid taper was completed and after 2 weeks, the patient again developed a pneumonitis flare with a similar radiographic pattern as the prior episodes. G, H. The sampled fragments of lung obtained by transbronchial biopsies showed interstitial pneumonitis evolving to organizing pneumonia. Findings included lymphocyte-predominant interstitial pneumonitis (arrowhead, O, H&E stain, 200X)with rare eosinophils (arrow, O), and areas of organizing pneumonia with fibroblast plugs and foamy macrophages filling the airspaces (asterisks, P, H&E stain, 200X). No tumor cells, microorganisms, or viral cytopathic changes were identified. The patient started another course of prednisone taper with subsequent clinical improvement, and is schedule for a follow-up CT scan.