Older, Male Patients More Likely to Have CIP, Prospective Study Reveals

Checkpoint inhibitor pneumonitis (CIP) is more common in patient who were male, were older, or were treated with ipilimumab (Yervoy) plus nivolumab (Opdivo), and over one-third of cases became chronic, according to data presented at the 2025 ESMO Annual Congress from a large prospective study of CIP across patients receiving various combinations of nivolumab with and without ipilimumab or chemotherapy.

Results presented by Jarushka Naidoo, MB, BCH, MHS, a professor of medical oncology and consultant medical oncologist at Beaumont Hospital, RCSI University of Health Sciences in Dublin, Ireland, revealed that 6.6% of male patients had CIP vs 4.9% of female patients.

CIP incidence in patients older than 75 years, ages 65 to 75, and younger than 65 were 8.5%, 7.0%, and 5.2%, respectively. Additionally, 34% of CIP cases became chronic, 8% became recurrent, and CIP was seen to progress regardless of treatment with corticosteroids.

The study observed 11,777 patients from 25 phase 3 global clinical trials of nivolumab with and without ipilimumab and/or chemotherapy or with another agent including 9 solid tumor types, where 716 (6.1%) developed CIP. The most common cancer types were non–small cell lung cancer (NSCLC; n = 2654), gastroesophageal (n = 2276), melanoma (n = 1910), renal cell carcinoma (RCC; n = 1323).

Among nivolumab combinations, the rate of CIP incidence was as follows:

• Ipilimumab plus nivolumab (8.0%; 305/2776)
• Ipilimumab plus nivolumab and chemotherapy (7.5%, 27/3580)
• Nivolumab (4.6%, 256/5517)
• Nivolumab plus chemotherapy (6.4%; 106/1639)
• Nivolumab plus another agent (4.5%; 22/487)

Severity and Management of CIP

The majority of cases of CIP were grade 1 (22.7%) to 2 (45.7%). CIP was grade 3, 4, and 5 in 27.1%, 4.1%, and 0.4% of cases. The median time to onset of CIP of any grade in with any treatment regimen was 17 weeks (range, 0.3-123.6). The median time to onset for CIP in patients receiving nivolumab and ipilimumab was 12.1 weeks and 23.7 weeks in patients receiving nivolumab plus chemotherapy. Time to onset was similar by grade.

Median time to resolution in grades 1 and 2 CIP was 9 weeks (range, 0.1-143) and in grades 3 and 4 was 4.3 weeks (range, 0.1-117.1). Time to resolution was shortest for patients receiving nivolumab and ipilimumab, at 6.29 weeks, and the longest in patients receiving nivolumab plus chemotherapy, at 14.8 weeks.

Treatment was held in 39.3% of patients with grade 1 events, 50.1% of grade 2 events, and 11.7% of grade 3 events; discontinued in 11.8% of grade 1 events, 29.2% of grade 2 events, 63.8% of grade 3 events, 81.2% of grade 4 events, and 66.7% of grade 5 events; and continued in 34.8% of grade 1 events, 4.5% of grade 2 events, and 0.9% of grade 3 events. Events occurred before treatment or in follow-up for 17.6% of cases.

“Reassuringly, 70% of pneumonitis events completely resolved,” explained Naidoo. “However, an important proportion, 22.5%, did not recover or resolve, and 4% were fatal.”

CIP was resolved in 62.9, 77.8%, 69.0%, and 40.6% of patients with grade 1, 2, 3, and 4 events, respectively. Events were not recovered or resolved in 34.2%, 19.4%, 17.8%, and 25%, respectively. CIP was fatal in all 3 grade 5 events as well as 0.5% of grade 2 events, 7.5% of grade 3 events, and 31.2% of grade 4 events.

Corticosteroids were used to treat 74% of any-grade pneumonitis, including 90% of grade 3 or higher events. Median initial corticosteroid dose was 1.13 mg/kg for any grade CIP and 1.39 mg/kg for grade 3 or higher CIP events. Median duration of treatment with corticosteroids was 7 weeks for CIP of any grade and 4.3 weeks when used in CIP grade 3 or higher. Median duration of corticosteroid taper was 5 weeks for events of any grade and 3.4 weeks for grade 3 or higher.

Second-line immunosuppression was used for the management of CIP in 3.4% of events of an grade and 8.7% of those grade 3 or worse. The most frequently used of these agents was infliximab (86%). Second-line immunosuppression was used in 21 patients with grade 3 or worse CIP/ In 26% of those cases, the issue was resolved/recovered or an end date was recorded; in 19.0% patients did not recover; and in 47.6% CIP became fatal. The median time to second therapy was 7 days.

Incidence of Recurrent and Chronic Pneumonitis

“There are 2 unique phenotypes of pneumonitis: recurrent pneumonitis…[which] is more common in men and those with RCC and HCC, and chronic pneumonitis, which can occur in up to 34.6% of patients,” said Naidoo.

The study identified recurrent pneumonitis, meaning a subsequent pneumonitis event without rechallenge after pneumonitis has been initially resolved, occurred as a pan-tumor event, rather lung cancer and melanoma, as previously thought.

Recurrent pneumonitis occurred in 8.5% of patients, with 69 total recurrent events. It was more common in White patients, patients with RCC (17.6%) and patients with hepatocellular carcinoma (HCC; 13.3%).

Most patients who experienced recurrence only had 1 recurrent event (91.8%), and the majority were grade 1 (25.7%) or grade 2 (40.9%); 28.8% were grade 3 and 4.5% were grade 4. Median time from first CIP event to recurrence was 6.1 weeks, and the median duration of recurrence was 5.1 weeks.

Treatment was continued in a minority of grade 1 recurrent cases and held or discontinued in all other cases. The majority of cases (75%) resolved, with 3% not resolving and 4% becoming fatal.

Chronic CIP, lasting at last 12 weeks, occurred in 34.6% of all cases, with the majority (94.5%) having a single chronic event.

Reference

Naidoo J, Johnson D, Possick J, et al. Patient-level analysis of pneumonitis from clinical trials of nivolumab-based regimens in solid tumour. Presented at: 2025 ESMO Congress; October 17-25, 2025; Berlin, Germany. Abstract 2799O.