Pneumonitis Risk, Management Examined For PD-1/PD-L1 Targeted Therapy

The incidence and outcome of pneumonitis in patients undergoing targeted cancer treatment with programmed cell death protein 1 or programmed cell death ligand 1 inhibitors is described

medwireNews: Study findings highlight a small but potentially serious risk of pneumonitis among patients undergoing treatment targeting programmed cell death protein 1 (PD-1) or its ligand programmed cell death ligand 1 (PD-L1).

While emphasizing that “most cases are mild and managed successfully”, the researchers caution in the Journal of Clinical Oncology that the adverse event can become more severe in some patients.

“Treating physicians should be aware of its diverse clinical, radiologic, and pathologic features and that it may develop at any time during a patient’s treatment course”, they write.

Pneumonitis developed in 5% of 915 patients with advanced solid tumours given anti-PD-1/PD-L1 therapy alone or alongside an anti-CTLA-4 agent at the Memorial Sloan Kettering Cancer Center in New York, USA, although there was a lower rate with monotherapy than combination treatment (3 vs 10%).

Five percent of patients treated at the Melanoma Institute of Australia in North Sydney, New South Wales, also experienced this adverse event, report Matthew Hellmann, from Memorial Sloan Kettering Cancer Center, and co-authors.

The majority of patients developed grade 1 (40%) or grade 2 (33%) pneumonitis but 23% had grade 3 toxicity, with one case each of grade 4 and grade 5 pneumonitis; severity did not differ with monotherapy versus combined treatment.

Pneumonitis occurred a median of 2.8 months after beginning treatment, ranging from 9 days to 19.2 months, and was generally earlier in patients who received monotherapy than those given combined treatment (2.7 vs 4.6 months).

Presenting symptoms included dyspnoea (53%), cough (35%), fever (12%) and chest pain (7%), but 33% of patients were asymptomatic at the onset of pneumonitis. And the majority (58%) of patients who developed pneumonitis had other immune-related toxicities, such as rash, colitis, arthritis, hypophysitis or thyroiditis, the researchers say.

Pneumonitis was successfully resolved in patients with a grade 1 or 2 event, requiring only outpatient care for the majority (81%) – mostly by drug withholding or oral corticosteroids – although 19% of patients, all of whom had grade 2 pneumonitis, required inpatient treatment.

All grade 3 patients required hospitalisation for steroid therapy with 42% given additional immunosuppressive therapy with infliximab alone or alongside cyclophosphamide.

Five patients with grade 3 or more severe pneumonitis experienced clinical worsening and died despite further immunosuppression, three of whom had complicating factors of immunosuppression-related infection and another who also had progressive disease.

The fifth patient, with grade 5 pneumonitis, was initially treated for grade 2 pneumonitis but experienced worsening after oral steroid tapering, and failed to respond to high-dose intravenous steroids, infliximab and cyclophosphamide.

Patients were more likely to have worsening pneumonitis if they were a current smoker or if they had an underlying lung condition, say Matthew Hellmann et al, but measures of lung function were not prognostic of pneumonitis outcome.

The authors believe that their study “fills an important gap in the literature” and while unable to give “firm recommendations about optimal pneumonitis management”, they suggest it is “reasonable” to treat grade 1 pneumonitis with drug withholding and close follow-up, with corticosteroids for patients whose pneumonitis does not resolve or is more severe.

“However, worsening pneumonitis may develop in a subset of patients despite additional immunosuppression, and they may suffer from the immunosuppressive consequences of pneumonitis treatment”, the researchers caution.

“Improvements in the treatment and understanding of the biology of pneumonitis are needed to optimize management.”

References

Naidoo J, Wang X, Woo KM, et al. Pneumonitis in patients treated with anti-programmed death-1/programmed death ligand 1 therapy. J Clin Oncol; Advance online publication 19 September 2016

doi: 10.1200/JCO.2016.68.2005

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