Risk of Radiation Pneumonitis in Patients Receiving Osimertinib and Thoracic Radiotherapy

Abstract

Purpose/Objective(s)Osimertinib has become first-line standard of care for patients with non-small cell lung cancer (NSCLC) and EGFR-sensitive mutations. Radiotherapy use in the setting of osimertinib is becoming more common, often in the setting of oligo-metastatic/progressive disease or palliation. Given the increased rates of symptomatic radiation pneumonitis associated with first-generation EGFR inhibitors given with thoracic radiotherapy (TRT) (up to 40%), there is concern that similar risks exist for osimertinib, though this remains unclear. Given the greater EGFR-mutant selectivity of osimertinib, we hypothesized less pneumonitis risk as compared to older EGFR inhibitors with TRT.Materials/MethodsWe conducted a retrospective cohort study of consecutive patients with EGFR-mutated NSCLC receiving TRT and osimertinib within 30 days prior to TRT start at a single institution from November 2017 to October 2021. The timing of osimertinib receipt relative to the radiation course was recorded, including if osimertinib was given concurrently with TRT. Chart review was conducted to document pneumonitis attributed to radiation therapy within 12 months of TRT and severity was assessed via CTCAE v5.0 grade. Additionally, clinical, radiation, and dosimetric details were abstracted. The primary endpoint of Grade 2+ pneumonitis was evaluated with descriptive statistics. Associations between pneumonitis and osimertinib-TRT overlap along with mean lung V20 and V5 were evaluated with Chi-Square and one-tailed T-tests (α=0.05) as appropriate.ResultsAnalysis included 41 patients with median follow-up of 10.4 months (interquartile range: 5.4-22.6). Mean prescription BED (α/β=10) was 75.8Gy (standard deviation: 30.9 Gy) and 15 (36.6%) were treated with stereotactic TRT. All patients received 80 mg/day osimertinib PO. For 32 patients (78.0%), osimertinib was held at a median of 2 days prior to TRT and resumed at a median of 2 days after TRT. For 9 patients (22.0%), osimertinib was continued during TRT. One patient had a history of chronic obstructive pulmonary disease. Overall, 8 patients (19.5%) developed Grade 2+ pneumonitis (6 Grade 2, 1 Grade 3, 1 Grade 5) at median of 4.7 months (range: 3.1 – 6.9). No episodes of radiation pneumonitis occurred in the osimertinib-concurrent group. Pneumonitis was associated with increased lung V20 (mean: 16.2% vs 10.0%, P=0.038) and V5 (35.7% vs 24.0%, P=0.032). Two patients, both in the osimertinib-held group (6.3%) had central nervous system disease progression during TRT, one with symptomatic leptomeningeal disease.ConclusionIn this single-institution study, the rate of radiation pneumonitis in patients receiving TRT and osimertinib was comparable to historical controls of TRT alone, and concurrent osimertinib did not increase risk compared to holding during TRT. These findings provide useful information for patients and providers weighing the risks and benefits of overlapping TRT with osimertinib and should be validated in larger cohorts. Osimertinib has become first-line standard of care for patients with non-small cell lung cancer (NSCLC) and EGFR-sensitive mutations. Radiotherapy use in the setting of osimertinib is becoming more common, often in the setting of oligo-metastatic/progressive disease or palliation. Given the increased rates of symptomatic radiation pneumonitis associated with first-generation EGFR inhibitors given with thoracic radiotherapy (TRT) (up to 40%), there is concern that similar risks exist for osimertinib, though this remains unclear. Given the greater EGFR-mutant selectivity of osimertinib, we hypothesized less pneumonitis risk as compared to older EGFR inhibitors with TRT. We conducted a retrospective cohort study of consecutive patients with EGFR-mutated NSCLC receiving TRT and osimertinib within 30 days prior to TRT start at a single institution from November 2017 to October 2021. The timing of osimertinib receipt relative to the radiation course was recorded, including if osimertinib was given concurrently with TRT. Chart review was conducted to document pneumonitis attributed to radiation therapy within 12 months of TRT and severity was assessed via CTCAE v5.0 grade. Additionally, clinical, radiation, and dosimetric details were abstracted. The primary endpoint of Grade 2+ pneumonitis was evaluated with descriptive statistics. Associations between pneumonitis and osimertinib-TRT overlap along with mean lung V20 and V5 were evaluated with Chi-Square and one-tailed T-tests (α=0.05) as appropriate. Analysis included 41 patients with median follow-up of 10.4 months (interquartile range: 5.4-22.6). Mean prescription BED (α/β=10) was 75.8Gy (standard deviation: 30.9 Gy) and 15 (36.6%) were treated with stereotactic TRT. All patients received 80 mg/day osimertinib PO. For 32 patients (78.0%), osimertinib was held at a median of 2 days prior to TRT and resumed at a median of 2 days after TRT. For 9 patients (22.0%), osimertinib was continued during TRT. One patient had a history of chronic obstructive pulmonary disease. Overall, 8 patients (19.5%) developed Grade 2+ pneumonitis (6 Grade 2, 1 Grade 3, 1 Grade 5) at median of 4.7 months (range: 3.1 – 6.9). No episodes of radiation pneumonitis occurred in the osimertinib-concurrent group. Pneumonitis was associated with increased lung V20 (mean: 16.2% vs 10.0%, P=0.038) and V5 (35.7% vs 24.0%, P=0.032). Two patients, both in the osimertinib-held group (6.3%) had central nervous system disease progression during TRT, one with symptomatic leptomeningeal disease. In this single-institution study, the rate of radiation pneumonitis in patients receiving TRT and osimertinib was comparable to historical controls of TRT alone, and concurrent osimertinib did not increase risk compared to holding during TRT. These findings provide useful information for patients and providers weighing the risks and benefits of overlapping TRT with osimertinib and should be validated in larger cohorts.