Pneumonitis in Non-Small Cell Lung Cancer Patients Receiving Atezolizumab Post Chemo-Radiation

Lung cancer is the second most common cancer and the leading cause of cancer-related death worldwide, largely due to late symptom onset and frequent advanced-stage diagnosis. Approximately 20–30% of NSCLC patients have stage III disease, many with unresectable tumors. For years, the standard of care for unresectable stage III NSCLC has been concurrent chemotherapy and radiation therapy. The phase III PACIFIC trial demonstrated that adding Durvalumab after concurrent chemoradiotherapy significantly prolonged progression-free and overall survival in this setting. In Lebanon, Durvalumab has not been reimbursed for this indication; therefore, the authors used Atezolizumab as consolidation after concurrent chemoradiation in stage III NSCLC patients. A high incidence of pneumonitis was observed clinically, prompting this study to quantify its incidence, characterize severity and timing, and explore potential predictive factors.

- Concurrent versus sequential chemoradiotherapy: A meta-analysis of randomized controlled trials supports concurrent chemoradiotherapy as superior in survival for advanced/stage III NSCLC. - PACIFIC trial: Durvalumab after concurrent chemoradiotherapy improved PFS and OS; adverse events were common, with pneumonitis leading to discontinuation in some patients. Pneumonitis occurred in 33.9% with Durvalumab vs 24.8% with placebo, mostly low grade; grade 3–4 rates were similar (3.4% vs 2.6%). - Atezolizumab safety: Systematic reviews suggest Atezolizumab has a favorable safety profile among immune checkpoint inhibitors, though immune-related pneumonitis can occur. - Attribution of pneumonitis: A phase II trial of concurrent Atezolizumab with chemoradiation suggested pneumonitis may be mainly attributable to radiotherapy, with the relative contribution of immunotherapy uncertain. Some hypotheses suggest anti-PD-1 agents may have slightly higher pneumonitis risk than PD-L1 inhibitors, but this remains unproven. - Chemotherapy backbones and pneumonitis: Prior trials indicate higher rates of radiation pneumonitis with paclitaxel/carboplatin-based chemoradiation compared to some alternatives, potentially influencing pneumonitis incidence irrespective of immunotherapy. - Histologic subtype: Prior reports associate squamous histology with higher pneumonitis risk during immune checkpoint inhibitor therapy.

Design: Retrospective analysis from the lung cancer registry at the American University of Beirut Medical Center. Eligibility: Patients ≥18 years with stage III NSCLC who received concurrent chemotherapy and radiotherapy followed by consolidation Atezolizumab since January 2018. Data collected exclusively from medical records; no patient contact. Pneumonitis assessment: Diagnosis based on clinical features (e.g., cough, dyspnea, weight loss) and radiologic findings (new consolidation or ground-glass opacities). Severity graded per CTCAE: grade 1 asymptomatic; grade 2 minimally symptomatic; grade 3 severe symptoms/life-threatening respiratory compromise; grade 4 requiring ventilatory support; grade 5 death. Variables: Patient demographics (age, gender, smoking status), tumor histology, PD-L1 status, pneumonitis incidence and grade, and timing of onset relative to chemoradiotherapy completion and Atezolizumab initiation. Statistical analysis: Two-sample t-test assuming unequal variances used to compare means between patients with versus without pneumonitis; p-values reported for potential predictors. Descriptive statistics summarized timing of pneumonitis onset by grade. Timeframe: January 2018 to January 2022. Ethics: Institutional approval noted; data sourced from institutional registry.

- Cohort: 14 patients; mean age 65.23 years; 50% female; 75% current/former smokers. Histology: 57.1% adenocarcinoma (n=8), 35.7% squamous cell carcinoma (n=5), 7.2% unknown (n=1). PD-L1 status (n=12 reported): <1% in 21.4%, 1–49% in 50%, >50% in 14.3%; 14.3% unknown overall. - Incidence of pneumonitis: 8/14 patients (57.1%) developed pneumonitis after starting Atezolizumab; 6 did not. - Predictors: - Age, gender, and smoking status were not associated with pneumonitis (p=0.98, 1.00, and 0.86, respectively). - Histology showed a notable trend: all patients with squamous cell carcinoma (5/5; 35.7% of total cohort) developed pneumonitis; among those with pneumonitis, 62.5% had squamous histology. This trend did not reach statistical significance (p=0.078), likely due to small sample size. - PD-L1 status findings were inconclusive due to small numbers and some unknown statuses. - Timing of onset (mean): - Overall: 3.62 months after completion of chemoradiotherapy; 2.45 months after initiation of Atezolizumab. - By CTCAE grade: - Grade 1: 4.76 months after chemoradiotherapy; 3.62 months after Atezolizumab start. Mostly incidental findings on routine chest CT; no steroids; Atezolizumab completed. - Grade 2: 2.89 months after chemoradiotherapy; 1.76 months after Atezolizumab start. Patients had mild symptoms (cough, dyspnea); diagnosis confirmed on CT. - Grade 3: 3.22 months after chemoradiotherapy; 1.96 months after Atezolizumab start. All received corticosteroids; Atezolizumab discontinued. - Management: Grade 3 pneumonitis prompted steroid therapy and immunotherapy discontinuation; lower grades managed conservatively.

This study addresses the risk of pneumonitis when using Atezolizumab as consolidation after concurrent chemoradiotherapy in unresectable stage III NSCLC, motivated by the unavailability of Durvalumab despite PACIFIC trial benefits. The observed pneumonitis rate (57%) is high compared with reports from randomized trials using Durvalumab, where pneumonitis (primarily low grade) occurred in roughly one-third of patients and grade 3–4 rates were low. The lack of association with age, sex, and smoking suggests these clinical factors may not be strong predictors in this context. A notable, though statistically non-significant, trend implicated squamous histology with higher pneumonitis risk (all squamous cases developed pneumonitis), aligning with prior literature associating squamous subtype with increased pneumonitis during immune checkpoint inhibitor therapy. The timing data indicate pneumonitis typically manifests within several months of chemoradiotherapy and soon after Atezolizumab initiation, with more severe cases occurring earlier after immunotherapy start than milder ones. Interpretation is nuanced because radiotherapy itself contributes substantially to pneumonitis risk, and chemotherapy backbone (e.g., paclitaxel/carboplatin) may elevate radiation pneumonitis risk independent of immunotherapy. Prior studies suggest pneumonitis during combined modality treatment may be primarily radiotherapy-driven, and differences between anti-PD-1 and PD-L1 inhibitors remain theoretical. Nonetheless, the consistently high incidence observed warrants caution and further investigation.

Consolidation Atezolizumab after concurrent chemoradiotherapy in stage III NSCLC was associated with a substantial incidence of pneumonitis in this single-center series. While age, sex, and smoking were not associated with risk, a trend toward higher risk in squamous histology was observed. Pneumonitis typically occurred within 2–4 months after starting Atezolizumab and 3–5 months after completing chemoradiotherapy; severe cases required corticosteroids and discontinuation of immunotherapy. Larger, prospective studies are needed to validate risk factors, disentangle the contributions of radiotherapy and immunotherapy, and guide patient selection and management strategies.

- Small sample size (n=14) limits statistical power and generalizability and likely underlies non-significant p-values for observed trends (e.g., histology). - Retrospective, single-center registry-based design subject to selection and information biases; no control group receiving standard Durvalumab. - Incomplete PD-L1 data for some patients limited analyses of biomarker associations. - Potential confounding from chemoradiotherapy regimens and radiation parameters (not fully detailed) that independently influence pneumonitis risk.