Real world data are needed to establish safety of adjuvant immune checkpoint inhibitors after pneumonectomy

For stage II–IIIA non-small cell lung cancer (NSCLC), surgical resection of the tumor is the mainstay treatment, but the 5-year recurrence rate is as high as 50% to 78%, and the overall survival rate at 5 years remains 48% to 64% (1,2). Conventional adjuvant chemotherapy improves 5-year survival by only 5% at best (3). Atezolizumab, anti-programmed death ligand 1 (PD-L1) monoclonal antibody, has demonstrated significant therapeutic benefit in combination with platinum-based chemotherapy in first-line treatment and as monotherapy in second-line treatment for patients with advanced NSCLC. Thus, it has been anticipated that this agent could be used as adjuvant therapy after surgical resection in patients with resectable NSCLC. The IMpower010 trial is a randomized, open-label phase III trial of adjuvant atezolizumab or best supportive care after adjuvant platinum-based chemotherapy in patients with pathologically stage IB–IIIA NSCLC that has been completely resected. Pre-planned interim analyses of this trial showed better disease-free survival [hazard ratio (HR) 0.66, 95% confidence interval (CI): 0.50–0.88, P=0.0039] at a median follow-up of 32.2 months (4) and a trend toward better overall survival (HR 0.71, 95% CI: 0.49–1.03) at a median follow-up of 45.3 months in the atezolizumab group in stage II–IIIA patients with programmed death-ligand 1 (PD-L1) expression in more than 1% of tumor cells (5). Toxicity of adjuvant atezolizumab was acceptable. Grade 3–4 and serious adverse events (AEs) were observed in 22% and 18% of patients in the atezolizumab group and in 12% and 8% for the best supportive care group, respectively (4). Immune-related grade 3–4 AEs developed in 8%, and the use of systemic corticosteroids was required in 12% of patients in the atezolizumab group. Treatment-related death was noted in 1.6% (atezolizumab-related death 0.8%) and 0.6% of patients in the atezolizumab and best supportive care groups, respectively (4). Although these initial data appear very promising, special considerations must be given to the postoperative drug treatment of patients with resectable stage disease. This is because such patients include those already cured by surgical resection alone. Therefore, safety considerations are very important when using immune checkpoint inhibitors (ICIs) in the postoperative period.

Dr. Lee and colleagues published a paper entitled “Safety of adjuvant atezolizumab after pneumonectomy/bilobectomy in stage II-IIIA non-small cell lung cancer in the randomized phase III IMpower010 trial” (6). Of 433 patients with stage II–IIIA NSCLC in the adjuvant atezolizumab group, 100 (23%) received pneumonectomy or bilobectomy and 332 (77%) received lobectomy or sleeve lobectomy. There was no difference in the frequency of grade 3–4 any AEs (21% vs. 23%), grade 3–4 pneumonitis (0% vs. 1.2%), atezolizumab discontinuation (32% vs. 35%), hospitalization for AEs (13% vs. 17%), or treatment-related death (1.0% vs. 1.2%) between the pneumonectomy or bilobectomy group and the lobectomy or sleeve lobectomy group, respectively. These exploratory findings may support the adjuvant use of atezolizumab in patients undergoing pneumonectomy. However, these results should be evaluated with caution because pneumonectomy, surgical removal of an entire lung, has traditionally been a great concern for its mortality and morbidity. After a literature review of more than 300 pneumonectomy cases published since 1990, contemporary 30-day mortality rates ranging from 3% to 12% and 90-day or in-hospital mortality rates ranging from 2% to 12% (Table 1) (7-15). The most common cause of 30-day death was acute respiratory distress syndrome (ARDS) in 51–54% of cases, followed by bronchopulmonary fistula in 11–23% and cardiac in 8–14% (10,13). These studies also identified risk factors for mortality. For example, Yu et al. retrieved 10,337 pneumonectomy cases from the Surveillance, Epidemiology, and End Results (SEER) cancer registry, and reported that old age, male gender, right-sided pneumonectomy, and squamous cell carcinoma histology were significant risk factors for death within 90 days after pneumonectomy (14). Major postoperative complications occurred in 20–26% of patients, with ARDS in 3–16%, pneumonia in 4–10%, bronchopulmonary fistula in 2–4%, and heart failure in 1–7% (9,10,15). Furthermore, pneumonectomy is associated with a variety of significant anatomic changes, which can lead to late complications. Postpneumonectomy syndrome characterized by gradually increasing shortness of breath, audible stridor, and recurrent airway infections 1 month to several years (median, 2 years) after pneumonectomy. This syndrome occurs in about 2% of pneumonectomies and results from extrinsic compression of the distal trachea or main bronchus by the vertebral body or aorta due to excessive movement and rotation of the mediastinum into the pneumonectomy space and hyperextension of the remaining lung and airway (16,17). Empyema in the postpneumonectomy space occurs at an incidence of 4% to 16% after pneumonectomy. Although most postpneumonectomy empyema has been thought to develop within 3 months of pneumonectomy, large case series studies found that the median interval between pneumonectomy and postpneumonectomy empyema was 3.4–4.3 months, ranging from 1–7 to 15.6–19.7 years (18,19).

Thus, in general, pneumonectomy has more postoperative complications than lobectomy, which raises some concerns about the interpretation of the results of the IMpower010 trial. The most serious concern is that these results were obtained from highly selected patients. The standard number of cycles of cisplatin-based chemotherapy in postoperative adjuvant therapy is four, but only half of patients actually complete four cycles of chemotherapy after surgical resection (20,21). In the IMpower010 trial, 264 of the 1,269 patients (21%) who started cisplatin-based chemotherapy dropped out of the study and were excluded from proceeding to atezolizumab treatment (4). As a result, patients in good enough general condition to receive four cycles of chemotherapy accounted for nearly 90% of those who received adjuvant atezolizumab therapy (6). The interval between surgery and the start of atezolizumab administration is also important. Most complications associated with pneumonectomy occur within the first 3 months after surgery. Therefore, careful monitoring of the postoperative clinical course during this period or longer can help select patients suitable for adjuvant therapy. The median time from surgery to atezolizumab adjuvant therapy in the IMpower010 trial was 5.1 months (6), which appears to have been a sufficient observation period to select appropriate patients. Another concern is the relatively short median observation period of 32.2 months (interquartile range, 27.4–38.3 months) for the evaluation of any difference in safety by surgical technique in IMpower010 trial (6). This is because a case was reported in which an immune-related AE occurred 58 months after the start of ICI administration (22), and in another case, an immune-related AE developed 28 months after discontinuation of ICI administration (23). Finally, the relatively small number of patients [100] makes it difficult to evaluate highly lethal immune-related AEs including myocarditis and toxic epidermal necrolysis, because the frequency of such immune-related AEs is less than 1% (24). Thus, to support use of adjuvant ICIs in patients undergoing pneumonectomy, real world data based on a sufficient number of patients with sufficiently long observation period are needed.

Acknowledgments

Funding: None.

Footnote

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