Should we change strategy for adjuvant therapy according to surgery type in stage II–IIIA non-small cell lung cancer?

Introduction

It is estimated that non-small cell lung cancer (NSCLC) patients account for about 85% of all lung cancer patients (1). Standard treatment for stage II–IIIA NSCLC is surgical resection, and preoperative neoadjuvant or postoperative adjuvant chemotherapy is often indicated. However, the survival benefit of traditional platinum-based adjuvant chemotherapy is not satisfactory with an absolute survival benefit of 5.4% at 5 years (2), and in fact, disease-free survival (DFS) at 5 years in stage II–IIIA was reported to be 27.8–49.7% in Japan (3). Therefore, further improvement of prognosis in these patients is an important unmet need, and various clinical trials have been conducted.

Immune checkpoint inhibitors (ICIs) have dramatically improved prognosis of unresectable advanced NSCLC, and ICI is now established as the forefront therapy for unresectable advanced NSCLC, especially those without driver oncogenes. Furthermore, durvalumab [anti-programmed death ligand-1 (PD-L1) inhibitor] after definitive chemoradiotherapy demonstrated a survival benefit for unresectable locally advanced stage III NSCLC (4). Regarding patients with early-stage resectable NSCLC, several clinical trials have been conducted to investigate the significance of ICIs as perioperative therapy (adjuvant or neoadjuvant). The phase III IMpower010 trial showed DFS benefit of adjuvant atezolizumab compared with best supportive care (BSC) after adjuvant platinum-based chemotherapy in resected patients with stage II–IIIA NSCLC (5). The primary endpoint of this trial was set as DFS, which was hierarchically investigated in three primary analysis population: first, the stage II–IIIA population whose tumors expressed PD-L1 on 1% or more of tumor cells (TC), then all patients in the stage II–IIIA population, and finally the intention-to-treat (ITT) population (stage IB–IIIA). The first report of IMpower010 showed that statistically significant DFS benefit in the PD-L1 TC ≥1% stage II–IIIA [hazard ratio (HR), 0.66; 95% confidence interval (CI): 0.50, 0.88] and all-randomized stage II–IIIA (HR, 0.79; 95% CI: 0.64, 0.96) populations (6). Based on these results, adjuvant atezolizumab following platinum-based chemotherapy after pulmonary resection was approved in several countries including Japan and the United States.

In general, pneumonectomy or bilobectomy (PB) is known to be a more invasive surgery for lung cancer patients than lobectomy or sleeve lobectomy (LS). The tolerability and safety of drug therapy for these patients after PB is of great concern, but few reports have investigated this point in more detail. This editorial commentary discusses the results of the exploratory analysis of IMpower010, which evaluated the tolerability and safety of adjuvant atezolizumab according to surgery type (PB or LS), and the possible perioperative strategies (7).

Safety profiles of adjuvant atezolizumab after PB compared with LS

In the phase III IMpower010 trial, 1,005 stage IB–IIIA NSCLC patients were randomly assigned to adjuvant atezolizumab group or BSC group. In stage II–IIIA population, PB was performed in 100 patients in atezolizumab group and 95 in BSC group, meanwhile, LS was performed in 332 in atezolizumab group and 342 in BSC group. The comparison of baseline characteristics between surgery types showed that PB was performed more in male patients, patients from Europe or the Middle East, with squamous carcinoma, and with more advanced stage. In terms of tolerability of cisplatin treatment, there were no significant differences in the median duration of the treatment (both groups, 2.1 months) and the completion rate [PB: 87.2% (170/191), and LS: 84.3% (568/674)] between surgery types. Furthermore, the incidence of hospitalization due to adverse event (AE) during cisplatin-based chemotherapy was 11–13% and 14–16% in PB and LS groups, respectively.

Next, the tolerability and the safety of adjuvant atezolizumab was investigated in PB group. The median duration from surgery/end of adjuvant chemotherapy to adjuvant atezolizumab was 5.1/1.0 and 5.2/1.1 months in PB and LS groups, respectively. The median number and duration time of atezolizumab administered were 16 and 10.4 months in each group. Furthermore, AE profiles in each surgery group was almost similar. First, incidences of any AEs and grade 3/4 AEs were 87% and 21% in PB group, and 95% and 23% in LS group. One patient in PB group experienced grade 5 events (1.0%: multiple organ dysfunction syndrome), and 4 patients in LS group experienced grade 5 events (1.2%: acute myeloid leukemia, arrhythmia, myocarditis, and pneumothorax). Accordingly, the occurrence of AEs related to atezolizumab were 59% and 70% in PB and LS groups, respectively, with grade 3/4 AEs being 8% and 12%, respectively. AEs leading to hospitalization were identified in 5% and 7% between PB and LS groups. Finally, the adjusted odds ratios (ORs) comparing major AE incidence (overall AE, grade 3/4 AE, serious AE, and treatment-related AE) between PB and LS groups ranged from 0.34 to 1.11, with 95% CI crossing 1 of OR for grade 3/4 AE, serious AE, and treatment-related AE (overall AE was more frequent in LS group for this OR result).

In patients who underwent PB, adjuvant atezolizumab therapy following platinum-based chemotherapy was well-tolerated, and no new safety signals were identified. Based on these results, the authors concluded that adjuvant atezolizumab sequentially administered after the platinum-based chemotherapy in patients undergoing complete resection could be used regardless of surgery type, even if pneumonectomy.

How to translate these results into clinical practice, and which concerns should be addressed?

Adjuvant atezolizumab following platinum-based chemotherapy can be the novel standard treatment for completely resected stage II–IIIA NSCLC with PD-L1 tumor cells 1% or more. According to this exploratory analysis, there was no concern regarding AE profiles of platinum-based chemotherapy followed by atezolizumab for patients undergoing PB. However, several issues need to be addressed to translate the results into clinical practice.

First one is the tolerability and safety of PB itself. The most commonly performed surgical procedure is lobectomy, which represents 60–70% of total pulmonary surgery type, and pneumonectomy accounts for 10–15%. The postoperative mortality of pneumonectomy or lobectomy was reportedly 5–10% (8,9) and 0.3–2.2% (10,11), respectively. Especially, right side pneumonectomy was reported to be associated with increased perioperative mortality with 8.2–13.6%, compared with left side one with 4.2–7.9% in NSCLC patients who underwent induction therapy (12). In addition, sleeve lobectomy is known to be an alternative surgical strategy to avoid pneumonectomy. In fact, as compared with pneumonectomy, sleeve lobectomy was associated with a lower 30- and 90-day mortality (1.5% and 3.91% vs. 0.60% and 0.90%) and lower morbidity (8.16% vs. 4.36%) (13). Furthermore, the mortality rate of bilobectomy is higher than that of lobectomy (14). Based on these considerations, preserving the lung is directly associated with a significant reduction in perioperative complications and mortality rates. Therefore, it is recommended to perform LS when feasible. However, pneumonectomy cannot be necessarily avoidable due to tumor-related or anatomical factors, and the results of this explanatory analysis highlighted the safety of sequential treatment with adjuvant platinum-based chemotherapy and atezolizumab in patients surgically treated with pneumonectomy, if fully recovered.

Second, not only safety but also efficacy of atezolizumab is important for its implementation into the clinical practice. Although the current report did not provide data on the efficacy of postoperative adjuvant therapy with atezolizumab on prolonging prognosis, the subgroup analysis of DFS according to the surgical procedures was presented at the American Association for Thoracic Surgery (AATS) in 2022 (15). This subgroup analysis demonstrated that in patients with stage II–IIIA NSCLC with PD-L1 expression of 1% or higher, the HR for atezolizumab versus BSC in the lobectomy group was 0.63 (95% CI: 0.45, 0.87). In contrast, the HRs in the pneumonectomy and bilobectomy groups were 0.83 (95% CI: 0.43, 1.58), and 0.78 (95% CI: 0.18, 3.33), respectively, with CIs crossing 1. This suggests that while the safety of postoperative atezolizumab is established, the treatment efficacy is not significant for patients who undergo PB. On the other hand, preliminary data regarding the surgical procedure-specific event free survival (EFS) analysis of the CheckMate 816 trial were presented at European Lung Cancer Congress (ELCC) in 2023 (16). This trial is a phase 3 study that compared the efficacy of neoadjuvant chemotherapy plus nivolumab with neoadjuvant chemotherapy alone in patients with clinical stage II–IIIA NSCLC. In the group receiving preoperative nivolumab plus chemotherapy, approximately 80% underwent LS and about 17% underwent pneumonectomy, while the proportion of pneumonectomy cases was 25% in the standard treatment group, suggesting that the addition of nivolumab to neoadjuvant chemoradiotherapy might potentially reduce the need for pneumonectomy. Additionally, in the subgroup analysis of EFS, a long EFS efficacy of neoadjuvant nivolumab plus chemotherapy was reported in both the lobectomy and pneumonectomy groups (lobectomy group: 64% vs. 49%, and pneumonectomy group: 67% vs. 48% at 3-year EFS).

Based on the above, we propose treatment strategies for lung cancer with clinical stage II–IIIA (Figure 1). Initially, we determine whether LS or pneumonectomy is necessary to achieve R0 resection. If LS is feasible, upfront surgery or preoperative nivolumab plus chemotherapy should be chosen. In the case of upfront surgery, atezolizumab or pembrolizumab after postoperative platinum-based combination chemotherapy should be considered. If pneumonectomy is necessary, preoperative nivolumab plus chemotherapy or concurrent chemoradiotherapy is considered. If LS is feasible, but pneumonectomy is performed during the actual surgery, it is possible to consider atezolizumab following postoperative platinum-based combination chemotherapy after the recovery from surgical and perioperative stress. However, this treatment strategy may potentially evolve based on the long-term follow-up data of respective perioperative clinical trials.

Figure 1 The treatment strategy for locally advanced stage II–IIIA NSCLC. NSCLC, non-small cell lung cancer; ICI, immune checkpoint inhibitor; SOC, standard of care.

Conclusions

As Lee et al. reported, adjuvant platinum-based chemotherapy and subsequent atezolizumab (for PD-L1 expression ≥1%) following complete resection in stage II–IIIA were safe and well-tolerated treatments, regardless of the surgical procedure type, even if PB. However, further long-term follow-up data are needed to assess the efficacy in the future.

Acknowledgments

Funding: None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, AME Clinical Trials Review. The article has undergone external peer review.

Peer Review File: Available at https://actr.amegroups.com/article/view/10.21037/actr-23-47/prf

Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://actr.amegroups.com/article/view/10.21037/actr-23-47/coif). T.M. receives honoraria from AstraZeneca, Chugai Pharmaceutical, MSD, and Nippon Boehringer Ingelheim outside the submitted work. The other author has no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

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