What is the role of perioperative immunotherapy and chemotherapy in stage III resectable non-small cell lung cancer?

Introduction

The current treatment paradigm for patients presenting with stage IIIA and IIIB non-small cell lung cancer (NSCLC) is rapidly evolving, with recently completed studies resulting in near real-time changes in practice. Prior to the development of neo-adjuvant immune-chemotherapy, preoperative chemotherapy and chemoradiotherapy had been used to treat resectable stage IIIA or IIIB NSCLC and there was no consensus on the heterogeneity of the disease. However, the introduction of immunotherapy has now provided high-quality, targeted treatment options for NSCLC. While preoperative cytotoxic chemotherapy had been shown to improve overall survival for those patients with resectable disease, outcomes for stage III NSCLC have remained poor, with an estimated 5-year overall survival of approximately 36% (1,2). However, the inclusion of immunotherapy into our treatment regimens for lung cancer has become an exciting advance in our field, with substantial impact on the conduct of research and care of patients. Trials including NADIM and CheckMate 816 have demonstrated the synergetic effect of chemotherapy and immunotherapy for pathological complete response (pCR) and event-free survival (3,4). Specifically, the NADIM trial revealed an overall survival of 81.9% at 36 months for patients receiving both chemotherapy and immunotherapy prior to surgery in comparison to preoperative platinum-based chemotherapy alone (3). However, neither NADIM nor CheckMate 816 investigated the use of further adjuvant immunotherapy following surgical intervention. Prior trials have examined timing of immunotherapy, including AEGAN and KEYNOTE671 which studied the effects of perioperative immunotherapy as well as NEOSTAR and Impower010 which evaluated only neoadjuvant immunotherapy and only adjuvant immunotherapy, respectively (5-8). Provencio and colleagues (9) recently explored the benefit of additional adjuvant immunotherapy for stage III disease, demonstrating that perioperative immunotherapy with chemotherapy led to a higher percentage of patients with a pathological complete response and longer survival than chemotherapy alone.

NADIM II study

Provencio and colleagues report on a comprehensive, well-designed randomized phase 2 clinical trial enrolling 86 patients with resectable stage IIIA or IIB NSCLC to receive neoadjuvant nivolumab plus platinum-based chemotherapy or chemotherapy alone, followed by surgical resection to compare pCR and overall survival (9). Patients in the experimental group who had R0 resections also received adjuvant treatment with nivolumab for 6 months. A complete pathological response (cPR) was found to be greater in the experimental group (37%) when compared to patients not receiving neoadjuvant immunotherapy with chemotherapy. In addition, progression-free survival at 24 months was greater in those patients receiving both concurrent treatment modalities (67.2%) than those receiving chemotherapy alone prior to surgical resection (40.9%). The trial included participants who were well-representative of the general population for results to be applicable. The methodology, selection of patients, and statistical analysis were appropriate given the results reported.

The NADIM II study; however, exclusively included only stage IIIA or IIB disease and therefore cannot be generalized for all patients with NSCLC. In addition, the study emphasized the utility of circulating tumor DNA (ctDNA) as a marker for prognosis after finding 67% of patients in the experimental group were ctDNA-negative after neoadjuvant treatment compared to 44% in the control group. Caution, however, should be taken in uniformly applying results as ctDNA platforms have not yet been formally standardized or evaluated.

The NADIM II study described key patient baseline characteristics to benefit from perioperative immunotherapy in combination with chemotherapy for stage III NSCLC. For example, according to NADIM II, programmed death-ligand 1 (PD-L1) positive patients benefited more from neoadjuvant immunotherapy than PD-L1 negative patients. In addition, when comparing histological subtypes of tumor burden, patients with non-squamous tumors benefited more compared to patients with squamous-cell tumors. Lastly, patients who achieved pCR after surgical resection had improved long-term efficacy than that of patients with major pathologic response (mPR).

Based upon these findings, Provencio and colleagues propose clarified recommendations for patients diagnosed with stage III NSCLC, for which there is no current accepted consensus by demonstrating improved outcomes with neoadjuvant and adjuvant immunotherapy with chemotherapy following surgical resection. The authors also report on the outcomes of adjuvant immunotherapy following R0 resection, which was not previously investigated in the CheckMate 816 trial. The improved survival among patients who completed adjuvant treatment compared to those who did not corroborated results of prior studies, such as Impower010 (8). Additionally, these analyses add to the results of the NADIM trial, which included assessing the addition of adjuvant nivolumab following R0 surgical resection in comparison to the standard-of-care neoadjuvant chemotherapy (3).

Safety data

Applying the NADIM II protocol into the clinical setting will require intensive oversight to ensure patient safety, specifically for monitoring of chemotherapy and immunotherapy side-effects. As such, special task forces may need to be created within hospital subdivisions to monitor and collect patient lab values. For instance, in the NADIM II trial, laboratory assessments were collected every 3 weeks to evaluate for adverse effects of medications. Awareness of such implications, establishing a plan for toxicity management, and setting-up follow-up arrangements for patients to have continuous monitoring while on chemotherapy and immunotherapy will need to be established by a hospital committee prior to initiating the NADIM II protocol at an institution. Furthermore, patients will need to be educated on the time commitment such an intensive protocol entails prior to setting-up similar programs within hospital systems.

Discussion

In this important contributory investigation, the authors provide invaluable guidance for clinicians in the treatment of stage III NSCLC. The precedent of combining neoadjuvant chemotherapy with nivolumab has already been proven to prolong event-free survival in the NADIM trial. Not unexpectedly, the Impower010 study found improved overall survival with adjuvant immunotherapy following chemotherapy in resected NSCLC (8,10). Given this successful application of immunotherapy with chemotherapy in the neoadjuvant treatment algorithm, exploring the utility of adjuvant immunotherapy following surgical resection is a natural next step. This trial comes in timely manner, as clinical practice in thoracic surgery is evolving to incorporate immunotherapy as a new treatment modality. In particular, the results from Provencio and colleagues offer particular clinical guidance in the management of stage III NSCLC. Therefore, publishing these results and discussing their application into practice has substantial value.

However, the NADIM II trial differed from other prior trials, including CheckMate 816 and Impower010. The NADIM II study only enrolled a total of 86 patients, which is less in comparison to other studies such as the Checkmate 816 and Impower010 study which enrolled a total of 358 and 1,280 patients, respectively. In addition, the NADIM II study is also limited in its design as a randomized phase II clinical trial rather than a phase III. The Impower010 study included patients across 22 countries in a phase 3 clinical trial. By contrast, the NADIM II study was conducted at 21 hospitals within 1-country. While patients positive for epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK) mutations were excluded in the NADIM II study, patients with receptor-positive disease were eligible to enroll in the Impower010 trial. Although both Impower010 and NADIM II supported the use of adjuvant immunotherapy following surgical resection of NSCLC, the NADIM II study uniquely also reinforced this concept by comparing baseline and post-treatment ctDNA levels. The level of ctDNA was also evaluated by the CheckMate 816 trial and found that patients undergoing neoadjuvant immunotherapy and chemotherapy had a higher clearance of ctDNA, and in turn, higher pCR and event-free survival. However, the NADIM II study showed impressive percentage of patients with ctDNA clearance in their experimental group, 67% versus 56% in CheckMate 816. In an era where personalized medicine is gaining more attention, having ctDNA as an additional prognostic tool for clinicians is key. Following the third cycle of neoadjuvant chemotherapy and immunotherapy, eligible patients in the NADIM II study underwent surgical resection within 3–4 weeks. By comparison, the Checkmate 816 trial scheduled patients for surgery within 6 weeks after the completion of 3 cycles of neoadjuvant treatment.

The Checkmate 77T randomized 461 patients as a part of a phase III, double-blind trial and showed that perioperative chemotherapy with immunotherapy followed by surgical resection and adjuvant immunotherapy further improved outcomes for patients with stage IIA/IIIB NSCLC disease (11). In the Checkmate 77T trial, 70% of patients in the nivolumab group experienced 18-month event-free survival compared to 50% in the chemotherapy group (P<0.001). It was also observed that a higher percentage of patients in the immunotherapy group had a pCR (25.3% versus 4.7%) and a mPR (35.4% versus 12.1%) compared to those in the chemotherapy group, respectively (11). While subgroup analysis in the Checkmate 77T found it underrepresented Black patients, its patient population was otherwise largely representative of the general population. The findings from Checkmate 77T are consistent with the results from the NADIM II trial for patients with resectable NSCLC.

In NADIM II, the addition of nivolumab to neoadjuvant chemotherapy resulted in a higher percentage of patients with a cPR (37% versus 7%) and mPR (53% versus 14%) compared to patients receiving chemotherapy alone. Irrespective of achieving mPR and cPR, the NADIM II study provided adjuvant therapy to all patients with an R0 resection. The results from NADIM II did not investigate the utility of adjuvant therapy in patients with pCR and mPR but instead focused on the combination of adjuvant immunotherapy with chemotherapy following surgical resection. This is an area of interest for future potential research, as all patients with R0 resection received adjuvant therapy in this particular study.

While the pCR rate was greater in the prior NADIM trial (63%) than the more recent NADIM II trial (37%), the authors discovered the planned dose of carboplatin differed, with an area under the concentration-time curve of 6 mg per milliliter per minute and 5 mg per milliliter per minute for each trial, respectively (3,9). Additionally, a previous comparative analysis of neoadjuvant nivolumab plus chemotherapy versus standard care with chemotherapy alone for 505 patients with stage IB to IIIA NSCLC was explored in the phase 3 CheckMate 816 trial, in which a pCR was achieved in 24% of patients in the experimental group compared to 2.2% for patients receiving chemotherapy alone (4). By comparison, the study by Provencio and colleagues found a greater percentage of pathologic complete response at 37%, although their study did include fewer randomized patients. These studies certainly laid the groundwork for promoting the use of immunotherapy while also raising awareness about the nuances that require additional evaluation in the future such as titrating chemotherapy dosages in combination with immunotherapy. We applaud the authors for actively looking into novel applications of immunotherapy in both the neoadjuvant and adjuvant settings for stage III NSCLC.

Conclusions

The nuanced treatment algorithm for lung cancer is constantly evolving as new immunotherapy regimens expand, enabling progress in our clinical practice. Provencio et al. (9) should be recognized for their dedication to excel beyond the current standards of treatment and apply new methodology in the treatment of stage III NSCLC.

Multiple studies have evaluated the timing and application of neoadjuvant versus adjuvant immunotherapy and chemotherapy. The NADIM II study showed promising results but may not necessarily be applicable to all patients. For patients achieving cPR after pre-operative, neoadjuvant therapy, the addition of adjuvant therapy may not be warranted; however, additional research will be needed to further investigate this topic. Additionally, personalizing adjuvant treatment options to the individual patient following neoadjuvant treatment will likely need additional research in the future. For instance, patients achieving cPR and mPR may not necessarily receive the same post-operative adjuvant treatment modalities. As we gain more insight into efficacious treatment options for NSCLC, we enter an exciting new field of study to titrate treatment options based on the individual patients’ clinical response.

Moving forward, we anticipate additional advances to stem as a result from this work, such as optimizing immunotherapy regimens based on histology and providing personalized medicine as a multimodal approach to lung cancer treatment. We again praise the authors on conducting a well-designed study that provides cutting-edge care to lung cancer patients.

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-24-88/prf

Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://actr.amegroups.com/article/view/10.21037/actr-24-88/coif). M.B.A. has served as a consultant for Merck, Astra Zeneca, ETHICON, and Bristol Myers Squibb. 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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