Neoadjuvant immunotherapy for resectable non-small cell lung cancer—what lies ahead

Immunotherapy has transformed the treatment paradigm for metastatic and unresectable non-small cell lung cancer (NSCLC) (1,2). Based on these encouraging reports, the role of neoadjuvant immunotherapy, with or without chemotherapy, has been explored in patients with resectable NSCLC. Neoadjuvant immunotherapy is proposed to confer benefits through the increased release of neoantigens from the tumor and by enhanced control of micro-metastases (3). It also allows for histopathological assessment of patients’ responses to immunotherapy. Since the first study was published by Yang et al. (4), a number of trials (5,6) have assessed the safety and feasibility of this relatively novel regimen. A recent systematic review and meta-analysis identified eighteen studies, involving 507 patients who underwent surgical resection after treatment with neoadjuvant immunotherapy (7). Safety was demonstrated by a pooled perioperative mortality of 0.6%. In regard to efficacy, major pathological response was reported in 52%, and complete pathological response of the primary lung cancer was identified in 24%. When complete pathological response was specifically reported in both the primary lung lesion as well as the assessed lymph nodes, the rate was reported as 20%.

To address the question of long-term oncological efficacy, Rosner and colleagues should be congratulated on their recent publication that examined the 5-year follow-up outcomes of patients who underwent neoadjuvant nivolumab (8). Existing data now suggest a trend towards favourable oncological outcomes for patients who had increased programmed death ligand 1 (PD-L1) expression (9), or those found to have major pathological response (10). Of the 20 patients who underwent definitive resection, 10 remained alive, with those who were found to have a major pathological response showing a trend towards improved recurrence-free survival. Tumor mutational burden and PD-L1 were also examined for their prognostic value, with a trend favouring those who had pre-treatment tumor PD-L1 positivity having improved recurrence-free survival. Tumour mutational burden was not associated with overall or recurrence-free survival outcomes. When the exploratory analysis was performed for patients who had 50% residual viable tumor or those who had ‘partial response’, patients were shown to have a trend towards improved recurrence-free survival. Overall, the greatest limitation of this study was its relatively small size, with 20 patients analyzed for their 5-year survival.

There is little doubt that the pathological response to neoadjuvant immunotherapy with chemotherapy is superior to historical data on neoadjuvant chemotherapy alone. However, a number of questions remain, and some will be more challenging than others to answer in the coming years. Whilst short-term (and cheaper to measure) surrogate endpoints such as major and complete pathological response have been demonstrated to correlate with improved survival by studies such as “Neoadjuvant chemotherapy and nivolumab in resectable non-small-cell lung cancer (NADIM): an open-label, multicentre, single-arm, phase 2 trial” (5) and “Neoadjuvant nivolumab or nivolumab plus ipilimumab in operable non-small cell lung cancer: the phase 2 randomized NEOSTAR trial” (6), do these correlate to traditional endpoints such as overall survival at long-term follow-up? What predictors can help with patient selection to identify those who will benefit the most from immunotherapy in the neoadjuvant setting? From a surgeon’s perspective, what are the predictors of dense adhesions that may be encountered intraoperatively, that may pose a challenge to safe anatomical dissection? What is the role of adjuvant immunotherapy for those who responded, or did not respond to neoadjuvant treatment? This would be significant from both a clinical and financial perspective, as additional adjuvant immunotherapy was prescribed routinely in some trials (11,12).

Part of the challenge of the single-arm design of this study was due to the relative novelty of immunotherapy, with limited data on perioperative safety and feasibility. Rather than providing definitive evidence, this study serves as a useful template for future studies with larger cohorts of patients to report on the long-term survival outcomes of patients who underwent neoadjuvant immunotherapy and the predictive value of pathological response and serological markers on oncological efficacy. Further data on quality of life and functional outcomes following neoadjuvant immunotherapy and surgery would be paramount to identify patient-centred endpoints in conjunction with oncological outcomes. With longer follow-up from larger trials (13,14) imminently due to mature in the coming years, we await with great anticipation and interest for insightful data to guide our clinical practice for patients with resectable NSCLC.

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-23-6/prf

Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://actr.amegroups.com/article/view/10.21037/actr-23-6/coif). CC is a proctor for Device Technologies Australia and is also on the scientific committee/education steering committees for AstraZeneca, BeiGene, Bristol Myers Squibb Medical, Johnson & Johnson, Lexington Medical, and Roche. DKYN 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.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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