An Updated Review of Management of Resectable Stage III NSCLC in the Era of Neoadjuvant Immunotherapy

Abstract

Immune-checkpoint inhibitors (ICIs) have an established role in the treatment of locally advanced and metastatic non-small cell lung cancer (NSCLC). ICIs have now entered the paradigm of early-stage NSCLC. The recent evidence shows that the addition of ICI to neoadjuvant chemotherapy improves the pathological complete response (pCR) rate and survival rate in early-stage resectable NSCLC and is now a standard of care option in this setting. In this regard, stage III NSCLC merits special consideration, as it is heterogenous and requires a multidisciplinary approach to management. As the neoadjuvant approach is being adopted widely, new challenges have emerged and the boundaries for resectability are being re-examined. Consequently, it is ever more important to carefully individualize the treatment strategy for each patient with resectable stage III NSCLC. In this review, we discuss the recent literature in this field with particular focus on evolving definitions of resectability, T4 disease, N2 disease (single and multi-station), and nodal downstaging. We also highlight the controversy around adjuvant treatment in this setting and discuss the selection of patients for adjuvant treatment, options of salvage, and next line treatment in cases of progression on/after neoadjuvant treatment or after R2 resection. We will conclude with a brief discussion of predictive biomarkers, predictive models, ongoing studies, and directions for future research in this space.

Neoadjuvant and Adjuvant Immunotherapy in Resectable NSCLC

“…Given that the intent of all these approaches is curative, it is of great importance to minimize potential risks of lifetime consequences in patients that could otherwise be free of disease, and since most of AEs occur in the adjuvant setting of the perioperative schemes, mainly due to its longer duration, it is crucial to tailor the therapeutic schedule according to the patient in question. For instance, although underrepresented in many trials, patients with stage II disease have better OS rates [75]. Additionally, as mentioned above, patients who achieve pathologically complete response also achieve better EFS and OS rates.…”

“…HRQoL data are also awaited from other immunotherapy trials, especially in the postsurgical period, that better assess the effect of adjuvant immunotherapy on the quality of life, as longer follow-up data become available. Clearly, all future research should entail health-related symptoms and quality of life measures, defined by both patients and physicians, to capture the holistic effects of this landscape-reshaping approach on patients [75].…”

“…Checkmate-159 was the first trial to demonstrate a positive correlation between pretreatment PD-L1 levels and favorable outcomes, with several similar results from NADIM, NADIM II, and LCMC3 following it. It is unquestionably a useful marker of clinical benefit; however, selecting or excluding patients based on PD-L1 expression alone could have detrimental consequences, as patients with negative expression below 1% have achieved pCR after neoadjuvant ICI treatment [75]. Lastly, research on molecular biomarkers and signatures is currently under scrutiny; an interesting analysis was concluded by Checkmate-816, for instance, where a four-gene (CD8A, STAT1, LAG3, and CD274) inflammatory signature score was analyzed by pCR and MPR.…”

“…A high or low inflammatory signature score was also correlated with EFS, with rates at 36 months of 70% and 50%, respectively, for high and low scores for the immunotherapy arm compared to almost identical numerical rates for the chemotherapy arm (Awad et al, ESMO 2023 [39]). Such analyses harbor great potential regarding decision making in the future, although currently only at the very early stage, and nonetheless, they require more thorough research to be translated and incorporated into clinical practice [75][76][77].…”

“…A second question that remains unanswered is whether patients that fail to achieve pCR or MPR do actually benefit from continuing on the same immunotherapy protocol and whether treatment escalation attempts should be made, perhaps with the addition of another ICI agent-CTLA-4, LAG-3, etc.-or ADCs to achieve better therapeutic outcomes. To date, there is no strong evidentiary support that response to neoadjuvant treatment should further guide adjuvant treatment decisions [53,75,83,84].…”