At present, interest in the application of molecular-targeted therapy or immunotherapy in lung cancer has increased, especially in the neoadjuvant setting, whether combined or not with chemotherapy. In the future, this could become the standard of care in resectable NSCLC, in particular for LA cases, thus modifying the current standard surgical approach.
Surgery plays a role as part of a multidisciplinary strategy in LA NSCLC, which can be considered a systemic disease. Especially in N1-N2 cases, the goal is the radical resection of the local component of the disease, and established surgical principles can be identified. En bloc anatomical lung resection with removal of the involved structures (e.g., chest wall, pericardium) with or without proper reconstruction is the standard of surgical excision; lobectomy is the most common type of resection, while pneumonectomy, particularly on the right side, should be avoided when possible, and being replaced by sleeve lobectomy or bilobectomy where feasible [
47,
48,
49,
50].
At present, the high heterogeneity of patients, the lack of detailed surgical and clinical outcomes, and short follow-up represent limits in determining whether neoadjuvant immunochemotherapy can become the best treatment strategy, and further data are needed. However, these preliminary reports suggest that surgery is feasible in LA NSCLC stages after neoadjuvant treatment, although with slight risks. VATS is the most commonly used surgical approach (in 20–51% of cases) while conversion to open surgery ranges from 3–19% of cases. Lobectomies were performed in 77–85% of cases, and pneumonectomies in 8–17% of cases. Globally, the complication rate is relevant at about 40% of cases; however, perioperative deaths are no more than 4%.
5. Summary
Over the past decades, platinum-based chemotherapy has been the main systemic therapy option for LA NSCLC [
58].
The discovery of driver mutations, such as
EGFR in 2004, has led to the development of new molecular targeted therapies, which have shown an increase in survival and improved quality of life for patients carrying these mutations [
59].
In this scenario, there is a growing interest in neoadjuvant immunotherapy, whether or not in combination with chemotherapy, for the treatment of LA NSCLC.
More recently, ICIs have become a new strong approach against cancer; unlike chemo- and radiotherapy, which directly interferes with tumour growth and survival, immunotherapy addresses the tumour indirectly by increasing spontaneous immune responses. Immunotherapy works on ICs through action against CTLA-4 and the PD-1/PD-L1 pathway [
60,
61].
In advanced cases, the combination of chemotherapy plus immunotherapy has been demonstrated to be effective in terms of EFS and OS [
62,
63].
Several trials have investigated neoadjuvant single-agent ICI in NSCLC, with promising results. In the phase II Lung Cancer Mutation Consortium 3 (LCMC3) trial, the administration of two cycles of atezolizumab followed by one year of adjuvant treatment resulted in an MPR rate of 21% and pCR rate of 7% in stage IB-IIIB NSCLC patients [
64]. Any unexpected toxicities were determined in the safety study PRINCEPS, which explored a single dose of atezolizumab in 30 resectable NSCLC patients [
65]. In the phase II NEOMUN trial, two cycles of pembrolizumab before surgery were demonstrated to be safe and feasible; indeed, 27% of patients experienced MPR [
66]. Gao et al. reported encouraging results with the anti-PD-1 inhibitor sintilimab in 40 stage IA-IIIB NSCLC patients, with fifteen (40.5%) patients achieving MPR [
67]. The phase II IONESCO trial evaluating neoadjuvant durvalumab was stopped due to excessive 90-day postoperative mortality (9%); MPR was 18.6% [
68]. Neoadjuvant nivolumab alone and in combination with ipilimumab demonstrated a 22% and 38% MPR rate, respectively, in the phase II NEOSTAR trial [
69].
Results from clinical trials show promising results of both PD-1/PD-L1 inhibitors and immunochemotherapy as neoadjuvant treatments. Data on the anti-CTLA-4 antibody as a neoadjuvant single agent are not reported; however, promising results have been described with a dual-agent immune checkpoint blockade. A large number of ongoing phase III trials for ICI therapies are showing promising results, with longer overall survival and better response to treatment in both pre-operative and adjuvant settings [
70].
In clinical trials investigating immunotherapy, women are always underrepresented compared to men. However, an individual’s sex is known to be an important modulator of the efficacy and toxicity associated with anticancer treatments, particularly for ICIs. Indeed, it is well established that sex-associated hormones can interfere with immune responses, with females showing stronger innate and adaptive immune responses compared to males. Further studies focused on improving the efficacy of ICIs in women are needed [
72,
73].
To date, there is no consensus on the use of PD-L1 expression as a predictive biomarker for neoadjuvant immunotherapy. In several trials, including LCMC3 and NCT02716038, MPR was described regardless of PD-L1 tumour expression. However, patients with elevated pre-treatment PD-L1 levels had a greater pathologic response in the NEOSTAR trial [
74].
LA NSCLC is usually referred to as stage III, as stated by ESMO and the American College of Chest Physician (ACCP) [
47,
75]; however, this is not a standardized and widespread definition. Referring to cancer invading contiguous lung structures and limited to locoregional lymph nodes and no distant metastasis [
75] should be described by T3-T4 and N0-N2 as stages IIB-IIIA (and T3-T4 N2 of IIIB). From a surgical point of view, when considering resectability criteria LA NSCLC should be defined as IIB-IIIA. At present, there is no consensus on whether neoadjuvant treatment should be used to achieve otherwise impossible resection or to increase survival in already potentially resectable patients [
76,
77].
Some concerns must be kept in mind when proposing induction treatment in LA NSCLC cases, especially if downstaging of the disease to achieve resectability is the goal.
The aforementioned trials suggest that among LA NSCLC patients who are candidates for neoadjuvant immunochemotherapy, a variable number (up to 46%) are excluded from resection. This group can benefit from definitive chemoradiotherapy and eventually biological therapy [
47,
78]; moreover, in the absence of a neoadjuvant chemotherapy comparison arm in the different studies, it would be interesting to compare the outcomes of patients from the same populations in the same institutions subjected to standard neoadjuvant chemotherapy. However, further data are needed on the full comparison between no induction treatment and neoadjuvant chemotherapy-only groups regarding TRAEs, surgical outcomes, EFS, and OS.
Immunotherapy is generally well tolerated, although significant toxicities have been reported in patients treated with ICIs [
79]. The incidence of immune-related AEs (irAEs) with ICIs varies depending on the agent. To date, the most common irAEs described are dermatological toxicity, diarrhoea, hepatitis, endocrinopathies, and pneumonitis [
80].
6. Conclusions
In conclusion, neoadjuvant immunotherapy, whether combined or not with chemotherapy, appears to offer a promising survival benefit for patients with LA NSCLC. However, a definitive comparison with neoadjuvant chemotherapy remains to be found. Progress is being made in the identification of the best candidates for neoadjuvant regimens and immunotherapy. Of note, a variable percentage of patients obtain long-term survival; these findings could create a paradigm shift in NSCLC treatment. Nevertheless, the LA NSCLC treatment strategy is difficult to standardize, as it should generally be tailored to single patients and their particular context; a multidisciplinary discussion is mandatory in these cases. Alternative neoadjuvant therapies represent a relatively new and less explored field, and more studies are needed.