Predicting the response to neoadjuvant chemoimmunotherapy in patients with resectable non-small cell lung cancer (NSCLC) facilitates clinical treatment decisions. Our study aimed to establish a machine learning model that accurately predicts the pathological complete response (pCR) using 18F-FDG PET radiomics features.

We retrospectively included 210 patients with NSCLC who completed neoadjuvant chemoimmunotherapy and subsequently underwent surgery with pathological results, categorising them into a training set of 147 patients and a test set of 63 patients. Radiomic features were extracted from the primary tumour and lymph nodes. Using 10-fold cross-validation with the least absolute shrinkage and selection operator method, we identified the most impactful radiomic features. The clinical features were screened using univariate and multivariate analyses. Machine learning models were developed using the random forest method, leading to the establishment of one clinical feature model, one primary tumour radiomics model, and two fusion radiomics models. The performance of these models was evaluated based on the area under the curve (AUC).

In the training set, the three radiomic models showed comparable AUC values, ranging from 0.901 to 0.925. The clinical model underperformed, with an AUC of 0.677. In the test set, the Fusion_LN1LN2 model achieved the highest AUC (0.823), closely followed by the Fusion_Lnall model with an AUC of 0.729. The primary tumour model achieved a moderate AUC of 0.666, whereas the clinical model had the lowest AUC at 0.631. Additionally, the Fusion_LN1LN2 model demonstrated positive net reclassification improvement and integrated discrimination improvement values compared with the other models, and we employed the SHapley Additive exPlanations methodology to interpret the results of our optimal model.

Our fusion radiomics model, based on 18F-FDG-PET, will assist clinicians in predicting pCR before neoadjuvant chemoimmunotherapy for patients with resectable NSCLC.

Programmed-death-1/ligand-1 inhibitors (PD-1/L1is) have emerged as pivotal treatments for many cancers. A notable feature of this class of medicines is the dichotomous response pattern: A small (but clinically relevant) percentage of patients (5%-20%) benefit from deep and durable responses resembling functional cures (durable responders), while most patients experience only a modest or negligible response. Accurately predicting durable responders remains elusive due to the lack of a reliable biomarker. Another notable feature of these medicines is that different PD-1/L1 is have obtained statistically significant results, leading to marketing approval for some cancer indications but not for others, with no discernible pattern. These puzzling inconsistencies have generated extensive discussions among oncologists. Proposed (but not entirely convincing) explanations include true underlying differences in efficacy for some types of cancer but not others; or subtle differences in trial design. To investigate a less-explored hypothesis-the durable-responder effect: An initially unidentified group of durable responders generates more statistical noise than anticipated, leading to low-powered randomized controlled trials (RCTs) that report randomly variable results.

Employing simulation, this investigation divides participants in PD-(L)1i RCTs into two groups: durable responders and patients with a more modest response. Drawing on published data for melanoma, lung and urothelial cancers, multiple prespecified scenarios are replicated 50,000 times, systematically varying the durable-responder percentage from 5% to 20% and the modest-response hazard ratio for overall survival [HR(OS)] from 0.8 to 1.0. This allowed evaluation of the effect of durable responders on power, point estimates of the treatment effect for OS, and the probability of a misleading signal for harm.

When the treatment effect for the modest responders is similar to the comparator arm, statistical power remains below 80%, limiting the ability to reliably detect durable responders. Conversely, there is a material probability of obtaining a statistically significant result that exaggerates the treatment effect by chance. For instance, with an average HR(OS) of 0.93 (corresponding to 5% durable responders), statistically significant trials (7.2%) show an average HR(OS) of 0.77. Additionally, when 5% are durable responders, there is a 20% probability that the HR(OS) will exceed 1.0-suggesting potential harm when none exists.

This article adds to the possible explanations for the puzzlingly inconsistent results from PD-(L)1i RCTs. Initially, unidentified durable responders introduce features typical of imprecise, low-powered studies: a propensity for false-negative results; estimates of benefit that might not replicate; and misleading signals for harm.

Programmed-death-1/ligand-1 (PD-1(L)1) inhibitors are crucial cancer treatments, with global spending expected to surpass $75 billion by 2026. Multiple versions of these medicines are available, all designed to boost the immune system to fight cancer. We would expect them all to work similarly, but clinical trials show mixed results-some seem effective for certain cancers but not others, without a clear pattern. This article uses simulations (virtual trials) to suggest that these inconsistent results may be due to chance, caused by a small group of patients who respond very well to the treatment. Larger trials or specific analysis methods could help reduce the chance effects and provide more robust data for clinician and patient decision-making.

Therapeutic strategies for early-stage non-small cell lung cancer (NSCLC) are advancing, with immune checkpoint inhibitors (ICIs) and targeted therapies making their way into neoadjuvant and adjuvant settings. With recent advances, there was a need for multidisciplinary lung cancer healthcare providers from across Ontario to convene and review recent data from practical and implementation standpoints. The focus was on the following questions: (1) To what extent do patient (e.g., history of smoking) and disease (e.g., histology, tumor burden, nodal involvement) characteristics influence treatment approaches? (2) What are the surgical considerations in early-stage NSCLC? (3) What is the role of radiation therapy in the context of recent evidence? (4) What is the impact of biomarker testing on treatment planning? Ongoing challenges, treatment gaps, outstanding questions, and controversies with the data were assessed through a pre-meeting survey, interactive cases, and polling questions. By reviewing practice patterns across Ontario cancer centers in the context of evolving clinical data, Health Canada indications, and provincial (Cancer Care Ontario [CCO]) funding approvals, physicians treating lung cancer voiced their opinions on how new approaches should be integrated into provincial treatment algorithms. This report summarizes the forum outcomes, including pre-meeting survey and polling question results, as well as agreements on treatment approaches based on specific patient scenarios.

Immune checkpoint inhibitors (ICIs) have become standard-of-care at different stage disease in non-small cell lung cancer (NSCLC). Based on the increasing characterization of molecular aberrations and oncogenic drivers in NSCLC, it is expected that more and more patients will benefit from orally small targeted therapies in NSCLC. However, their concomitant or sequential use is associated with an increased risk of a various toxicity pattern.

Relevant publications were included if they reported data on the question of toxicities associated with sequential or combined use of ICIs and small targeted therapies used in NSCLC treatment. MEDLINE, Google Scholar, and the Cochrane Library were searched for the following request, from database inception until June 2023.

This review highlighted a various pattern of toxicities (i.e., interstitial lung disease, hepatitis, dermatoses) in the context of both sequential and concomitant administration of ICIs and small targeted therapies. Such toxicities seem rather a "drug-effect" than a "class-effect" and some of these toxicities are more specific of a small targeted therapy. This review highlights on the impact of treatment sequence administration and emphasis for physicians to be particularly careful whether small targeted therapy is administered within one to three months after last ICIs injection.

Physicians have to be aware of severe toxicities in case of both concomitant or sequential ICIs/small targeted therapies administration in NSCLC. Further studies are needed to better understand the mechanisms underlying these toxicities in order to prevent them and to refine ICIs and small targeted therapy sequencing strategy.

Optimal personalized treatment planning for resectable lung cancer requires quality-assured, standardized and prompt processing of tissue samples in pathological laboratories, as well as the determination of relevant predictive and prognostic biomarkers. Pathological diagnostic testing includes histological tumor typing, staging and tumor grading, resection status and, if necessary, regression grading after neoadjuvant systemic therapy. Histopathological typing is performed according to the current WHO classification and includes adenocarcinomas, squamous cell carcinomas, other non-small cell lung carcinomas (NSCLCs), carcinoids, small cell and large cell neuroendocrine carcinomas. Standardized tumor grading currently plays an important role in invasive non-mucinous adenocarcinoma in particular and enables prognostic risk assessment. The R classification and regression grading are also prognostically relevant. In the early stages of NSCLC, molecular biomarkers such as EGFR, ALK and PD-L1, are relevant for decisions on individual treatment. Testing is performed on FFPE tissue samples and must be carried out in a quality-assured manner and in accordance with international standards.

Patients with stage III NSCLC with N2 lymph node involvement carry a complex and diverse disease entity. Challenges persist in the areas of diagnosis, staging, multimodal management, and the determination of surgical indications and resectability criteria. Therefore, this review focuses on the latest updates in N2 disease staging and its prognostic and treatment implications. Emphasis is placed on the importance of accurate staging using imaging modalities such as [18F]FDG-PET/CT as well as minimally invasive mediastinal staging endoscopic techniques. The evolving role of surgery in the management of N2 disease is also explored. The benefits of neoadjuvant and adjuvant treatments have been demonstrated, along with the efficacy of a combined multimodal approach with chemo-immunotherapy in the perioperative setting, reigniting the debate of N2 disease subsets and optimal treatment options. Furthermore, this review addresses the controversies surrounding surgical approaches in upfront "borderline" resectable stage III NSCLC as well as the benefits of combined chemoradiotherapy with consolidation immunotherapy for patients with unresectable tumors. In conclusion, personalized diagnostic and treatment approaches tailored to individual patient characteristics, resource availability, and institutional expertise are essential for optimizing outcomes in patients with stage III-N2 NSCLC.

The resected pⅢA-N2 non-small-cell lung cancer (NSCLC) patients who could benefit from postoperative radiotherapy (PORT) are not well-defined. The study explored the role of PORT on EGFR mutant and wild-type NSCLC patients. We retrospectively searched for resected pIIIA-N2 lung adenocarcinoma patients who underwent EGFR mutation testing. 80 patients with EGFR wild-type and 85 patients with EGFR mutation were included. 62 patients received PORT. In overall population, the median disease-free survival (DFS) was improved in PORT arm compared to non-PORT arm (22.9 vs. 16.1 months; p = 0.036), along with higher 2-year locoregional recurrence-free survival (LRFS) rate (88.3% vs. 69.3%; p = 0.004). In EGFR wild-type patients, PORT was associated with a longer median DFS (23.3 vs. 17.2 months; p = 0.044), and a higher 2-year LRFS rate (86.8% vs. 61.9%; p = 0.012). In EGFR mutant patients, PORT was not significantly correlated with improved survival outcomes. EGFR wild-type may a biomarker to identify the cohort that benefits from PORT.

Lung cancer poses a significant public health challenge, with resectable non-small cell lung cancer (NSCLC) representing 20 to 25% of all NSCLC cases, staged between I and IIIA. Despite surgical interventions, patient survival remains unsatisfactory, with approximately 50% mortality within 5 years across early stages. While perioperative chemotherapy offers some benefit, outcomes vary. Therefore, novel therapeutic approaches are imperative to improve patient survival. The combination of chemotherapy and immunotherapy emerges as a promising avenue. In this review, we explore studies demonstrating the benefits of this combination therapy, its impact on surgical procedures, and patient quality of life. However, challenges persist, particularly for patients failing to achieve pathologic complete response (pCR), those with stage II lung cancer, and individuals with specific genetic mutations. Additionally, identifying predictive biomarkers remains challenging. Nevertheless, the integration of immunotherapy and chemotherapy in the preoperative setting presents a new paradigm in managing resectable lung cancer, heralding more effective and personalized treatments for patients.

The therapeutic landscape of the management of stage III non-small cell lung cancer (NSCLC) has drastically evolved with the incorporation of immunotherapy and targeted therapy. Stage III NSCLC accounts for one-third of the cases and the treatment strategy of these locally advanced presentations are diverse, ranging from surgical to non-surgical options; with the incorporation of chemo-immunotherapy, radiation, and targeted therapies wherever applicable. The staging of this disease has also changed, and it is essential to have a strong multidisciplinary approach to do justice to patient care. In this article, we aim to navigate the nuanced approaches in the diagnosis and treatment of stage III NSCLC and expand on the evolution of the management of this disease.

For much of the past two decades, the treatment options for patients with stage III NSCLC were mostly stagnant. In the past 5 years, ongoing innovations have dovetailed alongside advances in biomarker testing, novel therapeutics, precision surgery, and radiotherapy, all of which are leading to an increase in more personalized option for the treatment. This review article will focus on several completed and ongoing initiatives involving treatment of patients with stage III NSCLC. First, it will tackle the progress made in curative treatment of unresectable stage III NSCLC, starting with PACIFIC, and branching out into topics such as concurrent immunotherapy and chemoradiation, intensification of consolidative immunotherapy, dual immunotherapy consolidation, and a reflection on those subpopulations that may not benefit from consolidative immunotherapy. Second, there will be discussion of novel strategies in the setting of resectable stage III disease, most notably neoadjuvant therapy using combined chemoimmunotherapy and immunotherapy alone before surgical resection. Third, it will delve into recent data evaluating adjuvant immunotherapy for resectable stage III NSCLC, including adjuvant targeted therapy (for those harboring driver mutations) and postoperative radiotherapy. Finally, a look to future trials/initiatives will be interspersed throughout the review, to reveal the ongoing efforts being made to continue to improve outcomes in this group of patients.

Lung cancer is the most common cause of cancer-related deaths worldwide. Non-small-cell lung cancer (NSCLC) represents the majority of lung cancer cases, and its standard treatment is primarily surgery. Nonetheless, this type of cancer exhibits an important rate of tumor recurrence. Immune checkpoint inhibitors (ICIs) have demonstrated significant survival benefits in many cancers, especially in early-stage NSCLC. This review considers the latest CheckMate816, IMpower010 and KEYNOTE-091 trials that led to US FDA approvals. The new wave of resectable NSCLC trial results are also summarized. Finally, the latest challenges for these treatment modalities, such as the choice between neoadjuvant and adjuvant use, the accurate identification of biomarkers and the presence of driver mutations such as EGFR, are discussed.

Tumor samples from the phase III IMpower010 study were used to compare two programmed death-ligand 1 (PD-L1) immunohistochemistry assays (VENTANA SP263 and Dako 22C3) for identification of PD-L1 patient subgroups (negative, positive, low, and high expression) and their predictive value for adjuvant atezolizumab compared with best supportive care (BSC) in resectable early-stage non-small cell lung cancer (NSCLC).

PD-L1 expression was assessed by the SP263 assay, which measured the percentage of tumor cells with any membranous PD-L1 staining, and the 22C3 assay, which scored the percentage of viable tumor cells showing partial or complete membranous PD-L1 staining.

When examining the concordance at the PD-L1-positive threshold (SP263: tumor cell (TC)≥1%; 22C3: tumor proportion score (TPS)≥1%), the results were concordant between assays for 83% of the samples. Similarly, at the PD-L1-high cut-off (SP263: TC≥50%; 22C3: TPS≥50%), the results were concordant between assays for 92% of samples. The disease-free survival benefit of atezolizumab over BSC was comparable between assays for PD-L1-positive (TC≥1% by SP263: HR, 0.58 (95% CI: 0.40 to 0.85) vs TPS≥1% by 22C3: HR, 0.65 (95% CI: 0.45 to 0.95)) and PD-L1-high (TC≥50% by SP263: HR, 0.27 (95% CI: 0.14 to 0.53) vs TPS≥50% by 22C3: HR, 0.31 (95% CI: 0.16 to 0.60)) subgroups.

The SP263 and 22C3 assays showed high concordance and a comparable clinical predictive value of atezolizumab at validated PD-L1 thresholds, suggesting that both assays can identify patients with early-stage NSCLC most likely to experience benefit from adjuvant atezolizumab.

NCT02486718.

Therapeutic strategies harnessing the immune system to eliminate tumour cells have been successfully used for several cancer types, including in patients with advanced-stage non-small-cell lung cancer (NSCLC). In these patients, immune-checkpoint inhibitors (ICIs) can provide durable responses and improve overall survival either as monotherapy, or combined with chemotherapy or other immunotherapeutic agents. However, the implementation of ICIs in early stage NSCLC has been hampered by the continuous struggle to develop robust end points to assess their efficacy in this setting, especially those enabling a fast and reproducible evaluation of the clinical activity of neoadjuvant strategies. Several trials are testing ICIs, alone or in combination with chemotherapy, in early stage NSCLC as an adjuvant, neoadjuvant or perioperative approach. As a novelty, most trials in the neoadjuvant setting have adopted pathological response as a primary end point. ICIs have been approved for use in the neoadjuvant and adjuvant settings on the basis of event-free survival and disease-free survival benefit, respectively; however, the correlation of these end points with overall survival remains unclear in these settings. Unresolved challenges for the optimal use of ICIs with curative intent include concerns about their applicability in daily clinical practice and about improving patient selection based on predictive biomarkers or assessment of pathological response and minimal residual disease. In this Review, we discuss the rationale, available strategies and current trial landscape for the implementation of ICIs in patients with resectable NSCLC, and we further elaborate on future approaches to optimize their clinical benefit.

Adjuvant atezolizumab is a standard of care after chemotherapy in completely resected stage II-IIIA programmed death ligand-1 tumor cell 1% or greater non-small cell lung cancer based on results from the phase III IMpower010 study. We explored the safety and tolerability of adjuvant atezolizumab by surgery type in IMpower010.

Patients had completely resected stage IB-IIIA non-small cell lung cancer (Union Internationale Contre le Cancer/American Joint Committee on Cancer, 7th Ed), received up to four 21-day cycles of cisplatin-based chemotherapy, and were randomized 1:1 to receive atezolizumab 1200 mg every 3 weeks (≤16 cycles or 1 year) or best supportive care. Adverse events and clinical characteristics were investigated by surgery type (pneumonectomy/bilobectomy or lobectomy/sleeve lobectomy) in the randomized stage II-IIIA population who received 1 or more atezolizumab dose or with 1 or more postbaseline assessment (safety evaluable) for best supportive care.

Overall, 871 patients comprised the safety-evaluable randomized stage II-IIIA population. In the atezolizumab arm, 23% (100/433) received pneumonectomy/bilobectomy and 77% (332/433) received lobectomy/sleeve lobectomy. Atezolizumab discontinuation occurred in 32% (n = 32) and 35% (n = 115) of the pneumonectomy/bilobectomy and lobectomy/sleeve lobectomy groups, respectively. Grade 3/4 adverse events were reported in 21% (n = 21) and 23% (n = 76) of patients in the atezolizumab arms in the pneumonectomy/bilobectomy and lobectomy/sleeve lobectomy groups, respectively. In the atezolizumab arms of the surgery groups, 13% (n = 13) and 17% (n = 55) had an adverse event leading to hospitalization. Atezolizumab-related adverse events leading to hospitalization occurred in 5% (n = 5) and 7% (n = 23) of the surgery groups.

These exploratory findings support use of adjuvant atezolizumab after platinum-based chemotherapy in patients with completely resected stage II-IIIA programmed death ligand-1 tumor cell 1% or more non-small cell lung cancer, regardless of surgery type.

Neoadjuvant and adjuvant immune checkpoint blockade (ICB) have recently become standard of care in resectable non-small cell lung cancer (NSCLC). Yet, biomarkers that inform patients who benefit from this approach remain largely unknown. Here, we interrogated the tumor immune microenvironment (TIME) in early-stage NSCLC patients that underwent up-front surgery.

A total of 185 treatment-naïve patients with early-stage NSCLC, that underwent up-front surgical treatment between 2006 and 2018 at Hospital del Mar were included. 124 lung adenocarcinomas (LUADs), and 61 squamous cell carcinoma (LUSCs) were included in a tissue microarray. Immunohistochemistry for CD3, CD4, CD8, CD68, CD80, CD103, FOXP3, PD-1, PD-L1, PD-L2 and HLA class II were evaluated by digital image analysis (QuPath software). TIME was categorized into four groups using PD-L1 expression in tumor cells (<1 % or ≥1 %) and tumor resident memory (CD103⁺) immune cells (using the median as cut-off). We explored the association between different TIME dimensions and patient's clinicopathological features and outcomes.

We found increased levels of T cell markers (CD3⁺, CD4⁺, CD8⁺ cells), functional immune markers (FOXP3⁺ cells) as well as, higher HLA-II tumor membrane expression in LUADs compared to LUSCs (p < 0.05 for all). In contrast, LUSCs displayed higher percentage of intratumor macrophages (CD68⁺ cells) as well as, higher PD-L1 and PD-L2 tumor membrane expression (p < 0.05 for all). Unsupervised analysis revealed three different tumor subsets characterized by membrane tumor expression of PD-L1, PD-L2 and HLA-class II. Enrichment of T cells (CD3⁺, CD8⁺ cells), regulatory T cells (FOXP3⁺ cells) and macrophages (CD68⁺ cells) was observed in the CD103⁺/PD-L1⁺ group (p < 0.05 for all). Multivariate analysis showed that infiltration by CD103⁺ immune cells was associated with improved OS (p = 0.009).

TIME analysis in resected NSCLC highlighted differences by histology, PD-L1 expression and molecular subgroups. Biomarker studies using IHC might aid to individually tailor adjuvant treatment in early-stage NSCLC.

For patients with non-small-cell lung cancer (NSCLC), the outcomes for patients with resectable disease are historically poor compared with other solid organ malignancies. In recent years, there have been significant advances in multidisciplinary care, which have resulted in improved outcomes. Innovations in surgical oncology include the use of limited resection and minimally invasive techniques. Recent data in radiation oncology have suggested refinements in pre- and postoperative radiation therapy, resulting in optimization of techniques in the curative setting. Finally, the success of immune checkpoint inhibitors and targeted therapies in the advanced setting has paved the way for inclusion in the adjuvant and neoadjuvant settings, resulting in recent regulatory approvals for four regimens (CheckMate-816, IMpower010, PEARLS, ADAURA). In this review, we will provide an overview of the seminal studies informing advancements in optimal surgical resection, radiation treatment, and systemic therapy for resectable NSCLC. We will summarize the key data on survival outcomes, biomarker analyses, and future directions for perioperative studies.

Lung cancer is one of the most common solid malignancies. Tissue biopsy is the standard method for accurately diagnosing lung and many other malignancies over decades. However, molecular profiling of tumors leads to establishing a new horizon in the field of precision medicine, which has now entered the mainstream in clinical practice. In this context, a minimally invasive complementary method has been proposed as a liquid biopsy (LB) which is a blood-based test that is gaining popularity as it provides the opportunity to test genotypes in a unique, less invasive manner. Circulating tumor cells (CTC) captivating the Circulating-tumor DNA (Ct-DNA) are often present in the blood of lung cancer patients and are the fundamental concept behind LB. There are multiple clinical uses of Ct-DNA, including its role in prognostic and therapeutic purposes. The treatment of lung cancer has drastically evolved over time. Therefore, this review article mainly focuses on the current literature on circulating tumor DNA and its clinical implications and future goals in non-small cell lung cancer.

The phase III ADAURA (ClinicalTrials.gov identifier: NCT02511106) primary analysis demonstrated a clinically significant disease-free survival (DFS) benefit with adjuvant osimertinib versus placebo in EGFR-mutated stage IB-IIIA non-small-cell lung cancer (NSCLC) after complete tumor resection (DFS hazard ratio [HR], 0.20 [99.12% CI, 0.14 to 0.30]; P < .001). We report an updated exploratory analysis of final DFS data.

Overall, 682 patients with stage IB-IIIA (American Joint Committee on Cancer/Union for International Cancer Control, seventh edition) EGFR-mutated (exon 19 deletion/L858R) NSCLC were randomly assigned 1:1 (stratified by stage, mutational status, and race) to receive osimertinib 80 mg once-daily or placebo for 3 years. The primary end point was DFS by investigator assessment in stage II-IIIA disease analyzed by stratified log-rank test; following early reporting of statistical significance in DFS, no further formal statistical testing was planned. Secondary end points included DFS in stage IB-IIIA, overall survival, and safety. Patterns of recurrence and CNS DFS were prespecified exploratory end points.

At data cutoff (April 11, 2022), in stage II-IIIA disease, median follow-up was 44.2 months (osimertinib) and 19.6 months (placebo); the DFS HR was 0.23 (95% CI, 0.18 to 0.30); 4-year DFS rate was 70% (osimertinib) and 29% (placebo). In the overall population, DFS HR was 0.27 (95% CI, 0.21 to 0.34); 4-year DFS rate was 73% (osimertinib) and 38% (placebo). Fewer patients treated with osimertinib had local/regional and distant recurrence versus placebo. CNS DFS HR in stage II-IIIA was 0.24 (95% CI, 0.14 to 0.42). The long-term safety profile of osimertinib was consistent with the primary analysis.

These updated data demonstrate prolonged DFS benefit over placebo, reduced risk of local and distant recurrence, improved CNS DFS, and a consistent safety profile, supporting the efficacy of adjuvant osimertinib in resected EGFR-mutated NSCLC.

Immunotherapy with immune-checkpoint inhibitors (ICIs) targeting programmed cell death 1 or programmed death-ligand 1 has revolutionised the treatment of advanced non-small cell lung cancer (NSCLC) and has been investigated in early NSCLC, alone or in combination with chemotherapy, anti-CTLA-4 antibodies and radiotherapy. Although more mature data are needed before setting a change of paradigm in early stages, reports of pathological response rates and disease-free survival are promising, especially with neoadjuvant multimodality approaches. Nevertheless, major pathological response rates for neoadjuvant anti-PD-(L)1 monotherapy rarely exceed 40%, and biomarkers for characterising patients who may benefit the most from ICIs are lacking. These biomarkers have a distinct value from the metastatic setting, with highly different tumour biologies. Among the most investigated so far in this context, programmed death-ligand 1 expression and, to a lesser extent, tumour mutational burden seem to correlate better with higher pathological response rates and survival. Epidermal growth factor receptor, Serine/Threonine Kinase 11and Kelch-like ECH-associated protein 1 mutations rise as essential determinations for the treatment selection in early-stage NSCLC. Emerging and promising approaches comprise evaluation of blood-based ratios, microbiota, and baseline intratumoural TCR clonality. Circulating tumour DNA will be of great help in the near future when selecting best candidates for adjuvant ICIs, monitoring the tumour response to the neoadjuvant treatment in order to improve the rates of complete resections in the early stage.

Surgery followed by adjuvant chemotherapy is the standard of care for selected patients with early-stage or locally advanced non-small cell lung cancer (NSCLC). However, many of these patients still experience postoperative recurrence at 5 years. At present, peri-operative treatment methods are emerging to prevent early relapse, such as targeted therapy and immunotherapy. Investigation on predictive biomarkers of responses to adjuvant and neoadjuvant therapies is also continuously ongoing. Immunotherapy represented by immune checkpoint inhibitors (ICIs), either by monotherapy or in combination with chemotherapy, has shown benefit in promoting pathological responses and prolonging survival for patients with NSCLC without oncogenic mutations. Exploratory studies have also provided evidence regarding the selection of patients who benefit from ICI-based perioperative treatment. This review focuses on the existing data of current clinical trials of adjuvant and neoadjuvant strategies with ICIs in resectable NSCLC, the exploration of predictive biomarkers, and the perspectives and urgent challenges in the future.

As the immunotherapeutic milieu in resectable nonsmall cell lung cancer continues to evolve, the field of thoracic oncology actively moves towards better patient selection based on biomarkers and oncogenic drivers. In this article, we review the current standard of oncologic care in this population and discuss the ongoing phase III clinical trials investigating the use of immunotherapy or targeted therapy in the perioperative period. We also discuss genotyping initiatives, biomarkers, and trial endpoints.

Currently, chemotherapy is the standard adjuvant treatment for early-stage non-small cell lung cancer (NSCLC). However, adjuvant cisplatin-based chemotherapy after surgery has been shown to improve 5-year survival rates by only 4-5%. Immunotherapy using immune checkpoint inhibitors (ICIs) has revolutionized the treatment of advanced NSCLC, there is a growing interest in the role of immunotherapy in early-stage NSCLC. Here, we summarize the rationale for adjuvant immunotherapy, including the postoperative immunosuppressive environment and immunological effects of platinum chemotherapy. Many ongoing clinical trials and the related progress in adjuvant immunotherapy in early-stage resectable NSCLC are discussed. Furthermore, we highlight several unresolved challenges, including markers predictive of treatment benefit, the efficacy of treatment for some oncogene-addicted tumors, the optimal combination therapy, the duration of adjuvant immunotherapy, and optimal selection between neoadjuvant and adjuvant immunotherapy. Early findings in some clinical trials are promising, and updated overall survival results will be useful for validating the current role of adjuvant immunotherapy, particularly in the context of perioperative strategy.

Lung cancer is one of the leading causes of cancer-related death. Lung cancer mortality has decreased over the past decade, which is partly attributed to improved treatments. Curative surgery for patients with early-stage lung cancer is the standard of care, but not all surgical treatments have a good prognosis. Adjuvant and neoadjuvant chemotherapy are used to improve the prognosis of patients with resectable lung cancer. Immunotherapy, an epoch-defining treatment, has improved curative effects, prognosis, and tolerability compared with traditional and ordinary cytotoxic chemotherapy, providing new hope for patients with non-small cell lung cancer (NSCLC). Immunotherapy-related clinical trials have reported encouraging clinical outcomes in their exploration of different types of perioperative immunotherapy, from neoadjuvant immune checkpoint inhibitor (ICI) monotherapy, neoadjuvant immune-combination therapy (chemoimmunotherapy, immunotherapy plus antiangiogenic therapy, immunotherapy plus radiotherapy, or concurrent chemoradiotherapy), adjuvant immunotherapy, and neoadjuvant combined adjuvant immunotherapy. Phase 3 studies such as IMpower 010 and CheckMate 816 reported survival benefits of perioperative immunotherapy for operable patients. This review summarizes up-to-date clinical studies and analyzes the efficiency and feasibility of different neoadjuvant therapies and biomarkers to identify optimal types of perioperative immunotherapy for NSCLC.

The mainstay of treatment for early-stage non-small-cell lung cancer (NSCLC) is surgical resection. Traditionally, chemotherapy has been used perioperatively in locally extensive disease to improve the oncologic outcomes of surgery, with a 5-year absolute survival benefit of approximately 5%. In recent years, immunotherapy and molecular targeted therapy have shown excellent results in the treatment of locoregionally advanced and metastatic NSCLC, replacing chemotherapy as first-line treatment in certain cases. Consequently, researchers have been increasingly investigating the use of immunotherapy or targeted therapy in combination with surgery for the treatment of early-stage disease. This growing research interest has resulted in several published and ongoing studies of various size and design. In this mini review, we provide a succinct and up-to-date overview of recently published, phase 3 randomized clinical trials on adjuvant and neoadjuvant immunotherapy or targeted therapy for NSCLC. We subsequently discuss some important unresolved clinical issues, including the optimal duration of treatment, scheduling with respect to surgery, and potential combinations of different systemic therapies. Finally, we reference large, randomized, phase 3 studies that are currently in progress and may give answers to those and other clinical questions.

Over the past decade, targeted therapy for oncogene-driven NSCLC and immune checkpoint inhibitors for non-oncogene-driven NSCLC, respectively, have greatly improved the survival and quality of life for patients with unresectable NSCLC. Increasingly, these biomarker-guided systemic therapies given before or after surgery have been used in patients with early-stage NSCLC. In March 2022, the US FDA granted the approval of neoadjuvant nivolumab and chemotherapy for patients with stage IB-IIIA NSCLC. Several phase II/III trials are evaluating the clinical efficacy of various neoadjuvant immune checkpoint inhibitor combinations for non-oncogene-driven NSCLC and neoadjuvant molecular targeted therapies for oncogene-driven NSCLC, respectively. However, clinical application of precision neoadjuvant treatment requires a paradigm shift in the biomarker testing and multidisciplinary collaboration at the diagnosis of early-stage NSCLC. In this comprehensive review, we summarize the current diagnosis and treatment landscape, recent advances, new challenges in biomarker testing and endpoint selections, practical considerations for a timely multidisciplinary collaboration at diagnosis, and perspectives in emerging neoadjuvant precision systemic therapy for patients with resectable, early-stage NSCLC. These biomarker-guided neoadjuvant therapies hold the promise to improve surgical and pathological outcomes, reduce systemic recurrences, guide postoperative therapy, and improve cure rates in patients with resectable NSCLC.

Patients with resectable stage IIIA - N2 lung cancer represent a very heterogeneous population with variable risks of postoperative recurrence depending on the type of N2 involvement (unisite N2, multisite N2, bulky N2, extra-capsular rupture, incomplete resection…). This heterogeneity associated with the difficulty of carrying out prospective randomized studies with sufficient power in stages IIIA - 2, results in the absence of clear and consensual recommendations (except for stages IIIA - N2 resectable R0, since LungART and PORT-C studies). The objective of this article is to make an update on the place of postoperative radiotherapy in the management of stages IIIA - N2 following the publication of two recent randomized trials (PORT-C and LungART) but also compare them fort a better understanding of the current issues raised by these first published results. Indeed, these two trials do not find any benefit in terms of progression free survival and overall survival of postoperative radiotherapy but exploratory analyzes from these two studies seem to show a potential benefit of postoperative in some pN2 populations at high risk of locoregional recurrence (N2 multisite, N2 bulky…). In addition, the advent of immunotherapy (atezolizumab or pembrolizumab) and targeted therapies (osimertinib) in the adjuvant situation are redebating the place of a possible indication for postoperative radiotherapy in stage IIIA - 2.

Molecular factors predicting relapse in early-stage non-small-cell lung cancer (ES-NSCLC) are poorly understood, especially in inoperable patients receiving radiotherapy (RT). In this study, we compared the genomic profiles of inoperable and operable ES-NSCLC.

This retrospective study included 53 patients with nonsquamous ES-NSCLC (stage I-II) treated at a single institution (University of Chicago) with surgery (ie, operable; n = 30) or RT (ie, inoperable; n = 23) who underwent tumor genomic profiling. A second cohort of ES-NSCLC treated with RT (Stanford, n = 39) was included to power clinical analyses. Prognostic gene alterations were identified and correlated with clinical variables. The primary clinical end point was the correlation of prognostic genes with the cumulative incidence of relapse, disease-free survival, and overall survival (OS) in a pooled RT cohort from the two institutions (N = 62).

Although the surgery cohort exhibited lower rates of relapse, the RT cohort was highly enriched for somatic STK11 mutations (43% v 6.7%). Receiving supplemental oxygen (odds ratio [OR] = 5.5), 20+ pack-years of tobacco smoking (OR = 6.1), and Black race (OR = 4.3) were associated with increased frequency of STK11 mutations. In the pooled RT cohort (N = 62), STK11 mutation was strongly associated with inferior oncologic outcomes: 2-year incidence of relapse was 62% versus 20% and 2-year OS was 52% versus 85%, remaining independently prognostic on multivariable analyses (relapse: subdistribution hazard ratio = 4.0, P = .0041; disease-free survival: hazard ratio, 6.8, P = .0002; OS: hazard ratio, 6.0, P = .022). STK11 mutations were predominantly associated with distant failure, rather than local.

In this cohort of ES-NSCLC, STK11 inactivation was associated with poor oncologic outcomes after RT and demonstrated a novel association with clinical hypoxia, which may underlie its correlation with medical inoperability. Further validation in larger cohorts and investigation of effective adjuvant systemic therapies may be warranted.

This study aimed to use evidence mapping to provide an overview of immune checkpoint inhibitors (ICIs) as perioperative treatments for non-small cell lung cancer (NSCLC) and to identify areas of this field where future research is most urgently needed.

Multiple databases (PubMed, EMBASE, Cochrane Library, and Web of Science) were searched to identify clinical trials published up to November 2021 that examined the effect of perioperative ICIs for perioperative treatment of NSCLC. Study design, sample size, patient characteristics, therapeutic regimens, clinical stages, short-term and long-term therapeutic outcomes, surgery associated parameters, and therapeutic safety were examined.

We included 66 trials (3564 patients) and used evidence mapping to characterize the available data. For surgery associated outcomes, sixty-two studies (2480 patients) provided complete information regarding the use of surgery after neoadjuvant immunotherapy and data on R0 resection were available in 42 studies (1680 patients); for short-term clinical outcomes, 57 studies (1842 patients) evaluated pathologic complete response (pCR) after neoadjuvant immunotherapy and most of included studies achieved pCR in the range of 30 to 40%; for long-term clinical outcomes, 15 studies (1932 patients) reported DFS, with a median range of 17.9-53.6 months; and only a few studies reported the safety profiles of perioperative immunotherapies.

Our evidence mapping systematically summarized the results of all clinical trials and studies that examined ICIs as perioperative treatments for NSCLC. The results indicated more studies that evaluate long-term patient outcomes are needed to provide a stronger foundation for the use of these treatments.

Over the last decade, the use of targeted therapies and immune therapies led to drastic changes in the management lung cancer and translated to improved survival outcomes. This growing arsenal of therapies available for the management of non-small cell lung cancer added more complexity to treatment decisions. The genomic profiling of tumors and the molecular characterization of the tumor microenvironment gradually became essential steps in exploring and identifying markers that can enhance patient selection to facilitate treatment personalization and narrow down therapy options. The advent of innovative diagnostic platforms, such as next-generation sequencing and plasma genotyping (also known as liquid biopsies), has aided in this quest. Currently, programmed cell death ligand 1 expression remains the most recognized and fully validated predictive biomarker of response to immune checkpoint inhibitors. Other markers such as tumor mutational burden, tumor infiltrating lymphocytes, driver mutations, and other molecular elements of the tumor microenvironment bear the potential to be predictive tools; however, the majority are still investigational. In this review, we describe the advances noted thus far on currently validated as well as novel emerging biomarkers that have the potential to guide the use of immunotherapy agents in the management of non-small cell lung cancer.

A significant proportion of patients with non-small cell lung cancer (NSCLC) is diagnosed in the early and resectable stage. Despite the use of platinum-based adjuvant chemotherapy, there was only a marginal increase in overall survival and a 15% decrease in relapse. With the advents of immunotherapy and epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI), the landscape of adjuvant treatment in completely resectable NSCLC is changing. Postoperative radiotherapy can be beneficial to patients who underwent surgical resection in certain clinical settings. In addition, new biomarkers that predict efficacy of EGFR TKI and immunotherapy as adjuvant treatment are also necessary. In this review, recent updates in adjuvant treatment in resectable NSCLC were briefly explained.

To assess the cost-effectiveness of adjuvant atezolizumab in the treatment of early-stage NSCLC patients (stage II-IIIA) with expression PD-L1 ≥ 50% without mutations in EGFR or ALK rearrangements in Spain.

A 5-states Markov model (DFS, locoregional recurrence, 1 L-metastatic recurrence, 2 L-metastatic recurrence, and death states) was adapted to the Spanish setting. Demographic characteristics of the hypothetical cohort, transition probabilities from the DFS state, and safety parameters were obtained from IMpower010 study (GO29527). Transition probabilities from locoregional and metastatic health states were obtained from the literature. The usual clinical practice in Spain (use of health resources, management of the disease, etc.) was obtained from a previous analysis carried out by the authors of this study. A societal perspective was considered so both direct and indirect costs were included (expressed in € of 2021). A lifetime horizon was used, so costs and health outcomes were discounted at 3% per year. Sensitivity analyses were performed to evaluate uncertainty.

Over a lifetime horizon, treatment with adjuvant atezolizumab provided greater effectiveness (+2.61 life years [LY] and +1.95 quality-adjusted life years [QALY]) and higher cost (€+22,538) than BSC. The incremental cost-effectiveness ratio (ICER) and incremental cost-utility ratios (ICUR) of the analysis were €8,625/LY gained and €11,583/QALY gained, respectively. Robustness of these base-case results was confirmed by the sensitivity analyses performed. In the probabilistic sensitivity analysis, 90% of the simulations performed showed that adjuvant atezolizumab is cost-effective versus BSC, considering a threshold of €30,000/QALY.

Our results showed that adjuvant treatment with atezolizumab in patients with early-stage resected NSCLC with overexpression of PD-L1 and without EGFR and ALK mutations is cost-effective versus BSC as the ICERs and ICURs obtained are below the cost-effectiveness thresholds commonly considered in Spain, thus offering a new treatment alternative for these patients.

As the non-small cell lung cancer (NSCLC) adjuvant treatment landscape evolves, an evaluation of treatment patterns and outcomes of patients with early-stage, resected NSCLC eligible for adjuvant treatment in routine clinical practice is needed to better understand the unmet needs in this patient population.

Data from the Surveillance, Epidemiology, and End Results (SEER)-Medicare database (2007-2019) were used to identify patients with newly diagnosed stage IB (tumor size ≥4cm)-IIIA (AJCC 7th edition) NSCLC who received primary surgery (index date). We assessed adjuvant treatment patterns, real-world disease-free survival (rwDFS; time from index date to first recurrence or death) and overall survival (OS; time from index date to death), and loco-regional recurrence pattern and treatment distribution.

Among 1761 patients with primary surgery, mean age was 73.8 years; 47.9% were male; and 83.9% were white. Approximately 41% of patients received adjuvant chemotherapy; median time from surgery to adjuvant chemotherapy initiation was 48 days, and the most frequently observed adjuvant chemotherapy regimen was carboplatin+paclitaxel (24.5%). In the overall population, median rwDFS was 24.8 months and OS was 76.7 months; 5-year rwDFS and OS rates were 29.3% and 57.5%, respectively. Among 392 patients with loco-regional recurrence, the most frequently observed treatment was curative radiation monotherapy (28.2%).

Despite clinical guideline recommendations, rate of adjuvant chemotherapy among patients with resected early-stage NSCLC was low in clinical practice. Overall, among patients with early-stage NSCLC treated with conventional primary surgery, poor survival outcomes were observed, highlighting the need for and importance of more effective adjuvant treatments.

The global phase 3 IMpower010 study evaluated adjuvant atezolizumab versus best supportive care (BSC) following platinum-based chemotherapy in patients with resected stage IB-IIIA non-small cell lung cancer (NSCLC). Here, we report a subgroup analysis in patients enrolled in Japan. Eligible patients had complete resection of histologically or cytologically confirmed stage IB (tumors ≥4 cm)-IIIA NSCLC. Upon completing 1-4 cycles of adjuvant cisplatin-based chemotherapy, patients were randomized 1:1 to receive atezolizumab (fixed dose of 1200 mg every 21 days; 16 cycles or 1 year) or BSC. The primary endpoint of the global IMpower010 study was investigator-assessed disease-free survival, tested hierarchically first in patients with stage II-IIIA NSCLC whose tumors expressed programmed death-ligand 1 (PD-L1) on ≥1% of tumor cells, then in all randomized patients with stage II-IIIA NSCLC, and finally in the intention-to-treat (ITT) population (stage IB-IIIA NSCLC). Safety was evaluated in all patients who received atezolizumab or BSC. The study comprised 149 enrolled patients in three populations: ITT (n = 117; atezolizumab, n = 59; BSC, n = 58), all-randomized stage II-IIIA (n = 113; atezolizumab, n = 56; BSC, n = 57), and PD-L1 tumor cells ≥1% stage II-IIIA (n = 74; atezolizumab, n = 41; BSC, n = 33). At the data cutoff date (January 21, 2021), a trend toward disease-free survival improvement with atezolizumab vs BSC was observed in the PD-L1 tumor cells ≥1% stage II-IIIA (unstratified hazard ratio [HR], 0.52; 95% confidence interval [CI], 0.25-1.08), all-randomized stage II-IIIA (unstratified HR, 0.62; 95% CI, 0.35-1.11), and ITT (unstratified HR, 0.61; 95% CI, 0.34-1.10) populations. Atezolizumab-related grade 3/4 adverse events occurred in 16% of patients; no treatment-related grade 5 events occurred. Adjuvant atezolizumab showed disease-free survival improvement and a tolerable toxicity profile in Japanese patients in IMpower010, consistent with the global study results.

Recent data from a phase 3 trial have shown that the addition of immunotherapy to neoadjuvant chemotherapy improves event-free survival in patients with non-small-cell lung cancer (NSCLC). This is the first positive phase 3 trial in this setting, although several phase 3 trials are currently investigating the efficacy of neoadjuvant and adjuvant immunotherapy in resectable NSCLC.

Tobacco is a known risk factor for lung cancer, and continued tobacco use is associated with poorer outcomes across multiple lung cancer treatment modalities including surgery, chemotherapy and radiation therapy. Less is known about the association of tobacco use and outcomes with immune checkpoint inhibitors (ICIs), which are becoming an important part of the treatment landscape in lung cancer, both in metastatic and curative settings. We reviewed the literature on the association of tobacco and tumor biology as it relates to immunotherapy. We also reviewed the association of tobacco use on outcomes among phase III randomized clinical trials involving ICIs in non-small cell lung cancer (NSCLC). We identified that patients with a smoking history may have a greater benefit with ICI treatment compared to never smokers in both treatment-naïve (HR 0.82, 95% CI 0.69-0.97, vs. HR 1.06, 95% CI 0.81-1.38) and pre-treated (HR 0.79, 95% CI 0.70-0.90 vs. 1.03, 95% CI 0.74-1.43) settings. In trials where smoking status was further defined, ex-smokers appear to demonstrate greater benefit with ICI therapy compared to current smokers (HR 0.78, 95% CI 0.59-1.01 vs. 0.91, 95% CI 0.72-1.14). We conclude by offering our perspective on future directions in this area of research, including implementation of standardized collection and analysis of tobacco use in clinical trials involving ICI therapy in lung cancer and other disease sites, and also evaluating how tobacco may affect toxicities related to ICI therapy. Based on our review, we believe that a patient's history of tobacco smoking does have a role to play in guiding treatment decision making in patients with lung cancer.

In recent years, immunotherapy has become a pillar in the treatment of advanced, non-oncogene-addicted non-small cell lung cancer (NSCLC). Programmed death ligand 1 (PD-L1) expression is currently the only factor used to predict response to immunotherapy in clinical practice. Specifically, single agent pembrolizumab as first line therapy is approved for tumors with high expression of PD-L1 (≥50%) while immunotherapy and chemotherapy are approved for any PD-L1. However, combinations of immune-checkpoint inhibitors (ICIs) and other agents may confer higher benefit than immunotherapy alone in some circumstances.

We reviewed the available data regarding the combined use of ICIs and chemotherapy in patients with advanced, treatment-naïve NSCLC. In light of the benefit demonstrated in advanced disease, these combinations have been subsequently tested in other settings. We collected the most relevant findings regarding efficacy and safety of chemo-immunotherapy combinations in early and locally advanced NSCLC.

Immune-chemotherapy combinations demonstrated benefit in the advanced setting, and this strategy in now being applied in the early and local advanced settings. A description of clinical and biological predictors of response is required in order to identify patients who may benefit the most from combination therapy.

Immune checkpoint inhibition (ICI) has revolutionized the field of non-small cell lung cancer (NSCLC); currently, most patients with advanced disease receive upfront ICI either alone or in combination with chemotherapy. These advances have recently extended into early-stage NSCLC, with ICI incorporation into neoadjuvant and adjuvant treatment regimens. However, despite these successes, immunotherapy (IO) resistance remains a fundamental challenge in NSCLC, introducing a central quandary of how to precisely select the appropriate IO therapy or IO combination therapy for each individual patient. To address this vital need in the field, there has been an explosion of research in immuno-oncology to identify mechanisms of resistance, ranging from genomic alterations in the tumor to immunosuppressive conditions in the tumor microenvironment (TME). There remain many questions about how this complex interplay between the tumor and the immune microenvironment translates into clinical phenotypes of primary and acquired resistance. In NSCLC, a number of novel therapeutics are being developed to prevent and overcome resistance to ICI. Particular promise has been shown with therapeutics targeting novel T cell immune checkpoint inhibitors and targeting innate immune cells in the TME, chief among these cells are natural killer cells, neutrophils, and macrophages. Further research into tissue-based and non-invasive biomarkers that can be prospectively integrated into therapeutic trial design will be critical to advance the field's understanding of individual resistance patterns and enable the ultimate goal of precision immuno-oncology.