IASLC Neoadjuvant Therapy in Lung Cancers Initiatives
Overall Goal: To establish pathologic response in surgical resection specimens following neoadjuvant therapies as predictors of long-term clinical benefit in patients with stages I to III lung cancers.
Neoadjuvant therapies have unique advantages and opportunities in lung cancer, but there are also challenges as well. Advantages of the neoadjuvant approach include attacking micrometastases at the earliest possible time, shortening trial timelines (for assessment of a pathologic response endpoint) compared to adjuvant trials, creating more time to identify unsuspected metastases, potentially improving systemic therapy drug delivery and tolerability, and potentially improved compliance with subsequent therapies. Challenges of the neoadjuvant approach to lung cancer therapies include a lack of established guidance on how to process and evaluate resected lung cancer specimens following neoadjuvant therapy in both clinical practice and clinical trials the lack of an established relationship between pathologic response and efficacy endpoints of DFS and OS and the different types of systemic therapies being investigated. Currently, there is a lack of precise definitions on the degree of PR, MPR or CPR post neoadjuvant therapy as a surrogate endpoint for overall survival. The IASLC Neoadjuvant Therapy in Lung Cancers Initiatives aim to take on these challenges, with the goal of establishing pathologic response in surgical resection specimens following neoadjuvant therapies (MPR and pCR) as predictors of long-term clinical benefit in patients with stages I to III lung cancers.
Phase 0: Organize, Host, and Report Consensus Opinions from the FDA-IASLC Workshop on Neoadjuvant Therapy in Lung Cancers.
Phase 1: Publish IASLC recommendations to process and analyze resection specimens after neoadjuvant therapy and report results of pathologic response.
In order to address the lack of uniform processing and response definitions, the IASLC published an article in the Journal of Thoracic Oncology outlining detailed recommendations on how to process lung cancer resection specimens and to define pathologic response including major pathologic response and complete pathologic response following neoadjuvant therapy. A standardized approach is recommended to assess the percentage of 1) viable tumor, 2) necrosis, and 3) stroma (including inflammation and fibrosis). These recommendations are intended as guidance for clinical trials, although it is hoped they can be viewed as a suggestion for good clinical practice outside of clinical trials to improve the consistency of pathologic assessment of treatment response.
Phase 2: IASLC Reproducibility Study
The IASLC Reproducibility Study aims to determine reproducibility among pathologists of pathologic response determinations using the IASLC multidisciplinary recommendations for pathologic assessment of lung cancer resection specimens following neoadjuvant therapy. This study brings together an international cohort of 11 pathologists to evaluate 60-90 NSCLC tumors, including both adenocarcinoma and squamous cell carcinomas histologies, that received anti-PD-1 or PD-L1 alone or in combination with chemotherapy or anti-CTLA-4 therapy, treated in a clinical trial to ensure proper sampling of the resected specimen. This initiative is currently ongoing but is expected to conclude with a publication in the Journal of Thoracic Oncology in mid-2023.
Phase 2B: IASLC Digital Quantification of Pathologic Response in Neoadjuvant Treated Non-Small Cell Lung Cancer (NSCLC)
In this project, PathAI and IASLC will collaborate to apply an AI-driven digital pathology assessment of pathologic response and compare this to manual assessments from the 11 pathologists participating in the IASLC Pathologic Response Interobserver study. PathAI will use neoadjuvant lung cancer quantification algorithms on the 60-90 NSCLC tumors from clinical trials using immune checkpoint inhibitors. These algorithms will allow us to classify cases by the level of pathologic response achieved through digital quantification of the percent viable tumor remaining after neoadjuvant therapy. The use of AI to determine pathologic response presents advantages such as high-resolution, fully quantitative assessments and a high level of standardization and reproducibility. This study will support the validation of an AI-powered assessment of pathological response, which could potentially be used as a clinical endpoint in studies of neoadjuvant treatment to predict survival benefits at the time of surgery.
Phase 3: Lung Cancer Neoadjuvant Trial Endpoint Database (LCNTED)
In the final phase of the IASLC Neoadjuvant Therapies in Lung Cancer Initiative, a multidisciplinary group will identify the data necessary, collect the required information from neoadjuvant trials worldwide, and execute the statistical analyses to support the use of pathologic response as a determinant of long-term outcomes. This process has been accomplished in the CTNeoBC pooled analysis project analyzing neoadjuvant trials in breast cancers.
Following the lead of CTNeoBC in breast cancers, Phase 3 of the initiative will:
- Establish the association between pathologic response and event-free survival (EFS) and overall survival (OS)
- Establish the definition of pathologic response, including MPR and CPR that correlates best with long-term outcomes
- Identify the lung cancer subtypes in which pathologic response best correlate with long-term outcomes
- Assess whether increases in pathologic response between treatment groups predict improved EFS and OS
An initiative of this magnitude and importance requires the collaboration of many partners and stakeholders, as no one organization or company can act alone to make meaningful progress. Therefore, this initiative will bring together the IASLC membership, FDA regulators, and various leading industry partners, who all share the common goal of eliminating lung cancer as a cause of death.