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 II to III lung cancers.

The IASLC is working to address key knowledge gaps in clinical practice related to the use of neoadjuvant therapies in lung cancer through the establishment of the IASLC Neoadjuvant Therapy in Lung Cancers Initiative. These projects aim to knowledge gaps by providing clear definitions and guidance for the lung cancer community to rely on , with the ultimate 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.

The IASLC and FDA held a joint international multidisciplinary conference on neoadjuvant therapies in lung cancers in March 2018 to review available data on neoadjuvant therapies in lung cancers, catalog the benefits of neoadjuvant therapies, and identified three next steps to establish neoadjuvant therapy as a standard of care.

Goals:

Review the prior neoadjuvant experience in lung cancer
Discuss the advantages and challenges of neoadjuvant strategies, lessons learned from neoadjuvant efforts in other cancers, and new modalities to assess therapeutic response
Outline standards for the pathologic evaluation of resection specimens, to discuss if pathologic response can predict long-term outcomes

Next steps defined during the workshop:

Standardize the definition of MPR and pCR to use in all ongoing and planned neoadjuvant trials of immunotherapy, targeted therapy, and combination therapy.
Use meta-analyses of neoadjuvant trials in lung cancer to determine if MPR or pCR can be used as efficacy endpoints to determine overall survival.
Use residual tumor in surgical resection specimens to understand determinants of persistent cell survival which may inform trials investigating post-operative approaches (FDA Paper).

This IASLC-FDA joint workshop laid the groundwork for the IASLC Neoadjuvant Therapies in Lung Cancer Initiatives that are outlined below.

Read the full article here

Leadership

Mark G. Kris

MD

Attending Physician

Memorial Sloan Kettering Cancer Center

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.

Read the Full Recommendations here

Leadership

William Travis

MD

Director, Thoracic Pathology

Memorial Sloan Kettering Cancer Center

Ignacio I. Wistuba

MD

Professor

University of Texas MD Anderson Cancer Center

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.

Leadership

Wendy Cooper

MD

Associate Professor, Department of Pathology

Royal Prince Alfred Hospital

Sanja Dacic

MD, PhD, MSc

Vice Chair and Director of Anatomic Pathology

Yale University Medical School

Keith Kerr

MD, FRCPath

Professor of Pulmonary Pathology

University of Aberdeen, School of Medicine and Dentistry

William Travis

MD

Director, Thoracic Pathology

Memorial Sloan Kettering Cancer Center

Ignacio I. Wistuba

MD

Professor

University of Texas MD Anderson Cancer Center

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.

Leadership

Wendy Cooper

MD

Associate Professor, Department of Pathology

Royal Prince Alfred Hospital

Sanja Dacic

MD, PhD, MSc

Vice Chair and Director of Anatomic Pathology

Yale University Medical School

Keith Kerr

MD, FRCPath

Professor of Pulmonary Pathology

University of Aberdeen, School of Medicine and Dentistry

William Travis

MD

Director, Thoracic Pathology

Memorial Sloan Kettering Cancer Center

Ignacio I. Wistuba

MD

Professor

University of Texas MD Anderson Cancer Center

Phase 3: Lung Cancer Neoadjuvant Trial Endpoint Database (LCNTED)

In the final phase of the IASLC Neoadjuvant Therapies in Lung Cancer Initiative, aims to accomplish the ultimate 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. 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.

Leadership

Mark G. Kris

MD

Attending Physician

Memorial Sloan Kettering Cancer Center

Yu Shyr

PhD

Director

Vanderbilt Center for Quantitative Sciences

Vanderbilt Technologies for Advanced Genomics Analysis and Research Design