Assessing pathological response after neoadjuvant treatment for NSCLC

Over several decades, many studies have shown that patients with lung cancer who demonstrate a major pathological response (MPR) after neoadjuvant chemotherapy have significantly improved survival. However, guidance on how to process and evaluate resected lung cancer specimens was lacking, as were precise definitions on the degree of pathological response, including MPR and complete pathological response (CPR). An international panel of members of the International Association for the Study of Lung Cancer (IASLC), together with an additional group multidisciplinary experts, including surgeons, pathologists, radiologists and medical oncologists, proposed the first set of recommendations for the pathological assessment of lung cancer resection specimens after neoadjuvant therapy, which was published in 2020 (J Thorac Oncol. 2020;15:709–740).

One of the key reasons for developing these recommendations is the increasing number of treatment modalities being explored in the neoadjuvant setting – single-agent immunotherapies, different combinations of immunotherapy and chemotherapy and molecular targeted therapies – and the need for standardised surrogate endpoints. In the recent phase II LCMC3 study, pre-operative treatment with atezolizumab met the primary endpoint with a 20% MPR, which is similar to neoadjuvant cisplatin-based therapy, and with a CPR of 7% (J Thorac Oncol. 2021;16(3_suppl):S59–S61). Regarding combination therapy, in the phase III CheckMate 816 trial, neoadjuvant nivolumab plus platinum-doublet chemotherapy significantly increased CPR – one of the primary endpoints – versus chemotherapy (24.0% versus 2.2%), with improved MPR rates (36.9% versus 8.9%) (Cancer Res 2021:81(13_suppl):CT003). Incorporating MPR as a defined surrogate endpoint, rather than the somewhat restrictive criteria of CPR with its low achievement rates, may be an important step for the future.

Historically, MPR was defined in chemotherapy trials as 10% or less viable tumour; however, one must not assume that optimal thresholds are necessarily the same for immunotherapy or molecular targeted therapy as chemotherapy, and this is an important area for investigation. In addition, previous studies have analysed histological types together, particularly adenocarcinoma and squamous cell carcinoma. Working with colleagues at the Memorial Sloan Kettering Cancer Center and elsewhere, we have shown that the optimal cutoff percentage of viable tumour for predicting lung cancer-specific cumulative incidence of death was 10% for squamous cell carcinoma, but was 65% for adenocarcinoma (J Thorac Oncol. 2019;14:482–493). Very similar findings were demonstrated by Swiss investigators (Mod Pathol. 2021;34:1333–1344), supporting 65% as the optimal cutoff for MPR in adenocarcinomas and highlighting the need to record and analyse the actual percentages, rather than simply noting whether the 10% cutoff was reached.

Following on from the IASLC recommendations, a reproducibility study led by the IASLC Pathology Committee is currently being conducted with investigators from all over the world. Using the same set of neoadjuvant resected specimens, we hope to determine the degree of reproducibility of the criteria used to assess the percentages of viable tumour versus necrosis and stroma. Taking advantage of technological advances may also improve pathological response quantification and may help provide more precise quantification of the proportion of viable tumour after neoadjuvant therapy. In a study of data from the LCMC3 trial, artificial intelligence (AI)-powered assessment was compared with manual assessment (J Clin Oncol 2021;39(15_suppl):106). Good inter-reader agreement was noted between the pathologists and importantly, there was strong correlation between AI-powered digital and manual pathological response assessment, supporting further studies of automation methods.

Given the unique source of information from ongoing neoadjuvant studies with targeted therapies and immunotherapies, the IASLC is also actively involved in creating an international clinical trial data repository to uniformly collect clinical and pathological information. I believe this type of international cooperation is another exciting way that future work can be brought together to advance our understanding in this field.