SUMMARY: Lung cancer is the second most common cancer in both men and women and accounts for about 13% of all new cancers and 21% of all cancer deaths. The American Cancer Society estimates that for 2024, about 234,580 new cases of lung cancer will be diagnosed and 125,070 patients will die of the disease. Lung cancer is the leading cause of cancer-related mortality in the United States. Non-Small Cell Lung Cancer (NSCLC) accounts for approximately 85% of all lung cancers. Of the three main subtypes of NSCLC, 30% are Squamous Cell Carcinomas (SCC), 40% are Adenocarcinomas and 10% are Large Cell Carcinomas.
Immunotherapy with Immune Checkpoint Inhibitors (ICIs) has revolutionized cancer care and has become one of the most effective treatment options by improving Overall Response Rate and prolongation of survival across multiple tumor types. These agents target Programmed cell Death protein-1 (PD-1), Programmed cell Death Ligand-1 (PD-L1), Cytotoxic T-Lymphocyte-Associated protein-4 (CTLA-4), and many other important regulators of the immune system. Immune Checkpoint Inhibitors enhance antitumor immunity by unleashing the T cells. However, this benefit may vary among patients and tumor types. Biomarkers predicting responses to ICIs include Tumor Mutational Burden (TMB), Mismatch Repair (MMR) status, and Programmed cell Death Ligand 1 (PD‐L1) expression.
First line treatment options for patients with NSCLC include Pembrolizumab as a single agent or a combination Pembrolizumab with Carboplatin and Taxane/Pemetrexed. However, it remains unclear which patients would benefit from Pembrolizumab monotherapy and which group should receive combination immuno/chemotherapy. Further, such therapeutic decisions are not currently supported by either tumor PD-L1 or TMB status. There is therefore an urgent unmet need to implement molecular response-driven approaches to guide therapy selection in the immunotherapy space. Liquid biopsy analyses of circulating cell-free tumor DNA (ctDNA) can capture the tumor burden dynamics during immune checkpoint blockade, and may help guide therapy, to maximize therapeutic benefit and minimize toxicities to patients.
The Canadian Cancer Trials Group (CCTG) BR.36 is an international, multi-center, open-label, biomarker-directed Phase II trial, designed to establish the role of circulating tumor DNA (ctDNA) as a potential early measurement of immunotherapy response, in patients with advanced NSCLC. The trial design consists of two stages. In Stage 1 (observational), the objectives were to ascertain ctDNA response and determine optimal timing and concordance with radiologic Response Evaluation Criteria in Solid Tumors (RECIST) response. The researchers in this publication reported the findings of the First stage (Stage 1). The Second stage of the trial (Stage 2) will evaluate the potential clinical benefit of tailoring treatment to ctDNA molecular response (whether adding chemotherapy to Pembrolizumab for patients with advanced PD-L1+NSCLC who have persistent ctDNA at 6 weeks will result in better Progression Free Survival (PFS) and Overall Survival (OS) compared to patients who remain on Pembrolizumab therapy until clinical progression).
The first stage (observational stage) of the BR.36 trial enrolled 50 patients with advanced/metastatic NSCLC who did not harbor clinically actionable genomic alterations in EGFR or ALK, and had a PD-L1 expression level of 1% or more. Majority of patients had Stage IV NSCLC (98%) and had no prior systemic therapy (92%), 82% were white, 52% female and 56% were 65 years or older, 76% tumors were adenocarcinomas, and 96% had a PD-L1 Tumor Proportion Score (TPS) of 50% or more.
Patients received Pembrolizumab as per local standard of care, and radiographic response assessments were performed per RECIST criteria every 6 weeks until week 12 and at longer intervals thereafter. Serial liquid biopsies were collected and ctDNA molecular response assessments were performed before treatment administration on C1D1 (baseline), C2D1 (3 weeks) and C3D1 (6 weeks). Molecular response was defined as maximal mutant allele fraction clearance at the third cycle of Pembrolizumab. The Primary endpoint of the trial was to determine the optimal time point of ctDNA molecular response, and validate the concordance of ctDNA molecular response with radiographic response. Secondary endpoints included the evaluation of time to ctDNA response, and correlation with Progression Free and Overall Survival. The median follow up time was 13.5 months, and of the 45 patients evaluable for both radiographic and ctDNA responses, 10 patients had undetectable ctDNA, which is consistent with previously reported ctDNA undetectable rate in patients with metastatic NSCLC.
The trial met its Primary endpoint, and the concordance between ctDNA and radiographic response in terms of sensitivity was 82%, and 75% for specificity. The median time to ctDNA response was 2.1 months, and patients with molecular response attained longer Progression Free Survival (5.03 months versus 2.6 months) and Overall Survival (Not Reached versus 7.23 months). These findings are incorporated into the second stage of the BR.36 trial in which patients at risk of progression are randomized to treatment intensification or continuation of therapy.
It was concluded from the first stage of the BR.36 trial that ctDNA analyses can be used as an early marker of immunotherapy response and has the potential to determine the early efficacy of investigational agents in clinical trials. The second stage of this study will assess whether outcomes can be improved in those metastatic NSCLC tumors expressing PD-L1 with ctDNA response, by continuation of Pembrolizumab or adding chemotherapy to immunotherapy.
ctDNA response after pembrolizumab in non-small cell lung cancer: phase 2 adaptive trial results. Anagnostou, V., Ho, C., Nicholas, G. et al. Nat Med 2023;29: 2559–2569. https://doi.org/10.1038/s41591-023-02598-9
