Discussion
Cancer, NSCLC, tumor, Tumor-informed, pembrolizumab, cancer, insufficiency, BOR, heterogenous tumor, tumors, molecular disease, response-driven
DISEASE PROGRESSION, TUMOR, CANCER, EVENT, METASTATIC DISEASE, NSCLC, TUMORS, CANCER
There is an unmet clinical need to implement real-time minimally invasive molecular analyses to capture therapeutic response and guide decision-making in the context of precision IO. We report here the findings of stage 1 of the Canadian Cancer Trials Group (CCTG) BR.36 trial, which aimed to define ctDNA molecular response, optimal timing of assessment and concordance with radiographic response. Employing a tumor-agnostic WBC DNA-informed panel NGS approach, ctDNA molecular response, defined as complete clearance of circulating tumor load after two cycles of pembrolizumab, was largely concordant with radiographic response assessments but, notably, was more informative in predicting OS. These findings are now incorporated into the second ctDNA molecular response-driven interventional randomized stage of the trial that will assess the value of adjusting therapy based on ctDNA response.The landscape of IO is expanding rapidly; however, optimal patient selection for immunotherapy represents a critical challenge that is intensified by the heterogeneity of clinical responses and insufficiency of imaging to fully and timely capture changes in tumor burden and therapeutic response. Snapshot biomarkers currently used to guide therapy selection, such PD-L1 expression and TMB, rely on analysis of tumor tissue obtained through invasive single-region biopsies, which may not sufficiently capture the clonal complexity of tumors, may be problematic in the event of low tumor purity sampling and, importantly, do not capture the evolving tumor under the selective pressure of immunotherapy. These challenges highlight the urgent unmet need to develop molecularly informed strategies to improve patient selection, enable early and accurate response assessment and facilitate long-term response monitoring during immunotherapy. To this end, liquid biopsies are emerging as powerful minimally invasive approaches to monitor tumor burden as cancer cells go through immunotherapy-induced evolutionary bottlenecks and to rapidly and precisely capture therapeutic response.We hypothesized that ctDNA molecular response can be used as an enrichment strategy to identify patients at high risk of clinical disease progression (those with molecular disease progression), thus limiting the heterogeneity of the target population, which, in turn, opens a therapeutic widow of opportunity for early intervention and interception of therapeutic primary resistance. An increasing number of studies support the role of ctDNA molecular response as an early endpoint of therapeutic responseHow early does molecular response occur? Several proof-of-concept studies have indicated that the optimal timepoint for ctDNA response lies between 4 weeks and 9 weeks from single-agent immune checkpoint blockade initiationFurthermore, we explored whether a tumor NGS-informed approach would be feasible and more informative than the tumor-agnostic WBC DNA-informed approach that we employed in BR.36. Tumor-informed liquid biopsy approaches for patients with metastatic disease may not be feasible from a tissue sufficiency standpoint and may restrict the evaluable plasma variants to these detected by single-region heterogenous tumor sample NGS. WBC DNA-informed liquid biopsy approaches can improve the specificity for tracking circulating tumor load compared to plasma-only approachesThis study has several limitations, including the cohort size and the RECIST BOR of 32%, which likely reflected the real-world nature of the trial and reduced the statistical power to assess correlation of ctDNA with RECIST responses. Furthermore, as expected, approximately 20% of patients enrolled were not evaluable for ctDNA molecular response due to undetectable ctDNA, which represents a limitation given the shrinkage of the study population. Conceptually, a more sensitive multiplex polymerase chain reaction (PCR) tumor-informed liquid biopsy bespoke approach may reduce the number of cases with undetectable ctDNA; however, such an approach may not be feasible, especially in the context of a real-time ctDNA molecular response-adaptive interventional trial. Finally, the BR.36 study was powered to address the concordance between ctDNA and radiographic response, and, as such, assessment of additional endpoints may be limited by the study design. Per the trial design, we were limited in assessing the lead time between ctDNA response and RECIST response. ctDNA molecular response was assessed on C3D1 (2.1 months, accounting for delays within the BR.36 study cohort, otherwise on week 6 after pembrolizumab initiation), whereas best radiographic response was assessed at 12 weeks after treatment initiation. Although RECIST responses were evaluated at 6 weeks, together with ctDNA responses, BOR did not occur at 6 weeks, rather at 12 weeks; as such, ctDNA response provides the earliest and most accurate readout of best overall therapeutic responses.Taken together, we show that ctDNA molecular response can identify patients with metastatic NSCLC less likely to attain favorable clinical outcomes with single-agent anti-PD-1 therapy, and this opens a therapeutic window of opportunity for treatment intensification for patients with molecular disease progression. Our findings were implemented in the design of the planned stage 2 of the BR.36 trial, which uses ctDNA detection after two cycles of standard-of-care pembrolizumab monotherapy to identify patients with metastatic NSCLC with PD-L1 ≥50% at high risk for disease progression, who are subsequently randomized to treatment intensification with pembrolizumab and chemotherapy versus continuation of pembrolizumab. Overall, our findings support the implementation of liquid biopsies in interventional IO clinical trials and further advance the evidentiary roadmap toward integration of ctDNA molecular responses in clinical decision-making for the increasing number of patients receiving immunotherapy.