Liquid biopsy guided addition of chemotherapy with TKI in advanced EGFR mutated NSCLC: An open-label, multicentric, phase 3 randomized controlled trial (LiquiACT)

EGFR (Epidermal Growth Factor Receptor) mutations are prevalent in non-small cell lung cancer (NSCLC), representing approximately 25-30% of cases in Indian patients. These mutations are pivotal in guiding treatment decisions, as they provide a critical therapeutic target. The introduction of Tyrosine Kinase Inhibitors (TKIs) has brought about a transformative shift in the treatment landscape for patients with EGFR-mutated advanced NSCLC. Moreover, the integration of various combination approaches, such as the addition of chemotherapy or antiangiogenic agents to TKIs, has further improved survival rates and has come to define a new standard of care. However, this advancement comes at the cost of higher rates of toxicities, increased cost of treatment and frequent hospital visits, warranting a more precise and adaptable approach to treatment.

Despite the progress made, the clinical course of EGFR-mutated NSCLC remains highly variable among patients. One of the primary contributing factors to this variability is the emergence of secondary resistance mechanisms. This complexity underscores the necessity for closely monitoring treatment response and detecting resistance as early as possible, as these factors hold the key to optimizing patient outcomes. In this context, liquid biopsy using plasma circulating tumor DNA (ctDNA) kinetics has emerged as a valuable tool for assessing disease progression and guiding treatment decisions in EGFR-mutated advanced NSCLC patients on TKIs.

CtDNA is the fragmented DNA released by tumor cells into the bloodstream. It can be extracted from a simple blood sample, making it a non-invasive and easily accessible biomarker using various technologies like RT-PCR, droplet digital PCR and next generation sequencing. Unlike tissue biopsies, which are invasive, ctDNA analysis allows for frequent monitoring of disease status without subjecting patients to repeated invasive and risky procedures. This non-invasive nature of ctDNA monitoring is particularly advantageous in EGFR-mutated advanced NSCLC, as it can potentially allow for timely adjustments to treatment regimens. The longitudinal evaluation of ct DNA has several advantages like, early response monitoring, assessment of minimal residual disease and early detection  of emergence of therapeutic resistance.

Various studies have shown that early clearance of plasma ct DNA (3 weeks to 9 weeks) while on TKI is associated with significantly better survival in EGFR mutated advanced NSCLC.

Whether treatment modifications guided by ctDNA kinetics can provide a better option, is not yet known. Several single arm phase 2 trials, including one at our centre are currently evaluating the feasibility of this approach.

We intend to answer if adding chemotherapy to only patients with high risk factors like base line ctDNA positivity, TP53 co-mutations or persistent plasma ct DNA after 3 weeks of TKI monotherapy results in non-inferior overall survival as compared to TKI-chemotherapy combination. Using this personalised approach, we would be able to avoid toxicities of chemotherapy, need of frequent hospital visits and associated cost in good risk patients. This study would generate the best quality evidence for the integration of liquid biopsy in routine clinical decision making. This approach would also give us an opportunity of understanding the ctDNA kinetics, timing of resistance emergence, and its mechanism in Indian patients of EGFR mutated NSCLC.