By Youquan Li, MD, FRCR, and Andrea Bezjak, MDCM, MSc, FRCPC
Posted: February 12, 2020
Targeted agents including TKIs of EGFR, ALK, and ROS1 have significantly improved the outcomes of advanced oncogene-driven NSCLC.1,2 Despite initial high response rates, durable and complete responses are rare, and most patients eventually experience treatment failure.3 Residual disease is defined as a population of tumor cells within a mostly therapy-sensitive tumor that survives the first wave of targeted therapy and regrows, eventually leading to treatment failure and tumor progression.4 Intra-tumor heterogeneity, tumor cell evolution during treatment, and pharmacokinetic failure are the main mechanisms of residual disease.4,5 Approximately 60% of patients develop first clinical failure at the initial sites of disease.6,7 Liquid biopsy results suggest that treatment failure develops before radiologic progression is seen.8
Targeting Residual Disease
Different strategies can be used to enhance the clinical response of targeted therapy. Upfront next-generation TKIs and polytherapy combining TKIs with anti-VEGF or cytotoxic chemotherapy have shown superior results in recent phase III studies.9,10 However, these approaches are limited by cost, accessibility of novel drugs, and toxicities related to combined treatment.
Local consolidation with cytoreductive surgery or radiation is another strategy to target residual tumors and improve patient outcomes. Recent randomized trials have increasingly provided evidence that this strategy works for oligometastatic lung cancer and for several other cancers such as oligometastatic renal cell carcinoma11 and prostate cancer.12 In oligometastatic NSCLC, two “proof of concept” phase II studies haves shown that local consolidative therapy tripled progression-free survival (PFS) compared with observation in the preimmunotherapy era.13,14 Gomez et al. updated survival data recently, and showed that local consolidation could lead to a significant OS benefit (median OS 41.2 months in the consolidation arm versus 17.0 months in the observation arm).15 However, both studies had either no or few patients with EGFR-positive NSCLC, which has distinct biologic behavior and treatment options. Another recent phase II study targeting metabolic residual disease after TKIs with stereotactic ablative body radiation (SABR) has shown that adding local therapy achieves an encouraging 1-year PFS of 62.5%.16
Such a strategy of early consolidation, targeting residual disease in oligometastatic NSCLC with radiation (or surgery) after initial response on TKIs, could potentially overcome the above-described biologic resistance mechanisms. Early consolidation requires increased collaboration among medical oncologists, radiation oncologists, and thoracic surgeons. It also creates unique opportunities to understand the biology of residual disease and to generate more patient-derived models to investigate the mechanisms of acquired resistance. Liquid biopsy including circulating tumor cells or ctDNA and genomic analysis could become potential biomarkers to select patients with oligometastatic disease who are likely to benefit from aggressive local therapy.
However, many important questions remain to be addressed in prospective studies before proceeding further. Safety of treatment has to be prioritized in the setting of local consolidation. Of note, there was a small treatment-related mortality (4.5%) in the recent SABR COMET trial.17 Although the practice of SABR or high-dose radiation to multiple targets in different organs is expanding quickly, there is a paucity of prospective evidence regarding the safety of concurrent TKIs and SABR versus the potential risk of progression when withholding TKIs. For locally advanced NSCLC, the safety data of concurrent TKIs with conventional fractionated thoracic radiation are mixed, with grade 3 to 5 toxicities as high as 37.5% in some small cohorts,18 whereas other studies suggest no increase in risk. The optimal consolidative option, especially for intrathoracic disease, mandates multidisciplinary collaboration among medical and radiation oncologists and thoracic surgeons to individualize treatment decisions. From the radiation oncologists’ perspectives, target volume for consolidative thoracic radiation will focus on residual disease instead of attempting to include pretherapy volume. “Ablative” SABR, moderate hypofractionation, or conventional fractionation radiotherapy are considerations, depending on the volume and location of the disease.
While awaiting the evidence of local consolidation in EGFR-positive advanced NSCLC (NCT03410043), we should proceed with caution so as not to cause severe toxicities and compromise the quality of life in patients already on effective and well-tolerated treatment. Integrating translational research and interdisciplinary collaboration in the thoracic oncology community is the key to providing better clinical outcomes for oligometastatic NSCLC harboring EGFR mutations and other oncogenic drivers. ✦
About the Authors: Dr. Li is an associate consultant in the Department of Radiation Oncology at the National Cancer Centre Singapore. Dr. Bezjak is a professor in the Department of Radiation Oncology at the University of Toronto.
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