Increasing the Role of Local Consolidation in Oncogenic-Driven Advanced NSCLC

Dr. Youquan Li & Dr. Andrea Bezjak

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.

1. Mok TS, Wu YL, Thongprasert S, et al. Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma. N Engl J Med. 2009;361(10):947-957.

2. Solomon BJ, Mok T, Kim DW, et al. First-line crizotinib versus chemotherapy in ALK-positive lung cancer. N Engl J Med. 2014;371(23):2167- 2177.

3. Zhong WZ, Chen KN, Chen C, et al. Erlotinib Versus Gemcitabine Plus Cisplatin as Neoadjuvant Treatment of Stage IIIA-N2 EGFR-Mutant Non-Small-Cell Lung Cancer (EMERGING-CTONG 1103): A Randomized Phase II Study. J Clin Oncol. 2019 Jun 13. [Epub ahead of print].

4. Bivona TG, Doebele RC. A framework for understanding and targeting residual disease in oncogene-driven solid cancers. Nat Med. 2016;22(5):472-478.

5. Nahar R, Zhai W, Zhang T, et al. Elucidating the genomic architecture of Asian EGFR-mutant lung adenocarcinoma through multi-region exome sequencing. Nat Commun. 2018;9(1):216.

6. Al-Halabi H, Sayegh K, Digamurthy SR, et al. Pattern of Failure Analysis in Metastatic EGFRMutant Lung Cancer Treated with Tyrosine Kinase Inhibitors to Identify Candidates for Consolidation Stereotactic Body Radiation Therapy. J Thorac Oncol. 2015;10(11):1601-1607.

7. Sorensen BS, Wu L, Wei W, et al. Monitoring of epidermal growth factor receptor tyrosine kinase inhibitor-sensitizing and resistance mutations in the plasma DNA of patients with advanced nonsmall cell lung cancer during treatment with erlotinib. Cancer. 2014;120(24):3896-3901.

8. Oxnard GR, Paweletz CP, Kuang Y, et al. Noninvasive detection of response and resistance in EGFR-mutant lung cancer using quantitative next-generation genotyping of cell-free plasma DNA. Clin Cancer Res. 2014;20(6):1698- 1705.

9. Saito H, Fukuhara T, Furuya N, et al. Erlotinib plus bevacizumab versus erlotinib alone in patients with EGFR-positive advanced nonsquamous non-small-cell lung cancer (NEJ026): interim analysis of an open-label, randomised, multicentre, phase 3 trial. Lancet Oncol. 2019;20(5):625-635.

10. Vanita N, Amit J, Vijay MP, et al. Phase III randomized trial comparing gefitinib to gefitinib with pemetrexed-carboplatin chemotherapy in patients with advanced untreated EGFR mutant non-small cell lung cancer (gef vs gef+C) [abstract]. J Clin Oncol. 2019; 37(15): Suppl 9001.

11. Flanigan RC, Salmon SE, Blumenstein BA, et al. Nephrectomy followed by interferon alfa- 2b compared with interferon alfa-2b alone for metastatic renal-cell cancer. N Engl J Med. 2001;345(23):1655-1659.

12. Parker CC, James ND, Brawley CD, et al. Radiotherapy to the primary tumour for newly diagnosed, metastatic prostate cancer (STAMPEDE): a randomised controlled phase 3 trial. Lancet.2018;392(10162):2353-2366.

13. Gomez DR, Blumenschein GR Jr, Lee JJ, et al. Local consolidative therapy versus maintenance therapy or observation for patients with oligometastatic non-small-cell lung cancer without progression after first-line systemic therapy: a multicentre, randomised, controlled, phase 2 study. Lancet Oncol. 2016;17(12):1672-1682.

14. Iyengar P, Wardak Z, Gerber DE, et al. Consolidative Radiotherapy for Limited Metastatic Non-Small-Cell Lung Cancer: A Phase 2 Randomized Clinical Trial. JAMA Oncol. 2018;4(1): e173501.

15. Gomez DR, Tang C, Zhang J, et al. Local Consolidative Therapy Vs. Maintenance Therapy or Observation for Patients with Oligometastatic Non-Small-Cell Lung Cancer: Long-Term Results of a Multi-Institutional, Phase II, Randomized Study. J Clin Oncol. 2019;37(18):1558-1565.

16. Chan OSh, Lam KC, LI J, et al. ATOM: A Phase II Study to Assess Efficacy of Preemptive Local Ablative Therapy to Residual Oligometastases After EGFR TKI[abstract]. J Thorac Oncol. 2018;13(10S):Suppl S336.

17. Palma DA, Olson R, Harrow S, et al. Stereotactic ablative radiotherapy versus standard of care palliative treatment in patients with oligometastatic cancers (SABR-COMET): a randomised, phase 2, open-label trial. Lancet. 2019;393(10185):2051-2058.

18. Zhuang H, Yuan Z, Chang JY, et al. Radiation pneumonitis in patients with non-small-cell lung cancer treated with erlotinib concurrent with thoracic radiotherapy. J Thorac Oncol. 2014;9(6):882-885.