The value of local consolidative therapy in Osimertinib-treated non-small cell lung cancer with oligo-residual disease

Ya Zeng, Jianjiao Ni, Fan Yu, Yue Zhou, Yang Zhao, Shuyan Li, Tiantian Guo, Li Chu, Xi Yang, Xiao Chu, Xuwei Cai, Zhengfei Zhu, Ya Zeng, Jianjiao Ni, Fan Yu, Yue Zhou, Yang Zhao, Shuyan Li, Tiantian Guo, Li Chu, Xi Yang, Xiao Chu, Xuwei Cai, Zhengfei Zhu

Abstract

Background: There was no study investigating real-world utilization and outcome of LCT in Osimertinib-treated NSCLC with oligo-residual disease. This study was to analyze the clinical value of local consolidative therapy (LCT) in Osimertinib-treated non-small cell lung cancer (NSCLC) patients with oligo-residual disease.

Methods: Patients receiving standard Osimertinib treatment and developing oligo-residual disease (five or fewer residual metastatic lesions) were retrospectively reviewed. Local therapies performed to the oligo-residual tumor lesions or primary lung site before Osimertinib treatment failure were considered as LCT.

Results: Of 108 patients recruited, first-line and second-line Osimertinib were administered in 25 and 83 patients, respectively, while LCT was performed in 14 patients. With a median follow-up of 43.6 months, 69 patients developed progressive disease. LCT significantly improved progression-free survival (PFS) (NR vs 12.8 months, p = 0.01) and was independently associated with prolonged PFS (HR = 0.29, 95%CI 0.12 to 0.68, p = 0.004). Patients receiving LCT had a numerically longer overall survival (OS) (85.8 vs 77.1 months, p = 0.58) and after adjusting for potentially confounding factors, LCT was associated with a non-significantly prolonged OS (HR = 0.37, 95%CI 0.12-1.16, p = 0.089). Pattern of failure analyses indicated that progressive disease developed at the originally existed oligo-residual lesions in 76.2% of the 63 patients who didn't receive LCT and had Osimertinib treatment failure. Of note, 7 (70%) of the 10 patients who had oligo-residual cranial disease but didn't receive LCT, developed more than five progressive lesions in the brain, which were no longer suitable for stereotactic radiosurgery.

Conclusion: Among Osimertinib-treated NSCLC patients having oligo-residual lesions, LCT could improve local control and significantly increase PFS, which need to be verified by further investigations.

Keywords: Local consolidative therapy; Non-small cell lung cancer; Oligo-residual disease; Osimertinib.

Conflict of interest statement

The authors declare that they have no competing interests.

Figures

Fig. 1
Fig. 1
Patients enrollment flowchart
Fig. 2
Fig. 2
Progression-free survival (PFS) curves of LCT group and non-LCT group. The median PFS of LCT group was not reached and 12.8 months for patients in non-LCT group. LCT: local consolidative therapy
Fig. 3
Fig. 3
Overall survival (OS) curves of LCT group and non-LCT group. The median OS were respectively 85.8 months and 77.1 months for patients in LCT group and non-LCT group. LCT: local consolidative therapy
Fig. 4
Fig. 4
The details of failure patterns of two groups. LCT: local consolidative therapy

References

    1. Planchard D, Popat S, Kerr K, et al. Metastatic non-small cell lung cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2018;29:iv192–iv237. doi: 10.1093/annonc/mdy275.
    1. Wu YL, Zhou C, Liam CK, et al. First-line erlotinib versus gemcitabine/cisplatin in patients with advanced EGFR mutation-positive non-small-cell lung cancer: analyses from the phase III, randomized, open-label, ENSURE study. Ann Oncol. 2015;26:1883–1889. doi: 10.1093/annonc/mdv270.
    1. Zhou C, Wu YL, Chen G, et al. Erlotinib versus chemotherapy as first-line treatment for patients with advanced EGFR mutation-positive non-small-cell lung cancer (OPTIMAL, CTONG-0802): a multicentre, open-label, randomised, phase 3 study. Lancet Oncol. 2011;12:735–742. doi: 10.1016/S1470-2045(11)70184-X.
    1. Mitsudomi T, Morita S, Yatabe Y, et al. Gefitinib versus cisplatin plus docetaxel in patients with non-small-cell lung cancer harbouring mutations of the epidermal growth factor receptor (WJTOG3405): an open label, randomised phase 3 trial. Lancet Oncol. 2010;11.
    1. Kobayashi S, Boggon TJ, Dayaram T, et al. EGFR mutation and resistance of non–small-cell lung Cancer to Gefitinib. N Engl J Med. 2005;352:786–792. doi: 10.1056/NEJMoa044238.
    1. Oxnard GR, Arcila ME, Sima CS, et al. Acquired resistance to EGFR tyrosine kinase inhibitors in EGFR-mutant lung cancer: distinct natural history of patients with tumors harboring the T790M mutation. Clin Cancer Res. 2011;17:1616–1622. doi: 10.1158/1078-0432.CCR-10-2692.
    1. Yu HA, Arcila ME, Rekhtman N, et al. Analysis of tumor specimens at the time of acquired resistance to EGFR-TKI therapy in 155 patients with EGFR-mutant lung cancers. Clin Cancer Res. 2013;19:2240–2247. doi: 10.1158/1078-0432.CCR-12-2246.
    1. Cross DA, Ashton SE, Ghiorghiu S, et al. AZD9291, an irreversible EGFR TKI, overcomes T790M-mediated resistance to EGFR inhibitors in lung cancer. Cancer Discov. 2014;4:1046–1061. doi: 10.1158/-14-0337.
    1. Wu YL, Ahn MJ, Garassino MC, et al. CNS efficacy of Osimertinib in patients with T790M-positive advanced non–small-cell lung Cancer: data from a randomized phase III trial (AURA3) J Clin Oncol. 2018;36:2702–2709. doi: 10.1200/JCO.2018.77.9363.
    1. Goss G, Tsai C-M, Shepherd FA, et al. Osimertinib for pretreated EGFR Thr790Met-positive advanced non-small-cell lung cancer (AURA2): a multicentre, open-label, single-arm, phase 2 study. Lancet Oncol. 2016;17:1643–1652. doi: 10.1016/S1470-2045(16)30508-3.
    1. Yang JC, Ahn MJ, Kim DW, et al. Osimertinib in pretreated T790M-positive advanced non-small-cell lung Cancer: AURA study phase II extension component. J Clin Oncol. 2017;35:1288–1296. doi: 10.1200/JCO.2016.70.3223.
    1. Mok TS, Wu Y-L, Ahn M-J, et al. Osimertinib or platinum–Pemetrexed in EGFR T790M–positive lung Cancer. N Engl J Med. 2016;376(7):629–640. doi: 10.1056/NEJMoa1612674.
    1. Soria JC, Ohe Y, Vansteenkiste J, et al. Osimertinib in untreated EGFR-mutated advanced non–small-cell lung Cancer. N Engl J Med. 2018;378:113–125. doi: 10.1056/NEJMoa1713137.
    1. Ramalingam SS, Vansteenkiste J, Planchard D, et al. Overall survival with Osimertinib in untreated, EGFR-mutated advanced NSCLC. N Engl J Med. 2020;382:41–50. doi: 10.1056/NEJMoa1913662.
    1. Hu F, Xu J, Zhang B, et al. Efficacy of local consolidative therapy for oligometastatic lung adenocarcinoma patients harboring epidermal growth factor receptor mutations. Clin Lung Cancer. 2018;20(1):e81–e90. doi: 10.1016/j.cllc.2018.09.010.
    1. Xu Q, Zhou F, Liu H, et al. Considative local AblativeTherapy improves the survival of patients with SynchronousOligometastatic NSCLC harboring EGFR activating mutation treated with first-line EGFR -TKIs. J Thorac Oncol. 2018;13:1383–1392. doi: 10.1016/j.jtho.2018.05.019.
    1. Weickhardt AJ, Scheier B, Burke JM, et al. Local ablative therapy of Oligoprogressive disease prolongs disease control by tyrosine kinase inhibitors in oncogene-addicted non–small-cell lung Cancer. J Thorac Oncol. 2012;7:1807–1814. doi: 10.1097/JTO.0b013e3182745948.
    1. 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 fi rst-line systemic therapy: a multicentre, randomised, controlled, phase 2 study. Lancet Oncol. 2016;17:1672–1682. doi: 10.1016/S1470-2045(16)30532-0.
    1. 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;37:1558–1565. doi: 10.1200/JCO.19.00201.
    1. Hayakawa D, Takahashi F, Mitsuishi Y, et al. Activation of insulin-like growth factor-1 receptor confers acquired resistance to osimertinib in non-small cell lung cancer with EGFR T790M mutation. Thorac Cancer. 2020;11:140–149. doi: 10.1111/1759-7714.13255.
    1. Mu Y, Hao X, Xing P, et al. Acquired resistance to osimertinib in patients with non-small-cell lung cancer: mechanisms and clinical outcomes. J Cancer Res Clin Oncol. 2020;146(9):2427–2433. doi: 10.1007/s00432-020-03239-1.
    1. Guo T, Ni J, Yang X, et al. Pattern of recurrence analysis in metastatic EGFR-mutant NSCLC treated with Osimertinib: implications for consolidative stereotactic body radiation therapy. Int J Radiat Oncol Biol Phys. 2020;107:62–71. doi: 10.1016/j.ijrobp.2019.12.042.
    1. Dingemans AC, Hendriks LEL, Berghmans T, et al. Definition of synchronous Oligometastatic non-small cell lung Cancer-a consensus report. J Thorac Oncol. 2019;14:2109–2119. doi: 10.1016/j.jtho.2019.07.025.
    1. Al-Halabi H, Sayegh K, Digamurthy SR, et al. Pattern of failure analysis in metastatic EGFR-mutant lung Cancer treated with tyrosine kinase inhibitors to identify candidates for consolidation stereotactic body radiation therapy. J Thorac Oncol. 2015;10:1601–1607. doi: 10.1097/JTO.0000000000000648.
    1. Schmid S, Klingbiel D, Aeppli S, et al. Patterns of progression on osimertinib in EGFR T790M positive NSCLC: a Swiss cohort study. Lung Cancer. 2019;130:149–155. doi: 10.1016/j.lungcan.2019.02.020.
    1. Yang JJ, Chen HJ, Yan HH, et al. Clinical modes of EGFR tyrosine kinase inhibitor failure and subsequent management in advanced non-small cell lung cancer. Lung Cancer. 2013;79:33–39. doi: 10.1016/j.lungcan.2012.09.016.
    1. Chan OSH, Lam KC, Li JYC, et al. ATOM: a phase II study to assess efficacy of preemptive local ablative therapy to residual Oligometastases of NSCLC after EGFR TKI. Lung Cancer. 2020;142:41–46. doi: 10.1016/j.lungcan.2020.02.002.
    1. Wang X, Zeng M. First-line tyrosine kinase inhibitor with or without aggressive upfront local radiation therapy in patients with EGFRm oligometastatic non-small cell lung cancer: interim results of a randomized phase III, open-label clinical trial (SINDAS) (). J Clin Oncol. 2020;38:9508.
    1. Wang S, Yan B, Zhang Y, et al. Different characteristics and survival in non-small cell lung cancer patients with primary and acquired EGFR T790M mutation. Int J Cancer. 2019;144:2880–2886. doi: 10.1002/ijc.32015.
    1. Parikh RB, Cronin AM, Kozono DE, et al. Definitive primary therapy in patients presenting with oligometastatic non-small cell lung cancer. Int J Radiat Oncol Biol Phys. 2014;15:880–887. doi: 10.1016/j.ijrobp.2014.04.007.
    1. Luketich JD, Martini N, Ginsberg RJ, et al. Successful treatment of solitary extracranial metastases from non-small cell lung cancer. Ann Thorac Surg. 1995;60(6):1609–1611. doi: 10.1016/0003-4975(95)00760-1.
    1. Johnson KK, Rosen JE, Salazar MC, et al. Outcomes of a highly selective surgical approach to Oligometastatic lung Cancer. Ann Thorac Surg. 2016;102(4):1166–1171. doi: 10.1016/j.athoracsur.2016.04.086.
    1. Miyawaki E, Kenmotsu H, Mori K, et al. Optimal sequence of local and EGFR-TKI therapy for EGFR-mutant non-small cell lung Cancer with brain metastases stratified by number of brain metastases. Int J Radiat Oncol Biol Phys. 2019.
    1. Iyengar P, Wardak Z, Gerber DE, et al. Consolidative radiotherapy for LimitedMetastatic non–small-cell lung Cancer a phase 2 randomized clinical trial. JAMA Oncol. 2018;4:e173501. doi: 10.1001/jamaoncol.2017.3501.
    1. Lee JH, Chen HY, Hsu FM, et al. Cranial irradiation for patients with epidermal growth factor receptor (EGFR) mutant lung Cancer who have brain metastases in the era of a new generation of EGFR inhibitors. Oncologist. 2019;24:e1417–e1425.

Source: PubMed

Sponsorit ja yhteistyökumppanit

Sairaudet

Huumeiden interventiot

3
Tilaa