Chinese Herbal Medicine Combined With EGFR-TKI in EGFR Mutation-Positive Advanced Pulmonary Adenocarcinoma (CATLA): A Multicenter, Randomized, Double-Blind, Placebo-Controlled Trial

Lijing Jiao, Jianfang Xu, Jianli Sun, Zhiwei Chen, Yabin Gong, Ling Bi, Yan Lu, Jialin Yao, Weirong Zhu, Aihua Hou, Gaohua Feng, Yingjie Jia, Weisheng Shen, Yongjian Li, Ziwen Zhang, Peiqi Chen, Ling Xu, Lijing Jiao, Jianfang Xu, Jianli Sun, Zhiwei Chen, Yabin Gong, Ling Bi, Yan Lu, Jialin Yao, Weirong Zhu, Aihua Hou, Gaohua Feng, Yingjie Jia, Weisheng Shen, Yongjian Li, Ziwen Zhang, Peiqi Chen, Ling Xu

Abstract

Background: To determine the clinical activity and safety of Chinese herbal medicine (CHM) combined with epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKI) in patients with advanced pulmonary adenocarcinoma (ADC) and the ability of CHM combined with EGFR-TKI to activate EGFR mutations. Methods: Three hundred and fifty-four patients were randomly assigned to EGFR-TKI (erlotinib 150 mg/d, gefitinib 250 mg/d, or icotinib 125 mg tid/d) plus CHM (TKI+CHM, N = 185) or EGFR-TKI plus placebo (TKI+placebo, N = 169). Progression-free survival (PFS) was the primary end point; the secondary end points were overall survival (OS), objective response rate (ORR), disease control rate (DCR), quality of life [Functional Assessment of Cancer Therapy-Lung (FACT-L) and Lung Cancer Symptom Scale (LCSS)], and safety. Results: The median PFS was significantly longer for the TKI+CHM group (13.50 months; 95% CI, 11.20-16.46 months) than with the EGFR-TKI group (10.94 months; 95% CI, 8.97-12.45 months; hazard ratio, 0.68; 95% CI, 0.51-0.90; P = 0.0064). The subgroup analyses favored TKI+CHM as a first-line treatment (15.97 vs. 10.97 months, P = 0.0447) rather than as a second-line treatment (11.43 vs. 9.23 months, P = 0.0530). Patients with exon 19 deletion had a significantly longer PFS than with 21 L858R. The addition of CHM to TKI significantly improved the ORR (64.32% vs. 52.66%, P = 0.026) and QoL. Drug-related grade 1-2 adverse events were less common with TKI+CHM. Conclusions: TKI+CHM improved PFS when compared with TKI alone in patients with EGFR mutation-positive advanced non-small-cell lung cancer (NSCLC). Clinical Trial Registration: www.ClinicalTrials.gov, identifier NCT01745302.

Keywords: Chinese herbal medicine; EGFR activating mutations; EGFR-TKI; drug resistance; pulmonary adenocarcinoma.

Figures

Figure 1
Figure 1
CONSORT diagram: trial profile at the cut-off date for analysis (January 5, 2018) PD, progressive disease.
Figure 2
Figure 2
PFS in the (A) intent-to-treat population, (B) first-line EGFR-TKI subgroup, (C) second-line EGFR-TKI subgroup, (D) exon 19 deletion subgroup, (E) 21 L858R point mutation subgroup; PFS, progression-free survival; EGFR-TKI, epidermal growth factor receptor tyrosine kinase inhibitors.
Figure 3
Figure 3
The proportion of patients with different QoL changes during the treatment according to the results of FACT-L, TOI, LCS and the LCSS. The assessments (and improvement rate) were calculated for the FACT-L, TOI, and LCS scores (“improved,” “stabled,” and “worsened”). A clinically relevant improvement was defined as a change from a baseline of six points for FACT-L and TOI and two points for LCS, here maintained for 21 or more days. To demonstrate trends, the baseline score for each item of the LCSS and for the average score was subtracted from the 7-month scores and then categorized as worse (>10 mm), stable (−10 to 10 mm), or improved (

References

    1. Califano R., Tariq N., Compton S., Fitzgerald D. A., Harwood C. A., Lal R., et al. (2015). Expert consensus on the management of adverse events from EGFR tyrosine kinase inhibitors in the UK. Drugs 75 (12), 1335–1348. 10.1007/s40265-015-0434-6
    1. Cella D., Eton D. T., Fairclough D. L., Bonomi P., Heyes A. E., Silberman C., et al. (2002). What is a clinically meaningful change on the functional assessment of cancer therapy-lung (fact-l) questionnaire? Results from eastern cooperative oncology group (ecog) study 5592. J. Clin. Epidemiol. 55 (3), 285–295. 10.1016/S0895-4356(01)00477-2
    1. Cheng Y., Murakami H., Yang P. C., He J., Nakagawa K., Kang J. H., et al. (2016). Randomized phase II trial of gefitinib with and without pemetrexed as first-line therapy in patients with advanced nonsquamous non-small-cell lung cancer with activating epidermal growth factor receptor mutations. J. Clin. Oncol. 34 (27), 3258–3266. 10.1200/JCO.2016.66.9218
    1. Furuyama K., Harada T., Iwama E., Shiraishi Y., Okamura K., Ijichi K., et al. (2013). Sensitivity and kinase activity of epidermal growth factor receptor (EGFR) exon 19 and others to EGFR-tyrosine kinase inhibitors. Cancer Sci. 104 (5), 584–589. 10.1111/cas.12125
    1. Han Y., Wang H., Xu W., Cao B., Han L., Jia L., et al. (2016). Chinese herbal medicine as maintenance therapy for improving the quality of life for advanced non-small cell lung cancer patients. Complement. Ther. Med. 24, 81–89. 10.1016/j.ctim.2015.12.008
    1. Hollen P. J., Gralla R. J., Kris M. G., Eberly S. W., Cox C. (1999). Normative data and trends in quality of life from the lung cancer symptom scale (LCSS). Support Care Cancer 7 (3), 140–148. 10.1007/s005200050244
    1. Hung H. Y., Tseng Y. H., Liao C. M., Chen S. Y., Wu T. P., Lee Y. C., et al. (2017). The efficacy of traditional chinese herbal medicine in the treatment of EGFR mutated stage iv pulmonary adenocarcinoma patients who received first-line EGFR-TKI treatment. Integr. Cancer Ther. 16 (1), 126–131. 10.1177/1534735416645181
    1. Jiao L., Dong C., Liu J., Chen Z., Zhang L., Xu J., et al. (2017). Effects of chinese medicine as adjunct medication for adjuvant chemotherapy treatments of non-small cell lung cancer patients. Sci. Rep. 7, 46524. 10.1038/srep46524
    1. Ke E. E., Zhou Q., Zhang Q. Y., Su J., Chen Z. H., Zhang X. C., et al. (2017). A higher proportion of the EGFR T790M mutation may contribute to the better survival of patients with exon 19 deletions compared with those with L858R. J. Thorac. Oncol. 12 (9), 1368–1375. 10.1016/j.jtho.2017.05.018
    1. Kim E. S., Hirsh V., Mok T., Socinski M. A., Gervais R., Wu Y. L., et al. (2008). Gefitinib versus docetaxel in previously treated non-small-cell lung cancer (INTEREST): a randomised phase III trial. Lancet 372 (9652), 1809–1818. 10.1016/S0140-6736(08)61758-4
    1. Lee C. K., Davies L., Wu Y. L., Mitsudomi T., Inoue A., Rosell R., et al. (2017). Gefitinib or erlotinib vs chemotherapy for EGFR mutation-positive lung cancer: individual patient data meta-analysis of overall survival. J. Natl. Cancer Inst. 109 (6). 10.1093/jnci/djw279
    1. Li L., Wang S., Zheng F., Wu W., Hann S. S. (2016). Chinese herbal medicine Fuzheng Kang-Ai decoction sensitized the effect of gefitinib on inhibition of human lung cancer cells through inactivating PI3-K/Akt -mediated suppressing MUC1 expression. J. Ethnopharmacol. 194, 918–929. 10.1016/j.jep.2016.10.077
    1. Li S. G., Chen H. Y., Ou-Yang C. S., Wang X. X., Yang Z. J., Tong Y., et al. (2013). The efficacy of Chinese herbal medicine as an adjunctive therapy for advanced non-small cell lung cancer: a systematic review and meta-analysis. PLoS One 8 (2), e57604. 10.1371/journal.pone.0057604
    1. Liang W., Wu X., Fang W., Zhao Y., Yang Y., Hu Z., et al. (2014). Network meta-analysis of erlotinib, gefitinib, afatinib and icotinib in patients with advanced non-small-cell lung cancer harboring EGFR mutations. PLoS One 9 (2), e85245. 10.1371/journal.pone.0085245
    1. Melosky B., Hirsh V. (2014). Management of common toxicities in metastatic NSCLC related to anti-lung cancer therapies with EGFR-TKIs. Front. Oncol. 4, 238. 10.3389/fonc.2014.00238
    1. Mitsudomi T., Morita S., Yatabe Y., Negoro S., Okamoto I., Tsurutani J., et al. (2010). 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. 11 (2), 121–128. 10.1016/S1470-2045(09)70364-X
    1. Mok T. S., Wu Y. L., Ahn M. J., Garassino M. C., Kim H. R., Ramalingam S. S., et al. (2017). Osimertinib or platinum-pemetrexed in EGFR T790M-positive lung cancer. N. Engl. J. Med. 376 (7), 629–640. 10.1056/NEJMoa1612674
    1. Mok T. S., Wu Y. L., Thongprasert S., Yang C. H., Chu D. T., Saijo N., et al. (2009). Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma. N. Engl. J. Med. 361 (10), 947–957. 10.1056/NEJMoa0810699
    1. Ramalingam S. S., Yang J. C., Lee C. K., Kurata T., Kim D. W., John T., et al. (2018). Osimertinib as first-line treatment of EGFR mutation-positive advanced non-small-cell lung cancer. J. Clin. Oncol. 36 (9), 841–849. 10.1200/JCO.2017.74.7576
    1. Riely G. J., Pao W., Pham D., Li A. R., Rizvi N., Venkatraman E. S., et al. (2006). Clinical course of patients with non-small cell lung cancer and epidermal growth factor receptor exon 19 and exon 21 mutations treated with gefitinib or erlotinib. Clin. Cancer Res. 12 (3 Pt 1), 839–844. 10.1158/1078-0432.CCR-05-1846
    1. Rosell R., Carcereny E., Gervais R., Vergnenegre A., Massuti B., Felip E., et al. (2012). Erlotinib versus standard chemotherapy as first-line treatment for European patients with advanced EGFR mutation-positive non-small-cell lung cancer (EURTAC): a multicentre, open-label, randomised phase 3 trial. Lancet Oncol. 13 (3), 239–246. 10.1016/S1470-2045(11)70393-X
    1. Rosell R., Moran T., Queralt C., Porta R., Cardenal F., Camps C., et al. (2009). Screening for epidermal growth factor receptor mutations in lung cancer. N. Engl. J. Med. 361 (10), 958–967. 10.1056/NEJMoa0904554
    1. Shi Y., Zhang L., Liu X., Zhou C., Zhang L., Zhang S., et al. (2013). Icotinib versus gefitinib in previously treated advanced non-small-cell lung cancer (ICOGEN): a randomised, double-blind phase 3 non-inferiority trial. Lancet Oncol. 14 (10), 953–961. 10.1016/S1470-2045(13)70355-3
    1. Shi Y. K., Wang L., Han B. H., Li W., Yu P., Liu Y. P., et al. (2017). First-line icotinib versus cisplatin/pemetrexed plus pemetrexed maintenance therapy for patients with advanced EGFR mutation-positive lung adenocarcinoma (CONVINCE): a phase 3, open-label, randomized study. Ann. Oncol. 28 (10), 2443–2450. 10.1093/annonc/mdx359
    1. Thongprasert S., Duffield E., Saijo N., Wu Y. L., Yang J. C., Chu D. T., et al. (2011). Health-related quality-of-life in a randomized phase III first-line study of gefitinib versus carboplatin/paclitaxel in clinically selected patients from Asia with advanced NSCLC (IPASS). J. Thorac. Oncol. 6 (11), 1872–1880. 10.1097/JTO.0b013e31822adaf7
    1. Thress K. S., Paweletz C. P., Felip E., Cho B. C., Stetson D., Dougherty B., et al. (2015). Acquired EGFR C797S mutation mediates resistance to AZD9291 in non-small cell lung cancer harboring EGFR T790M. Nat. Med. 21 (6), 560–562. 10.1038/nm.3854
    1. Wang Q., Jiao L., Wang S., Chen P., Bi L., Zhou D., et al. (2018). Maintenance chemotherapy with chinese herb medicine formulas vs. Front. Pharmacol. 9, 1233. 10.3389/fphar.2018.01233
    1. Wei S. (2018). Yin-yang regulating effects of cancer-associated genes, proteins, and cells: an ancient chinese concept in vogue in modern cancer research. Biosci. Trends. 11 (6), 612–618. 10.5582/bst.2017.01259
    1. Xu L., Meng X., Xu N., Fu W., Tan H., Zhang L., et al. (2018). Gambogenic acid inhibits fibroblast growth factor receptor signaling pathway in erlotinib-resistant non-small-cell lung cancer and suppresses patient-derived xenograft growth. Cell Death Dis. 9 (3), 262. 10.1038/s41419-018-0314-6
    1. Yang X. B., Wu W. Y., Long S. Q., Deng H., Pan Z. Q. (2014). Effect of gefitinib plus Chinese herbal medicine (CHM) in patients with advanced non-small-cell lung cancer: a retrospective case-control study. Complement. Ther. Med. 22 (6), 1010–1018. 10.1016/j.ctim.2014.10.001
    1. Yang X. B., Chai X. S., Wu W. Y., Long S. Q., Deng H., Pan Z. Q., et al. (2017). Gefitinib plus Fuzheng Kang’ai Formula (扶正抗癌方) in patients with advanced non-small cell lung cancer with epidermal growth factor receptor mutation: a randomized controlled trial. Chin. J. Integr. Med. 24 (10), 734–740. 10.1007/s11655-017-2819-8
    1. Yu P. P., Vose J. M., Hayes D. F. (2015). Genetic cancer susceptibility testing: increased technology, increased complexity. J. Clin. Oncol. 33 (31), 3533–3534. 10.1200/JCO.2015.63.3628
    1. Yu H. A., Arcila M. E., Rekhtman N., Sima C. S., Zakowski M. F., Pao W., et al. (2013). 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. 19 (8), 2240–2247. 10.1158/1078-0432.CCR-12-2246
    1. Zhang Y., Sheng J., Kang S., Fang W., Yan Y., Hu Z., et al. (2014). Patients with exon 19 deletion were associated with longer progression-free survival compared to those with L858R mutation after first-line EGFR-TKIs for advanced non-small cell lung cancer: a meta-analysis. PLoS One 9 (9), e107161. 10.1371/journal.pone.0107161
    1. Zhou C., Wu Y. L., Chen G., Feng J., Liu X. Q., Wang C., et al. (2011). 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. 12 (8), 735–742. 10.1016/S1470-2045(11)70184-X

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