PD-1 inhibitor combined with chemotherapy in preoperative neoadjuvant treatment of stage Ⅲ non-small cell lung cancer: A randomized controlled trial_Chinese Journal of Clinical Thoracic and Cardiovascular Surgery

Authors：

BAI Yue ^1,3 ,  SUN Daqiang ² , ZHANG Xun ² , ZHU Gongjian ³ , LANG Lili ³ , CAO Qun ³

1. Graduate School of Tianjin Medical University, Tianjin, 300070, P.R.China;
2. Department of Thoracic Surgery, Tianjin Chest Hospital, Tianjin, 300222, P.R.China;
3. Department of Thoracic Surgery, Gansu Cancer Hospital, Lanzhou, 730050, P.R.China;

Corresponding?author：

SUN Daqiang, Email: sdqmd@163.com

Keywords：

Non-small cell lung cancer; preoperative neoadjuvant therapy; PD-1 inhibitor; efficacy; safety

DOI：

10.7507/1007-4848.202012106

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Objective To evaluate the efficacy and safety of programmed cell death receptor 1 (PD-1) inhibitor combined with chemotherapy in the preoperative neoadjuvant treatment of stage Ⅲ non-small cell lung cancer (NSCLC).Methods The clinical data of 68 patients with stage Ⅲ NSCLC who underwent preoperative neoadjuvant treatment in our hospital from June 2019 to October 2020 were analyzed and divided into two groups according to a random number table. There were 34 patients in the control group including 19 males and 15 females with an average age of 59.41±4.77 years. In the observation group, there were 34 patients including 21 males and 13 females with an average age of 61.15±6.24 years. The patients in the control group were treated with albumin-bound paclitaxel and cisplatin for injection, and the patients in the observation group were treated with carrelizumab on the basis of the control group, and both groups received 2 cycles of preoperative neoadjuvant therapy. We compared the clinical efficacy of imaging, T lymphocyte subsets, drug side effects, surgical resection rate, major pathological remission (MPR), complete pathological remission (pCR) and postoperative complications of the two groups of patients, and analyzed the influencing factors for MPR.Results The objective response rate (ORR) of imaging in the observation group (70.6%) was higher than that in the control group (38.2%, P<0.05). The positive rate of CD₃⁺ cells, the positive rate of CD₄⁺ cells, the positive rate of CD₈⁺ cells and the ratio of CD₄⁺/CD₈⁺ cells in the observation group after treatment were higher than those in the control group (P<0.05). The drug toxicity of the observation group was higher than that of the control group in the reactive cutaneouscapillary endothelial proliferation (RCCEP)/rash, abnormal thyroid function, and abnormal myocardial enzymes (P<0.05). The MPR (66.7%) and pCR (51.9%) of the surgical observation group were higher than those of the surgical control group (MPR: 19.2%, pCR: 7.7%, P<0.05). There was no statistical difference in surgical resection rate and postoperative complications between the two groups (P>0.05). Univariate analysis showed that ECOG score, pathological type, neoadjuvant treatment plan and surgical resection were related to MPR (P<0.05). The results of binary logistic regression analysis showed that Eastern Cooperative Oncology Group (ECOG) score and neoadjuvant treatment plan were independent risk factors for MPR (P<0.05).Conclusion The clinical efficacy of PD-1 inhibitor combined with chemotherapy in the preoperative neoadjuvant treatment of stage Ⅲ NSCLC patients is definite, and it can significantly improve the patients' MPR, pCR and cellular immune function, but the side effects caused by immunotherapy drugs need to be concerned.

Citation： BAI Yue, SUN Daqiang, ZHANG Xun, ZHU Gongjian, LANG Lili, CAO Qun. PD-1 inhibitor combined with chemotherapy in preoperative neoadjuvant treatment of stage Ⅲ non-small cell lung cancer: A randomized controlled trial. Chinese Journal of Clinical Thoracic and Cardiovascular Surgery, 2021, 28(8): 963-971. doi: 10.7507/1007-4848.202012106 Copy

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9.	Provencio M, Nadal E, Insa A, et al. Neoadjuvant chemotherapy and nivolumab in resectable non-small-cell lung cancer (NADIM): An open-label, multicentre, single-arm, phase 2 trial. Lancet Oncol, 2020, 21(11): 1413-1422.
10.	Shu CA, Gainor JF, Awad MM, et al. Neoadjuvant atezolizumab and chemotherapy in patients with resectable non-small-cell lung cancer: An open-label, multicentre, single-arm, phase 2 trial. Lancet Oncol, 2020, 21(6): 786-795.
11.	Forde PM, Chaft JE, Smith KN, et al. Neoadjuvant PD-1 blockade in resectable lung cancer. N Engl J Med, 2018, 378(21): 1976-1986.
12.	Zhang B, Chikuma S, Hori S, et al. Nonoverlapping roles of PD-1 and FoxP3 in maintaining immune tolerance in a novel autoimmune pancreatitis mouse model. Proc Natl Acad Sci U S A, 2016, 113(30): 8490-8495.
13.	Keir ME, Butte MJ, Freeman GJ, et al. PD-1 and its ligands in tolerance and immunity. Annu Rev Immunol, 2008, 26: 677-704.
14.	Xia B, Herbst RS. Immune checkpoint therapy for non-small-cell lung cancer: An update. Immunotherapy, 2016, 8(3): 279-298.
15.	Puzanov I, Diab A, Abdallah K, et al. Managing toxicities associated with immune checkpoint inhibitors: Consensus recommendations from the Society for Immunotherapy of Cancer (SITC) Toxicity Management Working Group. J Immunother Cancer, 2017, 5(1): 95.
16.	O'Kane GM, Labbé C, Doherty MK, et al. Monitoring and management of immune-related adverse events associated with programmed cell death protein-1 axis inhibitors in lung cancer. Oncologist, 2017, 22(1): 70-80.
17.	Chen X, Ma L, Wang X, et al. Reactive capillary hemangiomas: A novel dermatologic toxicity following anti-PD-1 treatment with SHR-1210. Cancer Biol Med, 2019, 16(1): 173-181.
18.	Hellmann MD, Chaft JE, William WN, et al. Pathological response after neoadjuvant chemotherapy in resectable non-small-cell lung cancers: Proposal for the use of major pathological response as a surrogate endpoint. Lancet Oncol, 2014, 15(1): e42-e50.

1. Bray F, Ferlay J, Soerjomataram I, et al. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin, 2018, 68(6): 394-424.
2. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2020. CA Cancer J Clin, 2020, 70(1): 7-30.
3. Goldstraw P, Chansky K, Crowley J, et al. The IASLC lung cancer staging project: Proposals for revision of the tnm stage groupings in the forthcoming (eighth) edition of the TNM classification for lung cancer. J Thorac Oncol, 2016, 11(1): 39-51.
4. Shin S, Kim HK, Cho JH, et al. Adjuvant therapy in stage ⅢA-N2 non-small cell lung cancer after neoadjuvant concurrent chemoradiotherapy followed by surgery. J Thorac Dis, 2020, 12(5): 2602-2613.
5. Kim JH, Kim BJ, Jang HJ, et al. Comparison of the RECIST and EORTC PET criteria in the tumor response assessment: A pooled analysis and review. Cancer Chemother Pharmacol, 2017, 80(4): 729-735.
6. Trotti A, Colevas AD, Setser A, et al. CTCAE v3.0: Development of a comprehensive grading system for the adverse effects of cancer treatment. Semin Radiat Oncol, 2003, 13(3): 176-181.
7. Reidy-Lagunes D, Thornton R. Pancreatic neuroendocrine and carcinoid tumors: What's new, what's old, and what's different? Curr Oncol Rep, 2012, 14(3): 249-256.
8. Xiong L, Li R, Sun J, et al. Erlotinib as neoadjuvant therapy in stage ⅢA (N2) EGFR mutation-positive non-small cell lung cancer: A prospective, single-arm, phaseⅡstudy. Oncologist, 2019, 24(2): 157-e64.
9. Provencio M, Nadal E, Insa A, et al. Neoadjuvant chemotherapy and nivolumab in resectable non-small-cell lung cancer (NADIM): An open-label, multicentre, single-arm, phase 2 trial. Lancet Oncol, 2020, 21(11): 1413-1422.
10. Shu CA, Gainor JF, Awad MM, et al. Neoadjuvant atezolizumab and chemotherapy in patients with resectable non-small-cell lung cancer: An open-label, multicentre, single-arm, phase 2 trial. Lancet Oncol, 2020, 21(6): 786-795.
11. Forde PM, Chaft JE, Smith KN, et al. Neoadjuvant PD-1 blockade in resectable lung cancer. N Engl J Med, 2018, 378(21): 1976-1986.
12. Zhang B, Chikuma S, Hori S, et al. Nonoverlapping roles of PD-1 and FoxP3 in maintaining immune tolerance in a novel autoimmune pancreatitis mouse model. Proc Natl Acad Sci U S A, 2016, 113(30): 8490-8495.
13. Keir ME, Butte MJ, Freeman GJ, et al. PD-1 and its ligands in tolerance and immunity. Annu Rev Immunol, 2008, 26: 677-704.
14. Xia B, Herbst RS. Immune checkpoint therapy for non-small-cell lung cancer: An update. Immunotherapy, 2016, 8(3): 279-298.
15. Puzanov I, Diab A, Abdallah K, et al. Managing toxicities associated with immune checkpoint inhibitors: Consensus recommendations from the Society for Immunotherapy of Cancer (SITC) Toxicity Management Working Group. J Immunother Cancer, 2017, 5(1): 95.
16. O'Kane GM, Labbé C, Doherty MK, et al. Monitoring and management of immune-related adverse events associated with programmed cell death protein-1 axis inhibitors in lung cancer. Oncologist, 2017, 22(1): 70-80.
17. Chen X, Ma L, Wang X, et al. Reactive capillary hemangiomas: A novel dermatologic toxicity following anti-PD-1 treatment with SHR-1210. Cancer Biol Med, 2019, 16(1): 173-181.
18. Hellmann MD, Chaft JE, William WN, et al. Pathological response after neoadjuvant chemotherapy in resectable non-small-cell lung cancers: Proposal for the use of major pathological response as a surrogate endpoint. Lancet Oncol, 2014, 15(1): e42-e50.

Chinese Journal of Clinical Thoracic and Cardiovascular Surgery

PD-1 inhibitor combined with chemotherapy in preoperative neoadjuvant treatment of stage Ⅲ non-small cell lung cancer: A randomized controlled trial

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