Neoadjuvant therapy for locally advanced non-small cell lung cancer: TKIs or immunotherapy?

Our medical group recently published a study in the Journal of Thoracic Disease reporting the surgical experience in six patients with resectable epidermal growth factor receptor (EGFR) mutated non-small cell lung cancer (NSCLC) after gefitinib as neoadjuvant therapy (1). The publication of this manuscript has triggered a round of interest and discussion. As discussed in the article (1) and related editorials (2), our research was a retrospective study with limitations, consisting of six pooled cases for the purpose of revealing the procedure of neoadjuvant treatment. In this letter to the editor, we attempt to address several issues that were not revealed in the article due to the article type (1).

The article mainly retrospectively illustrated the procedure of radical resection after neoadjuvant targeted therapy (1). We described a typical case of radical surgical resection of residual disease after dramatic response to gefitinib in a patient with locally advanced lung adenocarcinoma harboring EGFR gene mutation to explore the efficacy of preoperative targeted neoadjuvant therapy. Five of the patients had preoperative stage IIIA of the disease, and one case had stage IIIB, according to the 7th edition of the clinical TNM (cTNM). The standard surgery included lobectomy and the mediastinal lymph node dissection. While preoperative gefitinib treatment made it possible to perform radical resection in these six cases, the surgery was performed and the suitable adjuvant therapy was arranged after the operation. Some other patients were excluded because radical resection was not permitted due to disease progression. One patient refused further surgical intervention even when PR (partial response) was achieved by neoadjuvant targeted treatment. They continued to accept conservative therapy. The postoperative pathology of one of the patients who underwent surgery revealed small cell lung cancer mixed with adenocarcinoma, which led to the correct implementation of adjuvant therapy. The postoperative staging statistics are available in Table 1. The impact of treatment on the down-staging in these six cases was significant. Postoperative staging statistics show that one of the patients had stage IA of the disease, two cases had stage IIB, and three cases had stage IIIA. Although the results of the EMERGING-CTONG 1103 study and the primary objective were negative [The ORR for neoadjuvant treatment was 54.1% in the erlotinib arm compared with 34.3% in the control (CT) group (odds ratio, 2.26; 95% CI, 0.87–5.84; P=0.092)], and the median of PFS was significantly longer in patients treated with erlotinib (21.5 months) compared with the CT arm (11.4 months) (3). Our retrospective single-arm research also showed a long median of progression-free survival (PFS) than this multicenter-randomized-controlled trial study. Patients who received neoadjuvant therapy had a better physical situation before surgery than the patients who accepted neoadjuvant chemotherapy. Only the case of small cell lung cancer mixed with adenocarcinoma had bone metastasis with a PFS of 15 months, with no other recurrence happening. The patients were followed up for 12 to 30 months. Overall survival (OS) might not have been a good endpoint for this trial, because patients might have received back-line therapy, such as chemotherapy/anti-VEGF drugs after disease progression. We still try to enroll more patients into this clinical trial. Complete follow-up data will also be collected, and the results of this study will be published in the corresponding article.

The immunotherapy (IO) is now suggested in patients with advanced NSCLC, both in the first-line of treatment and in later lines (4). The IMPOWER 150 study demonstrated that the addition of IO to the scheme of CT (carboplatin/paclitaxel) plus bevacizumab improved the PFS and the objective response rate (ORR) in EGFR-mutated patients (5). Forde et al. published a challenging study that evaluates the use of neoadjuvant nivolumab in a small cohort of patients (NCT02259621). Most of the patients were early-stage lung cancer, with all information about the status of EGFR unknown (6). IO in monotherapy or combined with CT is being evaluated in several clinical trials, such as KEYNOTE671, as a new induction treatment in patients with potentially resectable disease. These studies seem to suggest that IO has been firmly established in induction/neoadjuvant therapy for NSCLC. What we are concerned with is that there are still a number of issues to consider in the application of neoadjuvant IO, such as immune-related adverse events (irAEs), the possibility of disease hyperprogression in patients with EGFR mutations, the cost, and so on. The irAEs include endocrine disease, hepatitis, pneumonia, and neurologic syndromes (7). Postoperative pneumonia is difficult to distinguish from immune-related pneumonia. In fact, we have explored several cases of preoperative neoadjuvant IO for lung cancer in the monotherapy or combined with the CT method. Postoperative severe immune-related interstitial pneumonia and respiratory failure happened on postoperative day five in one case, which was difficult to differentiate from bacterial pneumonia at that time. In 2017, Kato et al. (8) also pointed out on CCR that EGFR mutation could initiate immune escape by up-regulating the expression of pd-1, pd-l1, and CTLA-1. The results showed that 20% (2/10) of patients with EGFR mutations had hyperprogression, which increases the rate of progression 40 times. The cost of IO and irAE therapy is very high for patients. Patients with EGFR mutations are not good candidates for neoadjuvant IO therapy.

Neoadjuvant targeted and IO therapies are quite effective treatments for stage IIIA lung cancer, which is highly heterogeneous. Despite the results of the use of TKIs and IO in the first-line of treatment, new studies should be designed to evaluate neoadjuvant strategies. High-quality prospective cohort studies remain highly valuable, and many unresolved issues require rigorous trial and complete data for verification.

Acknowledgments

We would like to thank Gaojie Lin for proofreading.

Funding: This work was supported by the Program for Innovative Research Team in Science and Technology in Fujian Province University & Fujian province science and technology innovation joint fund project (NO. 2018Y9034).

Footnote

Conflicts of Interest: The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

References

1. Zhang Z, Lin J, Peng S. Radical surgical resection after neoadjuvant targeted therapy in non-small cell lung cancer: a single-center retrospective study of 6 cases. J Thorac Dis 2019;11:248-51. [Crossref] [PubMed]
2. Franco F, Provencio M. Neoadjuvant treatment with tyrosine kinase inhibitors in patients with resectable non-small cell lung cancer. J Thorac Dis 2019;11:4092-5. [Crossref] [PubMed]
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;37:2235-45. [Crossref] [PubMed]
4. Rittmeyer A, Barlesi F, Waterkamp D, et al. Atezolizumab versus docetaxel in patients with previously treated non-small-cell lung cancer (OAK): a phase 3, open-label, multicentre randomised controlled trial. Lancet 2017;389:255-65. [Crossref] [PubMed]
5. Reck M, Mok TSK, Nishio M, et al. Atezolizumab plus bevacizumab and chemotherapy in non-small-cell lung cancer (IMpower150): key subgroup analyses of patients with EGFR mutations or baseline liver metastases in a randomised, open-label phase 3 trial. Lancet Respir Med 2019;7:387-401. [Crossref] [PubMed]
6. Forde PM, Chaft JE, Smith KN, et al. Neoadjuvant PD-1 Blockade in Resectable Lung Cancer. N Engl J Med 2018;378:1976-86. [Crossref] [PubMed]
7. Postow MA, Sidlow R, Hellmann MD. Immune-related adverse events associated with immune checkpoint blockade. N Engl J Med 2018;378:158-68. [Crossref] [PubMed]
8. Kato S, Goodman A, Walavalkar V, et al. Hyperprogressors after Immunotherapy: Analysis of Genomic Alterations Associated with Accelerated Growth Rate. Clin Cancer Res 2017;23:4242-50. [Crossref] [PubMed]

(English Language Editor: Gray John Ayric, AME Publishing Company)