Survival Benefit and Toxicity Profile of Adjuvant Icotinib for Patients With EGFR Mutation-Positive Non-Small Cell Lung Carcinoma

A Retrospective Study

Ziqing Zeng; Bo Yan; Yulong Chen; Lianmin Zhang; Jianquan Zhu; Fan Yang; Feng Wei; Terence Chi Chun Tam; Diego Kauffmann-Guerrero; Ross Andrew Soo; Xiubao Ren; Jian You

Disclosures

Transl Lung Cancer Res. 2020;9(6):2401-2410. 

In This Article

Discussion

EGFR-TKIs have been approved by Food and Drug Administration and Chinese National Medical Products Administration for use in the treatment of advanced NSCLC patients who cannot be surgically resected, and the efficacy of EGFR-TKIs were usually better than that of chemotherapy or no treatment.[31] A meta-analysis showed that, in advanced NSCLC, the median survival time was 13.26, 13.52, and 12.58 months for gefitinib, erlotinib and icotinib, respectively.[25] Icotinib has similar efficacy than gefitinib but a more favorable safety profile when used as a second- or further-line therapy in patients with advanced NSCLC,[25,26] but there is currently insufficient data for icotinib as adjuvant therapy in patients with EGFR mutation-positive NSCLC.[27]EGFR-TKIs are considered part of a new era for the tailored management of resectable EGFR mutation-positive NSCLC,[30] and our results suggest that the use of adjuvant icotinib in such cohort might be associated with a promising survival benefit with an acceptable toxicity profile.

It has been well documented that adjuvant platinum based chemotherapy improves the survival in patients with resected NSCLC,[9–12] but chemotherapy-related AEs and treatment related mortality were reported.[9] More recently, adjuvant gefitinib, erlotinib and osimertinib have shown improvement in PFS in resected stage I–III NSCLC with EGFR exon 19 and 21 mutations.[20–22] Compared with gefitinib, icotinib has similar efficacy, but a better safety profile,[25,26] and the CONVINCE trial showed better outcomes of the first-line icotinib vs. chemotherapy for stage IIIB-IV NSCLC.[27] A retrospective study of adjuvant icotinib revealed it has survival benefits in R0 NSCLC with EGFR mutations with acceptable toxicity.[28] In most EGFR adjuvant trials, there is the problem of the lacking OS data as well the problem regarding the treatment duration. The lack of OS data may be due to insufficient follow-up time and insufficient number of events, in which condition, OS data may be unreliable therefore have not been displayed. Follow-up data of these clinical trials can be collected and updated in the future. At ASCO 2020, the OS data of ADJUVANT was revealed, showing that the median OS of patients receiving adjuvant gefitinib was 75.5 months, which was nearly 13 months longer than the 62.8 months in the adjuvant chemotherapy group (HR: 0.92; 95% CI: 0.62–1.36; P=0.674).[32] Treatment duration is also an issue that have not been concluded. Current EGFR-TKI adjuvant trials differ in the choice of treatment duration. Regarding the exploration of treatment duration, some studies have been carried out, we look forward to the results of those studies. In present study, two years was adopted as treatment duration and the DFS/OS data was shown.

The present study showed that the 2-year DFS rate was 86.7% and the 3-year OS rate was 95.3%, which are better than the historical survival data with chemotherapy (2-year DFS of 57–76%, 3-year OS of 62–74%) or with no treatment (2-year DFS of 47–60%, 3-year OS of 57–72%),[9–12] suggesting a possible better survival benefit for adjuvant icotinib targeted therapy compared with adjuvant chemotherapy. The median DFS and OS were not reached in the present study. These results might be associated with excellent baseline characteristics of the patients since about 50% of the patients were stage IB, and the ECOG performance status was 0 in all patients. These findings suggest that adjuvant therapy with icotinib is feasible and might result in an excellent prognosis in patients with stage IB–IIIB NSCLC.

Further subgroup analysis showed that both DFS and OS were better for stage I/II disease than for stage III and T1–2 disease compared with T3–4. DFS was better for N0 tumors than for N1–2. Those results are in agreement with the recognized prognostic factors of NSCLC.[4,8]

In the present study, the most common AEs in the icotinib group were rash and diarrhea, with acceptable tolerability. Spontaneous relief was observed in most patients, and no severe AEs, including interstitial lung disease, occurred. If interstitial pneumonia occurs, the treatment mainly includes: stop taking EGFR-TKI immediately; clinical treatment strategies are mainly symptomatic and supportive treatment: oxygen inhalation, anti-inflammatory, anti-infective, and anti-fibrotic treatments. Previous studies of icotinib already revealed its favorable safety profile.[25–27,33] However, in terms of some specific side effects, some other EGFR-TKIs may have less side effects. For example, clinical trials[27,34,35] showed that although icotinib has the lowest overall incidence of diarrhea, many other EGFR-TKIs have a lower incidence of grade ≥3 diarrhea. In addition, compared with icotinib, osimertinib has a lower incidence of drug-induced liver injury, gefitinib and osimertinib have a lower incidence of grade ≥3 rash, etc. The results of this study suggest icotinib with a standard dose is suitable for adjuvant therapy in patients with R0 resected NSCLC, but further prospective clinical studies must validate this suitability. In clinical practice, we need to select the most suitable EGFR-TKI according to the specific situation.

This study has limitations. First, biases are unavoidable in single-center retrospective studies. In the future, we will actively carry out multi-center clinical study in order to obtain more generalized results. Second, multivariate analysis was statistically impractical due to the high censoring rate. Third, this was a single-arm study without a comparator. Furthermore, some issues need to be addressed: (I) whether icotinib monotherapy is enough; (II) the optimal duration of adjuvant icotinib therapy; (III) sequence and timing of adjuvant targeted therapy and chemotherapy; and (IV) optimal target patients. The present study indicated that adjuvant icotinib therapy may prolonged survival with an acceptable safety profile, Further randomized controlled trials must verify the efficacy and safety of adjuvant therapy with icotinib to support our hypothesis. These trials might further confirm the impact of adjuvant icotinib therapy on DFS and OS and will identify the target population.

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