Treatment options for adjuvant-targeted therapy in patients with EGFR mutation-positive NSCLC after relapse

Highlights from this issue

At present, there are limited studies on relapse of targeted adjuvant therapy, or post-drug resistance therapy, and in clinical work, a variety of factors such as the patient's willingness, the location of recurrence, the time of recurrence, and the genetic mutation spectrum at the time of recurrence can be combined to determine the follow-up treatment regimen 1-5 after comprehensive evaluation.

There may be differences in recurrence patterns and risk of recurrence at various sites after adjuvant therapy of the first generation EGFR-TKI and the third generation EGFR-TKI6-9.

In early patients, the mechanism of recurrence during adjuvant EGFR-TKI versus relapse after discontinuation may be different10-11.

The 2019 international consensus of experts on postoperative management of EGFR-mutated lung cancer recommends that EGFR-TKI12 be reused in patients who receive postoperative adjuvant therapy with EGFR-TKI if there is a recurrence after discontinuation.

The specific relapse mechanisms and treatment options for relapse during treatment and recurrence after discontinuation of the drug need to be further explored.

EGFR-TKI adjuvant targeted therapy

A generation of EGFR-TKI adjuvant targeted therapy: EVIDENCE study, including stage II-IIIA, and 322 patients with NSCLC who achieved R0 resection, were directly randomized to the extinib group or adjuvant chemotherapy group (vinorelbine/pemetrexed + cisplatin) without chemotherapy after surgery, and the results showed that the neutral DFS in the exetinib group reached 47 months, significantly better than the 22.1 months of adjuvant chemotherapy in the control group (HR=0.36, p1).

Adjuvant targeted therapy for the third generation EGFR-TKI: The ADAURA study was an international multicenter, double-blind, randomized controlled Phase III clinical study with a significant benefit in median DFS in patients with stage II-IIIA of the primary endpoint, an 83% reduction in the risk of disease recurrence or death in the osimtinib group, and a DFS HR value of 0.17 (99.06% CI 0.11-0.26, P<0.001)2.

From this, we can see that both the first and third generations of EGFR-TKI drugs have profoundly changed the clinical practice of patients with early EGFR mutation-positive NSCLC. But recurrence after adjuvant targeted therapy also brings some new challenges to clinical treatment: What is the recurrence pattern of lung cancer? How is treatment chosen after relapse and can EGFR-TKI be used?

Recurrence patterns of lung cancer with adjuvant targeted therapy

First, let's look at the recurrence site of lung cancer. A number of retrospective analyses have shown that postoperative disease recurrences in patients with early NSCLC are mostly distant recurrence3, and the common recurrence sites are: intracranial recurrence (17%-31%), ipsilateral lung (23%), contralateral lung (15%-23%), pleura (2%-36%), bone (7%-19%), 4-5, etc.

Data on adjuvant therapy for the first generation of EGFR-TKI are reviewed

Although the first generation of EGFR-TKI prolonged DFS in patients, it failed to effectively control distant metastases, especially CNS metastasis 6-7, in patients with relapse. A Japanese first-generation EGFR-TKI adjuvant therapy study found that 22.4% of patients with adjuvant targeted therapy developed CNS metastases and 12.1% of patients with adjuvant chemotherapy6; another first-generation EGFR-TKI adjuvant therapy study results were not optimistic, and 27.4% of patients with adjuvant targeted therapy developed CNS metastases7.

Are there differences in efficacy between first-generation EGFR-TKI adjuvant therapies? A real-world study published at the European Lung Cancer Congress 2021 suggested that adjuvant therapy using the first generation of EGFR-TKI was comparable in efficacy and that there was no significant difference in the reasons for treatment failure of the first-generation EGFR-TKI adjuvant therapy (brain metastases, p=0.29; bone metastases, p=0.69)8.

Review data on third-generation EGFR-TKI adjuvant therapy

The third generation of EGFR-TKI provides better control of distant metastases, particularly CNS transfers. Analysis of recurrence patterns in the ADAURA study showed that patients receiving adjuvant therapy with osimtinib had fewer local and distant recurrences compared with the placebo group, lower incidence of distant metastases in relapsed patients (38% vs 61%), and significantly lower rates of brain metastases recurrence (1% vs 10%), and further comparisons of the probability of CNS recurrence conditions at 18 months showed that oscitinib significantly reduced the risk of RECURRENCE or death of CNS disease (2% vs 11%)9.

Recurrence time and mechanism of lung cancer

Relevant small sample studies suggest that T790M resistance mutations occurred only in patients who relapsed during EGFR-TKI treatment, while secondary resistance mutations 10-11 were not detected in those who had completed EGFR-TKI adjuvant therapy. Suggests that EGFR-TKI may still be appropriate for patients who have completed EGFR-TKI adjuvant therapy prior to relapse. EGFR-TKI retherapy in patients with relapse after discontinuation of EGFR-TKI adjuvant therapy is similar to the benefit of OS survival for advanced NSCLC first-line therapy, so it is speculated that patients who relapse after discontinuation may be equivalent to the initial treatment10-11.

At present, the research on the recurrence of targeted adjuvant therapy, or post-drug resistance therapy is limited, and colleagues can combine various factors such as the patient's willingness, recurrence site, recurrence time and genetic mutation spectrum at the time of recurrence in clinical work, and decide on the follow-up treatment plan after comprehensive evaluation.

In addition, the mechanism of recurrence during adjuvant EGFR-TKI treatment in early patients and recurrence after discontinuation seems to be different, and the International Expert Consensus on Postoperative Management of EGFR-Mutant Lung Cancer (2019 Edition) recommends that in patients receiving EGFR-TKI adjuvant therapy after surgery, if recurrence occurs after discontinuation, EGFR-TKI can be considered again. However, further clinical evidence is needed regarding the specific differences between relapse during treatment and recurrence after discontinuation and treatment options.

bibliography:

1.He J, et al. Lancet Respir Med. 2021 Sep;9(9):1021-1029.

2.Wu YL, et al. N Engl J Med. 2020 Oct 29;383(18):1711-1723.

3.Boyd JA, et al. J Thorac Oncol 2010;5:211–214.

4.Taylor MD, et al. Ann Thorac Surg 2012;93:1813–1821.

5.Lou F, et al. Ann Thorac Surg 2014;98:1755–1761.

6.Hirohito Tada, et al. ASCO 2021 abstract 8501;

7.Xu ST, Xi JJ, Zhong WZ, et al. J Thorac Oncol. 2019;14(3):503-512.;

8.Wenhua Liang et al. 2021 ELCC. 68P#;

9.Masahiro Tsuboi, et al. ESMO. 2020 ,LBA1

10.J Oncol clin. 2019 Jan 10;37(2):97-104;

11.Clin Cancer Res. 2011 October 1; 17(19): 6322–6328.

12.Transl Lung Cancer Res 2019;8( 6):1163-1173.

*This information is for medical and scientific exchange by medical and health professionals only and is not intended for promotional purposes.

Approval Number CN-89592 Expiration Date2022-5-13

Source: Medical community

Editor-in-charge: Zheng Huaju

Proofreader: Zang Hengjia

Plate making: Xue Jiao