Is There a Role for First Generation TKIs in Adjuvant Setting of EGFR Mutated Early NSCLC?

Aylen Vanessa Ospina; Mariano Provencio

Chin Clin Oncol. 2023;12(3):30

In terms of cancer- related mortality, it is clear that lung cancer is the leading cause of death in men and the second in women. Non-small cell lung cancer (NSCLC) accounts for the vast majority of cases (85%) and only one of three patients is a candidate for curative treatment with complete surgery at the time of diagnosis.^[1]

Considering the risk of recurrence and metastasis after surgery, adjuvant chemotherapy with cisplatin has been established as the standard of care for patients with completely resected stage II and III NSCLC. This choice is also highly recommended for patients with adverse features stage IB disease. This approach provides a 5-year overall survival (OS) benefit of 5.4% compared to no systemic treatment.^[2]

Given the demonstrated effectiveness of EGFR (epidermal growth factor receptor) tyrosine kinase inhibitors (TKIs) in metastatic setting of NSCLC, their utility in the adjuvant setting has been explored over last years. Therefore, there are some meta-analyses and several randomized controlled trials that have supported that an adjuvant strategy with EGFR-TKIs may improve disease-free survival (DFS) in patients with early-stage NSCLC. However, no significant superiority has been demonstrated in any of the available studies. This has been interpreted as secondary to the immaturity of OS data due to insufficient follow-up period.

Table 1. Trials of tyrosine kinase inhibitors (TKIs) in adjuvant setting of non small cell lung cancer EGFR mutated
Study	Stage	N/Population	EXPERIMENTAL ARM	Control arm	Primary endpoint	Results
EVAN Phase II	III A, N2 in 94% and 100% of erlotinib and chemotherapy arms respectively.	102/100% Asian	Erlotinib for 3 years	Standard chemotherapy	2-year DFS	DFS: 42.2 months in erlotinib vs. 21.2 months in chemotherapy arm P<0.0063 HR 0.327
						5 years OS: 84.8% erlotinib vs. 51.1% chemotherapy, P=0.015, HR 0.318
						Adverse events: all grades in 29 (58%) of 50 patients receiving erlotinib and in 28 (65%) of 43 patients with chemotherapy
SELECT single-arm, open-label Phase II	IA to IIIA	100/White 72/100; Asian 17/100	Erlotinib for 2 years at the end of standard adjuvant chemotherapy +/− radiotherapy	Not applicable	2-year DFS	DFS: 88% (96% stage I, 78% stage II, 91% stage III). 40% of patients decrease erlotinib dose to 100 mg and 16% to 50 mg
ADJUVANT-CTONG1104 Phase III	II–IIIA (N1–2)	222/100% Asian	Gefitinib for 2 years	Standard chemotherapy	DFS	DFS: 30.8 months in gefitinib vs. 19.8 months in chemotherapy, P=0.001, HR 0.56
						5 years OS: 53.2% gefitinib vs. 51.2% chemotherapy, P=0.674, HR 0.92
						Post-progression therapy in 68.4% and 73.6% of patients gefitinib and chemotherapy
						Further targeted therapy vs. no retreatment OS (HR 0.23; 95% CI: 0.14–0.38)
ADAURA Phase III	IB to IIIA: 32% IB, 34% II, 34% IIIA	682: 64% Asian; 36% no Asian	Osimertinib for 3 years +/− standard chemotherapy	Placebo +/− standard chemotherapy	DFS stage II to IIIA	DFS at 2 years 89% in osimertinib vs. 52% in placebo arm; HR 0.20; 99% CI: 0.14–0.30)
						At 24 months, 98% of patients in osimertinib vs. 85% in placebo arm free of central nervous system (CNS) disease (overall HR of disease recurrence or death 0.18; 95% CI: 0.10–0.33). OS immature
						In patients with stage II and IIIA disease, 2-year DFS 90% and 44% (HR 0.17; 95% CI: 0.11–0.26)
						Serious adverse events in 16% of patients. osimertinib dose reductions 9% and discontinuation 11%
						DFS update: 4-year DFS rate 70% for osimertinib and 29% for placebo
						DFS HR overall population was 0.27 (95% CI: 0.21–0.34); 4-yr DFS rate was 73% for osimertinib and 38% for placebo
						HR for CNS DFS in stage II–IIIA was 0.24 (95% CI: 0.14–0.42)
						Long-term safety data of osimertinib was consistent with primary analysis
						Osimertinib received approval by the U.S. Food and Drug Administration (FDA) as adjuvant treatment for resected EGFR-mutated NSCLC on December 18, 2020
RADIANTPhase II	IB-IIIA expressing EGFR+ by immunohistochemistry or EGFR amplification by fluorescence in situ hybridization	973: ITT population (80% white, 17% Asian; EGFRm population (56% white, 42% Asian)	Erlotinib for 2 years	Placebo	DFS	DFS (median, 50.5 vs. 48.2; HR 0.90; 95% CI: 0.74–1.10; P=0.324)
						161 patients (16.5%) in the EGFRm-positive subset, DFS (median, 46.4 vs. 28.5 months; HR 0.61; 95% CI: 0.38–0.98; P=0.039). OS immature
						Brain metastases in 37.1% of relapsed patients
						Frequency of dose reductions in erlotinib arm was 46%

DFS, disease-free survival; OS, overall survival; HR, hazard ratio; yr, year.

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Is There a Role for First Generation TKIs in Adjuvant Setting of EGFR Mutated Early NSCLC?

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