Currently, osimertinib is the standard of care in patients with resected stage II–IIIA EGFR-mutated NSCLC globally. Meanwhile, both osimertinib and icotinib are the standard of care in this patient population in China. Osimertinib was approved by the China NMPA on April 7, 2021, for the adjuvant treatment of stage IB–IIIA EGFR-mutated NSCLC, while icotinib was approved on June 3, 2021, for stage II–IIIA EGFR-mutated NSCLC.
With a median follow-up of 78.3 months (IQR 71.3–95.6) for the icotinib group and 69.9 months (IQR 35.2–96.4) for the placebo group, the ICWIP study demonstrated that 3-year adjuvant icotinib treatment significantly prolonged IRC-assessed median DFS versus placebo (48.2 months [95% CI 33.0–63.4] in the icotinib group vs. 20.0 months [95% CI 14.7–32.9] in the placebo group; HR 0.54, 95% CI 0.34–0.87; p = 0.011) after completing four cycles of adjuvant chemotherapy. To our knowledge, this is the longest follow-up among adjuvant therapies of EGFR-TKIs in NSCLC and offers a more comprehensive view of 3-year treatment outcomes with first-generation EGFR-TKIs. The median follow-up was 47 months in the RADIANT study,11 36.5 months (IQR 23.8–44.8) in the ADJUVANT/CTONG1104 study,12 70 months in the IMPACT study,13 33.0 months (IQR 17.8–43.1) in the EVAN study,14 24.9 months (IQR 16.6–36.4) in the EVIDENCE study,15 59.9 months (range 0–82) for the osimertinib group and 56.2 months (range 1–86) for the placebo group in the ADAURA study.24 Notably, in the ICWIP study, the 5-year DFS rate was 39.4% (95% CI 22.2–56.2%) in the icotinib group and 25.8% (95% CI 8.7–47.1%) in the placebo group assessed by IRC, supporting the durable clinical benefit in delaying disease recurrence of adjuvant icotinib therapy. The treatment effect was more pronounced in the PPS (median DFS 51.4 months in the icotinib group vs. 19.6 months in the placebo group; HR 0.50, 95% CI 0.30–0.82; p = 0.0061). Icotinib exhibited a favorable safety profile and good compliance without negatively affecting HRQoL.
The ICWIP study is the first to extend a 3-year adjuvant EGFR-TKI treatment regimen, yielding a median DFS of 48.2 months (95% CI 33.0–63.4). The median DFS was 50.5 months in the RADIANT study,11 28.7 months (95% CI 24.9–32.5) in the ADJUVANT/CTONG1104 study,12 35.9 (95% CI 30.0–47.7) in the IMPACT study,13 42.4 months (95% CI 31.7–NR) in the EVAN study,14 and 47.0 months (95% CI 36.4–NR) in the EVIDENCE study.15 Importantly, unlike previous studies, the ICWIP study mandated four cycles of adjuvant chemotherapy prior to study entry, potentially enhancing DFS. The early separation of Kaplan‒Meier curves was sustained for approximately 7 years, similar to the ADAURA study,25 highlighting the durability of benefits not observed in the 2-year EGFR-TKI adjuvant therapy.11,12,13,14 This long-term efficacy is likely attributable to the extended icotinib treatment duration, as supported by the survival benefits observed in the ICOMPARE study.16 Nevertheless, the optimal duration of adjuvant EGFR-TKI therapy in EGFR-mutated NSCLC remains uncertain. Prior studies have established the efficacy of adjuvant icotinib administered for 1, 1.5, and 2 years.16,17,18 The ICWIP study extended this duration to 3 years. Ongoing studies, including the TARGET study (NCT05526755), are still evaluating the potential benefit of 5-year adjuvant osimertinib treatment. We observed that the ICTAN (GASTO1002) study recently reported shorter durations of adjuvant icotinib therapy and provided important evidence supporting the feasibility of treatment de-escalation in selected patients.19 However, the ICTAN and ICWIP studies were independent studies initiated during a similar period but designed to address different clinical questions. The ICWIP study initiated first-patient enrollment on June 3, 2014, earlier than the ICTAN study in July 2014. ICWIP was a randomized, double-blind, placebo-controlled phase III study evaluating three-year adjuvant icotinib treatment, whereas ICTAN was an open-label, randomized controlled phase III study investigating shorter durations of adjuvant icotinib treatment (1 year and 6 months) against an observation-only control group. Therefore, the two studies are not directly comparable. Taken together, these findings suggest that both prolonged EGFR-TKI exposure and treatment de-escalation strategies warrant further investigation to optimize the balance between efficacy, toxicity, treatment burden, and long-term disease control.
A key feature of the ICWIP study was sequential chemotherapy followed by EGFR-TKI therapy. Prior evidence has demonstrated an additive survival benefit of adjuvant chemotherapy in stage II-III NSCLC.7 The ADAURA study also supported this sequential strategy, showing that chemotherapy contributes to DFS improvement.20 Furthermore, the tolerability and adherence to 3-year icotinib treatment were favorable in the ICWIP study.
Central nervous system control is critical in EGFR-mutated NSCLC. Although icotinib demonstrated superior efficacy for brain metastases versus whole-brain irradiation in the BRAIN study,26 the most common recurrence sites in the ICWIP study were the brain (21.2% [14/66] with icotinib and 11.6% [8/69] with placebo) and lungs (16.7% [11/66] and 23.2% [16/69]).
Identifying suitable patients for adjuvant EGFR-TKI therapy remains a major issue that needs to be addressed. In the ICWIP study, patients with more advanced clinical or nodal stage appeared to have poorer DFS, likely related to the presence of occult metastatic disease in this patient population.27 This finding suggested that patients with lymph node-positive disease or more advanced disease should be considered at high risk of recurrence and should intensify treatment. This underscores the need to identify patients with MRD undetectable by standard imaging. In this context, ctDNA-based next-generation sequencing (NGS) analysis at baseline could serve as a valuable tool, as supported by a previous study.28 In the ICWIP study, patients with a positive ctDNA-MRD at baseline derived a significant DFS benefit in the icotinib group compared with the placebo group, whereas among ctDNA-MRD-negative patients, DFS was not significantly different between the two groups. Therefore, icotinib following chemotherapy represents a potential adjuvant strategy for baseline ctDNA-MRD-positive patients.
In the ICWIP study, most patients in the placebo group crossed over to icotinib treatment upon disease recurrence, and both study treatment groups received extensive subsequent anti-cancer therapies. Consequently, the DFS benefit did not translate to an OS benefit. The treatment landscape for this patient population has evolved significantly in recent years in China. The third-generation EGFR-TKI osimertinib was approved by the China NMPA on March 22, 2017. Since then, several other third-generation EGFR-TKIs have also been approved by the China NMPA.29,30,31,32,33 Patients in both groups could receive third-generation EGFR-TKI treatment after disease recurrence or progression on first-generation EGFR-TKI treatment. In the ICWIP study, both groups received extensive and relatively balanced postrecurrence therapies. Among patients who experienced recurrence, 53.0% in the icotinib group and 50.7% in the placebo group received subsequent anti-cancer treatment. In the placebo group, 44.9% of recurrent patients crossed over to icotinib treatment, and 26.1% subsequently received third-generation EGFR-TKI treatment. Meanwhile, among recurrent patients in the icotinib group, 42.4% received third-generation EGFR-TKIs as subsequent therapy. In the ADAURA study, only approximately 22% of patients in the osimertinib group received subsequent therapy, compared with approximately 54% in the placebo group, of whom approximately 43% received third-generation EGFR-TKIs as salvage treatment.24 Despite this substantial use of third-generation EGFR-TKIs in the placebo group after recurrence, a significant OS benefit in favor of adjuvant osimertinib was nonetheless demonstrated.24 This indicates that there was more benefit for OS of osimertinib treatment in the adjuvant setting than in the first-line setting. Both groups of the ICWIP study had access to effective salvage therapies, particularly sequential osimertinib-based treatment strategies and third-generation EGFR-TKIs, which may have attenuated potential OS differences despite the DFS benefit observed with adjuvant icotinib treatment.
Emerging treatment strategies for NSCLC patients progressing after EGFR-TKIs have demonstrated improved outcomes. Sintilimab plus bevacizumab plus chemotherapy (ORIENT-31)34 and ivonescimab plus chemotherapy (HARMONi-A)35 showed superior PFS versus chemotherapy alone in the second-line setting. The OptiTROP-Lung04 study demonstrated significantly improved PFS for sacituzumab tirumotecan compared to pemetrexed plus platinum-based chemotherapy in patients with EGFR-mutated locally advanced or metastatic nonsquamous NSCLC that had progressed after EGFR-TKI treatment.36 The SACHI study demonstrated significantly improved PFS for savolitinib plus osimertinib compared to chemotherapy for EGFR mutation-positive, MET-amplified advanced NSCLC patients after EGFR-TKI failure.37 The ALTER 0303 study demonstrated that OS was significantly longer in the anlotinib group than in the placebo group in patients with advanced NSCLC progressing after second-line or further treatment.38 The OptiTROP-Lung03 study demonstrated significantly improved PFS for sacituzumab tirumotecan compared to docetaxel in patients with locally advanced or metastatic EGFR-mutated NSCLC after previous treatment failure with EGFR-TKIs and platinum-based chemotherapy.39 More studies on the postline treatment of EGFR-mutated NSCLC patients are ongoing.
In contrast, the ADAURA study was an international, multi-center clinical trial, and patients in the ADAURA study had few subsequent treatment options, which may explain the observed OS benefit with osimertinib. In advanced NSCLC patients, third-generation EGFR-TKIs consistently demonstrated superior PFS versus first-generation EGFR-TKIs in several phase 3 trials.40,41,42,43,44,45 The FLAURA study demonstrated a significantly prolonged median OS of osimertinib compared to gefitinib or erlotinib, with 38.6 months (95% CI 34.5–41.8) versus 31.8 months (95% CI 26.6–36.0; HR 0.80, 95.05% CI 0.64–1.00; p = 0.046), respectively.46 Subsequent Chinese pharmaceutical companies developed third-generation EGFR-TKIs that did not demonstrate or report significant OS benefits compared to first-generation EGFR-TKIs, mainly due to the evolving postprogression treatment landscape in China.40,41,42,43,44,45,47
Notably, the 5-year OS outcomes (88.6% [95% CI 57.9–97.5%]) for the icotinib group in the ICWIP study were comparable to those reported for the osimertinib group in the ADAURA study (85% [95% CI 79–89%]).24 To date, no head-to-head clinical study has directly compared first- and third-generation EGFR-TKIs in the adjuvant setting. Therefore, current evidence is insufficient to definitively establish the superiority of third-generation EGFR-TKIs over first-generation EGFR-TKIs in the adjuvant treatment setting. Importantly, both icotinib and osimertinib have been established as the China NMPA-approved adjuvant options for EGFR-mutated NSCLC since June 1, 2021, and April 14, 2021, respectively. At present, icotinib is a standard adjuvant treatment option only in China, while osimertinib is approved not only in China but also in the United States of America and other countries. While the findings of the ICWIP study are specific to Chinese patients rather than global patients, the study provides important evidence supporting prolonged adjuvant icotinib treatment in Chinese patients within the context of local clinical practice.
The use of first-generation EGFR-TKIs in the adjuvant treatment setting enables a sequential treatment strategy, allowing patients to receive osimertinib or other third-generation EGFR-TKIs upon disease recurrence. Given that resistance mechanisms and subsequent treatment approaches following first-generation EGFR-TKIs are relatively well characterized, this comprehensive management strategy may facilitate a more continuous and manageable EGFR-targeted treatment paradigm.48
In the ICWIP study, TP53 mutations were frequent in recurrent patients, which may represent a mechanism of resistance to icotinib, consistent with previous studies.49,50 DNMT3A mutations may be associated with resistance and brain metastasis.51,52 Furthermore, EGFR T790M mutations were identified in 2 recurrent patients in the icotinib group, consistent with the known resistance mechanisms to first-generation EGFR-TKIs.48 In the ICWIP study, there was no significant difference in DFS between patients harboring Ex19del and those with L858R mutations, demonstrating consistent efficacy for these patients, similar to the CONVINCE study.23
The safety profile of icotinib in the ICWIP study was consistent with previous findings,15,22,23 and no new safety concerns emerged. Despite the 3-year icotinib treatment duration in the ICWIP study being longer than the 2-year treatment duration in the EVIDENCE study,15 no cumulative toxicities were observed. Compared with 3-year osimertinib treatment (91.4% of any grade; 10.7% of ≥grade 3), 3-year icotinib treatment (48.5% of any grade; 1.5% of ≥grade 3) was associated with a lower incidence of TRAEs.20 Notably, no AEs led to dose adjustment, treatment discontinuation, or death, and no serious AEs were reported in the ICWIP study. In contrast, the incidence of AEs leading to dose adjustment, treatment discontinuation, or death and the incidence of serious AEs for osimertinib were 12% (42/337), 12.3% (43/337), <1% (1/337), and 20% (68/337), respectively, in the ADAURA study.25 Furthermore, the percentage of patients who completed 3 years of planned adjuvant treatment with icotinib (87.9% [58/66]) in the ICWIP study was higher than that with osimertinib (66% [224/339]) in the ADAURA study,25 supporting the favorable tolerability of icotinib. HRQoL was not adversely affected by the 3-year icotinib treatment, reinforcing its suitability for long-term use in adjuvant settings.
Several limitations of the ICWIP study are acknowledged. This study enrolled exclusively Chinese patients, which may limit the generalizability of these findings to other ethnic patient populations. The biomarker analysis was exploratory, its prognostic and predictive value requires future validation. Additionally, the cost-effectiveness of available adjuvant EGFR-TKIs should be considered in clinical decision-making. Finally, OS data remain immature and are awaited with longer follow-up.
In conclusion, the ICWIP study met its primary endpoint, demonstrating that the 3-year adjuvant treatment of icotinib significantly improved DFS compared to placebo in patients with completely resected stage II-IIIA EGFR-mutated lung adenocarcinoma who had completed adjuvant chemotherapy, with a manageable safety profile.
