The third-generation EGFR TKI osimertinib could be a promising neoadjuvant therapy in patients with resectable EGFR-mutant NSCLC

Introduction

Recent advances in molecular targeted therapy and the development of immune checkpoint inhibitors have improved the clinical outcome of resectable and unresectable non-small cell lung cancers (NSCLC). Adjuvant and neoadjuvant immunotherapy have recently been approved for stage II (IB)–III resectable non-oncogene driven NSCLC (1-4). Osimertinib, a third-generation epidermal growth factor receptor tyrosine kinase inhibitor (EGFR TKI), has also recently been approved for adjuvant treatment after complete resection of EGFR-mutant NSCLC (5,6). However, the efficacy of EGFR TKI for EGFR-mutant NSCLC in neoadjuvant settings remains unclear (Table 1).

Recently, Lv et al. published the results of a phase 2 trial investigating the efficacy and safety of osimertinib as neoadjuvant therapy (NEOS trial) (7). The NEOS trial was the first published phase 2 study demonstrating the efficacy and safety of neoadjuvant osimertinib. This review article provides an overview of the NEOS trial and other ongoing clinical trials of neoadjuvant osimertinib, compared with other neoadjuvant treatments. Perspectives of resectable EGFR-mutant NSCLC management are also briefly discussed.

NEOS trial

The NEOS trial is a single-arm, open-label phase 2b trial conducted at six centers in Mainland China. Patients with stage IIA–IIIB (eighth edition of the American Joint Committee on Cancer TNM classification) resectable lung adenocarcinoma with confirmed EGFR mutation (exon 19 deletion or exon 21 mutation) were enrolled (7). The patients were treated with 80 mg oral osimertinib for 6 weeks, followed by surgical resection within 3–14 days after the last dose of osimertinib. The primary endpoint was the objective response rate (ORR) after the 6-week osimertinib treatment. The secondary endpoints were the R0 resection rate, major pathological response (mPR) rate, pathological complete response (pCR) rate, N2 downstaging rate, and safety.

In total, 40 patients were enrolled and treated with neoadjuvant osimertinib. Thirty-eight patients completed 6-week osimertinib treatment. ORR was 71.1% (27/38) of those who completed the 6-week osimertinib treatment. A proportion of 84.2% (32/38) patients underwent surgery and 93.8% (30/32) had R0 resection. The reasons for those patients who completed the neoadjuvant treatment but did not undergo surgical resection were the refusal of surgery (n=4), adverse events (AEs, n=1), and high risk for surgery (n=1). The mPR rate of evaluable patients was 10.7% (3/28), and the pCR rate was 3.6% (1/28). Overall downstaging was observed in 46.9% (15/32) patients, including 41.2% (7/17) of patients with clinically positive lymph node metastasis downstaged from N2 to N1 or N0. A proportion of 7.5% (3/40) of the enrolled patients had treatment-related grade 3 AEs, including rash, hypertension, and nephrotic syndrome. No grade 4 or 5 AEs were observed.

Other ongoing trials of neoadjuvant osimertinib (Table 2)

Preliminary results from other phase 2 trials of neoadjuvant osimertinib showed similar efficacy and safety (NCT03433469) (8). In 27 patients with stage I–III (TNM 7th edition) EGFR-mutant NSCLC patients who underwent 80 mg oral osimertinib for up to 8 weeks, 88.9% (24/27) of the patients underwent subsequent surgery while 11.1% (3/27) were converted to definitive chemoradiotherapy. The ORR was 51.9% (14/27), and lymph node downstaging was observed in 44.4% (4/9) of patients with positive lymph nodes. The mPR rate was 14.8% (4/27), and no pCR was observed. Grade 3 AE occurred in 7.4% (2/27) of patients.

In a phase 2 trial of induction treatment with osimertinib followed by sequential radiation therapy and/or surgery in unresectable stage III EGFR-mutant NSCLC patients who underwent 80 mg oral osimertinib for 12 weeks, the ORR was 95.2% (20/21) while only one patient (1/21, 4.8%) developed grade 3 AE and no grade 4 or 5 AEs were observed (9).

Recently published a retrospective analysis of 13 patients with stage IB–IIIB (TNM 8th edition) EGFR-mutant NSCLC who underwent 80 mg oral osimertinib for a median of 75 days [interquartile range (IQR), 60–90 days] followed by surgery showed an ORR of 69.2% (9/13) and lymph node downstaging rate of 66.7% (6/9) (10). The mPR or pCR was not observed in any patients. Another retrospective analysis of 13 patients with stage IA–IIIB (TNM version not specified) EGFR-mutant NSCLC who underwent 80 mg oral osimertinib for an average of 60 days before surgery, which was presented at a conference, showed ORR of 84.6% (11/13) and pathological downstaging rate of 38.5% (5/13) (11). In the four patients whose pathological response was evaluated, the mPR rate was 75% (3/4), and no pCR was observed. Due to the small sample size and retrospective nature of these studies, the provided rates of ORR, mPR, and pCR may be less reliable.

The results of a larger-scale phase 3 trial, NeoADAURA, are awaited (12). In this trial, 9 weeks of 80 mg oral osimertinib with/without platinum-based chemotherapy versus chemotherapy alone is compared in patients with EGFR-mutant resectable stage II–IIIB N2 (TNM version 8) non-squamous NSCLC. Primary analysis is expected to be reported in 2024.

Comparison with other neoadjuvant treatments

Pooled analysis of neoadjuvant chemotherapy in EGFR-mutant NSCLC patients reported an ORR of 37%, while pooled analysis of neoadjuvant first-generation TKI showed an ORR of 59–63% (13,14). Meta-analysis comparing the efficacy of a first-generation EGFR TKI erlotinib versus platinum-based chemotherapy suggested a significant advantage in terms of ORR in neoadjuvant erlotinib, although intriguingly, no significant superiority was observed for overall survival (OS) and progression-free survival (PFS) [OS, hazard ratio (HR) =0.74, 95% confidence interval (CI): 0.43–1.27; PFS, HR =0.81, 95% CI: 0.27–2.44] (14). The operation rate was significantly higher in the neoadjuvant erlotinib group compared with the neoadjuvant chemotherapy group [erlotinib, 83.8%; chemotherapy, 74.2%; relative risk (RR) =1.13, 95% CI: 1.01–1.26].

Because the reported ORR in neoadjuvant osimertinib ranges from 51.9–84.6% (7,8,10,11), which is not obviously superior to ORR in first-generation EGFR TKI, the superiority of neoadjuvant osimertinib in survival outcomes over neoadjuvant chemotherapy remains uncertain, and the results from NeoADAURA trial are anticipated.

The efficacy of neoadjuvant immunotherapy with/without chemotherapy in EGFR-mutant NSCLC is not reported, as most of the immunotherapy trials exclude oncogene-driven (EGFR/ALK mutant) tumors. Of note, in the Checkmate 816 study where neoadjuvant nivolumab plus platinum-based chemotherapy versus platinum-based chemotherapy alone were compared in non-EGFR/ALK mutant NSCLC, grade 3 or 4 treatment-related AEs occurred in 33.5% of the patients in the nivolumab-plus-chemotherapy group and in 36.9% of those in the chemotherapy-alone group (3). Nevertheless, the rate of patients who did not undergo surgery remained at 16.8% in the nivolumab-plus-chemotherapy group and 24.6% in the chemotherapy-alone group.

Raising questions and perspectives

Does neoadjuvant osimertinib have survival benefits, considering the relatively low mPR and pCR rates?

A prominent difference in the trial results between neoadjuvant immunotherapy for non-oncogene driven NSCLC and neoadjuvant osimertinib for EGFR-mutant NSCLC is the relatively low mPR and pCR rates after neoadjuvant osimertinib despite high ORR. The reported mPR and pCR after neoadjuvant immunotherapy with/without chemotherapy in phase 2 or 3 trials ranged from 23.8–82.9% and 9.5–63.4%, respectively (3,4,15-18). Chen et al. discussed in their review paper that recent studies of neoadjuvant treatment for NSCLC have shown a significant association between OS and mPR, but not ORR (19). If this is also true in neoadjuvant EGFR TKI, then the survival benefit of neoadjuvant osimertinib may be limited. Nevertheless, even if neoadjuvant osimertinib has low mPR and pCR, we can still expect the survival benefit of neoadjuvant osimertinib due to the stark survival benefit shown in the ADAURA trial. The investigators of the ADAURA trial speculated that the survival benefit might be due to the potential efficacy of osimertinib against central nervous system micrometastasis (6). This hypothesis may well be applied in the neoadjuvant setting.

Will a liquid biopsy be useful for biomarker testing at the time of diagnosis of early-stage NSCLC?

If neoadjuvant osimertinib is indeed beneficial for the EGFR-mutant surgically resectable NSCLC, then biomarker testing and profiling at initial diagnosis becomes ever crucial.

Liquid biopsy has become an established method to assess the presence of EGFR mutation in advanced NSCLC. However, the utility of liquid biopsy remains limited in early-stage lung adenocarcinoma due to the low sensitivity. A recent translational study estimated that 10 cm³ (=2.7 cm diameter cube) tumor volume was associated with circulating tumor DNA (ctDNA) levels of around 0.1% of plasma DNA (20). Lung adenocarcinoma has been reported to harbor lower positivity of ctDNA compared with non-adenocarcinoma histology tumors (20,21). Hence, in small early-stage lung adenocarcinomas, the sensitivity of EGFR mutation detection using ctDNA is expected to be low. On the other hand, preoperative ctDNA positivity is reported as an independent poor prognostic indicator and is also associated with extrathoracic relapse after surgery (21,22). Patients with positive EGFR mutation in liquid biopsy at the time of diagnosis may be a suitable candidate for neoadjuvant EGFR TKI, reasoned by their high risk of postoperative relapse.

Conclusions

In summary, the NEOS trial is the first phase 2 trial of neoadjuvant osimertinib for EGFR-mutant resectable NSCLC to show its efficacy and acceptable safety. Osimertinib could be a promising neoadjuvant therapy for EGFR-mutant NSCLC; however, relatively low mPR and pCR compared to ORR should also be noted. A larger-scale phase 3 trial of neoadjuvant osimertinib with or without chemotherapy versus chemotherapy alone is ongoing, and the result will determine whether neoadjuvant osimertinib becomes standard of care in resectable stage IB–III NSCLC.

Acknowledgments

Funding: None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, AME Clinical Trials Review. The article has undergone external peer review.

Peer Review File: Available at https://actr.amegroups.com/article/view/10.21037/actr-23-33/prf

Conflicts of Interest: The author has completed the ICMJE uniform disclosure form (available at https://actr.amegroups.com/article/view/10.21037/actr-23-33/coif). T.K. was supported by the JSPS Overseas Research Fellowships Program (No. 202060447) from April 2020 to January 2023, which was unrelated to the present manuscript. The author has no other conflicts of interest to declare.

Ethical Statement: The author is 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.

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