Phase II trial of neoadjuvant osimertinib for surgically resectable EGFR-mutated non-small cell lung cancer.

Abstract

8508 Background: Osimertinib is a third-generation EGFR tyrosine kinase inhibitor (TKI) effective in treating advanced EGFR-mutated non-small cell lung cancer (NSCLC). Adjuvant osimertinib significantly decreases disease recurrence in stage IB-IIIA EGFR-mutated NSCLC. However, the benefit of neoadjuvant osimertinib prior to surgical resection remains unknown. Methods: This was a multi-institutional phase II trial of neoadjuvant osimertinib for patients with surgically resectable stage I-IIIA (AJCC V7) EGFR-mutated (L858R or exon 19 deletion) NSCLC (NCT03433469). Patients received osimertinib 80 mg orally daily for up to two 28-day cycles prior to surgical resection. The primary endpoint was major pathological response (mPR) rate (≤10% residual viable tumor). 27 evaluable patients provide 87% power to detect a mPR rate of 50% with α = 0.05. Secondary endpoints included pathological response (PR) rate (≤50% residual viable tumor), pathological complete response (pCR) rate, unconfirmed objective response rate (ORR), rate of lymph node downstaging, unanticipated delays to surgery, surgical complication rate, disease-free survival (DFS), overall survival (OS), safety, and tumor mutational profile. Results: A total of 27 patients with early-stage (8 stage IA/B, 10 stage IIA/B, 9 stage IIIA) EGFR-mutated (11 exon 19 del, 16 L858R) NSCLC were treated with neoadjuvant osimertinib for a median 56 days prior to surgical resection. 24 (89%) patients underwent subsequent surgery; 3 (11%) patients were converted to definitive chemoradiotherapy. The mPR rate was 15% (4/27 patients) by intention-to-treat analysis. The PR rate was 48% (13/27). No pCR’s were observed. Partial responses by radiography were observed in 52% (14/27) of patients and stable disease in 44% (12/27) of patients. Lymph node downstaging was achieved in 44% (4/9) of patients with positive lymph nodes. Median DFS after surgical resection was 32 months (95% CI 26-not reached) with a median follow-up of 11 months. OS data are immature. Significant adverse events occurred in 3 patients with grade 2 (G2) dyspnea, grade 3 (G3) pulmonary embolism, and G3 atrial fibrillation. One patient developed G2 treatment-related pneumonitis that resolved without steroids. Perioperative complications occurred in 38% (9/24) of patients; most involved rapidly reversible postoperative G2 atrial fibrillation (6/9) unrelated to study drug. Tumors were evaluable for genetic alterations from 16 patients. 4/6 patients who did not achieve a PR had tumors that harbored loss of function mutations in RBM10 as compared to 0/10 patients who achieved a PR (p < 0.01). Conclusions: Neoadjuvant osimertinib in surgically resectable EGFR-mutated NSCLC achieved a 15% mPR, which did not meet the primary endpoint. Treatment was safe and may induce pathological responses and lymph node-downstaging of disease. Co-mutations in RBM10 may limit response. Clinical trial information: NCT03433469 .

A review of perioperative treatment strategies with immunotherapy and tyrosine kinase inhibitors in resectable and stage IIIA-N2 non-small cell lung cancer

“…Median DFS was 32 months with immature OS data. There were two grade 3 AEs (pulmonary embolism and atrial fibrillation) ( 49 ). The study also noted that in 4 of 6 patients who did not achieve a pathologic response, there was a loss of function mutation in RBM10 ( 50 ).…”

“…The NADIM II trial (2023) was a randomized phase II trial that showed that patients with resectable stage IIIA or IIIB NSCLC who received neoadjuvant nivolumab and platinum-based chemotherapy compared to neoadjuvant chemotherapy alone had a greater PCR (37% vs. 7%), greater MPR (53% vs. 14%), overall response (75% vs. 48%), improved 2-year PFS (67.2% vs. 40.9%), and greater 2-year OS (85% vs. 63.6%) (32). Patients who were treated with the combination neoadjuvant nivolumab and chemotherapy and who had PD-L1 expression of ≥ 1% had the greatest improvement in PCR rates.…”

“…The KEYNOTE-671 trial (2023) was a randomized phase III trial that showed that patients with resectable stage II-IIIB (N2) NSCLC who received 4 cycles of neoadjuvant pembrolizumab (200 mg every 3 weeks) and cisplatin-based chemotherapy, followed by surgery and up to 13 cycles adjuvant pembrolizumab had an improved 2-year EFS (62.4% vs. 40.6%), higher MPR (30.2% vs. 11%), and higher PCR (18.1% vs. 4%) compared to patients who received only neoadjuvant cisplatin with placebo, followed by surgery and adjuvant placebo (33). The EFS benefit was generally consistent across most subgroups, except for lack of significance in the PD-L1 expression < 1%, pathologic stage II, and never smoker subgroups; however, many of these subgroup analyses were not adequately powered.…”

“…An initial update from the CheckMate 77T trial (2023), a randomized, phase III trial, showed that patients with stage IIA-IIIB resectable NSCLC who received 4 cycles of neoadjuvant nivolumab and platinum-doublet chemo followed by surgery and adjuvant nivolumab for 1 year had improved median EFS (not reached vs. 18.4 months), 18-month EFS (70% vs. 50%), PCR (25.3% vs. 4.7%), and MPR (35.4% vs. 12.1%) compared to patients who received 4 cycles of neoadjuvant platinum-doublet chemotherapy with placebo, followed by surgery and adjuvant placebo for 1 year (34). Benefit was most pronounced in patients with stage III disease, PD-L1 ≥ 1%, current and former smokers, those with squamous histology (35).…”

Management of locally advanced non‐small cell lung cancer: State of the art and future directions

“…The downstaging rate was 53.3% when osimertinib was used as a neoadjuvant treatment strategy in patients with EGFR-mutated stage II-IIIB NSCLC [135,136]. Recently, another phase II singlearm trial testing the efficacy of neoadjuvant osimertinib in EGFR-mutated NSCLC also showed negative results: 15% MPR, 0% pCR, and 44% lymph node downstaging rate [137]. Considering these findings, the efficacy of neoadjuvant TKI therapy is unsatisfactory, despite the use of third-generation EGFR-TKIs (Table 8).…”