Neoadjuvant atezolizumab + chemotherapy for resectable NSCLC: 3-year clinical update of phase II clinical trial results and translational findings

Abstract

Introduction: Neoadjuvant chemoimmunotherapy has achieved overall survival (OS) benefit for patients with resectable non-small cell lung cancer (NSCLC). Here, we present outcomes after 3 years of follow-up from the first reported study of neoadjuvant atezolizumab+chemotherapy.

Methods: This open-label, multicenter single-arm investigator-initiated phase II study conducted at three US hospitals tested up to four cycles of atezolizumab, carboplatin, and nab-paclitaxel prior to surgery. Major pathological response (MPR, primary endpoint) was previously reported; here, we report 3-year disease-free survival (DFS), OS, and clinical characteristics of patients developing brain metastases (BM) with integrated data from tumor genomics, gene expression, and quantitative immunofluorescent measurement of immune markers.

Results: Of 30 enrolled patients, 29 were taken to the operating room. 26 underwent R0 resection, with 17 experiencing MPR (10 pCR). With a median follow-up of 39.5 months, the median OS was 55.8 months, and the median DFS was 34.5 months. Landmark OS at 36 months was 77%. Among 14 patients with recurrent disease, 6 patients had BM. Patients whose tumors had mutations in STK11 and KEAP1 did not have a significantly higher incidence of BM. Reduced copy number of STK11 and KEAP1, both residing on chromosome 19p, was observed in ~1/3 of tumors. Reduced CN of STK11 was significantly associated with worse pathological response and incidence of BM.

Conclusions: Consistent with recent phase III studies, 3-year OS data with neoadjuvant atezolizumab+chemotherapy was associated with prolonged PFS and OS. Establishing associations between STK11 and KEAP1 genomic alterations and key clinical outcomes in early-stage NSCLC requires further study.

Keywords: Biomarker; Immunotherapy; Lung Cancer; Neoadjuvant.

Figure 1. Disease-free and overall survival. (A) Disease-free survival probability. (B) Overall survival probability.

Figure 2. Swimmer’s plot indicating patient recurrence and survival status. Patients are grouped by pathological response status. Follow-up status is indicated by icons within each row. Patient and tumor characteristics are depicted by squares in each row.

Figure 3. Patient-level associations of molecular features with clinical outcomes for genes of interest. Variants are pooled from pre-tx and post-tx samples (N=21 patients). Per cent of patients with each alteration indicated to the right of the oncoprint, along with a count of alteration types (stacked bar graph).

Figure 4. Associations between copy number status of STK11 and KEAP1 with clinical outcome. (A, B) Brain metastasis status stratified by STK11 and KEAP1 mutation status. (C, D) Brain metastasis status by STK11 and KEAP1 copy number. (E, F) Histoplot comparing copy number of STK11 (E) and KEAP1 (F) in patients with pCR, MPR, and those without. MPR, major pathological response. * = p value < 0.05

Figure 5. Immune cell analysis by QIF and transcriptomic deconvolution. (A) Heat plot depicts magnitude and direction of associations between deconvolved immune cell populations and pathological regression. (B, C) Pathological response versus estimated macrophage fractions. Representative images of adenocarcinoma (D) and squamous cell carcinoma (E). (F, G) Pathological response versus CD8+T cell density. QIF, quantitative immunofluorescent. * = p value < 0.05, ** = p value < 0.01