Elsevier

The Lancet Oncology

Volume 21, Issue 11, November 2020, Pages 1413-1422
The Lancet Oncology

Articles
Neoadjuvant chemotherapy and nivolumab in resectable non-small-cell lung cancer (NADIM): an open-label, multicentre, single-arm, phase 2 trial

https://doi.org/10.1016/S1470-2045(20)30453-8Get rights and content

Summary

Background

Non-small-cell lung cancer (NSCLC) is terminal in most patients with locally advanced stage disease. We aimed to assess the antitumour activity and safety of neoadjuvant chemoimmunotherapy for resectable stage IIIA NSCLC.

Methods

This was an open-label, multicentre, single-arm phase 2 trial done at 18 hospitals in Spain. Eligible patients were aged 18 years or older with histologically or cytologically documented treatment-naive American Joint Committee on Cancer-defined stage IIIA NSCLC that was deemed locally to be surgically resectable by a multidisciplinary clinical team, and an Eastern Cooperative Oncology Group performance status of 0 or 1. Patients received neoadjuvant treatment with intravenous paclitaxel (200 mg/m2) and carboplatin (area under curve 6; 6 mg/mL per min) plus nivolumab (360 mg) on day 1 of each 21-day cycle, for three cycles before surgical resection, followed by adjuvant intravenous nivolumab monotherapy for 1 year (240 mg every 2 weeks for 4 months, followed by 480 mg every 4 weeks for 8 months). The primary endpoint was progression-free survival at 24 months, assessed in the modified intention-to-treat population, which included all patients who received neoadjuvant treatment, and in the per-protocol population, which included all patients who had tumour resection and received at least one cycle of adjuvant treatment. Safety was assessed in the modified intention-to-treat population. This study is registered with ClinicalTrials.gov, NCT03081689, and is ongoing but no longer recruiting patients.

Findings

Between April 26, 2017, and Aug 25, 2018, we screened 51 patients for eligibility, of whom 46 patients were enrolled and received neoadjuvant treatment. At the time of data cutoff (Jan 31, 2020), the median duration of follow-up was 24·0 months (IQR 21·4–28·1) and 35 of 41 patients who had tumour resection were progression free. At 24 months, progression-free survival was 77·1% (95% CI 59·9–87·7). 43 (93%) of 46 patients had treatment-related adverse events during neoadjuvant treatment, and 14 (30%) had treatment-related adverse events of grade 3 or worse; however, none of the adverse events were associated with surgery delays or deaths. The most common grade 3 or worse treatment-related adverse events were increased lipase (three [7%]) and febrile neutropenia (three [7%]).

Interpretation

Our results support the addition of neoadjuvant nivolumab to platinum-based chemotherapy in patients with resectable stage IIIA NSCLC. Neoadjuvant chemoimmunotherapy could change the perception of locally advanced lung cancer as a potentially lethal disease to one that is curable.

Funding

Bristol-Myers Squibb, Instituto de Salud Carlos III, European Union's Horizon 2020 research and innovation programme.

Introduction

Non-small-cell lung cancer (NSCLC) accounts for 80–85% of all lung cancer cases. Approximately 20% of patients with NSCLC are diagnosed with stage IIIA (N2) disease.1 Outcomes remain poor for this subset of patients, even in patients with potentially operable tumours, with a median progression-free survival of 13 months and a 3-year overall survival of 30%, with no major treatment advances made in the past 25 years.2

Pathological response to neoadjuvant treatment is a potential surrogate endpoint for survival; however, considering the low proportion of patients who achieve complete pathological response with induction chemotherapy (median 4%; range 0–16%), a definitive association has been difficult to establish, and has not been validated in NSCLC.3

In a 2018 study, neoadjuvant administration of two doses of nivolumab was associated with major pathological response in nine (45%) of 20 evaluable patients with NSCLC tumours, with two (10%) of 20 patients achieving a complete pathological response.4 Furthermore, in a 2020 study of neoadjuvant chemoimmunotherapy, 17 (57%) of 30 patients achieved a major pathological response, with ten (33%) of 30 patients achieving a complete pathological response.5 However, both studies included patients with stage I or II NSCLC, and disease-free survival (median duration of follow-up 12·9 months [IQR 6·2–22·9]) was not associated with pathological response.5

Research in context

Evidence before this study

We searched PubMed from Jan 1, 2010, to May 11, 2020, for clinical trials published in English using the search terms “neoadjuvant”, “lung cancer”, and “PD-L1” or “PD-1”. Our search yielded two studies. The first study described neoadjuvant nivolumab treatment in patients with stage I–IIIA non-small-cell lung cancer (NSCLC) with the primary endpoints of safety and feasibility; however, no survival data were reported. The second study assessed neoadjuvant atezolizumab plus chemotherapy for patients with stage II–IIIA NSCLC, and the authors identified no association between major pathological response and survival after a median of 1-year follow-up. Additionally, using the same search terms and date restrictions, we examined the websites of three major international conferences (American Society of Clinical Oncology, European Society for Medical Oncology, and World Conference on Lung Cancer) and ClinicalTrials.gov, and identified several ongoing phase 2 and phase 3 trials of different neoadjuvant immunotherapy approaches with estimated primary completion dates ranging from 2020 to 2024.

Added value of this study

To our knowledge, our study is the first published trial to assess the feasibility, safety, antitumour activity, and survival outcomes of neoadjuvant nivolumab plus standard chemotherapy in patients with resectable stage IIIA NSCLC. One of the main concerns regarding neoadjuvant therapy is risk of preoperative complications; however, we showed that treatment was well tolerated, was not associated with delays in surgery, and led to complete resection in all patients who had surgery. Our results showed that in this high-risk patient group, which included a high proportion of patients with multiple stage IIIA (N2) disease, favourable pathological responses and downstaging, and progression-free survival and overall survival at 24 months were observed after neoadjuvant nivolumab plus standard chemotherapy.

Implications of all the available evidence

Our results combined with existing evidence could support the addition of neoadjuvant nivolumab to platinum-based chemotherapy in patients with resectable stage IIIA NSCLC, and encourage the use of pathological response as an early surrogate endpoint for survival, while considering specific somatic mutations that might limit its survival-predictive value. These observations have important implications for future clinical trial design and could improve outcomes for patients with resectable stage IIIA NSCLC.

We hypothesised that neoadjuvant chemoimmunotherapy could increase the proportion of patients with resectable stage IIIA NSCLC who achieve a complete pathological response, and that this approach would increase the number of patients that can ultimately be cured. We designed our study to investigate the nivolumab plus paclitaxel-carboplatin regimen, as this regimen was associated with a 2-year overall survival of 62% in patients with advanced NSCLC (both squamous and non-squamous) in the Checkmate012 trial.6 We aimed to assess the feasibility, safety, antitumour activity, and survival outcomes of neoadjuvant nivolumab plus standard chemotherapy in treatment-naive patients with potentially resectable stage IIIA NSCLC.

Section snippets

Study design and participants

This open-label, multicentre, single-arm, phase 2 trial was done at 18 hospitals in Spain. Eligible patients were aged 18 years or older and had histologically or cytologically documented, treatment-naive NSCLC of stage IIIA (American Joint Committee on Cancer 7th edition criteria)7, 8 that was deemed locally to be surgically resectable by a multidisciplinary clinical team.9 Patients were required to have an Eastern Cooperative Oncology Group performance status of 0 or 1,10 adequate organ

Results

Between April 26, 2017, and Aug 25, 2018, 51 patients were assessed for eligibility, of whom 46 patients were enrolled at 18 sites (appendix 1 pp 4, 13). Baseline characteristics of the patients are shown in table 1.

All patients received neoadjuvant treatment and thus were included in the modified ITT population. 41 (89%) of 46 patients had surgery, all of whom achieved complete tumour resection without associated morbidity or mortality. Of the 41 patients who had surgery, 37 (90%) received at

Discussion

To our knowledge, this is the first study to assess the feasibility, safety, antitumour activity, and survival outcomes of neoadjuvant chemoimmunotherapy specifically in patients with resectable stage IIIA NSCLC. The addition of neoadjuvant nivolumab to chemotherapy was well tolerated, and the frequency of treatment-related adverse events was similar to that commonly observed with induction chemotherapy, and that described in the KEYNOTE-189 trial.18 Furthermore, treatment with neoadjuvant

Data sharing

De-identified individual data might be made available following publication by reasonable request to the corresponding author. A research proposal should be included, which will be evaluated by the Spanish Lung Cancer Group and the ethics committee for clinical investigation.

References (30)

  • M Garassino et al.

    OA04.06 Evaluation of TMB in KEYNOTE-189: pembrolizumab plus chemotherapy vs placebo plus chemotherapy for nonsquamous NSCLC

    J Thorac Oncol

    (2019)
  • RL Siegel et al.

    Cancer statistics, 2020

    CA Cancer J Clin

    (2020)
  • PM Forde et al.

    Neoadjuvant PD-1 blockade in resectable lung cancer

    N Engl J Med

    (2018)
  • NA Rizvi et al.

    Nivolumab in combination with platinum-based doublet chemotherapy for first-line treatment of advanced non-small-cell lung cancer

    J Clin Oncol

    (2016)
  • SB Edge et al.

    AJCC Cancer Staging Manual

    (2010)
  • Cited by (476)

    View all citing articles on Scopus
    View full text