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by Dr. C.H. Weaver M.D. updated 03/2022

The United States Food and Drug Administration approved neoadjuvant Opdivo (nivolumab) and platinum-doublet chemotherapy for early-stage non-small cell lung cancer (NSCLC) effective in March 2022. This represents the first FDA approval for neoadjuvant therapy for early-stage NSCLC.

The approval was based on results from the Checkmate-816 clinical trial in patients with resectable, Stage IB, II, or IIIA NSCLC.  Patients were enrolled regardless of the tumor PD-L1 status.

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Preliminary results from clinical trials in patients with early-stage NSCLC treated with neoadjuvant therapy were presented at the 2019 ASCO Annual Meeting and suggested that neoadjuvant treatment is well-tolerated, and yields encouraging responses.

The current standard treatment of early stage NSCLC consists of surgical removal of the cancer followed by adjuvant chemotherapy to reduce the risk of cancer recurrence.2 

Checkpoint inhibitors are a precision cancer immunotherapy that helps to restore the body’s immune system in fighting cancer by releasing checkpoints that cancer uses to shut down the immune system. PD-1 and PD-L1 are proteins that inhibit certain types of immune responses, allowing cancer cells to evade detection and attack by certain immune cells in the body. A checkpoint inhibitor can block the PD-1 and PD-L1 pathway and enhance the ability of the immune system to fight cancer. By blocking the binding of the PD-L1 ligand these drugs restore an immune cells’ ability to recognize and fight the lung cancer cells. A diagnostic test to measure the level of PD-L1 is available.

Results from studies evaluating the checkpoint inhibitors Opdivo, Keytruda, and Tecentriq have demonstrated they are superior to chemotherapy and have become the standard of care in advanced NSCLC without driver mutations.2-5

Because patients with early stage NSCLC may already have small amounts of cancer that have spread outside the lung that cannot be detected with any of the currently available tests adjuvant therapy is offered following surgical removal of the cancer because it reduces the risk of cancer recurrence, and improves survival. A Canadian clinical study has demonstrated that adjuvant chemotherapy increased the number of patients who lived 5 years or more from 54% to 69% and US researchers have demonstrated that adjuvant chemotherapy increased the number of patients who survived 3 years or more from 69% to 82%. Many patients however still experience a recurrence of their cancer.

Neoadjuvant therapy is treatment that is delivered before surgery with the goal of providing immediate treatment and reducing the size of the cancer for easier resection.

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A large multicenter trial evaluated the benefit of neoadjuvant treatment with Tecentriq® (atezolizumab) in patients with stages IB to IIIB resectable NSCLC. Patients were treated with 2 cycles of before undergoing resection. Pretreatment with checkpoint inhibitor immunotherapy that targets PD-L1 is attractive because PD-L1 is thought to be critical for the cancer to spread.

Outcomes of the first 101 of 180 planned patients were reported. Overall, 90 patients underwent surgery and the neodjuvant immunotherapy was well tolerated. Several patients had evidence of complete or near complete disappearance of their cancer at surgery and additional information was obtained that could help further guide treatment with precision cancer medicines – the trial is ongoing.

A second trial evaluated Opdivo (nivolumab) with or without Yervoy (ipilimumab) in 44 NSCLC patients with stage I to IIIA disease. Overall 33% achieved a major pathologic response to treatment assessed at surgery. Rash and fatigue were the most common side effects.

In the pivotal trial leading to FDA approval a total of 358 patients were treated with either Opdivo plus platinum-doublet chemotherapy administered every 3 weeks for up to 3 cycles, or platinum-chemotherapy alone administered on the same schedule. Opdivo neoadjuvant treated patients survived 31.6 months without cancer recurrence compared to 20.8 months for those receiving chemotherapy alone. 

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The most common side effects occurring in patients were nausea, constipation, fatigue, decreased appetite, and rash. The addition of nivolumab to chemotherapy did not result in more frequent delays or cancellations of surgery. The median lengths of hospital stays following definitive surgery and the rates of adverse reactions identified as surgical complications were similar for patients in both arms of the trial.

Taken together the studies suggest that the use of neoadjuvant immunotherapy can be safely administered prior to surgery for early stage NSCLC and that significant eradication of cancer is possible. 


  1. Kwiatkowski DJ, Rusch VW, Chaft JE, et al. Neoadjuvant atezolizumab in resectable non-small cell lung cancer (NSCLC): Interim analysis and biomarker data from a multicenter study (LCMC3). Presented at: the 2019 ASCO Annual Meeting; May 31-June 4, 2019; Chicago, IL. Abstract 8503.
  2. The International Adjuvant Lung Trial Collaborative Group. Cisplatin-based adjuvant chemotherapy in patients with completely resected Non-Small Cell Lung Cancer. New England Journal of Medicine. 2004;350:351-360.
  3. N Engl J Med. 2018;378:1976
  4. Neoadjuvant atezolizumab in resectable non-small cell lung cancer (NSCLC): Interim analysis and biomarker data from a multicenter study (LCMC3).
  5. Gadgeel SM, Stevenson J, Langer C, et al. Pembrolizumab (pembro) plus chemotherapy as front-line therapy for advanced NSCLC: KEYNOTE-021 cohorts A-C. J Clin Oncol 34, 2016 (suppl; abstr 9016).