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Neoadjuvant nivolumab plus chemotherapy: Examining the clinical trial that led to FDA approval

Immunotherapy is transforming cancer treatment. One such immunotherapy drug called, nivolumab has been approved by FDA for lung cancer. But what was the evidence that led to this approval? How effective is nivolumab, and what can the patients expect from it?

Let’s closely look at the clinical trial that got nivolumab plus chemotherapy approved and try to answer these questions.

What is lung cancer?

When cancer starts in the lung, it is called lung cancer. Lung cancer can be of various types based on the site of origin in the lung and the mutations it harbors. Two major types are small-cell lung cancer and non-small cell lung cancer (NSCLC).

The current management of lung cancer consists of surgery followed by chemotherapy/radiotherapy or both [1]. Lung cancer is divided into various grades that help clinicians determine the feasibility and effectiveness of surgery. The emergence of immunotherapy and targeted drugs are changing the way lung cancer is treated.

Why is there a need for effective pre-surgical treatments?

Lung cancer

Approximately 20 to 25% of patients with NSCLC have resectable disease, meaning their tumor can be surgically removed. However, even after undergoing surgery, about 30 to 50% of these patients suffer from recurrence, which may lead to death. Chemotherapy may be provided before the surgery to control cancer which makes the surgery more effective in the context of long-term survival. However, neoadjuvant chemotherapy has only been successful in only about 4% of the patients who received it. Therefore, effective treatments are required before surgery to increase the survival rate.

Nivolumab when combined with chemotherapy and given prior to surgery holds promise for better long-term outcomes.

What is nivolumab?

Normally the immune system destroys any cell that has undergone mutations and has started acting strangely. But the cancer cells have a defense against this immune response – they inhibit the immune cells and thus continue to grow. T cells, a type of immune cells tasked with killing the tumor, have a receptor on their surface called the anti–programmed death 1 (PD-1) which acts as a checkpoint inhibitor meaning that it prevents the immune system from becoming overly aggressive. Cancer cells use this receptor to their advantage and trick the T-cells into not killing them.

Nivolumab is an immunotherapeutic drug. It is an antibody that binds to the PD-1 receptor on the T cells and prevents the cancer cells from making contact with this receptor. By doing so, it unleashes the immune system and allows it to attack the cancer cells.

Neoadjuvant (before surgery) nivolumab and chemotherapy combination in non-small cell lung cancer has previously shown survival benefits in early clinical trials. As a next step in evaluating its safety and efficacy in this patient population, a phase 3 clinical trial, called Check mate 816, was conducted [2].

Description of the clinical study

This clinical trial enrolled participants who had:

  • non-small cell lung cancer that is resectable i.e., in stage IB to IIIA

  • Eastern Cooperative Oncology Group (ECOG) performance-status score of 0 or 1. This score reflects a patient's ability to carry out daily activities. It ranges from 0 (fully active) to 5 (dead).

  • not received any anti-cancer therapy.

  • no known ALK translocations or EGFR mutations.

All the participants were randomly divided into two groups. One of the groups was given nivolumab and a platinum-based chemotherapeutic drug, whereas the other group was given only the platinum-based chemotherapeutic drug.

Participants continued on this regimen for 6 months and after that, surgery was performed to remove the tumor. After the surgery, the participants were given 4 additional cycles of chemotherapy/radiotherapy or both.

What was the outcome?

This clinical trial found that:

  • The median event-free survival (time during which the participants did not experience overt disease progression) was 31.6 months with nivolumab plus chemotherapy and 20.8 months with chemotherapy alone [3].

  • After 1 year, the estimated percentage of patients surviving without disease progression or disease recurrence was 76.1% in the nivolumab plus chemotherapy group and 63.4% in chemotherapy only group. After 2 years, these values were 63.8% and 45.3% respectively.

  • Common adverse effects were nausea, constipation, fatigue, decreased appetite, and rash.

  • Nivolumab plus chemotherapy did not lead to the prevention of the surgery.

Based on these outcomes, FDA has approved nivolumab plus chemotherapy in adults with resectable non-small cell lung cancer in neoadjuvant settings [4]. The recommended dose is 360 mg with platinum-doublet chemotherapy on the same day every 3 weeks for 3 cycles.

In a nutshell

This phase 3 clinical trial has shown that neoadjuvant nivolumab plus chemotherapy has a significant benefit over chemotherapy alone with respect to event-free survival and pathological complete response. This new regimen does not increase surgery-related adverse events or impede the feasibility of surgery. To conclude, neoadjuvant nivolumab plus chemotherapy has performed well in the clinical trial, and while it has been approved by the FDA, ongoing monitoring of its effectiveness and safety in real-world settings is important.


1. Neal, R.D. et al. 'Lung cancer'. BMJ. (2019) 365, l1725. DOI: 10.1136/bmj.l1725.

3. Forde, P.M. et al. 'Neoadjuvant Nivolumab plus Chemotherapy in Resectable Lung Cancer'. N Engl J Med. (2022) 386(21), 1973–1985. DOI: 10.1056/NEJMoa2202170.



IIT Guwahati
University of Manchester
Rhenix Lifesciences
American university of Sharjah
IIT Delhi
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