Best Pathological Response in Lung Cancer With Dual Immunotherapy Before Surgery

Lung cancer has two main types: small cell and non-small cell. Non-small cell lung cancer accounts for around 85% of cases, and approximately 30% of patients have surgically resectable, early-stage disease. Many can potentially be cured by surgery. Without additional treatment, however, more than half face a risk of recurrence afterwards.

Before immunotherapy, chemotherapy was our only treatment option for substantially reducing recurrence risk in early lung cancer, and its results were not very satisfactory. We now know that immunotherapy before or after surgery improves early-stage outcomes, and the FDA has approved these uses. In Türkiye, however, immunotherapy for non-small cell lung cancer has not yet been licensed for neoadjuvant preoperative tumour reduction or adjuvant postoperative protection.

In short, the success of immunotherapy transformed treatment for early-stage, operable non-small cell lung cancer during 2021 and 2022. There is now strong scientific evidence for adding immunotherapy before surgery:

1. The March 2022 approval based on CHECKMATE-816: FDA approval
2. Presented at the ASCO Congress in June 2022: the NADIM II study

Both studies added only one immunotherapy, nivolumab, to platinum-based chemotherapy. The phase II NEOSTAR study discussed here was published on 16 March 2023 in Nature Medicine and tested adding dual immunotherapy to chemotherapy.

Dual Immunotherapy Before Surgery

NEOSTAR found that adding ipilimumab to nivolumab and platinum-based chemotherapy as neoadjuvant treatment produced a major pathological response in half of patients with early-stage, surgically resectable non-small cell lung cancer (NSCLC). The findings supported neoadjuvant immunotherapy-based treatment as an approach to reduce viable tumour at surgery and improve NSCLC outcomes.

In the study:

• 22 patients received neoadjuvant nivolumab plus chemotherapy, the two-component combination,
• 22 patients received neoadjuvant ipilimumab, nivolumab and chemotherapy, the three-component combination.

All NEOSTAR participants had surgically resectable non-small cell lung cancer (NSCLC). All patients were between stage 1B-IIIA, with tumours that could be surgically removed.

Results

Major pathological response was 50% with the three-component combination and 32.1% with the two-component regimen.

Both groups exceeded the historical major pathological response rate of 15% with neoadjuvant chemotherapy alone.

Gut Microbiome and Immune Cell Infiltration Results

NEOSTAR also provided notable findings in areas that have rarely been studied. The researchers analysed immune cell infiltration and gut microbiome composition.

• Related topic: Tumour-Infiltrating T Cells and Their Importance in Cancer

Patients receiving the neoadjuvant three-component regimen had higher major pathological response rates than those receiving nivolumab plus chemotherapy. They also had higher levels of certain immune cell types and phenotypes, including effector memory CD8+ T cells, B cells, myeloid cells and markers of tertiary lymphoid structures. Gut microbiome composition was also analysed in relation to major pathological response, including increased beneficial microorganisms such as Akkermansia and fewer pro-inflammatory and pathogenic organisms. These findings suggest that the three-component regimen may improve pathological responses and merits further study in operable NSCLC.

The results support the conclusion that adding CTLA-4 blockade to nivolumab and chemotherapy before surgery improves outcomes and warrants further investigation.