When Should Immunotherapy Be Given in Early-Stage Lung Cancer?

Do patients with early-stage non-small cell lung cancer (NSCLC) benefit from continuing immunotherapy after surgery?

Unfortunately, we do not have a brief, definitive answer to this question.

Since October 2023, the United States Food and Drug Administration (FDA) has approved three immunotherapies used with platinum-containing chemotherapy for operable NSCLC, both before surgery (neoadjuvant) and after surgery (adjuvant): pembrolizumab (Keytruda), durvalumab (Imfinzi), and, most recently, nivolumab (Opdivo).

FDA Approvals in Operable Lung Cancer

The FDA has granted a total of 6 different treatment approvals for operable non-small cell lung cancer (NSCLC). These include atezolizumab and pembrolizumab as adjuvant treatments, nivolumab as a neoadjuvant treatment, and pembrolizumab, durvalumab, and nivolumab as perioperative (both neoadjuvant and adjuvant) treatments.

However, the clinical trials leading to these approvals have a serious design limitation. They could not distinguish when patients benefited from immunotherapy: before surgery, after surgery, or during both periods.

This gap makes treatment decisions more difficult for oncologists.

FDA Approvals and Controversial Clinical Trial Designs

The FDA's approval of these three immunotherapy combinations without clear guidance on timing seems curious at present. This issue needs to be addressed. The studies appear to have been designed in a way that prevents assessment of the separate contributions of the neoadjuvant and adjuvant phases.

The FDA's Oncologic Drugs Advisory Committee explicitly raised this limitation at its meeting in July 2024. The committee asked pharmaceutical companies to evaluate preoperative and postoperative immunotherapy separately.

Nevertheless, a month later, the FDA approved durvalumab for this indication. Similar approvals had previously been granted for pembrolizumab and nivolumab. Despite these approvals, no clinical trial has demonstrated in which period these treatments are more effective.

Risks and Benefits of Immunotherapy: Which Period Matters More?

Immunotherapies carry high costs and a risk of side effects. Incomplete information about when they provide the greatest benefit makes decisions difficult for both patients and physicians.

JAMA Network Open published a meta-analysis on 7 March 2024 showing that, in patients with operable NSCLC, combined neoadjuvant and adjuvant immunotherapy did not improve event-free survival (HR: 0.90; P = 0.59) or overall survival (HR: 1.18; P = 0.51) compared with neoadjuvant immunotherapy.

This meta-analysis finding creates a clear impression that the neoadjuvant phase alone is "more important than the neoadjuvant + adjuvant phases." It also raises the question: "Are we overtreating some patients by giving them adjuvant immunotherapy?"

In this situation, stopping adjuvant treatment appears appropriate in patients who achieve a pathological complete response after neoadjuvant chemotherapy and immunotherapy, because current data suggest that these patients have most likely been cured by treatment.

The Future and Clinical Research

The FDA's Oncologic Drugs Advisory Committee recommends requiring pharmaceutical companies to demonstrate the benefits of immunotherapy in both the neoadjuvant and adjuvant phases. However, this could increase the cost of immunotherapy development and delay new clinical trials.

However, companies are unlikely to invest in such expensive, time-consuming studies for immunotherapies already on the market under current market conditions. Instead, studies to fill this knowledge gap are expected to be conducted by cooperative groups of the US National Cancer Institute. Results from these studies, however, may take many years.

Conclusion: Physicians' Decision-Making

At present, without definitive evidence from clinical trials, oncologists must make decisions based on each patient's individual characteristics.

When assessing whether immunotherapy is beneficial after surgery, we consider disease stage, histology, genetic mutations, and pathological response. Patients' preferences also influence treatment decisions.

Our patients have a right to know that the additional risks and costs they take on are justified by clinical outcomes. Only time will tell how far the FDA follows these recommendations.

Commentary

The lack of clear evidence on the timing of immunotherapy in early-stage operable non-small cell lung cancer leaves a major gap for both patients and doctors. More extensive clinical trials are needed to answer these questions. However, this process may be time-consuming and costly.

In the meantime, physicians will try to make the best decisions using the available evidence and each patient's circumstances. This again demonstrates how critical scientific research is in guiding clinical practice in modern oncology.