The 2024 European Society for Medical Oncology (ESMO) Annual Congress was held from September 13 to 17 in Barcelona, Spain, where multiple advancements in lung cancer research were presented. Dr. Jonathan D. Spicer from the McGill University Health Centre in Montreal, Canada, shared the updated clinical data from the CheckMate 77T study. During the congress, Oncology Frontier interviewed Professor Spicer, who provided insights on the updated data and discussed how to choose between neoadjuvant therapy, adjuvant therapy, and perioperative strategies in resectable non-small cell lung cancer (NSCLC).

01. Oncology Frontier: The updated Phase III CheckMate 77T study data was presented at ESMO 2024. How do you view the safety and efficacy of perioperative nivolumab compared to placebo in treating resectable NSCLC patients? (LBA50)

Dr. Jonathan D. Spicer: CheckMate 77T is a Phase III study comparing the efficacy of perioperative nivolumab versus placebo in patients with stage IIa-IIIb resectable NSCLC (Abstract LBA50). The trial demonstrated a positive outcome in progression-free survival (PFS). In terms of safety, the study aligns with previous perioperative trials such as CheckMate 816, KEYNOTE-671, and AEGEAN. The combination of neoadjuvant nivolumab plus chemotherapy, followed by surgery and adjuvant nivolumab, shows strong efficacy. This combination is also safe and appropriate for patients with resectable NSCLC, regardless of their stage.

02. Oncology Frontier: Several significant lung cancer studies were presented at ESMO 2024. Could you share some research findings from the congress that stood out to you?

Dr. Jonathan D. Spicer: One of the most intriguing aspects of the CheckMate 77T study was the data on circulating tumor DNA (ctDNA) and its relationship with the depth of pathological response. While ctDNA testing is not yet ready for clinical decision-making, we observed some promising signs that ctDNA could be useful in the future. For instance, patients who did not clear ctDNA after neoadjuvant chemotherapy and nivolumab treatment had residual disease in their resection specimens. This suggests that ctDNA can help identify patients who may need additional local treatment to eliminate residual disease.

On the other hand, around 50% of patients who achieved a pathological complete response (pCR) had their ctDNA completely cleared. This indicates that if ctDNA is fully cleared after neoadjuvant chemotherapy and immunotherapy, the patient is more likely to achieve a pCR. Although the sensitivity of this marker is not yet high enough, it is still a promising indicator. Professor Martin Reck also presented ctDNA data from the AEGEAN trial, which showed that ctDNA clearance before and after surgery is associated with better survival outcomes. The worst scenario is when ctDNA remains detectable after surgery, as this small group of patients will likely require different adjuvant treatments to improve their outcomes.

Additionally, The Lancet recently published the overall survival (OS) and quality-of-life results from the KEYNOTE-671 study. Professor Marina C. Garassino presented the study results at the congress (Abstract 1210P), showing that neoadjuvant chemotherapy and pembrolizumab, followed by adjuvant pembrolizumab, significantly improved OS compared to placebo without negatively impacting the patients’ quality of life. This is the first time in 30 years that an OS benefit has been observed with a neoadjuvant chemo-immunotherapy strategy in NSCLC, clearly establishing this approach as the new standard of care.

03. Oncology Frontier: When considering perioperative strategies for resectable NSCLC, how should clinicians choose between adjuvant therapy, neoadjuvant therapy, and perioperative treatment approaches?

Dr. Jonathan D. Spicer: This is one of the most challenging questions because we do not have head-to-head comparative data to determine whether upfront surgery is better than neoadjuvant therapy for certain patients. Similarly, it remains unclear whether patients who receive neoadjuvant therapy require additional immunotherapy afterward.

In my view, for patients with resectable stage IIa-IIIb NSCLC, neoadjuvant chemotherapy and immunotherapy followed by surgery is more beneficial than upfront surgery followed by adjuvant therapy. Of course, there are situations where surgery is performed first, and only after the operation is it discovered that the patient has stage II or III disease. In these cases, adjuvant therapy is necessary. However, if I know from the start that the patient has resectable stage II or III disease, neoadjuvant therapy followed by surgery is my preferred approach over upfront surgery.

Regarding whether to use perioperative therapy or adjuvant immunotherapy, that is a tough question. We need to consider the potential toxicities associated with adjuvant treatment. For example, the CCTG BR.31 study, which investigated adjuvant durvalumab or placebo after surgery in patients with stage II/III NSCLC (Abstract LBA48), was a negative trial. If you look closely at the study, you’ll notice that there were seven deaths in the durvalumab group compared to just one in the placebo group due to treatment-related adverse events. This difference in toxicity likely explains why the trial had a negative outcome and highlights the serious risks of adding immunotherapy after surgery.

When we administer neoadjuvant therapy, we give patients neoadjuvant chemotherapy and immunotherapy before surgery. We must ensure that this additional treatment benefits the patient. During ESMO, data from the KEYNOTE-671 trial showed how the residual tumor burden after treatment correlated with event-free survival (EFS). It was clear that patients with more than 60% residual tumor after neoadjuvant chemo-immunotherapy had outcomes similar to the placebo group. In our practice, if a patient has this level of residual disease after surgery, we are less likely to give them additional therapy to avoid the toxic side effects of adjuvant treatment. However, if they relapse, we may consider adjuvant therapy at that point.

Patients who achieve pCR are the most likely to be cured. From the CheckMate 816 trial, we know that patients who reach pCR have a 95% overall survival rate at four years. For these patients, I don’t think we can improve their outcomes much more, so we choose not to provide additional adjuvant therapy. Patients with intermediate pathological responses—those with residual tumor burden of up to around 60%—are likely the ones who could benefit most from adjuvant therapy. Looking ahead, I believe the depth of pathological response will be the key factor guiding our clinical decisions.