Examining Neoadjuvant Chemoimmunotherapy Benefit in Stage III Lung Cancers

Chemotherapy has historically not been used in patients with stage I lung cancers due to its limited efficacy, according to Thomas Marron, MD, PhD. Additionally, although immunotherapy has also not been used for these patients, he suggested that its neoadjuvant use may help bolster cure rates with resection.

At the 2025 Chemotherapy Foundation Symposium (CFS), CancerNetwork spoke with Marron about his presentation titled, “Stage I-III Is Not What It Used to Be”.¹ Specifically, he touched upon how the benefit of neoadjuvant chemotherapy with or without immunotherapy differs among patients with lung cancer based on staging.

Between patients with stage II or III disease, Marron noted that a greater benefit was observed among patients with the latter, given a higher likelihood that a patient had micrometastatic disease. Although immunotherapy may be used in the perioperative setting for patients with stage II disease to train the body to potentially prepare for metastases, the benefit of neoadjuvant chemotherapy is more pronounced when the disease is already hyperproliferative.

Furthermore, Marron suggested that the data for neoadjuvant immunotherapy may follow a similar pattern as chemotherapy for patients with stage II disease, as these patients may already be cured from surgery alone and tend to have a lower likelihood of developing metastatic disease. He concluded by highlighting subgroup analysis data from the phase 3 CheckMate 77T trial (NCT04025879), which showed that patients with mediastinal lymph node-involved (N2) lung cancer had a greater risk of experiencing metastatic disease, and subsequently, could benefit more from chemoimmunotherapy.²

Marron is the director of the Early Phase Trials Unit at the Tisch Cancer Institute and a professor of Medicine, as well as Immunology and Immunotherapy at the Icahn School of Medicine at Mount Sinai.

Transcript:

We know, historically, that chemotherapy was not helpful in patients who had stage I disease. We really have not been using chemotherapy in that setting, and we do not have much data on the use of immunotherapy in patients with stage I disease. However, I think that it would be beneficial because we know around one-third of the patients with stage I tumors eventually have their cancer come back. If we could increase the likelihood that their surgery cures them, obviously, that would be an amazing move forward.

The trials that studied neoadjuvant chemoimmunotherapy included [patients with] stage II and III disease. We know, from the historical chemotherapy studies, that it’s always the [patients with] stage III disease who have the greatest benefit from the addition of any sort of perioperative therapy, because as you go from stage II to III, you are looking at more central lymph nodes, typically, and larger tumors. That really suggests a higher likelihood that you already have micrometastatic disease.

The issue around surgery is not that you are not cutting out the whole tumor, it’s that these patients have already metastasized. You are giving chemotherapy, historically, just to try to sterilize their body of those tiny, microscopic bits of cancer. Here, in the perioperative setting, we are using immunotherapy while the tumor is still present, hopefully, to train the immune system on what to be on the lookout for. Then it circulates around your body and searches out those micrometastatic foci. [Many] of them are not necessarily going to be hyperproliferative, so they might not be responsive to the chemotherapy in the first place. I think that’s one reason why we are seeing such great benefit.

Now, is immunotherapy more beneficial for [patients with] stage II or III disease? Most of the data has demonstrated the greatest benefit, similar to the chemotherapy data, is found in patients who have more advanced disease, but I think it’s also because those patients have a much higher likelihood of already having metastatic disease, while there probably are a subset of patients who have stage II: where they are getting cured of their cancer because it’s all being removed. That’s why we see the greatest benefit in stage III and not stage II.

The [phase 3] CheckMate 77T subgroup analysis shows that even patients who have significant N2 disease, which is mediastinal lymph nodes—those are the patients who have a [particularly] high risk of [experiencing] recurrent disease in the future—those are the ones who benefit most from the addition of immunotherapy to standard chemotherapy. We are seeing that, as the tumor grows bigger, you are going to have more benefit from systemic therapy. Smaller tumors are less likely to have metastasized, but still, there’s a good chance that they have.

References

1. Marron TU. Stage I-III is not what it used to be. Presented at: 43rd Annual Chemotherapy Foundation Symposium (CFS); November 12-14, 2025; New York, NY.
2. Cascone T, Awad MM, Spicer JD, et al. Perioperative nivolumab in resectable lung cancer. N Engl J Med. 2024;390(19):1756-1769. doi:10.1056/NEJMoa2311926