Elucidating Emergent Neoadjuvant Strategies For Stage I-III Lung Cancers

Although adjuvant immunotherapy has generally failed to demonstrate overall survival (OS) benefits among patients with stage I to III lung cancers, neoadjuvant therapies and treatment in the preoperative setting with immunotherapy have benefitted these patients, according to Thomas Marron, MD, PhD.

In an interview with CancerNetwork®, Marron, 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, gave an overview of the presentation titled, “Stage I-III Is Not What It Used to Be” that he delivered at the 2025 Chemotherapy Foundation Symposium (CFS).1

Initially, Marron disclosed that his presentation was composed of progress in the treatment paradigm for stage I to III lung cancers, in addition to insights into clinical trial data establishing standards of care for stage II and III disease. Furthermore, he suggested that these patients can be disaggregated into those with targetable and non-targetable mutations, and that most cancers evaluated were related to smoking.

Then, Marron highlighted a progression-free survival (PFS) benefit with tyrosine kinase inhibitors (TKIs) in patients with targetable mutations, with an OS benefit observed in patients with EGFR-mutated disease. Additionally, he highlighted that data support their use in adjuvant and neoadjuvant settings.

He further highlighted approvals for atezolizumab (Tecentriq) and pembrolizumab (Keytruda) following standard doublet chemotherapy and surgery for stage II or III lung cancer, which both exhibited disease-free survival (DFS) improvements. Next, he highlighted OS benefits seen with immunotherapy in the neoadjuvant space, highlighting data from the phase 3 CheckMate 816 trial (NCT02998528) assessing neoadjuvant chemotherapy/nivolumab (Opdivo) in stage II/III lung cancers, and the phase 3 KEYNOTE-671 trial (NCT03425643), which assessed perioperative pembrolizumab/chemotherapy in a similar patient population.2,3

Transcript:

We focused on the progress that has been made in stage I to III lung cancer, and we focused mostly on the clinical data that has established the standards of care for stage II and stage III lung cancer. You can break that down by patients who have targetable mutations, like EGFR and ALK, or patients who have non-targetable mutations, who are [most of] our patients with lung cancer. Most of that lung cancer is related to smoking.

In our [patients with] EGFR and ALK [mutations], we demonstrated the use of TKIs. These small molecules are improving, not only PFS, but, at least in the EGFR [population], we see that the adjuvant use of those therapies after surgery in patients with stage II and III lung cancer significantly improves OS. In patients who do not have targetable mutations, we have [many] data, both in the adjuvant and neoadjuvant space.

The first place that we had FDA approvals was in the adjuvant space after surgery for stage II or III lung cancer, and after patients received standard platinum doublet chemotherapy, there was an approval, first for atezolizumab and then for pembrolizumab. Both significantly improved DFS. In the adjuvant setting, neither has really demonstrated an OS benefit, which leads to the hypothesis that, similar to what we see in melanoma and many preclinical studies, it is in the neoadjuvant space that we get the greatest survival benefit from the inclusion of immunotherapy into the treatment algorithm. There have been many studies that have demonstrated a survival benefit in the preoperative setting, which is exciting.

The first we saw was [the phase 3 CheckMate 816 trial]. This was a study that looked at 3 cycles of neoadjuvant chemotherapy and nivolumab in patients with stage II or III lung cancer. They also included stage 1b, but they were using an old AJCC definition, and in AJCC v8, which is our current staging classification, they were only looking at patients with stage II and III disease. They took patients, they gave them 3 cycles of nivolumab plus chemotherapy [with] nothing in the adjuvant setting. That study has now read out not only a PFS or event-free survival [benefit], but also an OS benefit.

The next study that led to an approval was the [the phase 3] KEYNOTE-671 study, and that was using pembrolizumab and chemotherapy, giving 4 cycles in the preoperative setting and then additional pembrolizumab in the postoperative setting. This was the first study ever to demonstrate an OS benefit. It read out a survival benefit before CheckMate 816, and it significantly improved survival. No other study in the perioperative setting has ever actually demonstrated a survival benefit [with] the addition of either chemotherapy or immunotherapy. That was exciting.

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. Forde PM, Spicer J, Lu S, et al. Neoadjuvant nivolumab plus chemotherapy in resectable lung cancer. N Engl J Med. 2022;386(21):1973-1985. doi:10.1056/NEJMoa2202170
3. Wakelee H, Liberman M, Kato T, et al. Perioperative pembrolizumab for early-stage non–small-cell lung cancer. N Engl J Med. 2023;389(6):491-503. doi:10.1056/NEJMoa2302983