Optimizing Immunotherapy in Resectable NSCLC: Adjuvant, Neoadjuvant, and Perioperative Strategies

The administration of immunotherapy in the adjuvant, neoadjuvant, and perioperative settings offers distinct benefits and challenges, each playing a crucial role in the treatment landscape for resectable cancers. In the adjuvant setting, immunotherapy has the potential to restore antitumor immunity that may have been compromised by the immunosuppressive effects of surgery. By eliminating residual microscopic disease, adjuvant immunotherapy aims to reduce recurrence rates and improve long-term outcomes, explained Tina Cascone, MD, PhD, associate professor, director of translational research, and chair of Multidisciplinary Thoracic Oncology Working Group at the University of Texas MD Anderson Cancer Center in Houston, Texas, during a presentation at the 2025 inaugural American Association of Cancer Research Immunotherapy (AACR IO) Conference.¹

“In the neoadjuvant setting, we can trigger a robust activation of the immune system when the tumor and the lymph nodes are still in place prior to surgery,” Cascone said during her symposium presentation at AACR IO in Los Angeles, California. “The beauty of the neoadjuvant setting is the opportunity of a rapid readout of activity, especially in novel therapies, using surrogate end points of efficacy, specifically major pathological response [MPR] and pathological complete response [pCR] that can help us to guide adjuvant therapy.”

With this opportunity for in situ immune response, immune checkpoint inhibitors (ICIs) and other immune-based therapies can provide enhanced efficacy in the neoadjuvant setting. Additionally, neoadjuvant therapy can support translational research by allowing the collection of pre- and post-treatment samples for biomarker discovery and mechanistic studies, according to Cascone. However, a potential downside of neoadjuvant therapy is the risk of delaying surgery if significant toxicity or disease progression occurs.

Microscopic view of non–small cell lung cancer. Image Credit: © Keopaserth - stock.adobe.com

In the perioperative setting, one key disadvantage of administering immunotherapy is that patients with micrometastatic disease may not have sufficient tumor antigens remaining to trigger a robust immune response, potentially limiting efficacy. However, combining neoadjuvant and adjuvant therapy in the perioperative setting does have the potential to sustain antitumor immunity and eliminate micrometastases throughout the surgical process, according to Cascone. This approach can be seen in the FDA approval on October 3, 2024, of nivolumab (Opdivo; Bristol Myers Squibb), a PD-1 inhibitor, in combination with platinum-doublet chemotherapy for patients with resectable (tumors at 4 cm or greater and/or node positive) non–small cell lung cancer (NSCLC). As of 2025, the administration of nivolumab plus chemotherapy is approved in the neodjuvant, adjuvant, and perioperative setting for NSCLC.

Key clinical trials have solidified the role of immunotherapy in these settings. The CheckMate 816 trial (NCT02998528) showed that 3 cycles of neoadjuvant nivolumab plus platinum-based chemotherapy significantly improved pCR rates compared to chemotherapy alone, with event-free survival (EFS) benefits sustained over time. At 48 months, 49% of patients receiving neoadjuvant nivolumab plus chemotherapy were alive and without progression, compared to 38% in the chemotherapy-alone arm. However, Cascone noted there was a proportion of patients who relapsed during the trial.

The CheckMate 77T trial (NCT04025879) further explored the perioperative approach by incorporating nivolumab in both pre- and post-operative settings alongside chemotherapy. This global phase 3 study, which was led by Cascone, demonstrated a significant improvement in pCR rates and EFS, reinforcing the value of perioperative immunotherapy. However, across multiple studies, approximately 40% to 50% of patients still experienced disease relapse, underscoring the need for more effective treatment strategies.

“We must improve upon these benchmarks,” Cascone said. “More effective personalized treatments and biomarkers are needed.”

To address these challenges, Cascone’s team focused on integrating preclinical models, investigator-initiated clinical trials, and multiomic analyses to identify novel biomarkers and therapeutic targets. An example of these efforts can be seen in the NEOSTAR Platform trial, which was designed by Cascone’s team to rapidly test promising therapies using surrogate end points such as MPR. Initially comparing nivolumab plus chemotherapy vs nivolumab in combination with ipilimumab (Yervoy; Bristol Myers Squibb), a CTLA-4 inhibitor, plus chemotherapy, the study was quickly launched following the approval of the CheckMate 816 trial. With a single-arm design, Cascone’s team rapidly tested the addition of ipilimumab to the original CheckMate 816 study drugs using MPR rate end points. Results of this NEOSTAR study demonstrated improved MPR rates with the addition of ipilimumab, suggesting enhanced immune activation. Further translational analyses revealed an increase in CD8 effector memory T cells, CD4-positive effector T cells, and B cells, highlighting potential biomarkers for response.

“In a nutshell, not only did we validate the MPR rates of the CheckMate 816 trial with nivolumab plus chemotherapy at 32%, but you can see the numerical improvement at 50% with addition of ipilimumab,” Cascone said.

Following these results, Cascone and her team went back to the lab to further understand the mechanisms that regulate this increased response with the addition of ipilimumab to the backbone of chemotherapy plus nivolumab. Using both mouse models and patient tumor samples, Cascone investigated immune responses, focusing on T-cell and B-cell interactions within the tumor microenvironment. According to Cascone, the findings indicated that neoadjuvant therapy with PD-1 plus CTLA-4 inhibitors leads to an increase in CD4+ effector T helper 1 (Th1)-like cells, especially those expressing ICOS and T-bet, which correlate with improved tumor control and survival. Additionally, increased B-cell density and tertiary lymphoid structure (TLS) markers were observed in responders, highlighting the importance of B-cell and T-cell interactions in shaping an effective anti-tumor immune response. Spatial transcriptomics and proteomics of patient samples further revealed that well-organized TLS structures were present in responders, while non-responders exhibited disorganized lymphoid aggregates. Higher expression of CXCL13 and CXCL5, markers associated with TLS maturation, was also observed in responders.

To better understand these immune interactions, researchers developed engineered KP NSCLC tumor models expressing antigens recognized by T cells (Ninja model) or both T and B cells (Helo model). The Helo model, which included B-cell antigen expression, showed increased T follicular helper (TFH) cell recruitment, but also signs of T-cell exhaustion, leading to accelerated tumor growth. Orthotopic models further demonstrated the formation of TLS-like structures, particularly around airways.

These results demonstrate that CD4 effector Th1-like responses are dominant in mouse models and patients treated with neoadjuvant PD-1 plus CTLA-4–based therapy and in responders, according to Cascone. Additionally, MPR to neoadjuvant dual ICI-based therapy is associated with enhanced B-cell densities, TLS signature scores, and increased TFH cells in patients with NSCLC. Further, Cascone explained that the interaction between TFH cells and B cells may play a crucial role in immune responses to neoadjuvant therapy. Looking to the future, Cascone noted it will be important to identify novel therapeutic targets that integrate clinical and multi-omics analyses, with the goal of developing new treatment strategies for NSCLC.

REFERENCE

Cascone T. Neoadjuvant immunotherapy in lung cancer: Preclinical models, clinical trials, and reverse translation. Presented at: American Association of Cancer Research Immunotherapy; Los Angeles, California; February 22-26, 2025.