Editor's Note: In recent years, immunotherapy drugs, particularly PD-1/PD-L1 inhibitors, have gradually expanded from being used in later-line treatments to frontline therapy for non-small cell lung cancer (NSCLC). Perioperative immunotherapy has become a major focus in the field, with numerous breakthroughs reshaping the treatment landscape for operable NSCLC patients. However, challenges remain in patient selection, treatment regimens, and comprehensive perioperative management. As the year comes to an end, Oncology Frontier invited Dr. Changli Wang from Tianjin Medical University Cancer Institute and Hospital to review the progress and discuss the future prospects of perioperative immunotherapy for NSCLC in 2024.

Advances in Perioperative Immunotherapy for NSCLC

According to Professor Wang, 2024 marks a significant milestone as the “first year” of perioperative immunotherapy for NSCLC, with five perioperative immunotherapy indications approved this year. Multiple phase III clinical trials have provided clear evidence of its clinical value:

Currently, there are eight ongoing phase III trials for perioperative immunotherapy in NSCLC, with six focusing on neoadjuvant immunotherapy. Professor Wang’s team has led or participated in two key studies: the CheckMate 816 study and the RATIONALE-315 study.

CheckMate 816 Study This trial evaluated the efficacy of nivolumab combined with platinum-based chemotherapy versus chemotherapy alone as neoadjuvant therapy for patients with resectable stage IB-IIIA NSCLC. Results showed that the median event-free survival (EFS) was 31.6 months in the nivolumab-chemotherapy group compared to 20.8 months in the chemotherapy-only group. The pathological complete response (pCR) rates were 24.0% and 2.2%, respectively. Across most subgroups, the nivolumab-chemotherapy combination demonstrated superior EFS and pCR benefits. As a landmark study in neoadjuvant immunotherapy, CheckMate 816 confirmed that combining nivolumab with chemotherapy significantly improves EFS and pCR rates in patients with resectable NSCLC without increasing adverse events or affecting the feasibility of surgery.

RATIONALE-315 Study This randomized, double-blind, placebo-controlled phase III trial (NCT04379635) assessed the efficacy and safety of perioperative treatment with tislelizumab combined with platinum-based chemotherapy in resectable stage II-IIIA NSCLC. Results showed that the tislelizumab-chemotherapy group achieved a significantly higher pCR rate of 41% compared to 6% in the chemotherapy-only group, an improvement of 35% (P < 0.0001). Additionally, the major pathological response (MPR) rate was 56% in the tislelizumab group versus 15% in the control group, an increase of 41% (P < 0.0001). The treatment was well-tolerated, with manageable safety profiles.

These findings underscore the transformative potential of perioperative immunotherapy in NSCLC and set the stage for further advancements in treatment strategies.

Advances and Challenges in Perioperative Immunotherapy for NSCLC

Clinical Value of Neoadjuvant Immunotherapy

The clinical relevance of neoadjuvant immunotherapy in NSCLC continues to generate discussion. While some skepticism persists, neoadjuvant immunotherapy, along with the “neoadjuvant + adjuvant” approach, has fundamentally altered the perioperative treatment paradigm. Compared to the chemotherapy-centric era, when treatment for locally advanced lung cancer primarily revolved around surgery-based multimodal strategies, current data and clinical practice reveal that perioperative immunotherapy combined with surgery delivers significantly improved survival outcomes and quality of life. These advancements underscore the transformative potential of immunotherapy in the perioperative setting.

Patient Selection and Biomarker Identification

Identifying patients who are most likely to benefit from neoadjuvant immunotherapy is a critical area of ongoing research. Biomarkers play a vital role in this process. Among the biomarkers under investigation, circulating tumor DNA (ctDNA) and circulating tumor cells (CTCs) have emerged as promising tools for evaluating minimal residual disease (MRD) and guiding treatment decisions. However, robust predictors of immunotherapy efficacy remain scarce. Currently, PD-L1 expression is the most reliable biomarker, with multiple studies confirming its correlation with pCR (pathologic complete response), MPR (major pathological response), and EFS (event-free survival). Other molecular markers, while under investigation, have yet to demonstrate consistent predictive value.

Role of Adjuvant Therapy Following pCR

Another area of debate is whether patients who achieve pCR following neoadjuvant immunotherapy still require adjuvant treatment. While it is not universally necessary for all pCR patients to undergo adjuvant immunotherapy, there are no clear criteria for selecting individuals who would benefit from this additional intervention. Pathologic complete response is widely used to evaluate the efficacy of neoadjuvant therapy, representing the complete disappearance of tumors on pathological examination. However, variations in evaluation standards across regions and quality control issues have led to the misclassification of some patients as achieving pCR. These inaccuracies highlight the need for careful follow-up and monitoring. Moreover, data indicate that even patients who achieve pCR may face a risk of recurrence, with approximately 15% experiencing lymph node recurrence. This suggests that adjuvant therapy could still play a role in reducing recurrence risk for certain patients.

Comparing Perioperative Immunotherapy Approaches

The choice between different perioperative immunotherapy strategies—neoadjuvant immunotherapy, adjuvant immunotherapy, and the “neoadjuvant + adjuvant” approach—remains a highly debated topic. Current comparisons indicate minimal differences in efficacy and recurrence risks between neoadjuvant and adjuvant immunotherapy. However, the “neoadjuvant + adjuvant” approach appears to offer superior safety and efficacy, along with a lower risk of recurrence. Based on available evidence, this comprehensive approach may provide the most significant clinical benefit to patients.

Future Directions in Perioperative Immunotherapy

Developing Higher pCR Strategies

Clinical studies consistently show that higher pCR rates correlate with greater survival benefits in patients undergoing neoadjuvant immunotherapy. However, as the proportion of residual tumors increases, survival advantages diminish. Developing innovative drugs and clinical strategies to achieve higher pCR rates remains a key research priority. One such effort is the AK112-205 study, which evaluates the safety and efficacy of AK112 (ivonescimab, a PD-1/VEGF dual antibody) as monotherapy or in combination with chemotherapy in neoadjuvant/adjuvant treatment for NSCLC. Early results reveal promising efficacy, with pCR rates of 30% for monotherapy and 43.6% for the combination group, and manageable safety profiles. A phase III study is planned to further validate these findings.

Another study, ALTER-L043, investigates the efficacy and safety of perioperative treatment regimens based on penpulimab combined with anlotinib and/or chemotherapy in resectable stage IIB-IIIB NSCLC. Patients were randomized into three groups, receiving different combinations of these therapies for three to four cycles. Preliminary results showed objective response rates (ORR) of 77.8%, 58.6%, and 63.3%, and pCR rates of 52.0%, 50.0%, and 38.1%, respectively, across the three groups. Although median EFS data are not yet mature, the high pCR rates suggest potential long-term benefits.

Optimizing Clinical Trial Designs

The integration of innovative drugs such as antibody-drug conjugates (ADCs) into neoadjuvant immunotherapy underscores the need for optimized clinical trial designs. Immunotherapy combined with chemotherapy has reached a bottleneck, prompting a shift toward exploring ADCs and other advanced therapies. Regulatory bodies like the FDA and NMPA have raised the bar for clinical trial designs, requiring immunotherapy rather than chemotherapy as the control group, clearer definitions of treatment value at each stage (neoadjuvant, adjuvant, and perioperative), and larger sample sizes. These stricter requirements necessitate longer research cycles, greater investments, and collaborative efforts across the field to overcome these challenges.

Addressing Low pCR Rates

While neoadjuvant immunotherapy has demonstrated higher pCR rates than chemotherapy in many cases, some patients do not show significant improvements. For this subgroup, more effective treatment strategies are urgently needed. Ongoing studies exploring pembrolizumab combined with ADCs or vaccines are promising, but their results will not be available until after 2030. This highlights the need for accelerated research efforts to address the unmet needs of these patients.

Immunotherapy for Molecularly Altered NSCLC

The role of immunotherapy in NSCLC with specific molecular alterations remains an area of active exploration. Current data on immunotherapy strategies for EGFR-mutated NSCLC are inconclusive, suggesting the need for cautious and targeted approaches. For patients with ALK fusion, neoadjuvant immunotherapy is not recommended. Advanced ALK inhibitors have demonstrated five-year survival rates as high as 60% in late-stage patients, reducing the necessity for immunotherapy, particularly in early-stage disease.

As the field continues to evolve, a deeper understanding of these complex issues will be instrumental in maximizing the benefits of perioperative immunotherapy for NSCLC patients.

About Dr. Changli Wang

• Chief Physician, Professor, and Doctoral Supervisor, Department of Pulmonary Oncology, Tianjin Medical University Cancer Institute and Hospital
• Director, Department of Surgical Teaching and Research, Tianjin Medical University Cancer Institute and Hospital
• Director, Tianjin Lung Cancer Diagnosis and Treatment Center
• Honorary Chair, Lung Cancer Specialty Committee, Chinese Anti-Cancer Association
• Deputy Editor-in-Chief, Chinese Journal of Clinical Oncology