Editor's Note: The perioperative treatment of early-stage non-small cell lung cancer (NSCLC) has now entered the era of precision-targeted therapy and immunotherapy. At the NSCLC Medical Treatment Session of the International Lung Cancer Conference (CLC 2024) held from August 9-11, Dr. Huijuan Wang from Henan Cancer Hospital delivered a keynote speech titled "Advances in Perioperative Treatment of NSCLC." This article provides a brief overview of the content of her presentation.With the success of perioperative targeted therapy studies (ADJUVANT, ADAURA, and ALINA) and perioperative immunotherapy studies (IMpower010, CheckMate816, KEYNOTE-091, and Neotorch), perioperative treatment of early-stage lung cancer has evolved into a new paradigm guided by EGFR, ALK, and PD-L1 testing.
The U.S. Food and Drug Administration (FDA) and the Chinese National Medical Products Administration (NMPA) have approved multiple indications for perioperative targeted therapy and immunotherapy in early-stage NSCLC. The recent NCCN Guidelines 2024 V5 edition introduced the following updates: the title “Systemic Therapy Following Previous Neoadjuvant or Adjuvant Systemic Therapy” was revised to “Postoperative Systemic Therapy.” Under this title, the recommendation of alectinib for completely resected stage I-IIIA or IB (T3, N2) NSCLC patients with ALK rearrangement was added (Category 1). Additionally, the duration of adjuvant osimertinib therapy was extended to three years. The 2024 CSCO Guidelines update also emphasizes target detection for perioperative precision treatment.
Advances and Considerations in Perioperative Targeted Therapy for NSCLC
NSCLC targeted adjuvant therapy has undergone years of exploration, with osimertinib approved for postoperative adjuvant therapy by the FDA and NMPA based on the ADAURA study, and icotinib approved for postoperative adjuvant therapy by the NMPA based on the EVIDENCE study.
There are still several unresolved questions regarding perioperative treatment in early-stage EGFR-positive lung cancer patients, such as the optimal duration of neoadjuvant/adjuvant therapy, how to guide adjuvant therapy through ctDNA/MRD monitoring, and whether neoadjuvant/adjuvant targeted therapy can be applied to targets like ALK, ROS1, RET, and MET. The findings from studies such as ADAURA, ICTAN, NeoADAURA, and ALINA provide some clues to these questions.
ctDNA/MRD Monitoring to Guide Adjuvant Therapy: The ADAURA study found that MRD detection based on ctDNA has the potential to predict disease-free survival (DFS) events, with most MRD+ events occurring after treatment cessation. The MRD status of most patients remained negative during osimertinib adjuvant therapy, with the majority (19/28) of MRD/DFS events occurring after the end of adjuvant therapy, and 58% of these events occurred within 12 months after treatment ended. MRD detection may help identify patients who could benefit from longer durations of adjuvant osimertinib therapy (2024 ASCO, Abstract #8005), but this analysis has some limitations.
Duration of Adjuvant Therapy: The ICTAN study found no additional benefit from 12 months of adjuvant icotinib therapy compared to 6 months post-surgery.
Exploration of TKI Neoadjuvant Targeted Therapy: The Phase II NEOS study suggested initial efficacy with neoadjuvant osimertinib therapy for stage II-IIIB NSCLC. The NeoADAURA registration study of neoadjuvant osimertinib therapy for stage II-IIIB EGFR-mutated NSCLC is currently ongoing.
Perioperative Targeted Therapy Beyond EGFR: The ALINA study showed that postoperative adjuvant alectinib therapy for ALK+ early-stage NSCLC patients significantly improved health-related quality of life (HRQoL) compared to chemotherapy. Clinical studies targeting less common mutations such as BRAF, MET, and RET are ongoing, with multiple perioperative studies focused on these rare targets currently underway.
Advances and Considerations in Perioperative Immunotherapy for NSCLC
The exploration of perioperative treatment models involving immunotherapy, based on the timing of immunotherapy intervention, is ongoing. AEGEAN is the first global Phase III study to report positive results for the “sandwich” perioperative immunotherapy approach in lung cancer, achieving triple benefits of pathological complete response (pCR), major pathological response (MPR), and event-free survival (EFS) with manageable safety. Currently, evidence supporting the “sandwich” model in perioperative immunotherapy is growing. However, perioperative immunotherapy also faces several emerging challenges, four of which are particularly noteworthy.
Which Perioperative Immunotherapy Model to Choose?
The choice between different perioperative immunotherapy models remains a subject of debate, with questions about the relative merits of neoadjuvant alone, adjuvant alone, or the “sandwich” approach (neoadjuvant + adjuvant).
Advantages of Neoadjuvant Immunotherapy: It works while the primary tumor is intact, potentially leading to early induction of anti-cancer immunity and a broader T-cell response. Preoperative patients are in better physical condition with an intact lymphatic system; the presence of the complete tumor may result in a higher antigen load.
Advantages of Adjuvant Immunotherapy: It reactivates the immune response after surgery, thereby stimulating T-cell surveillance of residual tumor cells. Adjuvant immunotherapy helps eliminate micrometastases and monitor residual tumor cells, activating a broader T-cell response to monitor residual tumor cells.
“Sandwich” Approach: The neoadjuvant + adjuvant model. This model may offer further benefits in EFS and overall survival (OS). Early landmark studies like LCMC3 have provided evidence for the feasibility of the “sandwich” immunotherapy model. The KEYNOTE-671 study showed statistically and clinically significant OS improvements with this treatment model; however, follow-up times in other neoadjuvant + adjuvant studies are still short, and further EFS/OS follow-up is needed.
Safety of Perioperative Immunotherapy: Incidence of Pneumonitis Varies Across Different Immunosuppressants
Differences Between PD-1/PD-L1 Inhibitors: From a mechanistic perspective, PD-L1 inhibitors retain PD-L2 function, avoiding severe side effects like interstitial pneumonitis. A systematic review and meta-analysis showed that PD-L1 inhibitors have a lower incidence of pneumonitis.
Incidence of Pneumonitis Varies Across Different Immunosuppressants: An analysis of fatal immune-related adverse events associated with PD-1 and PD-L1 inhibitors revealed that pneumonitis is the leading cause of death, with varying incidence rates of pneumonitis-related adverse events across different drugs.
Predictive Biomarkers of Efficacy: PD-L1 Expression or ctDNA?
PD-L1 Expression: In most Phase III clinical trials, perioperative immunotherapy efficacy tends to improve with higher PD-L1 expression levels. For instance, the CheckMate-816 study results showed that PD-L1 can predict efficacy, with EFS improving as PD-L1 expression increases. In the IMpower010 study, benefits were primarily driven by patients with high PD-L1 expression. In KEYNOTE-091, no DFS benefit was observed in patients with high PD-L1 expression. The AEGEAN and KEYNOTE-671 studies found that pCR rates and EFS improved as PD-L1 expression levels increased.
ctDNA: The CheckMate 816 study suggested that patients with ctDNA clearance had better pCR rates/mEFS compared to those without ctDNA clearance, regardless of whether they were in the nivolumab + chemotherapy group or the chemotherapy-alone group. The AEGEAN study indicated that patients with baseline ctDNA positivity had higher ctDNA clearance rates in the durvalumab group. Early ctDNA clearance may be associated with higher pCR and MPR, with all patients achieving pCR and over 90% achieving MPR showing ctDNA clearance at C4D1.
Do EGFR/ALK+ NSCLC Patients Benefit from Perioperative Immunotherapy?
The IMpower010 study showed that in the stage II-IIIA subgroup, EGFR+ NSCLC patients did not benefit from adjuvant atezolizumab.
The KEYNOTE-671 study found that in the EGFR+ subgroup, patients benefited more significantly from neoadjuvant + adjuvant pembrolizumab treatment in terms of EFS.
In the KEYNOTE-091 study, subgroup analysis of stage IB-IIIA patients showed a trend towards benefit in the EGFR+ subgroup receiving adjuvant pembrolizumab.
The AEGEAN study found that the EFS benefit in the EGFR-mutated subgroup was less than that in the mITT population.
These subgroup analyses are based on small sample sizes, and it is unclear whether the baseline characteristics are balanced. Population selection bias may exist, so these results should be interpreted with caution.
Outlook and Summary
Perioperative Targeted Therapy for NSCLC
- Adjuvant targeted therapy for EGFR-mutated NSCLC, represented by the ADAURA regimen, has become a recommended approach in both domestic and international guidelines.
- The dawn of neoadjuvant targeted therapy is emerging, with the best regimen and treatment duration still requiring further exploration.
Perioperative Immunotherapy for NSCLC
- The results of neoadjuvant immunotherapy combined with chemotherapy are encouraging, and immunotherapy as an adjuvant treatment offers new options for patients.
- The “sandwich” (neoadjuvant + adjuvant) immunotherapy approach offers a new treatment option for resectable stage II-III NSCLC patients, providing similar triple benefits even in cases with a heavy disease burden.
Perioperative treatment is gradually entering an era of precision and personalized therapy, where treatment strategies should be “tailored” rather than “one-size-fits-all.”
Dr. Huijuan Wang
- PhD in Oncology, Chief Physician, Professor
- Director of the Second Respiratory Oncology Ward, Henan Cancer Hospital
Positions Held:
- Standing Committee Member, Immunotherapy Expert Committee, Chinese Society of Clinical Oncology (CSCO)
- Standing Committee Member, Patient Education Expert Committee, CSCO
- Standing Committee Member, Tumor Overall Assessment Committee, Chinese Anti-Cancer Association
- Member, Lung Cancer Committee, Chinese Anti-Cancer Association
- Vice Chair, Thoracic Tumor Precision Treatment Committee, China Primary Health Care Foundation
- Vice Chair, Youth Committee, China Respiratory Oncology Collaboration Group, National Clinical Research Center
- Standing Committee Member, Difficult Tumor Committee, Chinese Medical Education Association
- Executive Member, Youth Council, Henan Anti-Cancer Association
- Chair, Youth Committee, Lung Cancer Committee, Henan Anti-Cancer Association
- Member, Tumor Drug Clinical Research Committee, Chinese Anti-Cancer Association
- Member, Tumor Supportive Care Committee, Chinese Anti-Cancer Association
- Member, International Medical Exchange Committee, Chinese Anti-Cancer Association
