Surgical Perspective on Neoadjuvant Immunotherapy in Non-Small Cell Lung Cancer
Jay M Lee1, Masahiro Tsuboi2, Alessandro Brunelli3
1Division of Thoracic Surgery, David Geffen School of Medicine at UCLA, Los Angeles, California.
Background:
With a 5% improvement in 5-year overall survival achieved with current neoadjuvant or adjuvant chemotherapy, new treatments for resectable non-small cell lung cancer (NSCLC) are urgently needed. The use of immune checkpoint inhibitors (ICIs) is established in metastatic NSCLC and is being evaluated in resectable NSCLC.
Methods:
Publications and conference databases and clinicaltrials.gov were searched for reports on clinical studies of neoadjuvant immunotherapy in patients with early resectable NSCLC.
Results:
Potential advantages of neoadjuvant ICIs include the following: earlier treatment of micrometastatic disease; activation of a broader, potentially durable immune response by the whole tumor and associated lymph nodes; and pathologic assessment of neoadjuvant treatment response, which may guide adjuvant therapy. Surgical considerations include delays to surgery, potential disease progression preventing curative resection, and perioperative morbidity and mortality. Surrogate end points of efficacy (pathologic complete response, major pathologic response) and biomarkers predictive of outcome (programmed death ligand 1 expression, tumor mutational burden, and circulating tumor DNA) can accelerate clinical trial completion and early-stage treatment development; their application in neoadjuvant ICI studies in NSCLC is reviewed.
Conclusions:
Phase 2 trials of neoadjuvant ICIs alone or in combination with chemotherapy showed encouraging safety and efficacy in patients with resectable NSCLC, thus warranting the ongoing phase 3 studies of neoadjuvant immunotherapy combined with chemotherapy. Preoperative and intraoperative unresectability after neoadjuvant ICIs appears comparable to that observed with neoadjuvant chemotherapy. To help thoracic surgeons and medical oncologists to distinguish among ICIs beyond efficacy as phase 3 data emerge, surgery-related end points for perioperative morbidity, mortality, and complexity should be defined, standardized, incorporated into trial designs, and reported.
Insights
New treatments are needed for resectable non-small cell lung cancer (NSCLC). Neoadjuvant immune checkpoint inhibitors (ICIs) show promise, with ongoing phase 3 trials evaluating their combination with chemotherapy for early-stage NSCLC.
Area of Science:
- Oncology
- Immunotherapy
- Thoracic Surgery
Background:
- Current neoadjuvant or adjuvant chemotherapy offers limited survival benefits for resectable non-small cell lung cancer (NSCLC).
- Established efficacy of immune checkpoint inhibitors (ICIs) in metastatic NSCLC necessitates their evaluation in early-stage, resectable disease.
Purpose of the Study:
- To review clinical studies on neoadjuvant immunotherapy in early resectable NSCLC.
- To discuss the advantages and surgical considerations of neoadjuvant ICIs.
- To examine the role of surrogate endpoints and biomarkers in accelerating neoadjuvant ICI trial development.
Main Methods:
- Literature search of publications, conference databases, and clinicaltrials.gov for neoadjuvant immunotherapy studies in resectable NSCLC.
Main Results:
- Neoadjuvant ICIs offer potential benefits including earlier treatment of micrometastatic disease and broader immune activation.
- Pathologic response assessment can guide adjuvant therapy decisions.
- Surgical challenges include potential delays, disease progression, and perioperative complications.
- Surrogate efficacy endpoints (pCR, MPR) and predictive biomarkers (PD-L1, TMB, ctDNA) can expedite clinical trials.
Conclusions:
- Phase 2 trials demonstrate encouraging safety and efficacy of neoadjuvant ICIs in resectable NSCLC, supporting ongoing Phase 3 studies.
- Unresectability rates with neoadjuvant ICIs are comparable to neoadjuvant chemotherapy.
- Standardized reporting of surgery-related endpoints is crucial for differentiating ICIs as Phase 3 data emerge.
