Surgical Insights Are Essential to Integration of Immune Therapy in Resectable NSCLC.

In the spring of 2021, two large phase 3 trials that combine lung resection with immune checkpoint inhibition (ICI) for NSCLC reported their primary end points; both trials were positive, favoring the addition of ICI to the current standard of care, one as an adjuvant therapy and the other in a neoadjuvant approach. These trials should ushers in a new era in care for patients with resectable NSCLC, but adding a novel class of therapeutic agents to surgical treatment in a disease such as NSCLC comes with some challenges. Patients with lung cancer tend to be older, frailer, and with greater comorbidity than most other patients with solid organ tumors, and there is the added complexity when resecting a vital organ as a part of cancer therapy. Some of the lessons learned from the addition of adjuvant and neoadjuvant cytotoxic chemotherapies 15 years ago can be applied to the incorporation of ICI, but not all concerns translate directly between therapies.

One of the central considerations when combining ICI with NSCLC resections is the order of therapy. Neoadjuvant chemotherapy (with or without radiation) is currently recommended for patients with clinical stage IIIA NSCLC, but an adjuvant approach is the standard of care for patients with resectable stage IB and II diseases. Most trials evaluating ICI in resectable NSCLC combine stages IB, II, and IIIa in a single approach, either adjuvant or neoadjuvant. Although many of the advantages and disadvantages of each approach translate from chemotherapy, there are novel considerations for ICI; the most significant possibly being the importance of having the primary tumor in place for immune cell priming. The presence of the large primary tumor during ICI therapy seems to allow for greater expansion of T-cell clones that target tumor antigens and that this increase in T-cell clonality is dependent on the interaction between the tumor and peripheral blood and is less robust when ICI is given after the tumor is removed. Early analysis of T-cell clonality in patients with NSCLC resected after ICI indicates an association between the expansion of clonal populations and reduced viable tumor at resection.

Neoadjuvant therapies are inherently trickier to integrate in NSCLC resections. They carry greater potential for surgical delays, surgical attrition, disease progression, and perioperative complexity and complications. It seems that far too often the surgical aspects of care may not be considered in the design, conduct, and reporting of neoadjuvant trails. This is a key factor that makes the work from Lee et al. important. The authors outline important thoracic surgical end points that require contemplation with the integration of ICIs into the care of patients with resectable NSCLC. A therapy that effectively eradicates micrometastatic disease but simultaneously increases surgical morbidity and mortality will be challenging to integrate into early stage NSCLC care.

Adjuvant treatment approaches do not disrupt or complicate the process of surgery directly, but they place significant onus on the surgeon to help assure delivery of the recommended adjuvant therapies. Currently, only half of patients with resected NSCLC eligible for adjuvant chemotherapy undergo that therapy. Early evidence from ICI adjuvant trials indicates potential for a greater survival benefit than found with standard cytotoxic chemotherapy, increasing the importance of having resected patients physically and mentally prepared for adjuvant therapy in a timely manner. It is no longer enough for patients to survive lung cancer resections; they now need to recovery quickly and completely and in a time to start adjuvant therapy. It is also essential for surgeons to educate their patients on the potential benefits of adjuvant therapy to increase acceptance and compliance of patients. Furthermore, surgeons need to assure that molecular testing is performed on resected tumors. Appropriate use of ICIs and targeted agents in the adjuvant setting is dependent on tumor-based biomarkers, and this is a new step in the workflow for patients with resected NSCLC.

We are embarking on a new and exciting era for resectable NSCLC, with incredible potential to improve survival. These promising advances will increase the complexity of surgical care, and proper integration will require significant insights and input from the thoracic surgery community.

CRediT Authorship Contribution Statement

Jessica S. Donington: Conceptualization, Investigation, Writing—original draft, Writing—review and editing.