Standard of Care Curative Treatments for Early-Stage NSCLC

Sanjay Popat, FRCP, PhD Royal Marsden Hospital | Rahul Gosain, MD, MBA Wilmot Cancer Institute | Rohit Gosain, MD Roswell Park Comprehensive Cancer Center

Key Points

• When treating early-stage non-small cell lung cancer (NSCLC) with curative intent, next-generation sequencing (NGS) is essential to identify actionable mutations and guide use of immunotherapy or targeted agents.

• For patients with resectable disease, neoadjuvant chemotherapy plus perioperative immunotherapy regimens are standard of care, although the adjuvant immunotherapy component is debated.

• Targeted therapies are approved for patients with EGFR or ALK alterations, and targeted agents against other alterations may be feasible in certain patients.

• For patients with unresectable NSCLC, chemoradiation followed by either immunotherapy or targeted therapy is the standard of care curative treatment.

Standard of Care Curative Treatments for Early-Stage NSCLC 

Cohosts of the Oncology Brothers podcast, Rahul Gosain, MD, MBA, of Wilmot Cancer Institute, and Rohit Gosain, MD, of Roswell Park Comprehensive Cancer Center, discussed the standard of care curative treatments for early-stage NSCLC with Sanjay Popat, FRCP, PhD, a thoracic medical oncologist at the Royal Marsden Hospital. The doctors emphasized the importance of NGS, reviewed standard of care strategies for resectable and unresectable early-stage NSCLC, and considered ongoing debates around the role of immunotherapy and targeted therapy agents.

Resectable NSCLC Without Actionable Mutations

For stage IA NSCLC, the standard is surgery or stereotactic body radiation therapy. For resectable NSCLC from stage IB to IIIB without actionable mutations, the standard curative approach is neoadjuvant platinum-based chemotherapy plus perioperative immunotherapy. Approved immunotherapies include nivolumab, pembrolizumab, and durvalumab based on the CheckMate 816, KEYNOTE-671, and AEGEAN trials, respectively. 

Notably, the necessity of the adjuvant portion of immunotherapy is debated. For patients with a pathologic complete response (pCR) after surgery, adjuvant immunotherapy may not provide any additional benefit. Conversely, for patients without a pCR, the lack of response to neoadjuvant immunotherapy may suggest further adjuvant immunotherapy would not be effective. Trials are ongoing to better define the role of adjuvant immunotherapy. However, in the interim, the treatment approach should be a shared decision between physician and patient that considers financial burden, logistics, toxicity, and patient motivation, said Dr. Popat. 

Resectable NSCLC With Actionable Mutations

The standard treatment algorithm for resectable early-stage NSCLC with actionable mutations is surgery followed by adjuvant platinum-based chemotherapy followed by targeted therapy. Alectinib is approved for ALK fusion–positive NSCLC based on the ALINA trial, and osimertinib is approved for EGFR–mutated NSCLC based on the ADAURA trial. ADAURA data suggest that patients with stage IB may be able to skip adjuvant chemotherapy and directly start osimertinib, but for other EGFR–mutated patients and ALK fusion–positive patients, Dr. Popat prefers to start with adjuvant chemotherapy before moving on to the tyrosine kinase inhibitor. 

During the discussion, the doctors considered whether this adjuvant treatment paradigm could be extrapolated for other targeted therapies against HER2, MET, RET, or ROS1 alterations. For patients who are RET–positive, Dr. Popat said data will soon be presented for adjuvant selpercatinib that show a “massive” progression-free survival advantage, which will likely establish adjuvant targeted therapy as standard of care. Separately, trials are slowly enrolling for ROS1-directed agents, which are promising given the positive data for therapies against ALK, EGFR, and RET. Comparatively, MET inhibitors are associated with challenging toxicities, and Dr. Popat has not rushed to incorporate them in his practice.

Curative Treatment Algorithm for Unresectable NSCLC

For stage III unresectable NSCLC the standard of care is concurrent chemoradiation. For patients with PD-L1–positive disease without actionable mutations, this is followed by durvalumab based on the PACIFIC trial. For patients with EGFR–mutated disease, indefinite osimertinib was approved based on the LAURA trial. While randomized data for other actionable targets are not available, retrospective data strongly support alectinib in patients with ALK–positive disease, said Dr. Popat. Similar to the resectable treatment algorithm, it may be reasonable to use targeted therapies in patients with RET or ROS1 alterations, although MET or BRAF inhibitors may have too much toxicity. 

Overall, while there are several unanswered questions regarding the roles of immunotherapy and targeted agents, treatment options with curative intent are expanding for patients with early-stage NSCLC, and detailed metastatic NSCLC treatment algorithms exist for patients who experience progressive disease.