Clinical Implications of Advances in Resectable NSCLC

Positive trial results and US Food and Drug Administration (FDA) approvals have changed the standard of care for patients with resectable early-stage non-small cell lung cancer (NSCLC). New targeted therapies and immunotherapies previously confined to patients with advanced NSCLC are now administered in the perioperative setting.

“Developments in resectable NSCLC have arrived so rapidly that they have also created practical challenges of identifying optimal patients and prioritizing options among these new competing standards. In some cases, practical management requires clinical judgement and discussion with the patient to cover the gaps in prospective data. Caution should be exerted when extrapolating beyond the available data,” said Howard West, MD, MPhil, and Jae Kim, MD, in a review article published in JAMA Oncology [2024;10(2):249-255].

In the article, the authors looked at high-profile clinical trials and FDA approvals for resectable early-stage NSCLC and how they may refine clinicians’ approaches to treating this patient population.

Results from the ADAURA trial demonstrated statistically and clinically significant improvement in efficacy with targeted therapy for adjuvant osimertinib in patients with resected NSCLC harboring an epidermal growth factor receptor (EGFR) genomic abnormality. Treatment with adjuvant osimertinib for 3 years in patients with resectable stage IB to IIIA nonsquamous NSCLC harboring an exon 19 deletion or L858R substitution mutation in EGFR-positive NSCLC was associated with significant improvement in both disease-free survival (DFS) and overall survival (OS). Given the pattern of DFS benefit eroding after treatment duration, the optimal period of adjuvant osimertinib remains undefined by the ADAURA trial results. The current FDA label does not indicate a duration of treatment for adjuvant osimertinib. Additionally, adoption of adjuvant osimertinib requires molecular testing.

“Thoughtful oncologists will need to carefully consider the patient population that has been studied in the trial, the role for adjuvant chemotherapy prior to osimertinib, and whether the findings should lead us to extrapolate that a longer duration of therapy is the optimal strategy,” said the researchers. “Moreover, the need for molecular testing introduces questions of limited testing for EGFR or whether broader testing is more appropriate; if the latter, questions arise about whether the principles of osimertinib for EGFR mutation-positive NSCLC should be applied to other molecularly defined subgroups, without data to address them.”

The researchers also looked at immunotherapy in the adjuvant setting. Adjuvant atezolizumab or pembrolizumab, generally administered 1 year after postoperative chemotherapy, are appropriate considerations. Updated findings from the IMpower010 trial that evaluated the PD-L1 atezolizumab versus observation alone in patients with resected stage IB to IIIA NSCLC following platinum-based chemotherapy showed OS improvement limited to patients with tumor PD-L1 levels of 50% or higher. The results of the KEYNOTE-091/PEARLS trial provided further data on the potential use of the immune checkpoint inhibitor pembrolizumab as adjuvant therapy after resection of early-stage NSCLC. The findings showed an improvement in DFS, with preliminary OS results demonstrating a relatively modest and nonsignificant improvement in OS thus far.

“The language of the FDA labels for adjuvant atezolizumab and pembrolizumab creates ambiguity in terms of how to reconcile the study populations compared with populations included in their respective clinical trials,” noted the researchers.” It is likely that most prescribers will assume that the label indications refer to the staging system in use at the time of FDA approval.”

Neoadjuvant chemotherapy with nivolumab in the CheckMate 816 trial demonstrated a significant improvement in the rate of pathologic complete response with chemotherapy/nivolumab versus chemotherapy alone in patients with resectable IB to IIIA NSCLC, correlating to a significant improvement in event-free survival. According to the researchers, neoadjuvant chemotherapy with nivolumab has been widely adopted as a compelling option for eligible patients because it offers a shorter interval of treatment, high rate of deliverability, and in vivo feedback on the efficacy of the systemic therapy regimen. Because the CheckMate 816 trial left the decision of postoperative therapy to the investigator’s discretion, decisions about whether to pursue adjuvant therapy after neoadjuvant chemoimmunotherapy continue to be based on clinical judgement and shared decision-making with the patient.

The researchers also noted that recent randomized, clinical trials of perioperative immunotherapy, both combined with chemotherapy preoperatively and administered postoperatively, highlight the debatable value of adjuvant immunotherapy after prior chemoimmunotherapy.

The potential for neoadjuvant chemoimmunotherapy to shrink tumors and reduce the extent of surgery has led to research evaluating the possibility of extending the outer limits of resectability. However, the authors raised two leading issues defining the limits of resectability. The first issue is the practical challenge of an R0 resection in which there is no evidence of residual gross disease visible, nor microscopic viable cancer at the surgical margin. There is also the question of whether to pursue resection or a nonsurgical approach that extends beyond whether an R0 resection can be achieved. “While this work provides a valuable proof of principle, we urge caution in applying results obtained from research centers more broadly,” the researchers said.

“Newly FDA-approved options for neoadjuvant or adjuvant immunotherapy, generally combined concurrently or sequentially with platinum-based chemotherapy, have changed our standards of care for patients whose cancer does not harbor an EGFR mutation,” the authors concluded. “The rapidly growing number of currently available positive trial results offers multiple options; most of these trials also have yet to read out on long-term OS as a critical variable. Oncologists are left with room for judgment about which patients are strong candidates for which agent, when, and for how long.”