Adjuvant platinum-based chemotherapy for early-stage non–small cell lung cancer (NSCLC) is currently almost an afterthought and is taken for granted as a standard of care for patients with stage II to IIIA NSCLC after resection. The earliest meta-analysis, published in 1995,1 gave the first hint of a survival advantage with platinum-based chemotherapy. However, it was not until the results of the International Adjuvant Lung Trial2 (IALT) were published in 2004 that adjuvant chemotherapy became accepted in practice.
The relatively high recurrence rates for NSCLC compared with other resectable and curable malignancies underscored the importance of achieving an advance, and perhaps the bar did not need to be set high as a first step in the use of multimodality therapy to improve outcomes. The subsequent Lung Adjuvant Cisplatin Evaluation (LACE) meta-analysis of five “modern” adjuvant trials suggested a real but uninspiring absolute survival benefit of 5.4% at 5 years with cisplatin-based regimens, and the greatest benefit was noted in patients with stage II and III disease.3
James P. Stevenson, MD
Impower010 Trial: Real Progress
Although no significant progress was made in building on these results in the years since IALT, immunotherapy directed at the PD-1/PD-L1 axis has forever changed the way we view the treatment of stage IV NSCLC. Thankfully, the results of the IMpower010 trial, reported by Felip et al in The Lancet,4 represent real progress in improving outcomes for patients with early-stage NSCLC.
In this open-label trial of more than 1,000 patients, summarized in this issue of The ASCO Post, the investigators studied the PD-L1 monoclonal antibody atezolizumab for 1 year vs best supportive care following adjuvant platinum-based chemotherapy in patients with stage IB to IIIA NSCLC who underwent resection. The primary efficacy endpoint for the trial was met at a median duration of follow-up for investigator-assessed disease-free survival of 32.8 months in the patients with stage II to IIIA disease who had tumor PD-L1 expression of at least 1% by SP263 assay—the stratified hazard ratio (HR) for disease-free survival was 0.66 (median = not reached vs 35.3 months, P = .0039). The 3-year disease-free survival rate was 60% with atezolizumab vs 48% with best supportive care.
Not surprisingly, the disease-free survival benefit with atezolizumab therapy was most pronounced in those with stage II to IIIA disease who had at least 50% tumor PD-L1 expression (HR = 0.43, 95% confidence interval = 0.27–0.68). A benefit was not clearly seen when patients with stage II to IIIA disease who had tumor PD-L1 expression of less than 1% and stage IB tumors were included in hierarchical testing. Overall survival data were immature at the time of interim analysis. There were no new safety signals with atezolizumab treatment in this patient group.
Trial Findings Prompt Optimism
Based on the trial findings, atezolizumab was granted U.S. Food and Drug Administration (FDA) approval in October 2021 for the adjuvant treatment of patients with stage II to IIIA NSCLC with tumor PD-L1 expression of at least 1%, following resection and platinum-based chemotherapy. Should this news be greeted with caution or applause? Some are nonplussed by the lack of overall survival data, whereas others raise questions regarding the benefit in the tumor PD-L1 1% to 49% subgroup.
Adjuvant therapy discussions in NSCLC have always been nuanced, and now even more so. The approval of osimertinib as adjuvant therapy for patients with stage IB to IIIA disease who have EGFR 19 or 21–mutated NSCLC in December 2020 was similarly based on disease-free survival improvement, although more striking—a hazard ratio of 0.20, with a P value < .0001. Even this landmark approval was greeted with skepticism by some, with overall survival being held up as the gold standard endpoint for adjuvant trials.
Disease-free survival has long been examined, debated, and sometimes accepted by regulatory agencies as an endpoint for adjuvant trials in oncology.5 Approved immunotherapies such as atezolizumab are also highly likely to be a component of first-line therapy should a patient with early-stage NSCLC who has PD-L1–positive tumor relapse following adjuvant chemotherapy, which may ultimately blunt an overall survival effect in IMpower010. However, the “save it for later” argument typically rings hollow as effective drugs are developed in oncology.
Focus on Similarity of Hazard Ratios
Of interest here is the similarity in the hazard ratios for disease-free and overall survival in the five NSCLC adjuvant trials included in the LACE meta-analysis, even with a relatively small absolute magnitude of benefit, and the same likelihood that patients from the control arms in these trials could receive standard platinum-doublet chemotherapy at relapse. More recently, consolidation durvalumab following concurrent chemoradiation for unresectable stage III NSCLC was approved by the FDA based on the progression-free survival benefit shown in the PACIFIC trial; subsequent follow-up reports confirmed clinically meaningful improvement in overall survival with the addition of durvalumab despite more than twice as many patients in the placebo arm receiving immunotherapy at relapse.6,7
Based on these historic precedents, there is ample reason to believe that atezolizumab in the adjuvant setting may show an even greater impact on overall survival than platinum-doublet chemotherapy when applied to a targeted patient population with PD-L1–positive stage II to IIIA disease.
Atezolizumab should now clearly be part of our standard adjuvant therapy discussions with patients who have PD-L1–positive stage II to IIIA NSCLC following surgical resection. Treatment risks and expectations of potential benefit take on greater importance with the addition of newer agents such as immunotherapy or targeted therapy to adjuvant regimens. As always, the goal is for well-informed patients to make the best decision for themselves.
Dr. Stevenson is Vice Chairman, Department of Hematology and Medical Oncology, Cleveland Clinic Taussig Cancer Institute.
DISCLOSURE: Dr. Stevenson has received honoraria from Medtronic and Novartis; has held a consultant and/or advisory role with Novocure, Eli Lilly, Beigene, Boston Pharmaceuticals, and Trizell; and has received institutional research funding from Merck, Amgen, Bristol Myers Squibb, EMD Serono, and Alpha Oncology.
REFERENCES
1. Non-small Cell Lung Cancer Collaborative Group: Chemotherapy in non-small cell lung cancer: A meta-analysis using updated data on individual patients from 52 randomised trials. BMJ 311:899-909, 1995.
2. Arriagada R, Bergman B, Dunant A, et al; International Adjuvant Lung Cancer Trial Collaborative Group: Cisplatin-based adjuvant chemotherapy in patients with completely resected non-small cell lung cancer. N Engl J Med 350:351-360, 2004.
3. Pignon JP, Tribodet H, Scagliotti GV, et al: Lung adjuvant cisplatin evaluation: A pooled analysis by the LACE Collaborative Group. J Clin Oncol 26:3552-3559, 2008.
4. Felip E, Altorki N, Zhou C, et al: Adjuvant atezolizumab after adjuvant chemotherapy in resected stage IB-IIIA non-small-cell lung cancer (IMpower010): A randomised, multicentre, open-label, phase 3 trial. Lancet 398:1344-1357, 2021.
5. Gill S, Sargent D: End points for adjuvant therapy trials: Has the time come to accept disease-free survival as a surrogate end point for overall survival? Oncologist 11:624-629, 2006.
6. Antonia SJ, Villegas A, Daniel D, et al: Durvalumab after chemoradiotherapy in stage III non-small cell lung cancer. N Engl J Med 377:1919-1929, 2017.
7. Faivre-Finn C, Vicente D, Kurata T, et al: Four-year survival with durvalumab after chemoradiotherapy in stage III NSCLC: An update from the PACIFIC trial. J Thorac Oncol 16:856-867, 2021.
