The best way to treat resectable non-small cell lung cancer (NSCLC) is debatable-either neoadjuvant or adjuvant therapy. Two top lung cancer experts went head-to-head to make the case for these treatments at the 2022 Great Debates & Updates in Lung Cancers.
Neoadjuvant Therapy
"Neoadjuvant therapy is certainly superior to adjuvant therapy in resectable NSCLC," said Jamie Chaft, MD, Medical Oncologist at Memorial Sloan Kettering Cancer Center. She began her defense of this statement by presenting data from a meta-analysis of preoperative chemotherapy for patients with resectable NSCLC that examined 15 randomized controlled trials including 2,385 patients.
"The results showed a significant benefit in overall survival (OS), with a 13 percent reduction in the relative risk of death, and no evidence of a difference between trials. The trial curves look identical," Chaft noted.
The randomized Phase III NATCH trial had three arms: 1) preoperative chemotherapy (paclitaxel/cisplatin) and surgery, 2) surgery alone, and 3) surgery and postoperative chemotherapy. The trial demonstrated no difference in disease-free survival (DFS) between the groups. "The NATCH trial showed a greater compliance and lesser toxicity with preoperative therapy, and an equivalent benefit of preoperative versus postoperative therapy," Chaft stated. "We see unbelievable signals of efficacy with the neoadjuvant platinum-taxane immunotherapy combination following surgery."
The Phase III CheckMate 816 is the first of many trials to combine neoadjuvant chemotherapy plus or minus nivolumab. In this open-label trial, researchers randomly assigned patients with Stage IB-IIIA resectable NSCLC to receive nivolumab plus platinum-based chemotherapy or platinum-based chemotherapy alone, followed by resection.
The pathologic complete response rate showed significant improvement with neoadjuvant therapy (24%) compared to chemotherapy alone (2.2%). The median event-free survival (EFS) was 31.6 months with nivolumab plus chemotherapy and 20.8 months with chemotherapy alone. The majority of a subset of patients also showed an EFS benefit, Chaft said, and those who took carboplatin did very well.
"With neoadjuvant therapy, we get more complete resection, fewer pneumonectomies, and can shrink the tumor and as consequence save lung tissue. I recommend neoadjuvant therapy because it is better tolerated; predictive biomarker data can be obtained pre-treatment; immunotherapy may be more effective with the tumor in situ; there's a chance for a lesser lung resection; it requires 3 cycles versus 1 year or more of therapy; and pathologic data can guide postoperative prognosis and possibly further therapy."
Adjuvant Therapy
Taking the opposing view touting adjuvant therapy, Joel W. Neal, MD, PhD, Thoracic Medical Oncologist at Stanford University Medical Center, asked a series of questions about the cons of neoadjuvant therapy.
"Will the thoracic surgeon and the patient want to wait on definitive resection for a chance of shrinking the tumor? When we give neoadjuvant therapy, we rarely save lung parenchyma," he noted. "What is the EGFR/ALK molecular status? It may take 2 weeks or more to get molecular results from the time of biopsy, which means more waiting."
He also asked: "What is the actual pathologic stage of the tumor? Downstaging pathologic complete response with neoadjuvant therapy is a good prognostic factor, but were there actually nodes initially? What if there was incidental N2 or N3 disease?"
To make the decision to use chemotherapy plus immunotherapy, Neal suggested, "if the tumor is ALK-positive or EGFR-positive, you may use an off-label tyrosine kinase inhibitor or set up the patient for surgery. We don't really know whether there is nodal involvement or not, and may need more staging."
He cited data from Phase III adjuvant IMpower010 trial that showed a statistically significant DFS benefit with adjuvant atezolizumab compared with best supportive care in patients with resected NSCLC following platinum-based chemotherapy. Based on these findings, atezolizumab was approved as adjuvant treatment after complete resection and platinum-based chemotherapy in patients with PD-L1 >=1 percent Stage II-IIIA NSCLC in the United States.
"DFS was significantly improved in the PD-L1 1 percent or higher Stage II-IIIa population," Neal said. "The clearest benefit was in Stage III disease-the patients with the highest risk of recurrence in the next 5 years," he said.
At the recent 2022 World Conference on Lung Cancer, new data from the IMpower010 trial showed patients treated with atezolizumab had a trend toward OS benefit, particularly among those who had high PD-L1 expression. Neal noted that in the CheckMate 816 trial no adjuvant therapy was provided after neoadjuvant therapy.
"The EFS benefit was significant, but we are still waiting for OS data. There was more benefit in PD-L1 higher tumors, clinically Stage IIIA (over IB plus II) disease, and possibly using carboplatin versus cisplatin," he said.
Moving to another trial, Neal cited a newly released planned interim analysis of the AEGEAN Phase III trial in resectable NSCLC. Durvalumab in combination with neoadjuvant chemotherapy before surgery demonstrated a statistically significant and meaningful improvement in pathologic complete response compared to neoadjuvant chemotherapy alone. A statistically significant improvement in major pathologic response was also observed. The trial will continue as planned to assess the additional primary endpoint of EFS.
In conclusion, Neal noted that "the way of the future may be to select patients by minimal residual disease as a stratification and surveillance tool."
Mark L. Fuerst is a contributing writer.