David J. Kwiatkowski, MD, PhD
Neoadjuvant immunotherapy demonstrated substantial activity with a favorable toxicity profile in findings from 2 studies of patients with operable early-stage non–small cell lung cancer (NSCLC) reported at the 2019 ASCO Annual Meeting. The promising strategy is already being tested in larger phase III trials.
Investigators reported that the PD-L1 inhibitor atezolizumab (Tecentriq) induced a major pathological response (MPR) in 19% of patients and a pathologic complete response (pCR) in 5% of patients in the primary efficacy population who went on to complete surgical resection in the Lung Cancer Mutation Consortium (LCMC3) study.1
In the NEOSTAR study, investigators said the combined MPR and pCR rates in the intention-to-treat (ITT) population were 17% among patients who received nivolumab (Opdivo) and 33% in those who took the PD-1 inhibitor plus the CTLA-4 inhibitor ipilimumab (Yervoy).2
Several pilot studies have demonstrated that preoperative immune checkpoint immunotherapy may be effective in early-stage NSCLC, David J. Kwiatkowski, MD, PhD, lead author of the LCMC3 study who is a senior physician at Dana-Farber/Brigham and Women's Cancer Center, said in presenting the LCMC3 data. "Immune checkpoint therapy is included as a standard of care for patients with advanced (metastatic) lung cancer, and this study suggests that it may also have benefit in early-stage, operable lung cancer," he said in a press release.
More than 50% of patients with stage I to III resectable NSCLC relapse and perioperative chemotherapy has been associated with an absolute 5-year overall survival benefit of only 5% versus surgery alone, noted Tina Cascone, MD, PhD, lead author of the NEOSTAR study, during her presentation. Cascone is an assistant professor in the Department of Thoracic Head and Neck Medical Oncology at The University of Texas MD Anderson Cancer Center.
The advantages of administering immune checkpoint inhibitor therapies in the neoadjuvant setting include an opportunity to address micrometastases earlier in the disease process, the potential for increasing patient compliance with systemic therapy, and the use of pCR as an early surrogate for overall survival, according to Maximilian Diehn, MD, PhD, who served as a discussant during the session where the 2 abstracts were presented.3
Nevertheless, there are disadvantages, including a risk of progression prior to surgery, the potential for increased surgical complications, and the danger of overtreatment, said Diehn, an associate professor of radiation oncology at Stanford University in California.
He said additional research is needed to identify the clinical utility of neoadjuvant immunotherapy, including the identification of biomarkers to personalize treatment. He also said that MPR has not been accepted as a validated surrogate for survival in drug registration trials.
Additionally, Diehn said that although the 2 studies presented at the 2019 ASCO Annual Meeting show an impact for neoadjuvant MPR, the rates have been higher in other small trials that have combined immune checkpoint immunotherapy with chemotherapy in this population. He said several ongoing phase III clinical trials testing immunotherapy in this setting include an arm in which checkpoint blockade agents are combined with chemotherapy.LCMC3 Study Findings
In the ongoing phase II LCMC3 study (NCT02927301), investigators are seeking to recruit 180 patients with stage IB to IIIB NSCLC, including those with T3N2 or T4 tumors by size criteria. Participants receive 2 cycles of atezolizumab prior to surgery and are eligible to receive up to 12 months of the PD-L1 inhibitor postoperatively. The primary endpoint of the study is MPR, defined as ≤10% viable tumor cells at surgical resection.
In all, 101 patients were enrolled in the study as of the September 2018 data cutoff for the interim efficacy analysis. The participants were a median age of 65 years (range, 37-83) and were diagnosed with stage IB (11%), IIA (16%), IIB (28%), IIIA (39%), and IIIB (7%) disease.
Of this group, 95% completed 2 cycles of atezolizumab and 5% had 1 cycle. Ninety patients (89%) were candidates for surgery; of these, 84 patients (83%) completed surgical resection and underwent MPR assessment. Patients who had either progressive disease and did not receive surgery or were unresectable had stage IIIA or IIIB disease, whereas those with stage I and II disease were able to undergo surgical resection, Kwiatkowski noted.