Neoadjuvant treatment with single-agent atezolizumab in patients with stage IB to IIIB lung cancer resulted in a major pathologic response rate of 21% and a pathologic complete response rate of 7%, in the primary analysis of the Lung Cancer Mutation Consortium 3 (LCMC3) study.1 The findings were presented at the International Association for the Study of Lung Cancer (IASLC) 2020 World Conference on Lung Cancer Singapore by Jay M. Lee, MD, Chief of the Division of Thoracic Surgery at Ronald Reagan UCLA Medical Center, Los Angeles. The meeting was held in a virtual format in January 2021.
“The LCMC3 study successfully met its primary endpoint of achieving a major pathologic response (21%). Neoadjuvant atezolizumab monotherapy was well tolerated, and resection was performed with low perioperative morbidity and mortality—usually within a narrow protocol window and with a short time frame from completion of atezolizumab (median 22 days)—and with a correspondingly high complete resection (R0) rate (92%),” Dr. Lee said at a press briefing.
The LCMC3 study is the largest monotherapy trial of checkpoint inhibition in resectable NSCLC, validating results from smaller studies and serving as a benchmark for future ones.— Jay M. Lee, MD
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Approximately 90% of patients with resectable non–small cell lung cancer (NSCLC) were alive at 18 months, and 80% remained alive and disease free, according to an exploratory analysis.
The LCMC3 study is the largest monotherapy trial of checkpoint inhibition in resectable NSCLC and is “a landmark study,” validating results from smaller studies and serving as a benchmark for future ones, according to Dr. Lee.
Smaller phase II studies of checkpoint inhibition plus chemotherapy have shown higher rates of major or complete pathologic response, he acknowledged. However, whether combination therapy can be tolerated by most patients with NSCLC is questionable, and single-agent neoadjuvant therapy may be preferable in elderly and poor-performance patients, Dr. Lee said during a press briefing.
In the LCMC3 trial, 181 patients with stage IB to IIIB NSCLC and no targetable mutations received 1,200 mg of neoadjuvant atezolizumab for two cycles, followed by resection 30 to 50 days from the first cycle. Patients who benefited from the therapy could continue adjuvant atezolizumab for 12 months. The primary endpoint was major pathologic response, defined as up to 10% viable tumor cells at surgery.
Stage IIIA disease accounted for 40% of the study population and stage IIIB, for 9%. Assessment of PD-L1 showed that 55% of patients had less than 1% expression or unknown status. The median age of patients was 65.
Study Meets Primary Endpoint
Surgery was not performed on 22 patients, primarily because of progressive disease or physician decision; another 15 were excluded because EGFR or ALK mutations were identified postoperatively. The final surgical population included 159 patients; 155 had posttreatment pathologic stage evaluations; and 144 patients were included in the efficacy analysis.
After treatment with atezolizumab, 43% of patients had their disease downstaged, and 19% had their disease upstaged. Some degree of pathologic regression was observed in all but 3 of 159 patients who underwent resection. In the 144 patients in the efficacy analysis, the major pathologic response rate was 21%, with 7% of patients achieving a complete pathologic response, Dr. Lee reported.
Exploratory endpoints of disease-free and overall survival by stage “were both favorable,” he noted. The 1-year disease-free survival was 85% for patients with stage I or II disease and 85% for those with stage III disease; overall survival rates were 92% and 95%, respectively. At 1.5 years, these figures were 79% and 77%, and 91% and 87%, respectively.
“Although there are limitations to comparing outcomes with historical populations, at both time points, there is a suggestion that neoadjuvant atezolizumab has an overall survival advantage,” stated Dr. Lee, who showed a slide with the IASLC expectant survival by stage.2
A total of 88% of patients underwent surgery on study days 30 to 50 after starting neoadjuvant therapy, Dr. Lee reported. The median time from the end of neoadjuvant therapy to surgery was 22 days.
Such efficiency stands in contrast to a number of other neoadjuvant trials, according to Dr. Lee. “In LCMC3, patients were allowed to undergo surgery as early as 8 days after completion of atezolizumab. Comparatively, in neoadjuvant chemotherapy trials, most are allowed to have surgery only after 21 days or later,” he noted. “Our window for resection is a tight 20-day window and ends 28 days from the completion of cycle 2. Comparatively, in neoadjuvant chemotherapy trials, the window is often wider and longer, up to 56 days in SWOG 9900.” 3
“Surgical resection was performed with a minimally invasive approach (robotic or video-assisted thoracoscopic surgery) in the majority of patients. Remarkably, just 15% required conversion from a minimally invasive approach to open thoracotomy,” Dr. Lee further reported.
The majority (95%) underwent anatomic oncologic resection, mostly lobectomy (79%). R0 (clear surgical margins) status was achieved in 92%. “This is comparable, if not superior to, preoperative chemotherapy trials,” he said. It is good news for surgeons whose concern is whether neoadjuvant therapy changes the conduct of surgery itself, Dr. Lee added.
Intraoperative complications were rare; they included one bronchial complication and four vascular complications, all of which were successfully repaired in the same operation. One patient died by 30 days (sudden death), and another patient died between 30 and 90 days (pneumonitis). Most instances of immune-related adverse events occurred in less than 10%. The median hospital stay was 7.5 days.
“The study provides additional clinical evidence for the ongoing placebo-controlled phase III IMpower030 study of atezolizumab combined with platinum-based chemotherapy,” Dr. Lee said.
DISCLOSURE: Dr. Lee has served as a consultant or advisor to AstraZeneca, Bristol Myers Squibb, Genentech/Roche, and Novartis; has received research funding from Merck; and has been reimbursed for travel, accommodations, or other expenses by Genentech/Roche.
1. Lee JM, Chaft J, Nicholas A, et al: Surgical and clinical outcomes with neoadjuvant atezolizumab in resectable stage IB–IIIB NSCLC: LCMC3 trial primary analysis. 2020 World Conference on Lung Cancer. Abstract PS02.05. Presented January 30, 2021.
2. Chansky K, Detterbeck FC, Nicholson AG, et al: The IASLC Lung Cancer Staging Project: External validation of the revision of the TNM stage groupings in the eighth edition of the TNM Classification of Lung Cancer. J Thorac Oncol 12:1109-1121, 2017.
3. Pisters KMW, Vallières E, Crowley JJ, et al: Surgery with or without preoperative paclitaxel and carboplatin in early-stage non-small-cell lung cancer: Southwest Oncology Group Trial S9900, an intergroup, randomized, phase III trial. J Clin Oncol 28:1843-1849, 2010.
The ASCO Post reached out to Roy S. Herbst, MD, PhD, FACP, FASCO, Chief of Medical Oncology and Associate Cancer Center Director for Translational Research at Yale Cancer Center and Smilow Cancer Hospital, New Haven, for his thoughts on the LCMC3 trial of neoadjuvant atezolizumab.1 Dr. Herbst led...