Neoadjuvant treatment with single-agent atezolizumab for patients with stage IB to IIIB lung cancer resulted in a major pathologic response rate of 21% and pathologic complete response rate of 7% in the primary analysis of the Lung Cancer Mutation Consortium 3 (LCMC3) study. The findings were presented at by Jay M. Lee, MD, Chief of the Division of Thoracic Surgery at Ronald Reagan UCLA Medical Center, Los Angeles, at the International Association for the Study of Lung Cancer (IASLC) 2020 World Conference on Lung Cancer (WCLC) Singapore, which was moved to a virtual format and held January 28–31, 2021, in light of the COVID-19 pandemic (Abstract PS01.05).

“The LCMC3 study successfully met its primary endpoint of achieving 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%),” said Dr. Lee at a press briefing.

“The LCMC3 study successfully met its primary endpoint of achieving major pathologic response. 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—and with a correspondingly high complete resection rate.”

— Jay M. Lee, MD

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The LCMC3 study is the largest monotherapy trial of checkpoint inhibition in resectable NSCLC and is “a landmark study” that validated results from smaller trials—and can serve as a benchmark for future ones, explained Dr. Lee.

Smaller phase II studies have previously evaluated regimens consisting of a checkpoint inhibitor plus chemotherapy, and major pathologic response rates have been higher, he acknowledged. Whether combination therapy can be tolerated by the average patient with NSCLC is questionable, and single-agent neoadjuvant therapy could be preferred in many instances, he said.

Study Meets Primary Endpoint

In the LCMC3 trial, 181 patients with stage IB–IIIB NSCLC and no targetable mutations received 1,200 mg of neoadjuvant atezolizumab for two cycles and underwent surgical resection between 30 and 50 days from the first cycle. Patients who benefitted from the therapy could continue adjuvant atezolizumab for 12 months. The primary endpoint was major pathologic response, defined as ≤ 10% viable tumor cells at surgery.  Surgery was performed on 159 patients, and 144 were included in the efficacy analysis.

Treatment with atezolizumab was followed by tumor downstaging in 66 patients (43%) and upstaging in 29 patients (19%). Some degree of pathologic regression was observed in all but 3 of 159 patients who underwent resection. In the 144 patients included in the efficacy analysis, the major pathologic response rate was 21%, with 7% of patients achieving a complete pathologic response, Dr. Lee reported.

In an exploratory analysis of efficacy outcomes, at 1.5 years, disease-free survival was 79% for stage I/II patients and 77% for stage III patients (P = .88); overall survival was 91% and 87%, respectively (P = .45; P values are descriptive only.)

“While there are limitations to comparing outcomes to historical populations, at both time points, there is a suggestion that neoadjuvant atezolizumab has a survival advantage compared to historical information (ie, the IASLC expectant survival by stage III),” he said.  

Surgical Timing and Details

All but 19 patients (12%) had surgery within the protocol-specified window of 30 to 50 days after completing neoadjuvant therapy, meaning that 88% of patients underwent surgical resection “within that tight 20-day protocol window,” said Dr. Lee. Median time from end of neoadjuvant therapy to surgery was 22 days.

Dr. Lee pointed out that such efficiency stands in contrast to a number of other neoadjuvant trials, where surgery is performed much later.

“Surgical resection was performed with a minimally invasive approach (robotic or video-assisted thoracoscopic surgery [VATS]) …[which] was appropriate in the majority of patients,” he reported. “Remarkably, only 15% required conversion from a minimally invasive approach to open thoracotomy.”

The majority of patients (98%) underwent anatomic oncologic resection, of which 79% had lobectomy. R0 (clear surgical margins) status was achieved in 92%, which he noted was “comparable, if not superior to, preoperative chemotherapy trials.”

This is good news for surgeons “whose obvious concern is whether neoadjuvant therapy changes the conduct of surgery itself,” he added. 

Intraoperative complications and postoperative deaths were rare. 

“The study provides additional clinical evidence for the ongoing placebo-controlled phase III IMpower030 study of atezolizumab combined with platinum-based chemotherapy,” concluded Dr. Lee.

Disclosure: For full disclosures of the study authors, visit wclc2020.iaslc.org/disclosures.