Response and Resection Rates Following Neoadjuvant Atezolizumab Impress in Resectable NSCLC

Jay M. Lee, MD

Neoadjuvant atezolizumab (Tecentriq) followed by surgery led to a major pathologic response (MPR) in 21% of patients with resectable stage IB-IIIB non–small cell lung cancer (NSCLC), according to findings from the primary analysis of the LCMC3 trial (NCT02927301).¹ This neoadjuvant approach also led to significant surgical outcomes, including a high rate of R0 resection.

Primary findings from the open-label, multicenter, single-arm phase 2 study were presented in a press briefing during the International Association for the Study of Lung Cancer’s 2020 World Conference on Lung Cancer (WCLC) Singapore.

A total of 181 patients with resectable, untreated, unselected, stage IB-IIIB NSCLC were enrolled. Select patients with stage IIIB NSCLC, those with T3N2 or T4, were also included, although those with T4 disease due to mediastinal organ invasion were excluded.

Patients were given 2 cycles of atezolizumab at 1200 mg on days 1 and 22 followed by surgical resection on day 40 (±10 days) and were allowed to receive adjuvant atezolizumab or stage-appropriate therapy chosen by the investigator for up to 12 months along with surveillance. Tumor biopsy, as well as biospecimen collection, was conducted prior to treatment and after surgery.

Jay M. Lee, MD, chief, Division of Thoracic Surgery at Ronald Reagan UCLA Medical Center in Los Angeles, California, noted during the briefing that LCMC3 is the largest immune checkpoint inhibition monotherapy trial to date in patients with resectable NSCLC.

The primary end point of the study was MPR, defined as ≤10% visible tumor cells, and secondary end points included pathological response by PD-L1 and radiographic response by PD-L1, tumor mutational burden, and neoantigen gene expression profiling, and safety. Exploratory end points consisted of disease-free survival (DFS), overall survival (OS), and biomarker analyses.

Earlier findings from an interim analysis of the study, which included the first 101 patients, showed an MPR rate of 18% (95% CI, 11%-28%) in 82 evaluable patients and a pathological complete response (pCR) rate of 4.9%.2 By RECIST criteria, 6 patients had a partial response (7.3%), 72 had stable disease (87.8%), and 4 had progressive disease (4.9%).

Neoadjuvant atezolizumab was well tolerated with grade 3/4 treatment-related adverse events in 6% of patients and 2 grade 5 adverse events of cardiac death and disease progression that were considered unrelated to treatment.

In the primary analysis,1 the primary end point was met with the MPR rate of 21% and the pCR rate was 7%.

Forty-three percent of patients were downstaged following neoadjuvant treatment with atezolizumab and 19% were upstaged.

At 1 year, the DFS rate was 85% both in patients with stage I/II (n = 81) and stage III (n = 75) disease; at 1.5 years, the rates were 79% and 77% in the stage I/II and stage III groups, respectively (P = .88). The median follow-up for OS was 2.1 years. OS rates at 1 year were 92% in patients with stage I/II disease and 95% in those with stage III disease. At 1.5 years, the OS rates were 91% and 87% in patients with stage I/II and stage III disease, respectively (P = .45).

These OS rates compared favorable with historical OS outcomes, suggesting there may be an OS advantage with neoadjuvant atezolizumab, Lee said.

No new safety signals were observed with neoadjuvant atezolizumab.

Surgical Outcomes

Patients received the first dose of atezolizumab a median of 15 days (range, 1-82) after enrollment, and surgery was planned within a window of 30 to 50 days after initiating treatment. Eighty-eight percent of patients were able to undergo surgery within the protocol window, with 3 patients undergoing surgery only 8 days after the second cycle of atezolizumab. The median time from the end of cycle 2 (day 22) to surgery was 22 days (range, 11-74). 

The median time outside of the window for the other 12% of patients was 8 days (range, 1-45). The reason for undergoing surgery outside of the protocol window was treatment related for 4 patients, due to other medical reasons for 6 patients, and for logistical reasons from the patient or surgeon for 9 patients.

“Our study distinguishes itself from historical and neoadjuvant chemotherapy trials in that surgery was performed within a tight protocol window, and surgery was allowed a lot earlier from the completion of neoadjuvant atezolizumab,” Lee explained.

Comparatively, most neoadjuvant chemotherapy trials offered surgery as early as 14 days after neoadjuvant therapy through as late as 56 days after the completion of treatment. 

“More than half the patients underwent resection, with a minimally invasive approach utilizing advanced or robotic operation. And remarkably, only 15% of patients required conversion to thoracotomy,” Lee said.

Thirty-seven percent of patients received a robotic-assisted surgical approach and 17% had video-assisted thoracoscopic surgery while 46% ultimately underwent thoracotomy. The majority of patients (79%) received a lobectomy, 2% had a wedge resection, 1% had a segmentectomy, 6% had bilobectomy, and 9% had pneumonectomy. Five patients did not have any resection.

R0 surgical margins were achieved in 92% of patients, R1 in 4%, and R2 in 4%. “[These] findings are at least comparable, if not superior, to historical neoadjuvant chemotherapy [trials],” Lee commented.

Intraoperative complications were rare in the LCMC3 trial, and all complications were successfully repaired. One patient had a bronchial complication and 4 had vascular complications. The length of hospital stay was 7.5 days (range, 2-68). Two deaths were observed following surgery, 1 within 30 days of the procedure due to a sudden death that was considered unrelated to treatment and 1 within 2.5 months of the surgery due to pneumonitis that was possibly related to atezolizumab therapy.

These rates were comparable to historical findings with neoadjuvant cisplatin-based chemotherapy, and Lee said that the mortality rate was, in fact, superior to historical outcomes.

Lee noted that the LCMC3 trial provides further clinical evidence for the ongoing placebo-controlled phase 3 IMpower030 trial (NCT03456063) of neoadjuvant atezolizumab in combination with platinum-based chemotherapy in patients with resectable stage II, IIIA, or select IIIB NSCLC followed by adjuvant atezolizumab or best supportive care.

_References

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. Presented at: 2020 World Conference on Lung Cancer Singapore; January 28-31; Virtual. Abstract 3195.}

2. _{Kwiatkowski DJ, Rusch VW, Chaft JE, et al. Neoadjuvant atezolizumab in resectable non-small cell lung cancer (NSCLC): interim analysis and biomarker data from a multicenter study (LCMC3). J Clin Oncol. 2019;37(suppl 15):8503. doi:10.1200/JCO.2019.37.15_suppl.8503}