Neoadjuvant Atezolizumab Demonstrates Effectiveness in Resectable NSCLC

Findings of the phase 2 LCMC3 trial of atezolizumab in untreated, resectable, stage IB–IIIB non–small cell lung cancer show anti-PD-L1 monotherapy to be effective in this patient population.

Neoadjuvant treatment with single-agent atezolizumab (Tecentriq) led to a 20% major pathological response (MPR) rate in patients with stage IB–III non–small cell lung cancer (NSCLC) and demonstrated encouraging survival with no new safety signals.1

Findings come from the phase 2 LCMC3 trial (NCT02927301) of atezolizumab in patients with untreated, resectable, stage IB–IIIB NSCLC. The results of the trial were published in Nature Medicine and confirm that anti-PD-L1 monotherapy is effective in this patient population.

“This phase 2 LCMC3 study of neoadjuvant atezolizumab, the largest study of preoperative checkpoint inhibitor monotherapy in early-stage NSCLC to date, met its primary end point with an MPR rate of 20% (6% pCR) in primary tumors from patients with resectable stage IB–IIIB NSCLC. Neoadjuvant atezolizumab was well tolerated, with a low incidence of treatment-related grade ≥3 AEs,” wrote the study authors led by Jamie E. Chaft, MD, a medical oncologist and associate attending physican at Memorial Sloan Kettering Cancer Center, and associate professor of Medicine at Weill Cornell Medical College.

The ongoing, open-label, single-arm phase 2 study enrolled 181 patients with untreated, resectable, stage IB–IIIB NSCLC, as well as select patients with stage IIIB NSCLC, those with T3N2 or T4. However, those with T4 disease due to mediastinal organ invasion were excluded from the study.2

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

The primary end point of the trial was MPR defined as ≤10% viable malignant cells in resected tumors without EGFR or ALK alterations. Secondary end points were pathological response by PD-L1 and radiographic response by PD-L1, tumor mutational burden, and neoantigen gene expression profiling, and safety. Additional exploratory end points included disease-free survival (DFS), overall survival (OS), and biomarker analyses.

A total of 171 (94%) patients received both doses of atezolizumab. Ten (6%) did not due to 7 adverse events (AEs), 2 because of physician decisions, and 1 due to withdrawal. The 7 AEs which led to discontinuation of the trial were infusion-related reaction (n = 2), pyrexia (n = 2), fatigue (n = 1), diverticulitis (n =1), and dyspnea (n = 1).

Thirteen patients required dose interruption during the second infusion. Infusion-related reactions were the cause of 12 interruptions and 1 was due to ongoing (non-worsening) cough and dyspnea. Additionally, 159 (88%) patients had surgery with curative intent while 22 (12%) did not have surgery.

Among the 159 patients who underwent surgery, 16 (10%) had tumors harboring EGFR mutations (n = 10) or ALK rearrangements (n = 6). These patients were excluded from the primary efficacy analysis.

Findings revealed that in the primary analysis population, the primary end point was met with the MPR rate of 20% (95% CI, 14%-28%) and the pathological complete response (pCR) rate was 6% (95% CI, 3%-11%). With a minimum duration of follow-up of 3 years, the 3-year survival rate of 80% was encouraging.

In the exploratory analysis, MPR was predicted through pre-treatment peripheral blood immunophenotype based on 14 immune cell subsets. Immune cell subsets predictive of MPR in the peripheral blood were also identified in the tumor microenvironment and were associated with MPR.

The exploratory end points of median DFS and OS were not reached. The 3-year DFS and OS were 72% (95% CI, 62%-79%) and 80% (95% CI, 71%-87%), respectively.

Regarding safety, no unexpected safety signals were observed, and the most common AEs reported during the neoadjuvant phase were fatigue in 39% of patients (n= 71) and procedural pain in 29% (n = 53). Immune-related AEs were observed in 75 (41%) patients, with the most common being increases in aspartate aminotransferase (9%), alanine aminotransferase (8%), maculopapular rash (8%) and infusion-related reaction (8%). The safety profile was consistent overall with what has previously been observed in advanced disease.

Overall, the trial suggests that profiles of innate immune cells in pre-treatment peripheral blood may predict pathological response after neoadjuvant atezolizumab. Additional studies are needed to determine whether these profiles can inform patient selection and new therapeutic approaches.

“Neoadjuvant treatment with single-agent atezolizumab yielded a 20% MPR rate in patients with stage IB–III NSCLC, with no new safety signals and encouraging survival. These data confirm that anti-PD-L1 monotherapy is effective in a subset of patients and begins to address 2 major unmet needs: understanding which biomarkers are predictive of immunotherapy response and identifying patients who may not need chemotherapy,” wrote the study authors. “Our biomarker analyses showed that pre-treatment peripheral blood immune cell profiles may predict MPR in atezolizumab-treated patients with resectable NSCLC.”

Chaft JE, Oezkan F, Kris MG, et al. Neoadjuvant atezolizumab for resectable non-small cell lung cancer: an open-label, single-arm phase II trial [published online ahead of print, 2022 Sep 12]. Nat Med. 2022;10.1038/s41591-022-01962-5. doi:10.1038/s41591-022-01962-5
A study of atezolizumab as neoadjuvant and adjuvant therapy in resectable non-small cell lung cancer (NSCLC) - lung cancer mutation consortium (LCMC3). Updated August 2, 2022. Accessed September 20, 2022.