Promising Data for Preop Checkpoint Inhibition in NSCLC

A fifth of patients with operable early-stage non-small cell lung cancer (NSCLC) had major pathologic responses (MPR) and more than 40% had pathologic downstaging after neoadjuvant atezolizumab (Tecentriq), a prospective multicenter trial showed.

Results showed that 30 of 144 evaluable patients attained MPR, including pathologic complete response (pCR) in 10 patients. Downstaging occurred in 66 of 155 evaluable patients following preoperative treatment with atezolizumab, and 29 patients had upstaging of their disease status.

An exploratory analysis suggested improved overall survival (OS) as compared with historical results for similar patients, reported Jay M. Lee, MD, of the David Geffen School of Medicine at the University of California Los Angeles, during the virtual World Conference on Lung Cancer.

“The LCMC (Lung Cancer Mutation Consortium)3 study successfully met its primary endpoint of achieving major pathologic response in 21% of patients, and a pathologic complete response rate of 7%,” Lee said during a press briefing that followed his presentation. “Neoadjuvant atezolizumab monotherapy was well tolerated, with no new safety signals, and resection was performed with low perioperative morbidity and mortality, usually within a narrow protocol window, with a short time frame from completion of atezolizumab and with a corresponding high R0, or complete resection rate.”

About 90% of patients were alive at 18 months, and about 80% remained alive and disease free.

Evaluation of neoadjuvant atezolizumab in stage I-III NSCLC, in combination with platinum-based chemotherapy, is ongoing in the phase III IMpower030 trial, Lee added.

The results suggest that neoadjuvant therapy with an immune checkpoint inhibitor (ICI) is feasible and does increase the difficulty of surgery, said invited discussant Shinichi Toyooka, MD, of Okayama University Hospital in Japan. The results also showed similar outcomes for patients with stage I-II versus stage III disease, but the survival data remain immature. Longer follow-up is required to know whether single-agent (ICI) is sufficient for all patients with operable NSCLC.

“I think single ICI can be used for early-stage disease and poor performance status,” said Toyooka. “On the other hand, a combination of ICI and chemotherapy is suitable for advanced-but-resectable cases.”

Recent studies have provided support for Toyooka’s viewpoint. A trial of neoadjuvant nivolumab (Opdivo) plus chemotherapy showed a pCR rate of 57% in 46 patients with stage III NSCLC, and a small study of neoadjuvant atezolizumab and chemotherapy resulted in an MPR rate of 57% and pCR rate of 33% in patients with mostly stage III disease.

The LCMC3 trial included 181 patients with newly diagnosed, resectable stage Ib-IIIa and selected IIIb (T4 because of mediastinal invasion) NSCLC and no targetable mutations. Patients had radiographic staging before and after two cycles of atezolizumab and then had surgery within 30 to 50 days after completing neoadjuvant therapy. The primary endpoint was MPR, defined as ≤10% of viable tumor cells.

The patients had a median age of 65 and a balanced distribution of men and women. Stage IIIa disease accounted for 40% of the study population and stage IIIb for 9%. PD-L1 assessment by immunohistochemistry showed that 55% of patients had <1% expression or unknown status.

Lee said 22 patients did not have surgery, primarily because of progressive disease (n=10) and physician decision (n=6). Another 15 patients were found postoperatively to have EGFR– or ALK-positive disease and were excluded from the efficacy analysis. All but 19 patients had surgery within the protocol-specified window of 30-50 days after completing neoadjuvant therapy. The median time from end of neoadjuvant therapy to surgery was 22 days.

Some degree of pathologic regression occurred in all but three of the 159 patients who underwent surgery, including those with EGFR/ALK-positive disease. Regression met criteria for MPT in 21% of the 144 patients included in the efficacy analysis, including pCR in 7%.

Minimally invasive surgery (robotic or VATS) was successful in 86 patients, and 15 others required conversion to thoracotomy. Lee said 79% of patients underwent lobectomy, and 3% had segmentectomy or wedge procedures. R0 (clear surgical margins) status was achieved in 92% of the 159 patients who went to surgery.

Intraoperative complications consisted of vascular complications in four patients and bronchial complications in one. One patient died within 30 days and one from day 30 to day 90.

Preoperative treatment-related adverse events (TRAEs) occurred in 56% of patients (grade 1/2 in 50%) and postoperative TRAEs in 33% (19% grade 1/2), 11% grade 3, 2% grade 4, 1% grade 5). Immune-related AEs occurred in 23% of patients preoperatively (21% grade 1/2) and 28% postoperatively (19% grade 1/2).

Exploratory analyses of disease-free survival (DFS) and OS after a median follow-up of 2.1 years showed no differences between patients with stage I/II versus stage III NSCLC. The 1-year DFS was 85% in both stage groups and 1.5 year DFS was 79% for stage I/II and 77% for those with stage III. The 1-year OS analysis yielded values of 92% and 95% for stage I/II versus stage III and 1.5-year values of 91% and 87%.

Acknowledging the limitations of cross-trial comparisons, Lee said the OS values suggested substantive improvement over historical survival data for patients with stage I-III NSCLC.