In a phase II study reported in The Lancet Oncology, Catherine A. Shu, MD, of Columbia University Irving Medical Center, and colleagues found that neoadjuvant treatment with atezolizumab plus nab-paclitaxel/carboplatin produced a major pathologic response in 57% of patients and pathologic complete response (pCR) in 33% of patients with resectable predominantly stage IIIa non–small cell lung cancer (NSCLC).¹ The authors noted that studies of neoadjuvant chemotherapy alone have shown pCR rates of 5% to 8% in this setting.

Catherine A. Shu, MD

Study Details

The investigator-initiated trial enrolled 30 patients at Columbia University Medical Center, Massachusetts General Hospital, and Dana-Farber Cancer Institute. Study participants had stage Ib to IIIa disease, an Eastern Cooperative Oncology Group performance status of 0 or 1, and a history of smoking. Patients received atezolizumab at 1,200 mg on day 1; nab-paclitaxel at 100 mg/m² on days 1, 8, and 15; and carboplatin at AUC 5 on day 1 of 21-day cycles. Patients without disease progression after cycle 2 received two additional cycles, followed by surgical resection. The primary endpoint was a major pathologic response (defined as ≤ 10% of residual viable tumor at surgery) in the intention-to-treat population (n = 30), based on the hypothesis that major pathologic response would be increased from 22% (historical control) to 44%.

Median patient age was 67 years (interquartile range = 62–74 years), 15 (50%) were women, 17 (57%) had adenocarcinoma, 12 (40%) had squamous cell carcinoma, and 1 had large cell neuroendocrine carcinoma. Disease stage was IIa in 4 (13%), IIb in 3 (10%), and IIIa in 23 (77%). PD-L1 expression (tumor proportion score) was ≥ 50% in 8 (27%), ≥ 1% in 16 (55%), < 1% in 12 (40%), and unknown in 2 (7%).

Surgery and Responses

No treatment-related surgical delays occurred, with the median time between the last administration of systemic chemotherapy or atezolizumab being 26.5 days. Of the 30 patients, 29 were brought to the operating room with the intention of surgery, and 26 (87%) patients had an R0 resection. Among the four patients not receiving R0 resection, one developed brain metastases during neoadjuvant therapy and was ineligible for surgery, and three had disease considered to be unresectable at exploration. Among the 26 patients with R0 resection, 19 (73%) had lobectomy, 4 (15%) had bilobectomy, and 3 (12%) had pneumonectomy.

Among all 30 patients, 23 (77%) received treatment on at least day 1 of all four cycles, with 29 (97%) completing at least three cycles. Five patients (17%) went to surgery early due to treatment-related adverse events (myelosuppression in four and neuropathy in one).

Major pathologic response was observed in 17 (57%, 95% confidence interval [CI] = 37%–75%) of the 30 patients, thus meeting the study endpoint, and pCR was observed in 10 (33%, 95% CI = 17%–53%). Of the 10 with pCR, 6 had stage IIIa disease at baseline.

Among the patients with R0 resection, those with major pathologic response included 8 (53%) of 15 with adenocarcinoma (5 [33%] with pCR) and 8 (80%) of 10 with squamous cell carcinoma (5 [50%] with pCR). The median pathologic response among the patients who underwent R0 resection was –92.5%.

Analysis by PD-L1 expression status of < 50% vs ≥ 50% showed major pathologic response in 10 (63%; pCR in 5) of 16 vs 6 (75%; pCR in 4) of 8.There were no significant associations between major pathologic response or pCR and PD-L1 expression using a ≥ 50% cutoff (P = .67).

According to Response Evaluation Criteria in Solid Tumors (RECIST), 19 (63%) of the 30 patients had objective responses (all partial responses) and stable disease was observed in 9 patients (30%), with responses observed irrespective of PD-L1 status. Median best change in tumor size was –34% in patients with PD-L1 < 1% and –40% in those with PD-L1 ≥ 1% (P = .18). Two patients (7%) had suspected disease progression during treatment. A significant association between RECIST response and major pathologic response was observed (P = .0022). Surgical outcomes included negative margins in all 26 patients. Among the 19 patients with N2 status at baseline, downstaging to N0 occurred in 11 (58%) and to N1 in 2 (11%), with residual N2 disease in 5 (26%).

Survival Outcomes

At a median follow-up of 12.9 months from the first day of treatment, 19 patients (representing 63% of all 30 patients and 73% of 26 with R0 resection) were alive and had no evidence of disease. Disease recurrence/progression was observed in nine (30%), including the four patients (13%) who did not undergo resection.

In the entire population, median disease-free survival was 17.9 months (95% CI = 14.3 months to not reached) and median overall survival was not reached (95% CI = 27.6 months to not reached). Post hoc analyses showed median disease-free survival of 14.3 months vs 34.5 months in patients without vs those with a major pathologic response, and 14.3 months vs 17.9 months in those without vs those with residual N2 disease.

Molecular Analysis

Driver mutations were found in 10 of 13 patients with adenocarcinoma who underwent molecular tumor testing. Major pathologic response was observed in one (pCR) of two patients with KRAS mutation alone (one had unresectable disease), none of three patients with STK11 mutation (one with KRAS co-mutation, one had 100% and one had 72% residual tumor, and one had unresectable disease), two (pCR in one with L858R and one with L858R/S768I mutations) of four with EGFR mutations (53% and 29% residual tumor in one with exon 20 insertion and one with exon 19 deletion), and one patient with HER2 ­mutation.

Adverse Events

The most common treatment-related adverse events of any grade among all 30 patients included neutropenia (26 patients [87%]), anemia (21 [77%]), thrombocytopenia (19 [63%]), fatigue (17 [57%]), alopecia (14 [47%]), and nausea (13 [43%]). The most common treatment-related grade 3 or 4 adverse events were neutropenia (15 [50%]), increased alanine aminotransferase (2 [7%]), increased aspartate aminotransferase (2 [7%]), and thrombocytopenia (2 [7%]). Serious treatment-related adverse events consisted of grade 3 febrile neutropenia in one patient (3%), grade 4 hyperglycemia in one (3%), and grade 2 bronchopulmonary hemorrhage in one (3%). No treatment-related deaths were reported.

The authors concluded: “To our knowledge, our study is the first published trial of chemotherapy combined with an anti–PD-L1 antibody in patients with resectable non–small cell lung cancer. No new safety signals were identified with this regimen. Treatment resulted in a high proportion of patients who had a major pathologic response and pathologic complete response, as well as a radiographic response, in this high-risk patient population. Our findings suggest that neoadjuvant atezolizumab and chemotherapy could be a potential therapeutic option for patients with resectable non–small cell lung cancer.” 

DISCLOSURE: The study was funded by Genentech and Celgene. Dr. Shu has served in a consulting or advisory role for AstraZeneca, Boehringer Ingelheim, and Genentech/Roche; and has received institutional research funding from Celgene, Genentech/Roche, Janssen, and MedImmune.

REFERENCE

1. Shu CA, Gainor JF, Awad MM, et al: Neoadjuvant atezolizumab and chemotherapy in patients with resectable non-small-cell lung cancer: An open-label, multicentre, single-arm, phase II trial. Lancet Oncol. May 7, 2020 (early release online).