Introduction
Here we report surgical and clinical outcomes in the Phase II LCMC3 (NCT02927301) study evaluating pre-operative treatment with atezolizumab (anti-PD-L1) in untreated stage IB-IIIB resectable NSCLC.
Methods
Patients with stage IB-IIIB resectable NSCLC and ECOG PS 0/1 were eligible. Patients received neoadjuvant atezolizumab 1200 mg intravenously q3w for ≤2 cycles (days 1 and 22) followed by resection (day 40±10). Patients deemed to have benefit continued on adjuvant atezolizumab for ≤12 months. The primary endpoint was major pathological response (MPR; ≤10% viable tumor cells at surgery) in patients without EGFR/ALK+ mutations. Pre- and post-treatment positron emission tomography/computed tomography scans, pulmonary function tests and biospecimens were obtained. For safety analyses, adverse events (AEs) were classified as treatment-related (TRAE) or immune-related (irAE) and as pre-operative or post-operative (AE onset on or after date of surgery).
Results
Follow-up data from post-surgery visit were analyzed for all enrolled and dosed patients with NSCLC (N=181). Baseline characteristics were: mean age, 65.1 years; female, 93/181 (51%); current smoker, 35/181 (19%); nonsquamous histology, 112/181 (62%); and clinical stages IB (n=16), IIA (n=20), IIB (n=60), IIIA (n=71) and IIIB (n=14). In patients without EGFR/ALK mutations who underwent surgery, the MPR rate was 20% (30/147; 95% CI: 14%-28%) and the pathological complete response rate was 7% (10/147; 95% CI: 3%-12%) (see Carbone, WCLC 2020). Surgical and clinical outcomes and perioperative AEs are in the Table. Following atezolizumab, unresectability was detected pre-operatively in 22/181 (12%) and intra-operatively in 7/159 (4%). The majority of patients (151/159; 95%) had anatomic resections; only 15/101 (15%) converted to thoracotomy. Pathologic downstaging was seen in 57/181 (31%). Only 19/159 (12%) had surgery outside of protocol window. Intraoperative complications were rare (5/159; 3%). 145/159 (91%) had complete (R0) resection. Postoperative TRAEs and irAEs correlated with fewer viable tumor cells in the resected specimen (both P<0.05; Table). 30- and 30-to-90-day mortality were each 1/159 (0.6%). DFS and OS at 1 year and 18 months will be presented.
Conclusion
Neoadjuvant atezolizumab in resectable stage IB-IIIB NSCLC was well tolerated, with no safety concerns. The 20% MPR rate successfully met the primary study objective and was comparable to that with neoadjuvant cisplatin-based therapy. Following neoadjuvant atezolizumab, resection was performed (1) safely with low perioperative morbidity and mortality, (2) infrequently outside of the protocol window and (3) with high complete resection rates.
Tabled
1
| Enrolled and Dosed Patients With NSCLC (N = 181) | ||||||
|---|---|---|---|---|---|---|
| Clinical vs pathological staging | Pre-treatment cStage | Post-treatment pStage | ||||
| ypT0N0M0 | 0 | 8 (4) | ||||
| IA1 | 0 | 6 (3) | ||||
| IA2 | 0 | 7 (4) | ||||
| IA3 | 0 | 8 (4) | ||||
| IB | 16 (9) | 15 (8) | ||||
| IIA | 20 (11) | 11 (6) | ||||
| IIB | 60 (33) | 42 (23) | ||||
| IIIA | 71 (39) | 48 (27) | ||||
| IIIB | 14 (8) | 8 (4) | ||||
| IVA | 0 | 2 (1) | ||||
| Missing | – | 4 (2) | ||||
| No surgery | – | 22 (12) | ||||
| Patients downstaged following atezolizumab, n (%) | 57 (31) | |||||
| Timing of treatment and surgery | Median time from screening to first dose (range), days | 15 (0-82) | ||||
| Median time from enrolment to first dose (range), days | 12 (1-82) | |||||
| Median time from last cycle to surgical resection (range), days (n = 159) | 21 (10-73) | |||||
| Surgery | Stage | Pre-operative unresectable | Underwent surgery | Intra-operative unresectable | ||
| All, n (%) | 22 (12) | 159 (88) | 7 (4) | |||
| IA, n | 1 | 19 | 0 | |||
| IB, n | 1 | 15 | 0 | |||
| IIB, n | 8 | 52 | 1 | |||
| IIIA, n | 10 | 61 | 3 | |||
| IIIB, n | 2 | 12 | 3 | |||
| Patients with disease progression per RECIST while on therapy and had surgery, n (%) | 4 (2) | |||||
| Patients with disease progression per RECIST while on therapy and did not have surgery, n (%) | 9 (5) | |||||
| Patients with surgery outside 10-day window, n (%) | 19 (12) | |||||
| Stage IA, n | 2 | |||||
| Stage IB, n | 1 | |||||
| Stage IIB, n | 9 | |||||
| Stage IIIA, n | 5 | |||||
| Stage IIIB, n | 2 | |||||
| Median time outside window (range), days | 8 (1-45) | |||||
| Extent of resection (n = 159) | n (%) | |||||
| Pneumonectomy | 14 (9) | |||||
| Bilobectomy | 10 (6) | |||||
| Lobectomy | 125 (79) | |||||
| Segmentectomy | 2 (1) | |||||
| Wedge | 3 (2) | |||||
| Other | 5 (3) | |||||
| Mortality | Deaths before planned surgery, n (%)a | 0 | ||||
| Deaths ≤ 30 days after surgery, n (%) | 1b (0.6) | |||||
| Deaths between > 30 and ≤ 90 days after surgery, n (%) | 1c (0.6) | |||||
| Hospitalization | Median length of hospitalization (range), days (n = 48) | 7.5 (2-68) | ||||
| Intra-operative events (post hoc descriptive analysis) | Bronchial complications, n (%) | 1 (1) | ||||
| Vascular complications, n (%) | 4 (3) | |||||
| Lymphadenopathy, n (%) | 46 (29) | |||||
| Peripheral adhesions, n (%) | 43 (27) | |||||
| Peri-hilar/lobar adhesions, n (%) | 42 (26) | |||||
| Pathology | Completeness of resection, n (%) | |||||
| R0 | 145 (91) | |||||
| R1 | 7 (4) | |||||
| R2 | 7 (4) | |||||
| TRAE | Pre-operative (n = 181) | Post-operative (n = 159) | ||||
| Any TRAE, n (%) | 101 (56) | 57 (36) | ||||
| Grade 3-4 | 9 (5) | 20 (13) | ||||
| Grade 5 | 0 | 1 (1) | ||||
| irAE | Pre-operative (n = 181) | Post-operative (n = 159) | ||||
| Any irAE, n (%) | 44 (24.3) | 43 (27.0) | ||||
| Grade 3-4 | 4 (2.2) | 12 (8) | ||||
| Grade 5 | 0 | 1 (0.6) | ||||
cStage, clinical stage; pStage, pathological stage; VAT, video-assisted thoracic surgery. a Planned to occur on Day 40 ± 10 of the study. b Due to sudden death, not otherwise specified. c Due to pneumonitis, deemed related to atezolizumab.
Keywords
Neoadjuvant, atezolizumab, Early Stage Lung Cancer
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