Noemi Reguart

Purpose:EVOKE-02 (NCT05186974) is a multicohort, phase II trial evaluating first-line sacituzumab govitecan (SG) plus pembrolizumab with or without platinum-based chemotherapy in patients with metastatic non–small cell lung cancer (mNSCLC).Patients and Methods:Adults with mNSCLC, no prior systemic treatment, and no actionable genomic alterations received SG 10 mg/kg intravenously (reduced to 7.5 mg/kg following a preplanned safety evaluation) on days 1 and 8, plus pembrolizumab 200 mg intravenously on day 1 and carboplatin area under the curve 5 on day 1 in 21-day cycles. The primary endpoint was objective response rate (ORR) per independent review committee; secondary endpoints included progression-free survival (PFS) and safety.Results:As of June 3, 2024, 54 and 41 patients had nonsquamous and squamous histology, respectively. ORR (95% confidence interval [CI]) was 45.1% (3.1–59.7) for nonsquamous and 39.0% (24.2–55.5) for squamous histology. Median (95% CI) PFS was 8.1 (5.2–15.0) months for nonsquamous and 8.3 (4.3–11.2) months for squamous histology. ORR (95% CI) was 66.7% (34.9–90.1) for programmed cell death-ligand 1 tumor proportion score greater than or equal to 50%. SG dose was adjusted to 7.5 mg/kg due to myelosuppression. Grade greater than or equal to 3 treatment-emergent adverse events (TEAEs) occurred in 57 patients (86.4%). TEAEs leading to discontinuation of any study drug occurred in 12 patients (18.2%).Conclusions:SG plus pembrolizumab and carboplatin had activity in mNSCLC. When combined with pembrolizumab and carboplatin, SG was tolerated at a dose of 7.5 mg/kg.

Purpose:Complete pathologic response (CPR) correlates with long-term survival after perioperative chemoimmunotherapy (ChIO) in resectable non–small cell lung cancer (NSCLC). We provide a multiomic characterization of B cells and tertiary lymphoid structures (TLS) to dissect the immune landscape associated with CPR.Experimental Design:We integrated B-cell receptor (BCR) repertoire profiling (n = 87 tissue, n = 25 blood), multiplex immunofluorescence (n = 67), and bulk (n = 15), spatial (n = 12), and single-cell transcriptomics (n = 15) from tumor tissue and blood (baseline, surgery, and at 6 months of adjuvant therapy) in 123 patients (NADIM/NADIM II trials, NCT03081689/NCT03838159).Results:CPR tumors exhibited a more clonal baseline BCR repertoire (AUC 0.775; P = 0.030) that was better conserved and reinvigorated during neoadjuvant ChIO. In blood, patients with CPR tumors displayed a repertoire enriched in class-switched clones (AUC 0.833; P = 0.008), characterized by higher diversity, lower clonality, and upregulation of activation-related transcriptional programs. Neoadjuvant ChIO was associated with the induction of B-cell–related genes within TLS regions and with higher TLS density at surgery compared with Ch (P = 0.034). TLS density was not associated with CPR (P = 0.129); however, mature TLS in CPR tumors were enriched in immune activation and antigen-presenting pathways, estimated T follicular helper cells, plasmacytoid dendritic cells, and plasma cells, whereas low B-cell regions from CPR tumors displayed higher inferred infiltration of CD8+ T cells, NK cells, and macrophages, with reduced neutrophils and Tregs.Conclusions:Patients with CPR tumors exhibit a preexisting and more mature B-cell response that develops further during neoadjuvant ChIO. Our findings link B-cell–related features to CPR and highlight BCR metrics as promising predictive biomarkers in NSCLC.

Supplementary Figure 2. BCR repertoire dynamics.

Supplementary Figure 5. Areas of interest represent different biological entities and differ by pathological response.

Visium DEG per main phenotype by response

Table S10 from Decoding B-cell Signatures of Complete Pathologic Response to Perioperative Chemoimmunotherapy in Non–Small Cell Lung Cancer

Supplementary Figure 11. Comparison between Complete Pathological Response (CPR) (N=6) and Non-Complete Pathological Response (NCPR) (N=7) in pre- and post-treatment samples across all other cell types.