Shan Tang

DDR mutations. A, Mutation landscape of the 20 most frequently mutated DDR genes in baseline ctDNA. Kaplan–Meier plots for OS by (B) KEGG DDR mutation status and treatment arm, (C) KEGG DDR and TP53 mutation status with SG, (D) KEGG DDR and TP53 mutation status with docetaxel, and (E) HRR mutation status and treatment arm. MUT, mutant; NA, not assessable; NEv, not evaluable.

Trop-2 expression as (A) H-scores, (B) moderate/strong intensities, and (C) all intensities for the total Trop-2 BEP and by treatment arm, as well as H-scores in subgroups of patients based on (D) prior targeted therapy for AGA, (E) best response to last prior anti–PD-(L)1–containing therapy, (F) histology, and (G) sex. Distribution means are indicated by open diamonds. Bottom, middle, and top borders of boxes represent the first quartile (Q1), median, and third quartile (Q3), respectively. Whiskers represent the minimum and maximum values except for outliers that are greater than 1.5 times the interquartile range (Q3–Q1) from the median.

Baseline demographics and disease characteristics.

Mutation landscape of the 20 most frequently mutated DDR genes in baseline ctDNA for patients with (A) nonsquamous and (B) squamous histology, adjusted for TP53.

Kaplan-Meier plots for OS for median Trop-2 H-score subgroups by treatment arm among patients with (A) PD/SD and (B) CR/PR as best response to last prior anti-PD-(L)1–containing therapy.

CtDNA percent change at C2D1 compared with baseline by (A) treatment arm and (B) BOR per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 and treatment arm. Kaplan–Meier plots for OS by baseline ctDNA subgroups with (C) SG and (D) docetaxel and by ctDNA reduction subgroups with (E) SG and (F) docetaxel. NA, not assessable; NEv, not evaluable.

DDR pathway forest plot analysis, adjusted for TP53.

Purpose:This exploratory analysis assessed predictive biomarkers for sacituzumab govitecan (SG) in the open-label, phase III EVOKE-01 study of SG versus docetaxel in non–small cell lung cancer (NSCLC). Patients and Methods:Trophoblast cell-surface antigen (Trop) 2 membrane protein expression was analyzed using immunohistochemistry in the Trop-2 biomarker-evaluable population (BEP). Circulating tumor DNA (ctDNA) analyses evaluated baseline and reduction of ctDNA with treatment and identified oncogenic driver alterations (KRAS, TP53, KEAP1, and STK11) and other relevant mutations in the ctDNA BEP. Results:The median overall survival (OS) with SG versus docetaxel was 8.9 versus 9.8 months [hazard ratio (HR) = 0.96; 95% CI, 0.68–1.38] and 11.8 versus 10.7 months (HR = 0.89; 95% CI, 0.60–1.32) in subgroups with Trop-2 histologic scores greater than or equal to the median and less than the median, respectively. As expected, the median OS was longest in patients with undetectable baseline ctDNA. Reduction in ctDNA was observed after the first cycle with either treatment. KRAS driver alterations and potential immunotherapy resistance mutations (TP53, KEAP1, and STK11) were negative prognostic factors. Patients with TP53 mutations derived more benefit from SG than docetaxel. SG activity was observed independent of DNA damage repair (DDR) mutations. Conclusions:Trop-2 expression did not identify patients benefiting more from SG than from docetaxel. ctDNA reduction supported SG as active therapy in NSCLC. Evaluation of clinically relevant biomarkers in NSCLC identified KRAS, TP53, STK11, and KEAP1 mutations as negative prognostic factors in these second line–treated patients. Significance:The biomarker analyses of the phase III EVOKE-01 trial found that neither Trop-2 expression nor DDR alterations predicted benefit with SG versus docetaxel. Reduction in ctDNA in both treatment arms confirmed the activity of SG in this population. Further evaluation of predictive biomarkers for SG response in NSCLC is warranted.

Representativeness of study patients

Genomic alteration landscape based on the HRR 24-gene list.