Background: Comorbidities and renal impairment preclude many with advanced UC from receiving chemotherapy. Initial results from the phase 2 KEYNOTE-052 (NCT02335424) trial suggested first-line pembro is active and safe in cisplatin-ineligible advanced UC. We present updated efficacy and safety data (all patients [pts] have ≥6 months’ follow-up) and evaluate biomarkers correlated with outcomes.
Methods: Eligibility criteria included cisplatin-ineligible (ECOG PS 2, CrCl ≥30 to <60 mL/min, grade ≥2 neuropathy/hearing loss, NYHA Class 3 heart failure), advanced UC, and no prior systemic chemotherapy. Pts received pembro 200 mg IV Q3W. Imaging was performed at week 9, then Q6W for the first year, and Q12W thereafter. Primary end point was confirmed ORR (RECIST v1.1, independent review). Efficacy and safety were assessed in the 370 pts with ≥1 pembro dose. The associations of an 18-gene T-cell inflamed gene expression profile (GEP) and IHC PD-L1 combined positive score (CPS) with ORR were evaluated.
Results: As of the March 9, 2017, data cutoff, ORR was 29% (95% CI, 25%-34%): 27 (7%) and 81 (22%) pts achieved complete and partial responses. Another 67 pts (18%) had stable disease as best response, for a disease control rate of 47%. Median time to response was 2 months (range, 1-9). At a median follow-up of 10 months (range, 0.1-23) across all pts, median duration of response was not reached (95% CI, 12 months to not reached). 67% of responses were ongoing; 82% of responses lasted ≥6 months. Any-grade and grade ≥3 drug-related AEs occurred in 243 (66%) and 70 (19%) pts. Immune-mediated AEs occurred in 84 (23%) pts. In the IHC training set (n = 96), ORR for CPS ≥10 and CPS <10 was 37% (95% CI, 20%-56%) and 17% (95% CI, 9%-28%), respectively. In the IHC validation set (n = 265), ORR for CPS ≥10 and CPS <10 was 51% (95% CI, 40%-63%) and 23% (95% CI, 17%-29%), respectively. Evidence supporting a positive association with response was seen in the 275 available pts for both biomarkers (18-gene T-cell inflamed GEP: ROC AUC, 0.70; CPS: ROC AUC, 0.66).
Conclusions: With additional follow-up, results confirm that pembro elicits clinically meaningful, durable responses in cisplatin-ineligible advanced UC. Consistent with PD-1 pathway biology, biomarkers (GEP and CPS) showed the expected trends of positive association with response to pembro. Pembro was well tolerated across cisplatin-ineligible pts, including elderly and pts with poor performance status.
