Carlos Gallardo

BACKGROUND: In an interim analysis of this phase 3 trial, the addition of pembrolizumab to chemotherapy resulted in longer progression-free survival than chemotherapy alone among patients with advanced triple-negative breast cancer whose tumors expressed programmed death ligand 1 (PD-L1) with a combined positive score (CPS; the number of PD-L1-staining tumor cells, lymphocytes, and macrophages, divided by the total number of viable tumor cells, multiplied by 100) of 10 or more. The results of the final analysis of overall survival have not been reported. METHODS: We randomly assigned patients with previously untreated locally recurrent inoperable or metastatic triple-negative breast cancer in a 2:1 ratio to receive pembrolizumab (200 mg) every 3 weeks plus the investigator's choice of chemotherapy (nanoparticle albumin-bound paclitaxel, paclitaxel, or gemcitabine-carboplatin) or placebo plus chemotherapy. The primary end points were progression-free survival (reported previously) and overall survival among patients whose tumors expressed PD-L1 with a CPS of 10 or more (the CPS-10 subgroup), among patients whose tumors expressed PD-L1 with a CPS of 1 or more (the CPS-1 subgroup), and in the intention-to-treat population. Safety was also assessed. RESULTS: A total of 847 patients underwent randomization: 566 were assigned to the pembrolizumab-chemotherapy group, and 281 to the placebo-chemotherapy group. The median follow-up was 44.1 months. In the CPS-10 subgroup, the median overall survival was 23.0 months in the pembrolizumab-chemotherapy group and 16.1 months in the placebo-chemotherapy group (hazard ratio for death, 0.73; 95% confidence interval [CI], 0.55 to 0.95; two-sided P = 0.0185 [criterion for significance met]); in the CPS-1 subgroup, the median overall survival was 17.6 and 16.0 months in the two groups, respectively (hazard ratio, 0.86; 95% CI, 0.72 to 1.04; two-sided P = 0.1125 [not significant]); and in the intention-to-treat population, the median overall survival was 17.2 and 15.5 months, respectively (hazard ratio, 0.89; 95% CI, 0.76 to 1.05 [significance not tested]). Adverse events of grade 3, 4, or 5 that were related to the trial regimen occurred in 68.1% of the patients in the pembrolizumab-chemotherapy group and in 66.9% in the placebo-chemotherapy group, including death in 0.4% of the patients in the pembrolizumab-chemotherapy group and in no patients in the placebo-chemotherapy group. CONCLUSIONS: Among patients with advanced triple-negative breast cancer whose tumors expressed PD-L1 with a CPS of 10 or more, the addition of pembrolizumab to chemotherapy resulted in significantly longer overall survival than chemotherapy alone. (Funded by Merck Sharp and Dohme; KEYNOTE-355 ClinicalTrials.gov number, NCT02819518.).

Abstract Background: Pembrolizumab (pembro) monotherapy showed durable antitumor activity and manageable safety in patients (pts) with metastatic triple-negative breast cancer (TNBC) in the KEYNOTE-012, -086, and -119 studies. In a prespecified interim analysis of KEYNOTE-355 (NCT02819518), pembro combined with chemotherapy (chemo) showed a statistically significant improvement in PFS versus chemo alone in pts with previously untreated locally recurrent inoperable or metastatic TNBC whose tumors expressed PD-L1 CPS ≥10 (HR for progression or death, 0.65, 95% CI, 0.49-0.86; one-sided P=0.0012 [prespecified statistical criterion was alpha=0.00411 at this interim analysis]). Additionally, pembro + chemo was generally well tolerated, with no new safety signals. Here, we examine PFS outcomes for each chemo partner and present key secondary endpoints from KEYNOTE-355. Methods: 847 pts with measurable disease per RECIST v1.1, ECOG PS 0-1, and ≥6 mo DFI were randomized 2:1 to pembro + chemo (nab-paclitaxel 100 mg/m2 days 1, 8, and 15 every 28 days; paclitaxel 90 mg/m2 days 1, 8, and 15 every 28 days; or gemcitabine 1000 mg/m2 + carboplatin AUC 2 days 1 and 8 every 21 days) or pbo + chemo for up to 35 administrations of pembro/pbo or until progression/intolerable toxicity. Steroid premedication for paclitaxel was given according to local guidelines and practices, and was not restricted by the protocol. Crossover between arms was not allowed. Pts were stratified by chemo type (taxane vs gemcitabine/carboplatin), PD-L1 status (CPS ≥1 vs <1), and prior (neo)adjuvant treatment with same-class chemo (yes vs no). Dual primary endpoints are PFS (RECIST v1.1, blinded independent central review) and OS in pts with PD-L1 positive tumors (CPS ≥10 and ≥1) and in all pts. Secondary endpoints include ORR, DCR (CR + PR + SD ≥24 weeks), and DOR. The PFS treatment effect was assessed in subgroups descriptively using HRs and 95% CIs; although subgroup analysis by on-study chemo were pre-specified, the trial was not powered to compare efficacy among treatment groups by different chemo regimens. Results: As of Dec 11 2019, median follow-up was 25.9 mo for pembro + chemo (n=566) and 26.3 mo for pbo + chemo (n=281). The HR for PFS favored pembro regardless of choice of chemo or CPS population (Table). Results for the key secondary endpoints of ORR, DCR, and DOR favored pembro + chemo, with the treatment effect increasing as CPS increased (Table). Conclusion: In subgroup analysis, PFS with pembro + chemo compared to pbo + chemo in pts with metastatic TNBC was improved regardless of chemo partner. A trend toward improved efficacy with PD-L1 enrichment with pembro + chemo was observed for ORR, DCR and DOR endpoints. These data further support the potential of pembro + chemo as a first-line treatment option for metastatic TNBC. CPS ≥ 10CPS ≥ 1All ptsPembro + ChemoPbo + ChemoPembro + ChemoPbo + ChemoPembro + Chemo|Pbo + ChemoN = 220N = 103N = 425N = 211N = 566N = 281PFS, mo median (95% CI)9.7 (7.6 - 11.3)5.6 (5.3 - 7.5)7.6 (6.6 - 8.0)5.6 (5.4 - 7.4)7.5 (6.3 - 7.7)5.6 (5.4 - 7.3)HR (95% CI)0.65 (0.49 - 0.86)0.74 (0.61 - 0.90)0.82 (0.69 - 0.97)PFS by on-study chemo, (n [%)) mo median(95% CI)Nab-Paclitaxel(63 [28.6%]) 9.9(36 [35.0%]) 5.5(130 [30.6%]) 6.3(74 [35.1%)) 5.3(173 [30.6%]) 7.5(95 [33.8%]) 5.4HR (95% CI)0.57 (0.34 - 0.95)0.66 (0.26 - 0.82)0.69 (0.51 - 0.93)Paclitaxel(33 [15.0%]) 9.6(11 [10.7%]) 3.6(62 [14.6%]) 9.4(22 [10.4%]) 3.8(82 [14.5%]) 8.0(32 [11.4%]) 3.8HR (95% CI)0.33 (0.14 - 0.76)0.46 (0.26 - 0.82)0.57 (0.35 - 0.93)Gemcitabine-Carboplatin(124 [56.4%]) 8.0(56 [54.4%]) 7.2(233 [54.8%]) 7.5(115 [54.5%]) 7.5(311 [54.9%]) 7.4(154 [54.8%]) 7.4HR (95% CI)0.77 (0.53 - 1.11)0.86 (0.66 - 1.11)0.93 (0.74 - 1.16)ORR, % (95% CI)53.2 (46.4 - 59.9)39.8 (30.3 - 49.9)45.2 (40.4 - 50.0)37.9 (31.3 - 44.8)41.0 (36.9 - 45.2)35.9 (30.3 - 41.9)DCR, % (95% CI)65.0 (58.3 - 71.3)54.4 (44.3 - 64.2)58.6 (53.7 - 63.3)53.6 (46.6 - 60.4)56.0 (51.8 - 60.1)51.6 (45.6 - 57.6)DOR, mo, median (range)19.3 (1.6+ - 29.8)7.3 (1.5 - 32.5+)10.1 (1.0+ - 29.8)6.5 (1.5 - 32.5+)10.1 (1.0+ - 29.8)6.4 ( 1.5 - 32.5+)"+" indicates there is no progressive disease by the time of last disease assessment. Citation Format: Hope S. Rugo, Peter Schmid, David W. Cescon, Zbigniew Nowecki, Seock-Ah Im, Mastura Md Yusof, Carlos Gallardo, Oleg Lipatov, Carlos Henrique Barrios, Jose Perez-Garcia, Hiroji Iwata, Norikazu Masuda, Marco Torregroza Otero, Erhan Gokmen, Sherene Loi, Zifang Guo, Jing Zhao, Vassiliki Karantza, Gursel Aktan, Javier Cortes. Additional efficacy endpoints from the phase 3 KEYNOTE-355 study of pembrolizumab plus chemotherapy vs placebo plus chemotherapy as first-line therapy for locally recurrent inoperable or metastatic triple-negative breast cancer [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr GS3-01.

1065 Background: SG was evaluated in the phase 3 ASCENT-07 study (NCT05840211) of pts with HR+/HER2−, locally advanced unresectable or mBC who had received prior endocrine therapy (ET) and were eligible for first chemotherapy; the primary end point (PFS by blinded independent central review [BICR] vs chemotherapy treatment of physician’s choice [TPC]) was not met (HR 0.85; 95% CI, 0.69-1.05; P = .130). We report exploratory outcomes in pts with HER2 IHC0 expression status. Methods: Pts were randomized 2:1 to receive SG 10 mg/kg IV or TPC (capecitabine, nab-paclitaxel, or paclitaxel). Descriptive analyses of pts with HER2 IHC0 were performed for the primary end point of PFS by BICR, secondary end points of PFS by investigator (INV), overall survival (OS), objective response rate (ORR) and duration of response (DOR) by BICR, and safety. HER2 status was tested locally. Results: Of 690 pts enrolled, 292 (42%) had HER2 IHC0 (SG: 192; TPC: 100). Baseline demographics and pt characteristics were similar to the overall population. Median age was 58 yrs; 176 (92%) and 91 (91%) pts in SG and TPC groups, respectively, received prior ET + CDK4/6i in the metastatic setting; 88% and 86% had visceral disease. At 15.4-mo median f/u, SG showed numerical improvement in PFS vs TPC by BICR (HR 0.75; 95% CI 0.55-1.02; nominal P = .0601) and by INV (HR 0.66; 95% CI 0.50-0.86; nominal P = .0024). Although OS data were not mature (maturity rate for IHC0 subgroup, 28%), an early improvement trend favoring SG was observed. ORR by BICR was similar for SG and TPC, and median DOR by BICR was longer for SG vs TPC. Despite a higher proportion of pts experiencing grade ≥ 3 treatment-emergent adverse events (TEAEs) with SG vs TPC, the rate of treatment discontinuation was lower with SG (Table). The most common grade ≥ 3 TEAEs were neutropenia (SG: 54%; TPC: 21%), leukopenia (12%; 7%), and anemia (11%; 5%). Safety profile was consistent with overall population and prior reports. Conclusions: In this exploratory analysis from ASCENT-07, numerical trends of improved efficacy vs TPC and the overall population as well as a manageable safety profile support further investigation into the potential benefit of SG in patients with HR+/HER2− mBC and HER2 IHC0 status who are candidates for first chemotherapy. Clinical trial information: NCT05840211 . SG (n = 192) TPC (n = 100) Median PFS by BICR (95% CI), mo 9.2 (8.2-10.4) 8.1 (6.3-10.4) HR (95% CI) 0.75 (0.55-1.02); P = .0601 a Median PFS by INV (95% CI), mo 8.5 (8.2-10.4) 6.1 (4.5-8.1) HR (95% CI) 0.66 (0.50-0.86); P = .0024 a Median OS (95% CI), mo Not reached (NR-NR) 20.2 (19.5-NR) HR (95% CI) 0.68 (0.44-1.05); P = .0820 a ORR by BICR (95% CI), % 41 (34-48) 40 (30-50) Median DOR by BICR (95% CI), mo n = 78 10.8 (6.4-12.6) n = 40 8.3 (5.5-11.2) TEAEs, n (%)Any gradeGrade ≥ 3Led to dose reductionLed to treatment discontinuation n = 190 189 (99)139 (73)83 (44)4 (2) n = 100 97 (97)46 (46)35 (35)7 (7) a Nominal P value; unstratified log rank.