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Background: In the phase Ib KEYNOTE-012 study, the anti–PD-1 antibody pembrolizumab demonstrated promising antitumor activity and acceptable safety as a monotherapy in heavily pretreated patients (pts) with PD-L1+ mTNBC. The immunomodulatory properties of chemotherapy suggest that combining pembrolizumab with chemotherapy may lead to enhanced antitumor activity. KEYNOTE-355 (NCT02819518) is a global phase III study of the efficacy and safety of pembrolizumab + chemotherapy vs placebo + chemotherapy in pts with previously untreated, locally recurrent inoperable or mTNBC. Methods: Eligible pts for KEYNOTE-355 must be ≥18 y and have centrally confirmed TNBC; central determination of PD-L1 expression; locally recurrent inoperable breast cancer or mTNBC, which was not previously treated with chemotherapy (prior chemotherapy in the [neo]adjuvant setting is allowed); measurable disease per RECIST v1.1; ECOG PS 0-1; and an interval of ≥6 mo between definitive breast surgery or last dose of adjuvant chemotherapy, whichever occurred last, and first documented disease recurrence (or ≥12 mo if prior treatment was with the same-class agent). Part 1 is an open-label, unblinded safety run-in of ~30 pts divided evenly among 3 treatment arms (pembrolizumab + nab-paclitaxel, pembrolizumab + paclitaxel, pembrolizumab + gemcitabine/carboplatin). Part 2 is a double-blind, placebo-controlled study of ~828 pts who are to be randomly assigned 2:1 to receive pembrolizumab 200 mg every 3 weeks + chemotherapy (nab-paclitaxel 100 mg/m2 on d 1, 8, and 15 every 28 d; paclitaxel 90 mg/m2 on d 1, 8, and 15 every 28 d; or gemcitabine 1000 mg/m2 + carboplatin AUC 2 on d 1 and 8 every 21 d) or placebo + chemotherapy. Crossover is not allowed. Randomization will be stratified by study chemotherapy (taxane vs gemcitabine/carboplatin), tumor PD-L1 expression (positive vs negative), and prior treatment with the same-class agent in the (neo)adjuvant setting (yes vs no). Treatment will continue for ≤35 administrations (pembrolizumab/placebo only) or until confirmed disease progression, unacceptable toxicity, withdrawal of consent, or physician decision to discontinue. AEs will be monitored and graded per NCI CTCAE v4.0. Response (RECIST v1.1, central radiology review) will be assessed at wk 8, 16, and 24, then at 9-wk intervals up to 1 y after randomization, and at 12-wk intervals thereafter. In all pts and in those with PD-L1+ tumors, coprimary end points are PFS (RECIST v1.1, central radiology review) and OS; secondary end points are ORR, duration of response, and disease control rate. An interim safety analysis will be conducted after all pts complete 1 treatment cycle in part 1. An external data monitoring committee will review part 1 safety data; enrollment in part 2 will occur in parallel. Citation Format: Javier Cortes, Zifang Guo, Vassiliki Karantza, Gursel Aktan. KEYNOTE-355: Randomized, double-blind, phase III study of pembrolizumab plus chemotherapy vs placebo plus chemotherapy for previously untreated, locally recurrent, inoperable or metastatic triple-negative breast cancer (mTNBC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr CT069. doi:10.1158/1538-7445.AM2017-CT069

1000 Background: Pembrolizumab (pembro) monotherapy showed promising antitumor activity and manageable safety in patients (pts) with metastatic TNBC in KEYNOTE-012, -086 and -119. KEYNOTE-355 (ClinicalTrials.gov, NCT02819518) compared pembro + chemotherapy (chemo) vs placebo (pbo) + chemo for previously untreated locally recurrent inoperable or metastatic TNBC. Methods: Pts with ≥6 mo DFI were randomized 2:1 to pembro + chemo (nab-paclitaxel; paclitaxel; or gemcitabine/carboplatin) or pbo + chemo for up to 35 administrations of pembro/pbo or until progression/intolerable toxicity. 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 by tumor PD-L1 expression (CPS ≥10 and ≥1) and in all pts. PFS was estimated using the Kaplan-Meier method. Stratified log-rank tests were used to assess treatment group differences. HR and 95% CIs were based on a stratified Cox regression model. AEs were monitored throughout the study and graded per NCI CTCAE v4.0. Results: As of Dec 11 2019, median follow-up was 17.5 mo for pembro + chemo (n=566) and 15.5 mo for chemo (n=281). Pembro + chemo significantly improved PFS vs chemo alone in pts with CPS ≥10 tumors (Table), meeting one of the protocol-defined primary objectives. Although the boundary for a statistically significant benefit of pembro + chemo in pts with CPS ≥1 tumors was not met and formal testing in ITT was not performed, the pembro treatment effect increased with PD-L1 enrichment (Table). OS follow-up is ongoing. Grade 3-5 treatment-related AE rates were 68.1% with pembro + chemo (2 deaths) vs 66.9% with chemo (0 deaths); rates of grade 3-4 immune-mediated AEs and infusion reactions were 5.5% vs 0%. Clinical trial information: NCT02819518 . Conclusion: Pembro combined with several chemo partners showed a statistically significant and clinically meaningful improvement in PFS vs chemo alone in pts with previously untreated locally recurrent inoperable or metastatic TNBC whose tumors expressed PD-L1 (CPS ≥10). Pembro + chemo was generally well tolerated, with no new safety concerns. [Table: see text]

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