No abstract

No abstract

2565 Background: Approval of pembrolizumab for the treatment of unresectable or metastatic MSI-H/dMMR solid tumors that have progressed on prior therapy was supported by data from KEYNOTE-158 (NCT02628067). At the data cutoff of Dec 6, 2018, the ORR was 34.3% among 233 patients (pts) with MSI-H/dMMR solid tumors enrolled in all cohorts of KEYNOTE-158, 77.6% had duration of response (DOR) ≥24 mo, median PFS was 4.1 mo, and median OS was 23.5 mo. We present results from 351 pts enrolled in KEYNOTE-158 cohort K at the data cutoff of Oct 5, 2020. Methods: Cohort K of this phase 2, open-label study enrolled adults with any previously treated advanced noncolorectal MSI-H solid tumor, measurable disease per RECIST v1.1, and ECOG PS of 0–1. MSI-H/dMMR status was assessed locally from a tumor tissue sample and defined as ≥1 of 4 MMR proteins absent by immunohistochemistry or as ≥2 allelic loci size shifts of 5 microsatellite markers by PCR. Pts received pembrolizumab 200 mg Q3W for up to 35 cycles or until PD, unacceptable toxicity, investigator decision, or withdrawal of consent. The primary endpoint was ORR per RECIST v1.1 by blinded independent central review (BICR). Secondary endpoints were DOR and PFS per RECIST v1.1 by BICR, OS, and safety. Efficacy was assessed in all pts who received ≥1 dose of treatment with ≥6 mo follow-up; safety was assessed in all treated pts. Results: 351 pts were enrolled in KEYNOTE-158 cohort K across multiple tumor types, including endometrial (22.5%), gastric (14.5%), small intestine (7.4%), ovarian (7.1%), cholangiocarcinoma (6.3%), and pancreatic (6.3%). 41.0% had 1 prior line of therapy; 55.6% had ≥2 prior lines. Median time from first dose to database cutoff (Oct 5, 2020) was 37.5 (range, 0.2–55.6) mo; 16.0% were continuing treatment. The ORR among the 321 eligble pts was 30.8% (CR, 27; PR, 72); median DOR was 47.5 mo (Table). Treatment-related AEs occurred in 64.7% of pts (grade 3–5, 12.0%), led to discontinuation in 6.6%, and led to death in 3 pts (myocarditis, pneumonia, and Guillain-Barre syndrome). Immune-mediated AEs and infusion reactions occurred in 20.2% of pts (grade 3–4, 4.3%) and led to death in 2 pts with no other contributing factors (myocarditis [AE start, day 26; death, day 33] and Guillain-Barre syndrome [AE start, day 22; death, day 41]). Conclusions: Pembrolizumab demonstrated a high ORR (30.8%), durable clinical benefit, and a manageable safety profile in this heavily pretreated advanced MSI-H/dMMR noncolorectal pan-tumor population. Clinical trial information: NCT02628067. [Table: see text]

Background Everolimus (EVE), an mTOR inhibitor has shown activity in HER2+ advanced breast cancer (ABC) in both preclinical and clinical studies. In the pivotal BOLERO-1 trial (NCT00876395), the progression-free survival (PFS) was not significantly different between the EVE + trastuzumab (TRAS) + paclitaxel (PAC) combination and placebo (PBO) + TRAS + PAC in the full HER2+ population (EVE, 15.0 mo vs PBO, 14.5 mo; HR=0.89; 95% CI: 0.73-1.08; p=0.1166). Although not reaching protocol defined level for statistical significance, the hormone receptor negative (HR-) subpopulation appeared to benefit from EVE, with a 7.2 mo PFS benefit vs PBO arm (EVE, 20.3 mo vs PBO, 13.1 mo; HR=0.66; 95% CI: 0.48-0.91; p=0.0049). The final exploratory overall survival (OS) analysis from the study is presented here. Methods In this phase 3 randomized trial, 719 women with HER2+ ABC without prior TRAS or chemotherapy in the metastatic setting were randomized 2:1 to receive either EVE (10 mg/d) or placebo (PBO) and weekly PAC+TRAS, stratified by visceral metastasis (lung, liver, peritoneal or pleural: yes vs no) and prior adjuvant or neo-adjuvant treatment with TRAS (yes vs no). As the primary objectives (PFS on full population and on HR- subpopulation) of BOLERO-1 were not met, the key secondary endpoint of OS was not formally statistically tested. However, given the results of PFS, in particular in the HR- subpopulation, a change to the OS analysis plan was made by introducing one final exploratory OS analysis at the time of study termination. Results At data cutoff (Dec 31, 2015), the median duration of exposure was 40.8 weeks (range: 0.6-320.4) in the EVE arm and 48.1 weeks (range: 1.1-308.0) in the PBO arm. After a median follow-up of 60.3 mo, 350 deaths were recorded in the full population, 238 (49.6%) in the EVE arm and 112 (46.9%) pts in the PBO arm. In the full population, the median OS was comparable in the EVE vs PBO arms (48.6 mo vs 50.0 mo respectively; HR = 1.13; 95% CI: 0.90-1.42). In the HR- subpopulation, 138 deaths were recorded; 88 (42.3%) pts in the EVE arm and 50 (48.5%) pts in the PBO arm. In the HR- subpopulation, the median OS in the EVE arm was longer compared to PBO arm (57.0 mo vs 41.6 mo respectively; HR = 0.83; 95% CI: 0.59-1.18). Stomatitis, diarrhea, alopecia, cough, rash, pyrexia, neutropenia, and fatigue were the most frequent adverse events (AEs) reported in EVE arm (≥35%). AEs leading to dose interruption and/or change were reported in 441 (93.4%) pts in EVE arm and 165 (69.3%) pts in the PBO arm respectively. Overall, AEs leading to treatment discontinuation were reported in 262 (55.5%) pts in EVE arm and 98 (41.2%) pts in PBO arm. Serious AEs were reported in 171 (36.2%) pts in the EVE arm and 40 (16.8%) pts in the PBO arm respectively. On treatment AE related deaths were reported for 3.6% pts in the EVE arm and 0% pts in the PBO arm. Conclusions The median OS was similar in the EVE vs PBO arms for overall population. However, a prolongation of 15.4 mo in median OS of HR- subpopulation was observed in the EVE arm vs PBO arm in this exploratory analysis. Pts in the EVE arm had a manageable safety, consistent with the safety profile of EVE and no new safety signals were identified. Citation Format: Yardley D, Hurvitz S, Jiang Z-f, Toi M, Burris H, Buyse M, Slamon D, Makhson A, Elsaid A, Lerzo G, Hellerstedt B, Nuzzo F, Sohn J, Manzyuk L, Cabaribere D, Lincy J, Weimann A, Noel-Baron F, Pacaud L, Andre F. Everolimus plus trastuzumab and paclitaxel as first-line therapy in women with HER2+ advanced breast cancer: Overall survival results from BOLERO-1 [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P4-22-13.