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PURPOSE Combining standard of care (pertuzumab-trastuzumab [PH], chemotherapy) with cancer immunotherapy may potentiate antitumor immunity, cytotoxic activity, and patient outcomes in high-risk, human epidermal growth factor receptor 2 (HER2)–positive early breast cancer. We report the phase III IMpassion050 primary analysis of neoadjuvant atezolizumab, PH, and chemotherapy in these patients. METHODS Patients with a primary tumor of > 2 cm and histologically confirmed, positive lymph node status (T2-4, N1-3, M0) were randomly assigned 1:1 to atezolizumab/placebo with dose-dense doxorubicin/cyclophosphamide, followed by paclitaxel, and PH. After surgery, patients were to continue atezolizumab/placebo and PH (total: 1 year of HER2-targeted therapy); those with residual disease could switch to ado-trastuzumab emtansine with atezolizumab/placebo. Coprimary efficacy end points were pathologic complete response (pCR; ypT0/is ypN0) rates in intention-to-treat (ITT) and programmed cell death-ligand 1 (PD-L1)–positive populations. RESULTS At clinical cutoff (February 5, 2021), pCR rates in the placebo and atezolizumab groups in the ITT populations were 62.7% (n = 143/228) and 62.4% (n = 141/226), respectively (difference –0.33%; 95% CI, –9.2 to 8.6; P = .9551). The pCR rates in the placebo and atezolizumab groups in patients with PD-L1–positive tumors were 72.5% (n = 79/109) and 64.2% (n = 70/109), respectively (difference –8.26%; 95% CI, –20.6 to 4.0; P = .1846). Grade 3-4 and serious adverse events were more frequent in the atezolizumab versus placebo group. Five grade 5 adverse events occurred (four neoadjuvant, one adjuvant; two assigned to study treatment), all with atezolizumab. Overall, the safety profile was consistent with that of atezolizumab in other combination studies. CONCLUSION Atezolizumab with neoadjuvant dose-dense doxorubicin/cyclophosphamide–paclitaxel and PH for high-risk, HER2-positive early breast cancer did not increase pCR rates versus placebo in the ITT or PD-L1–positive populations. PH and chemotherapy remains standard of care; longer follow-up may help to inform the long-term impact of atezolizumab.

491 Background: VEGF blockade coupled with cytotoxic chemotherapy can promote an immune-permissive tumor microenvironment that can augment response to PD-L1 inhibition. IMbrave151 (NCT04677504) is a randomized, double-blind, global Phase II study evaluating the efficacy of atezolizumab (atezo), bevacizumab (bev) and cisplatin and gemcitabine (CisGem) as first-line treatment for patients with advanced biliary tract cancer (aBTC). Methods: Patients with previously untreated aBTC were randomized 1:1 to receive atezo (1200 mg every 3 weeks [q3w]) + bev (15 mg/kg q3w) or placebo + CisGem (cisplatin 25 mg/m2 and gemcitabine 1000 mg/m2 on Days 1 and 8 q3w) for up to 8 cycles, followed by atezo (1200 mg q3w) + bev (15 mg/kg q3w) or placebo until disease progression or unacceptable toxicity. Patients were stratified by disease status, geographic region and primary tumor location. The primary endpoint was progression-free survival (PFS). Secondary endpoints included overall survival (OS), objective response rate (ORR), duration of response (DOR), disease control rate and safety. No formal hypothesis testing was performed. Results: In total, 162 patients were randomized to receive either atezo + bev + CisGem (n=79) or atezo + placebo + CisGem (n=83). Median age 63 years, Asia/Rest of World (43/57%), ECOG PS 0/1 (53/48%), intrahepatic/extrahepatic cholangiocarcinoma and gallbladder (54/19/27%), and metastatic/locally advanced stage (82/18%). The HR for PFS was 0.76 (95% CI: 0.51, 1.14). Median PFS was 8.4 months for atezo + bev + CisGem and 7.9 months for atezo + placebo + CisGem; the 6-month PFS rates were 78% and 63%, respectively. The confirmed ORR was 24% for atezo + bev + CisGem and 25% for atezo + placebo + CisGem. DOR ≥6 months was 89% for atezo + bev + CisGem vs 47% for atezo + placebo + CisGem. The incidence of Grade 3 or 4 adverse events was 73% and 74% with atezo + bev + CisGem and atezo + placebo + CisGem, respectively. Median OS is not reached. Conclusions: Both combinations of IMbrave151 showed a manageable safety profile. The aggregate of data suggests that combining atezo with bev and chemotherapy may provide clinical benefit in a subset of patients with aBTC. Follow-up is ongoing for OS. Clinical trial information: NCT04677504 .

Background: AKT pathway activation has been implicated in the development of endocrine therapy resistance in hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR+/HER2–) advanced breast cancer (ABC). In the Phase II, placebo (PBO)-controlled FAKTION trial, the addition of the pan-AKT inhibitor capivasertib to fulvestrant significantly improved progression-free survival (PFS) and overall survival in postmenopausal women with aromatase inhibitor (AI)-resistant HR+/HER2– ABC. The Phase III, randomized, double-blind, PBO-controlled CAPItello-291 trial (NCT04305496) investigated the efficacy and safety of capivasertib + fulvestrant in patients with AI-resistant HR+/HER2– ABC. Methods: Eligible pre/peri or postmenopausal women or men with HR+/HER2– ABC that had recurred or progressed on or after AI therapy with or without a cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitor were randomized 1:1 to receive fulvestrant (per standard dosing schedule) with either PBO or capivasertib (400 mg twice daily; 4 days on, 3 days off). Randomization was stratified by the presence of liver metastases, prior use of CDK4/6 inhibitors, and geographic location. AKT pathway alteration status (at least one qualifying PIK3CA, AKT1, or PTEN alteration) was determined using next-generation sequencing in tumor tissue. The dual primary endpoint was investigator-assessed PFS in the overall population and in patients with AKT pathway-altered tumors. Results: A total of 708 patients were randomized: 355 to capivasertib + fulvestrant and 353 to PBO + fulvestrant. Overall, 41% of patients had AKT pathway-altered tumors (48% [n=289/602] of patients with tumor sequencing results), 22% were pre/perimenopausal and 77% postmenopausal, with 1% male. Prior therapy for advanced disease included: 87% of patients with ≥1 line of prior treatment, 69% with a prior CDK4/6 inhibitor, and 18% with prior chemotherapy. Demographic and baseline characteristics were broadly balanced between the overall and altered populations and by treatment groups. At primary analysis (data cut-off Aug 15, 2022), 551 and 236 PFS events had occurred in the overall and pathway-altered populations, respectively. Overall, the median PFS was 7.2 months with capivasertib + fulvestrant and 3.6 months with PBO + fulvestrant (hazard ratio [HR] 0.60; 95% confidence interval [CI] 0.51–0.71; p<0.001). In patients with AKT pathway-altered tumors, median PFS was 7.3 months with capivasertib + fulvestrant and 3.1 months with PBO + fulvestrant (HR 0.50; 95% CI 0.38–0.65; p<0.001). The objective response rate in patients with measurable disease was 22.9% for capivasertib + fulvestrant vs 12.2% for PBO + fulvestrant overall and 28.8% vs 9.7% in the AKT pathway-altered population. The most frequent all-grade adverse events (AEs) with capivasertib + fulvestrant were diarrhea (72.4% vs 20.0% PBO + fulvestrant arm), rash (group term of rash, rash macular, rash maculo-papular, rash papular, rash pruritic; 38.0% vs 7.1%) and nausea (34.6% vs 15.4%). The most frequently reported grade ≥3 AEs were rash (group term; 12.1% vs 0.3%), diarrhea (9.3% vs 0.3%), and hyperglycemia (2.3% vs 0.3%); grade ≥3 stomatitis was 2.0% vs 0%. AEs leading to discontinuation of capivasertib/placebo were reported in 13.0% and 2.3% of patients, respectively. Conclusions: Capivasertib + fulvestrant significantly improved PFS compared to fulvestrant alone in the overall population, and in patients with AKT pathway-altered tumors, and may become a future treatment option in this setting. The safety profile of capivasertib + fulvestrant was generally manageable and consistent with prior data. Funding: CAPItello-291 is sponsored by AstraZeneca. Editorial acknowledgment: AstraZeneca-funded medical writing support was provided by Suzanne Patel, Ph.D., from BOLDSCIENCE Inc. Capivasertib was discovered by AstraZeneca subsequent to a collaboration with Astex Therapeutics (and its collaboration with the Institute of Cancer Research and Cancer Research Technology Limited). Citation Format: Nicholas Turner, Mafalda Oliveira, Sacha J. Howell, Florence Dalenc, Javier Cortés, Henry Gomez, Xichun Hu, Komal Jhaveri, Sibylle Loibl, Serafin Morales Murillo, Zbigniew Nowecki, Meena Okera, Yeon H. Park, Masakazu Toi, Lyudmila Zhukova, Chris Yan, Gaia Schiavon, Andrew Foxley, Hope Rugo. GS3-04 Capivasertib and fulvestrant for patients with aromatase inhibitor-resistant hormone receptor-positive/human epidermal growth factor receptor 2-negative advanced breast cancer: results from the Phase III CAPItello-291 trial [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr GS3-04.