AstraZeneca (Netherlands)

The need for SARS-CoV-2 vaccines with improved potency, lower reactogenicity, broader coverage, and prolonged protection persists. We examined the safety and immunogenicity of two ferritin scaffold-based self-assembling SARS-CoV-2 mRNA virus-like particle (VLP) vaccines. In this, randomized, Phase I, open-label, active-controlled study (www. govNCT06147063) participants received a single 5μg or 10μg intramuscular injection of AZD9838 (BA.4/5 variant) or AZD6563 (XBB.1.5 variant), or 30μg BNT162b2, a licensed mRNA vaccine (XBB.1.5 variant). The primary safety endpoint was the incidence of solicited adverse reactions (ARs) through Day 8, unsolicited adverse events (AEs) through Day 29, and serious AEs (SAEs), medically attended AEs (MAAEs), and AEs of special interest (AESIs) through Day 361. The primary immunogenicity endpoint was to characterize the neutralizing antibody (nAb) responses to the ancestral and Omicron (BA.4/5, XBB.1.5) variants at Day 29; characterization of nAb response to Omicron JN.1 was an exploratory analysis. In total, 166 participants aged 18-64years and 76 participants ≥65years of age were vaccinated. AZD9838 and AZD6563 were well-tolerated at both dosages. Overall, fewer solicited ARs were reported with AZD9838 and AZD6563 versus BNT162b2. Unsolicited AEs were similar between groups; no related SAEs, AESIs, or MAAEs were reported to Day 180. Day 29 nAb GMTs were higher following 10μg AZD6563 versus 5μg and higher than AZD9838 across variants and age groups, remaining above baseline and similar to BNT162b2 at Day 180; 10μg AZD6563 resulted in nAb GMTs similar to BNT162b2 in both age groups. By combining mRNA vaccine technology with VLP-based antigen display, we developed two candidate SARS-CoV-2 vaccines, AZD9838 and AZD6563, that were well tolerated versus a licensed mRNA vaccine, BNT162b2. Furthermore, the variant-matched AZD6563 generated a similar immunogenicity to BNT162b2 but at one third of the dosage (10μg versus 30μg).

Abstract Background: T-DXd is approved for the treatment of adult pts with HER2+ mBC who have received a prior anti-HER2-based regimen. Recent results from the planned interim analysis of the Phase 3 DESTINY-Breast09 study demonstrated a statistically significant and clinically meaningful improvement in progression-free survival (PFS) by blinded independent central review for T-DXd + pertuzumab versus standard of care (taxane + trastuzumab + pertuzumab) in first-line (1L) HER2+ mBC (median 40.7 vs 26.9 months; hazard ratio 0.56 [95% CI 0.44, 0.71]). The T-DXd monotherapy module remains blinded until final PFS analysis. DESTINY-Breast07 (NCT04538742; initiated prior to DESTINY-Breast09) was a Phase 1b/2 multicenter, open-label, modular study exploring the safety, tolerability, and antitumor activity of T-DXd ± other anticancer agents in HER2+ mBC. Results presented are from the final analysis of the dose-expansion phase assessing T-DXd ± pertuzumab as 1L treatment in HER2+ mBC. Methods: Eligible pts had locally assessed HER2+ (immunohistochemistry [IHC] 3+ or IHC 2+ / in situ hybridization-positive) mBC. No prior therapy for mBC was allowed and a disease-free interval of ≥12 months from (neo)adjuvant therapy was required. Pts were stratified by hormone receptor status (positive [estrogen or progesterone receptor ≥1%] vs negative), disease status (recurrent vs de novo), and PD-L1 expression (positive [IHC ≥1%] vs negative). Pts received T-DXd 5.4 mg/kg intravenously (IV) every 3 weeks (Q3W) as monotherapy or in combination with pertuzumab 420 mg IV Q3W, with an 840-mg loading dose. Primary endpoints were safety and tolerability; secondary endpoints included objective response rate (ORR), duration of response, and PFS, per RECIST 1.1 by investigator, as well as time to progression on subsequent therapy (PFS2) by investigator, and overall survival (OS). Results: At final data cutoff (January 31, 2025), 75 pts in the T-DXd module and 50 pts in the T-DXd + pertuzumab module had received study treatment; demographics and disease characteristics were well balanced. Median follow up was 37.1 months with T-DXd and 38.6 months with T-DXd + pertuzumab. Median total treatment duration was 26.8 months in the T-DXd module, and 27.6 months for T-DXd and 26.0 months for pertuzumab in the T-DXd + pertuzumab module. Confirmed ORR (80% CI) was 78.7% (71.4, 84.7) with T-DXd and 84.0% (75.3, 90.5) with T-DXd + pertuzumab. At 36 months, 65.5% and 69.4% of pts remained in response in the T-DXd and T-DXd + pertuzumab modules, respectively. At study completion, median PFS and median OS were not reached for either module. The 80% CI lower limit for median PFS was 40.2 months for T-DXd + pertuzumab; all other CI limits were not evaluable. PFS rate (80% CI) at 24 months was 71.4% (63.5, 77.8) with T-DXd and 67.8% (58.2, 75.7) with T-DXd + pertuzumab. Grade ≥3 adverse events (AEs) occurred in 57.3% (n=43/75) and 62.0% (n=31/50), and serious AEs in 21.3% (n=16/75) and 28.0% (n=14/50), of pts in the T-DXd and T-DXd + pertuzumab modules, respectively. Adjudicated drug-related interstitial lung disease / pneumonitis events occurred in 11 (14.7%; Grade 1, n=3; Grade 2, n=8) pts who received T-DXd and 7 (14.0%; Grade 2, n=6; Grade 3, n=1) who received T-DXd + pertuzumab. Additional data by subgroup, including biomarker analyses, will be presented. Conclusion: In this Phase 1b/2 DESTINY-Breast07 study, safety profiles for T-DXd and pertuzumab were generally consistent with the known profiles of each agent. Encouraging clinical activity was demonstrated in pts who received either T-DXd monotherapy or T-DXd + pertuzumab as a 1L treatment for HER2+ mBC; results from the T-DXd + pertuzumab module are consistent with the interim findings from the Phase 3 DESTINY-Breast09 study. Citation Format: F. André, E. Hamilton, S. Loi, C. Anders, P. Schmid, E. Artamonova, R. Villanueva-Vázquez, J. Pedrini, D. Doval, S. C. Chen, S. Boston, A. Konpa, M. Markowska, G. Fabbri, K. Jhaveri. Trastuzumab deruxtecan (T-DXd) monotherapy and T-DXd + pertuzumab in patients (pts) with previously untreated HER2+ unresectable/metastatic breast cancer (mBC): final results from DESTINY-Breast07 [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS5-01-14.

Abstract Background: In patients with hormone receptor-positive/human epidermal growth factor receptor 2-negative metastatic breast cancer (MBC) with ≥ 1 PIK3CA, AKT1, or PTEN tumor alterations, capivasertib plus fulvestrant is approved in the US for use after progression on at least one endocrine-based treatment. This study assessed real-world treatment patterns of capivasertib in the US. Methods: This retrospective cohort study used Flatiron Health electronic health record-derived database. Eligible patients were ≥18 years, diagnosed with MBC, initiated capivasertib between November 16, 2023 and July 31, 2024, and had at least 6 months (mos) of potential follow-up time from capivasertib initiation (index date). Real-world time to treatment discontinuation (rwTTD) and time to next line of treatment (rwTTNT) were assessed from the index date. Summary statistics were used to describe patient characteristics at baseline and treatment patterns. rwTTD and rwTTNT were estimated using Kaplan-Meier methods. The line of therapy (LOT) was defined using an algorithm that incorporated prior treatment use. Results: This study identified 412 patients with MBC who received capivasertib. The median age was 67 years (IQR 60, 75). The majority were female (98.8%), white (71.6%), and from community practice settings (83.0%). Prior to capivasertib initiation, sites of disease included: bone (91.0%), liver (44.2%), lung (28.2%), and brain (7.0%). PIK3CA, AKT1, or PTEN alterations were documented in 90.3% of patients: PIK3CA (75.0%), PTEN (14.3%), and AKT1 (10.0%) alterations. Co-mutations with ESR1 mutations were observed in 25.5% of patients. Prior therapies for MBC included: CDK4/6 inhibitors (87.1%), fulvestrant (66.0%), chemotherapy (31.8%), alpelisib (20.6%), and antibody-drug conjugates (14.1%) in any prior LOT. Most patients received capivasertib with fulvestrant (n=387, 93.9%); in 25 patients (6.1%), use with another endocrine therapy/combination or alone was recorded in the chart, but could not be verified due to data limitations. Among patients recorded as having received capivasertib with fulvestrant (n=387/412, 93.9%), more than half of patients received capivasertib in second-line (2L) (n=115, 29.7%) or 3L (n=102, 26.4%), though many were treated in 4L+ (n=146, 37.7%). 2L and 3L median rwTTNT was 7.1 mos (IQR 5.8, NE) and 6.9 mos (IQR 6.1, 7.8), respectively. 2L and 3L median rwTTD was 6.9 mos (IQR 5.3, NE) and 6.6 mos (IQR 5.2, 7.1), respectively (Table 1). Conclusions: Findings from this large database analysis of US patients demonstrate the effectiveness of capivasertib + fulvestrant in real-world practice. Clinical outcomes in 2L and 3L closely match those observed in the CAPItello-291 Phase 3 randomized controlled trial, which supported FDA approval of the capivasertib + fulvestrant regimen. Numerically improved outcomes were observed in patients who used capivasertib in earlier vs later line settings. Citation Format: K. H. Natsuhara, L. Park, S. Udayachalerm, R. Mireia, B. Murphy, B. Nordstrom, L. A. Huppert. Real-world Treatment Patterns of Capivasertib in Metastatic Breast Cancer in the US [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS5-05-23.

HER2-directed treatments for HER2-overexpressing (HER2-OE; immunohistochemistry [IHC] 3+/2+) NSCLC are needed. DESTINY-Lung03 is an open-label, multi-arm, phase 1b study. Part 1 evaluated trastuzumab deruxtecan (T-DXd, 4.4 or 5.4 mg/kg) plus durvalumab (1120 mg) and cisplatin (60 or 75 mg/m2; Arm 1A)/carboplatin (area under the plasma concentration-time curve [AUC] 4 or 5; Arm 1B) or T-DXd 5.4 mg/kg monotherapy (Arm 1D) in pretreated metastatic HER2-OE NSCLC. Primary end points: dose-limiting toxicities (DLTs) and adverse events (AEs: Arms 1A and 1B). Secondary end points: safety (Arm 1D) and efficacy (all arms). At data cutoff (April 1, 2024), 11, 24, and 36 patients received treatment in Arms 1A, 1B, and 1D, respectively. DLTs reported in Arm 1A: febrile neutropenia (n = 1; grade [G] 5; 4.4 mg/kg/1120 mg/60 mg/m2 doses); decreased platelet count (n = 2; G4 and G5; 5.4 mg/kg/1120 mg/75 mg/m2 doses). DLTs reported in Arm 1B: febrile neutropenia (n = 1; G3; 4.4 mg/kg/1120 mg/AUC 5 doses; n = 1; G4; 4.4 mg/kg/1120 mg/AUC 4 doses); decreased platelet count (n = 1; G4; 5.4 mg/kg/1120 mg/AUC 5 doses). Drug-related serious AEs occurred in 63.6%, 37.5%, and 16.7% of Arms 1A, 1B, and 1D, respectively. Confirmed objective response rate (95% confidence interval) per investigator: 37.5% (18.8-59.4; Arm 1B) and 44.4% (27.9-61.9; Arm 1D). Data confirm the activity of T-DXd monotherapy in pretreated HER2-OE NSCLC but do not support T-DXd plus durvalumab and platinum chemotherapy use in this population. NCT04686305.