Sibylle Loibl’s research while affiliated with Vrana GmbH (Germany) and other places

LBA1008 Background: DESTINY-Breast09 (NCT04784715) is a global, randomized Phase 3 study assessing the efficacy and safety of 1L T-DXd ± P vs THP in 1157 pts with HER2+ a/mBC. The CLEOPATRA study established THP as standard of care in this setting over a decade ago. Methods: Eligible pts had centrally confirmed HER2+ (IHC 3+ or ISH+) a/mBC and no prior chemotherapy or HER2-directed therapy for a/mBC ([neo]adjuvant HER2-directed therapy / chemotherapy with a disease-free interval of >6 months [mo] and ≤1 line of endocrine therapy for metastatic disease permitted). Pts were randomized 1:1:1 to T-DXd 5.4 mg/kg (+ placebo), T-DXd + P, or THP, stratified by de-novo vs recurrent disease, and hormone receptor (HR) and PIK3CA mutation status. In this planned interim analysis, data for T-DXd + P vs THP are presented; the T-DXd + placebo arm remains blinded until final PFS analysis. The primary endpoint was progression-free survival (PFS) by blinded independent central review (BICR) in the intent-to-treat population. Other endpoints included overall survival (OS), PFS by investigator (INV), objective response rate (ORR), duration of response (DOR), and safety. Results: Among the pts randomized to T-DXd + P (n=383) and THP (n=387), 52% had de-novo disease and 54% had HR+ status; demographic and disease characteristics were well balanced. At this interim data cutoff (Feb 26, 2025; median follow up 29 mo; 38% mature for PFS), T-DXd + P significantly improved PFS by BICR (hazard ratio 0.56; 95% CI 0.44, 0.71; P<0.00001) and INV (Table). PFS benefit was consistent across all subgroups. OS data were immature. Median response duration with T-DXd + P exceeded 3 years (Table). Grade ≥3 treatment-emergent adverse events (TEAEs) occurred in 63.5% and 62.3%, and serious TEAEs in 27.0% and 25.1%, of pts in the T-DXd + P and THP groups, respectively. Adjudicated drug-related interstitial lung disease/pneumonitis occurred in 46 (12.1%; predominantly Gr 1/2; n=2 [0.5%] Gr 5) pts who received T-DXd + P, and 4 (1.0%; all Gr 1/2) who received THP. Conclusion: T-DXd + P demonstrated a statistically significant and clinically meaningful improvement in PFS vs THP that was consistently observed across all subgroups and may represent a new 1L standard of care in HER2+ a/mBC; no new safety signals were identified. Clinical trial information: NCT04784715 . T-DXd + P(n=383) THP(n=387) Median PFS by BICR (95% CI), mo 40.7(36.5, NC) 26.9(21.8, NC) Hazard ratio (95% CI) vs THP 0.56(0.44, 0.71); P<0.00001 – 24-mo PFS rate (95% CI), % 70.1(64.8, 74.8) 52.1(46.4, 57.5) Median PFS by INV (95% CI), mo 40.7 (36.5, NC) 20.7 (17.3, 23.5) Hazard ratio (95% CI) vs THP 0.49 (0.39, 0.61) – Confirmed ORR by BICR (95% CI), % 85.1(81.2, 88.5) 78.6(74.1, 82.5) Complete response rate, % 15.1 8.5 Median DOR by BICR (95% CI), mo 39.2 (35.1, NC) 26.4 (22.3, NC) NC, not calculable.

526 Background: The PALLAS trial (NCT02513394) investigated the efficacy of the addition of palbociclib (palbo) to standard adjuvant endocrine therapy (ET) to reduce breast cancer recurrence. Previous analyses of this trial have not shown significant benefit of combination palbo+ET over ET alone. Given prior data showing that extent of neutropenia is associated with response to palbo and other cell cycle-specific therapies, we evaluated whether extent of neutropenia could identify responders to palbo in the adjuvant setting. Methods: PALLAS is a global, open-label, phase III trial that randomized patients (pts) with stage II-III hormone-receptor positive, HER2-negative breast cancer to receive ET for ≥5 years with or without standard-dose palbo for 2 years in 28-day cycles. The primary endpoint is invasive disease-free survival (iDFS). For this exploratory analysis, the palbo population was classified into pts with treatment-emergent high-grade neutropenia (HGN) with maximum grade ≥3 (absolute neutrophil count <1000), or low-grade/no neutropenia (LGN) with maximum grade <2; these groups were compared to each other and to the ET alone group for 5-year iDFS outcomes. Logistic regression examined individual baseline characteristics associated with HGN during the first 3 cycles within the palbo group. Impact of HGN during the first 3, 6, and 12 cycles on iDFS was tested using univariate and multivariable landmark Cox regression. Results: The safety population included 5736 pts, 2840 allocated to palbo+ET, 2896 to ET alone. Prior publications reported no new safety signals, low rates of serious infection, and no grade 5 treatment-related events. The palbo+ET group consisted of 1006 (35.4%) LGN and 1834 (64.6%) HGN. 5-year iDFS results are shown in the table. Pts who received palbo+ET and developed HGN by the end of cycle 6 had significantly improved 5-year iDFS compared to those who received ET alone (p=0.04), which remained statistically significant when adjusting for body mass index (BMI), prior chemotherapy, and race. Multivariable logistic regression showed lower BMI, prior chemotherapy, Asian race, and prior mastectomy were significantly associated with HGN (all p<0.05). Conclusions: In this exploratory analysis of the phase III PALLAS adjuvant trial, addition of palbo to ET appeared to be superior to ET alone in pts who developed HGN in the first 6 cycles of treatment but not in those who had LGN. These findings are consistent with observations in the metastatic setting suggesting that neutropenia could be a useful biomarker for palbo concentration and efficacy. Clinical trial information: NCT02513394 . Maximum grade neutropenia measured at end of cycle: 5-year iDFS Palbo+ET HGN (%) Palbo+ET LGN (%) ET alone (%) Hazard Ratio p-value 3 84.9 84.4 1.06 0.54 84.9 82.9 1.17 0.06 6 85.6 84.9 1.08 0.44 85.6 83.4 1.19 0.04 12 86.3 85.9 1.06 0.57 86.3 85.0 1.12 0.20

1003 Background: INAVO, a highly potent and selective PI3Kα inhibitor that also promotes mutated p110α degradation, is FDA-approved in combination with PALBO + FULV for PIK3CA -mutated, HR+, HER2–, endocrine-resistant aBC, based on the primary analysis of INAVO120 (NCT04191499), which showed a statistically significant and clinically meaningful investigator-assessed progression-free survival (INV-PFS) benefit in the INAVO arm vs. the PBO arm (hazard ratio 0.43; 95% confidence interval [CI] = 0.32–0.59; p < 0.0001). At that analysis, interim OS results were immature. Here we report the final OS analysis, including updated efficacy and safety. Methods: Pts received INAVO (9 mg orally once daily [PO QD]; Days 1–28 of each 28-day cycle)/PBO + PALBO (125 mg PO QD; Days 1–21 of each cycle) + FULV (500 mg intramuscularly; Cycle 1 Days 1 and 15 then every ~4 weeks). OS and objective response rate (ORR) were formally tested; updated INV-PFS and safety analyses are descriptive. Results: Data cut-off was Nov 15, 2024, at 34.2 months (mo) of median follow-up. Median OS was 34.0 mo (95% CI = 28.4–44.8) in the INAVO arm and 27.0 mo (95% CI = 22.8–38.7) in the PBO arm (stratified hazard ratio 0.67; 95% CI = 0.48–0.94; p = 0.0190 [boundary = 0.0469]). The OS benefit was consistent across key subgroups. The survival probability at 6, 12, 18, 24, and 30 mo was 96.8%, 87.0%, 74.3%, 65.8%, and 56.5% in the INAVO arm and 90.1%, 76.7%, 67.2%, 56.3%, and 46.3% in the PBO arm. ORR was 62.7% (95% CI = 54.8–70.2) and 28.0% (95% CI = 21.3–35.6), respectively (p < 0.0001). Median time to chemotherapy (TTC) was 35.6 mo (95% CI = 25.4–not reached) in the INAVO arm and 12.6 mo (95% CI = 10.4–16.1) in the PBO arm (stratified hazard ratio 0.43; 95% CI = 0.30–0.60). Updated median INV-PFS was 17.2 mo (95% CI = 11.6–22.2) in the INAVO arm and 7.3 mo (95% CI = 5.9–9.2) in the PBO arm (stratified hazard ratio 0.42; 95% CI = 0.32–0.55), with landmark analyses supporting durable benefit. 90.7% of pts in the INAVO arm and 84.7% in the PBO arm had grade 3/4 adverse events (AEs); there were no new grade 5 AEs; 63.4% and 13.5% experienced any-grade hyperglycemia (grouped term); and AEs led to INAVO and PBO discontinuation in 6.8% and 0.6% of pts, respectively. Conclusions: INAVO + PALBO + FULV demonstrated a statistically significant and clinically meaningful OS benefit compared with PBO + PALBO + FULV. Improvement in INV-PFS was maintained during longer follow-up, along with a substantial and statistically significant improvement in ORR. TTC was also substantially delayed (by ~2 years) by the addition of INAVO to PALBO + FULV. With longer exposure to INAVO, no new safety signals, nor changes in the safety profile, were noted, supporting good tolerability (reflected in low discontinuation due to AEs). Clinical trial information: NCT04191499 .

BACKGROUND In the phase 3, double-blind, randomized INAVO120 trial, treatment with inavolisib plus palbociclib–fulvestrant led to a significant progression-free survival benefit, as compared with placebo plus palbociclib–fulvestrant, among patients with PIK3CAmutated, hormone receptor–positive, human epidermal growth factor receptor 2 (HER2)–negative locally advanced or metastatic breast cancer who had had relapse during or within 12 months after completion of adjuvant endocrine therapy. METHODS We randomly assigned patients with PIK3CA-mutated, hormone receptor–positive, HER2-negative locally advanced or metastatic breast cancer who had had disease recurrence or progression during or within 12 months after completion of adjuvant endocrine therapy to receive inavolisib plus palbociclib–fulvestrant (inavolisib group) or placebo plus palbociclib–fulvestrant (placebo group). In the current report, we provide the results of the final analysis of overall survival, including updated data on efficacy and safety. RESULTS A total of 161 patients were assigned to the inavolisib group, and 164 to the placebo group. After a median follow-up of 34.2 months in the inavolisib group and 32.3 months in the placebo group, the median overall survival was 34.0 months (95% confidence interval [CI], 28.4 to 44.8) with inavolisib and 27.0 months (95% CI, 22.8 to 38.7) with placebo (hazard ratio for death, 0.67; 95% CI, 0.48 to 0.94; P = 0.02 [prespecified boundary for statistical significance, P<0.0469]). An objective response occurred in 62.7% (95% CI, 54.8 to 70.2) of patients in the inavolisib group and 28.0% (95% CI, 21.3 to 35.6) of those in the placebo group (P<0.001). The updated hazard ratio for disease progression or death was 0.42 (95% CI, 0.32 to 0.55). Adverse events led to discontinuation of inavolisib in 6.8% of patients and discontinuation of placebo in 0.6%. The incidence of hyperglycemia, stomatitis or mucosal inflammation, gastrointestinal toxic effects (e.g., diarrhea), and ocular toxic effects (e.g., dry eye and blurred vision) was higher with inavolisib than with placebo. CONCLUSIONS Treatment with inavolisib plus palbociclib–fulvestrant led to a significant overall survival benefit, as compared with placebo plus palbociclib–fulvestrant. Hyperglycemia, stomatitis or mucosal inflammation, gastrointestinal toxic effects, and ocular toxic effects were reported more frequently with inavolisib than with placebo. (Funded by F. Hoffmann–La Roche; INAVO120 ClinicalTrials.gov number, NCT04191499.)

Breast cancer diagnosed during pregnancy (PrBC) is a rare occurrence but may become more prevalent as women nowadays tend to postpone childbearing until later in life. Further understanding of how pregnancy affects the tumor microenvironment (TME) is essential. We constructed Tissue Microarrays (TMA) of tumor specimens from 126 pregnant breast cancer (BC) patients and examined standard BC markers such as ER, PR, Ki67, HER2, tumor infiltrating lymphocytes (TILs), and immunomarkers HLA class I, HLA-G, PD-L1, TIGIT and Nectin-4. Subsequently, we compared our findings with those from a matched non-pregnant cohort of young BC patients. Pregnant BC patients were younger, had significantly higher proliferation rates and a higher expression of Nectin-4. Higher pregnancy related estrogen levels may boost proliferation und Nectin-4 overexpression, promoting BC progression. No further evidence supporting impaired maternal anti-tumor response in BC was observed in this study.

Triple-negative breast cancer (TNBC) is an aggressive biological subtype that accounts for 10–20% of invasive breast cancer and is associated with a worse prognosis. Advances in the understanding of tumor biology and the role of tumor-infiltrating lymphocytes (TILs) in breast cancer have paved way for clinical research evaluating immunotherapy in breast cancer, specifically TNBC. Efforts to delineate the role of immune checkpoint inhibitors in TNBC have culminated in several randomized controlled trials evaluating anti-PD-(L)1 antibodies in combination with chemotherapy, both in the metastatic and early breast cancer settings. As a result, therapy with immune checkpoint inhibitors has been integrated into the standard treatment regimens of stage II-III early TNBC, representing a crucial addition to the limited available treatments for this tumor subtype. In this chapter, we present a synthesis of the results of clinical trials that investigated the use of immunotherapy in breast cancer, particularly TNBC, with emphasis on efficacy and safety in the neoadjuvant and adjuvant settings.

The European Union-sponsored ONCOBIOME network has spurred an international effort to identify and validate relevant gut microbiota-related biomarkers in oncology, generating a unique and publicly available microbiome resource. ONCOBIOME explores the effects of the microbiota on gut permeability and metabolism as well as on antimicrobial and antitumor immune responses. Methods for the diagnosis of gut dysbiosis have been developed based on oncomicrobiome signatures associated with the diagnosis, prognosis and treatment responses in patients with cancer. The mechanisms explaining how dysbiosis compromises natural or therapy-induced immunosurveillance have been explored. Through its integrative approach of leveraging multiple cohorts across populations, cancer types and stages, ONCOBIOME has laid the theoretical and practical foundations for the recognition of microbiota alterations as a hallmark of cancer. ONCOBIOME has launched microbiota-centered interventions and lobbies in favor of official guidelines for avoiding diet-induced or iatrogenic (for example, antibiotic- or proton pump inhibitor-induced) dysbiosis. Here, we review the key advances of the ONCOBIOME network and discuss the progress toward translating these into oncology clinical practice.

As part of the COGNITION diagnostic registry program, residual tumor material after neoadjuvant therapy (NAT) of patients with early breast cancer (eBC), who are still at high-risk for relapse after NAT, is analyzed by next generation sequencing to identify biomarkers and actionable alterations. This strategy aims to stratify patients for subsequent genomics-guided therapies to reduce the significant risk of metastatic dissemination and hence to improve disease-free survival. COGNITION-GUIDE is a multicenter umbrella phase-II-trial to translate molecular biomarker profiles generated in the COGNITION platform into six molecular-guided post-neoadjuvant therapeutic options in addition to standard-of-care treatment. Patients can be allocated to The primary endpoint is invasive disease-free survival (IDFS) four years after surgery. Secondary endpoints include IDFS in each study arm separately, distant disease-free survival, overall survival and safety. 240 patients will be enrolled within four years. The COGNITION-GUIDE trial, which was activated in June 2023 and will recruit in different centers in Germany, empowers a risk-adapted, biomarker-guided therapy escalation algorithm in eBC patients who are still at high risk of metastasis.

PURPOSE The PENELOPE-B trial (ClinicalTrials.gov identifier: NCT01864746 ) recruited patients with hormone receptor+/human epidermal growth factor receptor 2– early breast cancer without a pathological complete response after taxane-containing neoadjuvant chemotherapy and at a high risk of relapse. Patients were randomly assigned (1:1) to receive 13 cycles of palbociclib once daily or placebo on days 1-21 in a 28-day cycle in addition to endocrine therapy (ET). PENELOPE-B did not show improved invasive disease-free survival (iDFS) after adding palbociclib to ET. This retrospective analysis investigated the impact of germline pathogenic variant (PV) status of BRCA1/2 and non- BRCA1/2 cancer predisposition genes on the outcomes of PENELOPE-B trial patients. METHODS In total, 445 patients were sampled following a case-cohort design and 442 were analyzed for germline PVs. Statistical analyses were performed for time-to-event end points (iDFS, distant disease-free survival [DDFS], and overall survival [OS]). RESULTS Of the 442 patients, 42 carried PVs in any cancer predisposition gene; 15 carried BRCA1/2 PVs. Irrespective of the treatment arms, PV status was not a prognostic factor. Regarding the treatment arms in BRCA1/2 PV carriers, numerically better 3-year outcomes were observed in the palbociclib arm (iDFS, 95%; DDFS, 95%; OS, 100%) than in the placebo arm (iDFS, 72.8%; DDFS, 72.8%; OS, 87.5%; hazard ratios palbociclib v placebo 0.349 [iDFS] and 0.562 [DDFS], not calculated for OS, too few events). In patients without BRCA1/2 PVs, the differences in 3-year outcomes were negligible. PVs in non- BRCA1/2 cancer predisposition genes did not influence the efficacy of palbociclib, although gene-specific effects could not be excluded. CONCLUSION Patients with BRCA1/2 PVs had numerically better outcomes after palbociclib. However, the number of BRCA1/2 carriers was small. Larger randomized clinical trials should consider the PV status to further evaluate whether BRCA1/2 PV carriers benefit from cyclin-dependent kinase 4 and 6 inhibitor treatment.