Search

Background: For HR+/HER2- metastatic breast cancer (MBC) patients, after resistance to endocrine therapy (ET), treatment options are mostly limited to traditional chemotherapies (CT) that offer poor survival and quality of life (QoL), creating an area of unmet need. The antibody-drug conjugate sacituzumab govitecan (SG) comprises an anti-Trop-2 antibody coupled to SN-38 via a hydrolyzable linker. In the phase 3 TROPiCS-02 trial, heavily pretreated patients with relapsed/refractory HR+/HER2- MBC received SG vs single-agent chemotherapy treatment of physician’s choice (TPC). The study met its primary endpoint of improved progression-free survival with SG vs TPC. Here, we report the effect of SG vs TPC on patient-reported outcomes (PROs) from TROPiCS-02. Patients and Methods: Patients who had received ≥1 CDK 4/6 inhibitor, ≥1 ET, and 2-4 prior lines of CT were randomized to receive SG (10 mg/kg intravenous on days 1 and 8 of a 21-day treatment cycle) or TPC (capecitabine, eribulin, gemcitabine, or vinorelbine). In the PRO-evaluable population (all randomized patients with an evaluable assessment at baseline (BL) and ≥1 post-BL visit) SG and TPC were compared regarding time to first clinically meaningful worsening (TTD) or death from BL on the EORTC QLQ-C30 domains (≥10 points), EQ-5D-5L health utility index (≥0.08 points), and EQ-VAS (≥7 points). For the EORTC QLQ-C30 function and global health status/QoL domains, patients with a BL score ≥10 and for symptom scales, patients with a BL score ≤90 were included. In the safety population (all randomized patients who received ≥1 dose of study drug), SG and TPC were compared regarding worst level of toxicities during treatment for the PRO-CTCAE items. For TTD, a stratified Cox proportional hazards regression analysis was conducted and the PRO-CTCAE items were summarized descriptively (numbers and percentages). Results: Of 543 randomized patients, 446 (82%), 445 (82%), and 517 (95%) were included in the PRO-evaluable population (EORTC QLQ-C30: SG vs TPC n=236 vs 210 and EQ-5D-5L: n=238 vs 207) and in the safety population for PRO-CTCAE (SG vs TPC n=268 vs 249), respectively. TTD of EORTC QLQ-C30 global health status/QoL, physical functioning, emotional functioning, fatigue, dyspnea, insomnia, and financial difficulties and EQ-VAS were significantly longer in the SG vs the TPC arm (Table). TTD of EORTC QLQ-C30 diarrhea was significantly shorter for SG vs TPC. For PRO-CTCAE items, decreased appetite, nausea, vomiting, constipation, abdominal pain, shortness of breath, and fatigue were similar between SG and TPC arms, whereas frequency of diarrhea and amount of hair loss were higher in the SG vs TPC arm. Conclusions: In this trial, SG significantly delayed worsening of overall QoL, physical and emotional functioning, and symptoms like fatigue, dyspnea, and insomnia. Overall, our findings suggest that SG has more favorable effects on PROs compared with TPC in pts with HR+/HER2- MBC. Table: Time to First Clinically Meaningful Deterioration PRO Scores Citation Format: Frederik Marmé, Aditya Bardia, Hope Rugo, Peter Schmid, Sara M. Tolaney, Mafalda Oliveira, Andreas Schneeweiss, Ling Shi, Wendy Verret, Mahdi Gharaibeh, Anju Shah, Javier Cortés. Effect of sacituzumab govitecan vs chemotherapy in HR+/HER2- metastatic breast cancer: patient-reported outcomes from the TROPiCS-02 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 P4-07-65.

Background: Residual disease (RD) following neoadjuvant chemotherapy (NAC) in early HER2-negative breast cancer (BC) remains an unmet medical need. However, no therapies to date have tested their activity directly in chemo-resistant RD. Here, we hypothesized that combining an oncolytic virus such as T-VEC with atezolizumab may offer clinical benefit in patients (pts) with RD after standard NAC. To our knowledge, PROMETEO is the first trial that examines the activity of immunotherapy in pts with RD prior to surgery. Methods: PROMETEO (NCT03802604) is a single-arm, open-label, multicenter phase II trial. Women with triple-negative BC (TNBC) or hormone receptor-positive/HER2-negative (HR+/HER2-) BC with baseline (i.e., before NAC) ki67 ≥ 20% were eligible. RD was confirmed with a magnetic resonance imaging (MRI) showing a tumor diameter ≥ 10 mm and a core-biopsy detecting the presence of invasive cells. Before surgery, T-VEC was administered intratumorally on week 1 (106 pfu/mL), then in week 4 and every 2 weeks thereafter (108 pfu/mL) for 4 injections. Atezolizumab (840 mg) was administered intravenously every 2 weeks for 4 infusions, starting at week 4. Surgery was performed in < 3 weeks after completing the treatment. The primary objective was to evaluate the efficacy of the combination, measured by the rate of residual cancer burden (RCB) class 0/1 at surgery. Tumor samples collected at 5 timepoints (before NAC, during screening period, after first dose of T-VEC, after first dose of T-VEC and atezolizumab and at surgery) were mandatory to assess gene expression, tumor-infiltrating lymphocytes (TILs), immune cells PD-L1 IHC (SP142), tumor mutational burden (TMB) by FoundationOne and other translational endpoints. Results: Between Dec 2018 to Feb 2022, 28 pts were enrolled: 20 pts with HR+/HER2- disease and 8 pts with TNBC. Median age was 47 (range 31-71) and 71% of pts were premenopausal. At diagnosis before NAC, clinical stage II disease represented 60.7%, cN+ 60.7%, median Ki-67 was 37.5% (range 20%-95%), high TILs (≥10%) 37%, median TMB was 3 (0-19) and only 1 of 27 pts (3.7%) had a PD-L1-positive tumor. After NAC, mean tumor size by MRI was 28.3 mm (10-93). Two pts discontinued from the trial (1 withdrawal of consent and 1 COVID infection). The completion of 5 cycles of treatment was achieved by 73% of pts. The overall RCB-0/1 rate was 25% (7 of 28, 95% IC 10.7 – 44.9%), all with RCB 0 (pathologic complete response [pCR]). The pCR rate was 30% in HR+/HER2- disease and 12.5 % in TNBC. Radiological response by MRI was achieved by 3 of 28 pts (10.7%). Interestingly, none of the 7 pts with a pCR had radiological response (stable disease n=5, progressive disease [PD] n=2). Six pts (21.4%) had radiological PD and had RCB 2/3. Overall, 27 (96%) patients had at least one treatment-emergent adverse event (TEAE) of any grade. Most common grade 1 or 2 AEs were fever (11 pts, 39.3%), ALT increased (9 pts, 32.1%), AST increased (8 pts, 28.6%), arthralgia (6 pts, 21.4%) and anemia (6 pts, 21.4%). Grade 3 reversible neutropenia occurred in 1 patient. Across all pts, significant increases (p< 0.001) in TILs, immune genes and immune PDL1+ cells were observed after 1 dose of TVEC, 1 dose of the combination and at surgery. Intrinsic subtype changes at surgery occurred in 73.1% of cases, mostly (46.1%) Luminal A/B converting to Normal-like. At surgery, 19 of 26 (73.1%) of tumors were PDL1+. Conclusions: Two months of T-VEC in combination with atezolizumab induced a pCR in a subgroup of pts with chemoresistant HER2- breast cancer. This effect is probably related to the immune activation provoked by the combined treatment. Interestingly, a high discrepancy was observed between the pre-surgical radiological imaging and the actual surgical pathological report. Pre-operative window-of-opportunity trials in this context might provide important clues regarding the activity of novel treatment strategies. Citation Format: Tomás Pascual, Maria Vidal, Juan Miguel Cejalvo, Estela Vega, Esther Sanfeliu, Sergi Ganau, Ana Julve, Esther Zamora, Ignacio Miranda, Ana Delgado, Begoña Bermejo, Luis de la Cruz-Merino, Manel Juan, Patricia Galván, Xavier Gonzalez-Farré, Juan Manuel Ferrero-Cafiero, Patricia Villagrasa, Mafalda Oliveira, Aleix Prat. PD11-04 Primary results of SOLTI-1503 PROMETEO phase 2 trial of Combination of Talimogene Laherparepvec (T-VEC) with Atezolizumab in patients with residual breast cancer after standard neoadjuvant multi-agent chemotherapy [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 PD11-04.

Background Within HR+/HER2- disease, patients with non-luminal subtypes of breast cancer (HER2-enriched [HER2-E] and Basal-like) have poorer prognosis than those with luminal subtypes, may be more sensitive to chemotherapy, and have higher expression of immune-related genes and tumor infiltrating lymphocytes (TILs). Here, we report the interim efficacy and safety data of the TATEN trial (NCT04251169), the first study designed to evaluate pembrolizumab and paclitaxel in HR+/HER2-negative, PAM50 non-luminal, metastatic breast cancer (MBC). Methods TATEN is a single-arm, multicenter phase II study evaluating pembrolizumab in combination with paclitaxel in patients with HR+/HER2-, PAM50 non-luminal, MBC. Key inclusion criteria include progression to prior CDK4/6 inhibitors, presence of measurable disease by RECIST V1.1, no prior chemotherapy for MBC, and ECOG 0-1. Patients receive pembrolizumab at 200 mg every 3 weeks (on D1 of each 21-day cycle, beginning at cycle 1) in combination with weekly paclitaxel at 80 mg/m2, beginning at cycle 2. The primary endpoint is to evaluate overall response rate (ORR), defined as the rate of complete (CR) and partial response (PR) according to RECIST V1.1. Secondary endpoints include clinical benefit rate (CBR; CR + PR + stable disease >24 weeks), progression free survival, overall survival, safety, and predictive biomarkers. Tumor samples collected during advanced/metastatic disease are mandatory to assess PAM50 and other translational endpoints. This study had a planned interim analysis after 15 patients were evaluable for ORR based on a Simon’s two stage design with 80% power and a type I error rate of 0.05. Stage I of the trial would be considered successful if at least 6 patients achieved a PR and/or CR. In that case, the trial would recruit up to 46 evaluable patients for a target ORR ≥ 41. Here we report results from the patients who received at least one dose of combination treatment and had a first, post-baseline, tumor assessment according to RECIST v1.1 (evaluable population). Results From July 2020 to December 2021, 119 patients were screened, and 25 PAM50 non-luminal tumors were identified (21%). From these, 17 (68%) patients were recruited, and 15 were evaluable for primary endpoint. Two patients discontinued the trial before the first dose of pembrolizumab and paclitaxel, because of clinical progressive disease (PD). Baseline patient characteristics were as follows: median age 53 years (range: 40-77), ECOG 0 52.9%, de novo MBC at diagnosis 29.4%, and visceral disease 64.7% (including 53.3% with liver metastasis). Ten patients had received paclitaxel treatment in the adjuvant setting. Regarding PAM50 intrinsic subtype, two patients had basal-like and 13 HER2-E tumors. At the time of data cut-off (May 17,2022), 8 patients (53.3%) had stopped their treatment because of PD and 2 (13.3%) due to toxicity. Five patients (33.3%) were still on treatment. The ORR was 53.3 % (8 of 15, 95% CI 26.6-78.7), meeting the pre-specified ORR for the first stage of the trial. The CBR was 86.6% (13 of 15, 95%CI 59.5-98.34), and median PFS was 7.5 months (95% CI: 5.6 – 10.2). Overall, all patients experienced treatment-related adverse events (TRAEs) of any grade, while 53.3% of patients experienced grade 3 TRAEs. No grade 4 or 5 TRAEs were reported in the evaluable population. Correlative analysis including gene expression analysis and centralized TILs scoring and PD-L1 IHC will be presented. Conclusions The first stage of TATEN combining pembrolizumab with paclitaxel after progression to CDK4/6 inhibitors in patients with HR+/HER2-negative, PAM50 non-luminal MBC met its pre-specified endpoint. Completion of the stage II part of the trial with the inclusion of up to 46 patients is warranted to assess the activity of this combination in this group of patients. Correlative studies to find predictive biomarkers of response to this regimen are ongoing and will be presented at the meeting. This study was funded by MSD. Citation Format: Aleix Prat, Tomás Pascual, Montserrat Muñoz, Cristina Hernando, Silvia Vazquez, Salvador Blanch, Manuel Alva, Mafalda Oliveira, Esther Sanfeliu, Lorea Villanueva, Fara Brasó-Maristany, Nuria Chic, Eva Ciruelos. TATEN TRIAL (SOLTI-1716) Targeting non-Luminal disease by PAM50 with pembrolizumab + paclitaxel in Hormone Receptor-positive/HER2-negative (HR+/HER2-) metastatic breast cancer (MBC): interim analysis [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 P3-06-02.

Background Patients with metastatic triple-negative breast cancer (mTNBC) have a poor prognosis. Treatment combinations of anti-programmed death protein 1 (anti–PD-1) agents with chemotherapy have shown promise in mTNBC. Ladiratuzumab vedotin (LV) is an investigational antibody-drug conjugate directed to LIV-1, a protein highly expressed on breast cancer cells, via a humanized IgG1 monoclonal antibody conjugated to approximately 4 molecules of monomethyl auristatin E (MMAE) by a protease-cleavable linker. LIV-1–mediated delivery of MMAE disrupts microtubules and induces cell cycle arrest and apoptosis. LV has also been shown to drive immunogenic cell death (ICD) to elicit an immune response. LV + pembrolizumab may result in synergistic activity through LV-induced ICD, creating a microenvironment favorable for enhanced anti–PD-1 activity. Interim results from an ongoing, multi-part, open-label study investigating the safety and efficacy of LV in patients with metastatic breast cancer (SGNLVA-001, NCT01969643), showed weekly LV monotherapy at doses up to 1.5 mg/kg were clinically active and generally well tolerated (Tsai 2021). Based on pharmacokinetic and pharmacodynamic modeling and simulation analysis, an intermittent LV + pembrolizumab dosing regimen is being evaluated to further enhance efficacy and improve the tolerability profile. Due to an unmet medical need for patients with unresectable locally advanced (LA)/mTNBC who are programmed death ligand 1 (PD-L1) low or negative, Part D will focus on this patient population. Trial Design SGNLVA-002 (NCT03310957) is an ongoing global single-arm, open-label phase 1b/2 study of LV + pembrolizumab as 1L therapy for patients with unresectable LA/mTNBC. Part D is currently enrolling ~40 patients. Eligible patients must have advanced disease with no prior cytotoxic/anti–PD-1 treatment, PD-L1 combined positive score < 10, measurable disease per RECIST v1.1, and an ECOG performance status ≤1. Patients with Grade ≥2 pre-existing neuropathy or active central nervous system metastases are not permitted. Patients will receive LV at 1.5 mg/kg on Days 1 and 8 every 21 days plus pembrolizumab 200 mg on Day 1 q3w. The primary objectives are to evaluate the safety/tolerability and objective response rate of LV + pembrolizumab. Secondary objectives include duration of response, disease control rate, progression-free survival, and overall survival. Safety and efficacy endpoints will be summarized with descriptive statistics. Global enrollment is ongoing in the US, EU, and Asia. Citation Format: Patrick Dillon, Reva Basho, Hyo S. Han, Hans-Christian Kolberg, Katherine Tkaczuk, George Zahrah, Maria Gion, Herman Voss, Jane Meisel, Timothy Pluard, Jenny Fox, Mafalda Oliveira, Ursa Brown-Glaberman, Erica Stringer-Reasor, Luis Manso, Sherko Küemmel, Lin Chi Chen, Sheng Wu, Brandon Croft, Valentina Boni. Phase 1b/2 study of ladiratuzumab vedotin (LV) in combination with pembrolizumab for first-line treatment of triple-negative breast cancer (SGNLVA-002, trial in progress) [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 OT1-03-06.

Supplementary Table S1. IC50 values of ipatasertib on cell viability in cell lines with or without alterations in PTEN or PIK3CA. Supplementary Table S2. Percent tumor growth inhibition (%TGI) in xenograft models with or without alterations in PTEN or PIK3CA. Supplementary Table S3. PI3K/Akt pathway status in archival tumors. Supplementary Table S4. Reasons for discontinuation of study. Supplementary Table S5. Common adverse events for ipatasertib in {greater than or equal to} 10% of patients in any presented group. Supplementary Table S6. All Grade {greater than or equal to} 3 adverse events related to ipatasertib. Supplementary Table S7. Hemoglobin A1C (HgbA1C) values for patients who had both pre-treatment and post-treatment values in Stages 1 and 2. Supplementary Table S8. Summary data for patients with best radiographic stable disease (SD) by RECIST version 1.0 criteria. Supplementary Figure S1. Exposure plots confirm that exposures achieved in patients in the dose-escalation stage (right side) correlated with exposures in preclinical models at TGI90 (left side). Supplementary Figure S2. Relationship between exposure of ipatasertib to the most common ipatasertib-related AEs of fatigue, diarrhea, nausea, and rash. Supplementary Figure S3. Suppression of pGSK3β in platelet-rich plasma versus ipatasertib concentrations. Supplementary Figure S4. Pharmacodynamic (PD) dose-dependent elevations in glucose and insulin following treatment with ipatasertib.

AURORA aims to study the processes of relapse in metastatic breast cancer (MBC) by performing multi-omics profiling on paired primary tumors and early-course metastases. Among 381 patients (primary tumor and metastasis pairs: 252 targeted gene sequencing, 152 RNA sequencing, 67 single nucleotide polymorphism arrays), we found a driver role for GATA1 and MEN1 somatic mutations. Metastases were enriched in ESR1, PTEN, CDH1, PIK3CA, and RB1 mutations; MDM4 and MYC amplifications; and ARID1A deletions. An increase in clonality was observed in driver genes such as ERBB2 and RB1. Intrinsic subtype switching occurred in 36% of cases. Luminal A/B to HER2-enriched switching was associated with TP53 and/or PIK3CA mutations. Metastases had lower immune score and increased immune-permissive cells. High tumor mutational burden correlated to shorter time to relapse in HR+/HER2− cancers. ESCAT tier I/II alterations were detected in 51% of patients and matched therapy was used in 7%. Integration of multi-omics analyses in clinical practice could affect treatment strategies in MBC.Significance:The AURORA program, through the genomic and transcriptomic analyses of matched primary and metastatic samples from 381 patients with breast cancer, coupled with prospectively collected clinical data, identified genomic alterations enriched in metastases and prognostic biomarkers. ESCAT tier I/II alterations were detected in more than half of the patients.This article is highlighted in the In This Issue feature, p. 2659

File with the supplementary material & methods, supplementary tables and supplementary figure.

Supplementary file with the listing of the liver genes excluded from transcriptomic analyses.

Purpose:Despite extensive genomic and transcriptomic profiling, it remains unknown how signaling pathways are differentially activated and how tumors are differentially sensitized to certain perturbations. Here, we aim to characterize AKT signaling activity and its association with other genomic or IHC-based PI3K/AKT pathway biomarkers as well as the clinical activity of ipatasertib (AKT inhibitor) in the FAIRLANE trial.Experimental Design:In FAIRLANE, 151 patients with early triple-negative breast cancer (TNBC) were randomized 1:1 to receive paclitaxel with ipatasertib or placebo for 12 weeks prior to surgery. Adding ipatasertib did not increase pathologic complete response rate and numerically improved overall response rate by MRI. We used reverse-phase protein microarrays (RPPA) to examine the total level and/or phosphorylation states of over 100 proteins in various signaling or cell processes including PI3K/AKT and mTOR signaling. One hundred and twenty-five baseline and 127 on-treatment samples were evaluable by RPPA, with 110 paired samples at both time points.Results:Tumors with genomic/protein alterations in PIK3CA/AKT1/PTEN were associated with higher levels of AKT phosphorylation. In addition, phosphorylated AKT (pAKT) levels exhibited a significant association with enriched clinical benefit of ipatasertib, and identified patients who received benefit in the absence of PIK3CA/AKT1/PTEN alterations. Ipatasertib treatment led to a downregulation of AKT/mTORC1 signaling, which was more pronounced among the tumors with PIK3CA/AKT1/PTEN alterations or among the responders to the treatment.Conclusions:We showed that the high baseline pAKT levels are associated with the alterations of PI3K/AKT pathway components and enriched benefit of ipatasertib in TNBC.

PARP inhibitors (PARPi) are approved drugs for platinum-sensitive, high-grade serous ovarian cancer (HGSOC) and for breast, prostate, and pancreatic cancers (PaC) harboring genetic alterations impairing homologous recombination repair (HRR). Detection of nuclear RAD51 foci in tumor cells is a marker of HRR functionality, and we previously established a test to detect RAD51 nuclear foci. Here, we aimed to validate the RAD51 score cut off and compare the performance of this test to other HRR deficiency (HRD) detection methods. Laboratory models from BRCA1/BRCA2-associated breast cancer, HGSOC, and PaC were developed and evaluated for their response to PARPi and cisplatin. HRD in these models and patient samples was evaluated by DNA sequencing of HRR genes, genomic HRD tests, and RAD51 foci detection. We established patient-derived xenograft models from breast cancer (n = 103), HGSOC (n = 4), and PaC (n = 2) that recapitulated patient HRD status and treatment response. The RAD51 test showed higher accuracy than HRR gene mutations and genomic HRD analysis for predicting PARPi response (95%, 67%, and 71%, respectively). RAD51 detection captured dynamic changes in HRR status upon acquisition of PARPi resistance. The accuracy of the RAD51 test was similar to HRR gene mutations for predicting platinum response. The predefined RAD51 score cut off was validated, and the high predictive value of the RAD51 test in preclinical models was confirmed. These results collectively support pursuing clinical assessment of the RAD51 test in patient samples from randomized trials testing PARPi or platinum-based therapies.Significance:This work demonstrates the high accuracy of a histopathology-based test based on the detection of RAD51 nuclear foci in predicting response to PARPi and cisplatin.

RPPA data analysis

Purpose:FGFR1 amplification (FGFR1amp) is recurrent in metastatic breast cancer (MBC) and is associated with resistance to endocrine therapy and CDK4/6 inhibitors (CDK4/6is). Multi-tyrosine kinase inhibitors (MTKIs) and selective pan-FGFR inhibitors (FGFRis) are being developed for FGFR1amp breast cancer. High-level FGFR amplification and protein expression by IHC have identified breast cancer responders to FGFRis or MTKIs, respectively.Experimental Design:Here, we used preclinical models and patient samples to identify predictive biomarkers to these drugs. We evaluated the antitumor activity of an FGFRi and an MTKI in a collection of 17 breast cancer patient–derived xenografts (PDXs) harboring amplification in FGFR1/2/3/4 and in 10 patients receiving either an FGFRi/MTKI. mRNA levels were measured on FFPE tumor samples using two commercial strategies. Proliferation and angiogenesis were evaluated by detecting Ki-67 and CD31 in viable areas by immunofluorescence.Results:High FGFR1–4 mRNA levels but not copy-number alteration (CNA) is associated with FGFRi response. Treatment with MTKIs showed higher response rates than with FGFRis (86% vs. 53%), regardless of the FGFR1–4 mRNA levels. FGFR-addicted PDXs exhibited an antiproliferative response to either FGFRis or MTKIs, and PDXs exclusively sensitive to MTKI exhibited an additional antiangiogenic response. Consistently, the clinical benefit of MTKIs was not associated with high FGFR1–4 mRNA levels and was observed in patients previously treated with antiangiogenic drugs.Conclusions:Tailored therapy with FGFRis in molecularly selected MBC based on high FGFR1–4 mRNA levels warrants prospective validation in patients with CDK4/6i-resistant luminal breast cancer and in patients with TNBC without targeted therapeutic options.

Purpose:AZD5363/capivasertib is a pan-AKT catalytic inhibitor with promising activity in combination with paclitaxel in triple-negative metastatic breast cancer harboring PI3K/AKT-pathway alterations and in estrogen receptor–positive breast cancer in combination with fulvestrant. Here, we aimed to identify response biomarkers and uncover mechanisms of resistance to AZD5363 and its combination with paclitaxel.Experimental Design:Genetic and proteomic markers were analyzed in 28 HER2-negative patient-derived xenografts (PDXs) and in patient samples, and correlated to AZD5363 sensitivity as single agent and in combination with paclitaxel.Results:Four PDX were derived from patients receiving AZD5363 in the clinic which exhibited concordant treatment response. Mutations in PIK3CA/AKT1 and absence of mTOR complex 1 (mTORC1)-activating alterations, for example, in MTOR or TSC1, were associated with sensitivity to AZD5363 monotherapy. Interestingly, excluding PTEN from the composite biomarker increased its accuracy from 64% to 89%. Moreover, resistant PDXs exhibited low baseline pAKT S473 and residual pS6 S235 upon treatment, suggesting that parallel pathways bypass AKT/S6K1 signaling in these models. We identified two mechanisms of acquired resistance to AZD5363: cyclin D1 overexpression and loss of AKT1 p.E17K.Conclusions:This study provides insight into putative predictive biomarkers of response and acquired resistance to AZD5363 in HER2-negative metastatic breast cancer.

Purpose:Report results of the phase Ib dose-escalation/expansion study of triplet therapy with cyclin-dependent kinases 4 and 6 (CDK4/6) inhibitor (ribociclib), mTOR inhibitor (everolimus), and endocrine therapy (exemestane).Patients and Methods:Postmenopausal women with hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2−), pretreated, advanced breast cancer (ABC) were enrolled. The primary objective of the dose-escalation phase was to estimate the MTD and recommended phase II dose (RP2D) of triplet therapy through evaluation of the incidence of dose-limiting toxicities. Safety, tolerability, and efficacy of the RP2D were evaluated in the dose-expansion phase in patients naïve or refractory to CDK4/6 inhibitor therapy.Results:Patients (N = 116) received triplet therapy (n = 83 in the dose-escalation phase; n = 33 in the dose-expansion phase). A dose-dependent drug–drug interaction was observed for everolimus, with exposure increasing two- to fourfold in the presence of ribociclib. The RP2D was determined to be ribociclib 300 mg once daily, 3 weeks on/1 week off in a 4-week cycle, plus everolimus 2.5 mg once daily, plus exemestane 25 mg once daily taken with food. The safety profile was consistent with the known profiles of the combination partners, and preliminary evidence of antitumor activity was observed. Higher ESR1 gene expression trended with better treatment response to triplet therapy; higher gene expression of MAPK pathway genes trended with worse treatment response.Conclusions:Triplet therapy with endocrine therapy and mTOR and CDK4/6 inhibition provides clinical benefit and an acceptable safety profile in previously treated postmenopausal women with HR+, HER2− ABC.

Supplementary Table from Preclinical In Vivo Validation of the RAD51 Test for Identification of Homologous Recombination-Deficient Tumors and Patient Stratification

Supplementary Data from Preclinical In Vivo Validation of the RAD51 Test for Identification of Homologous Recombination-Deficient Tumors and Patient Stratification

Study disposition

Supplementary Table S2 HTG OBP panel raw data

Pharmacokinetics: Z-endoxifen levels per taselisib dose level

Low pAkt S473 is associated with resistance to AZD5363 monotherapy

Supplementary Data

Participant PIK3CA-mutation central testing results

Purpose:The strategy of combining endocrine therapy with PI3K-mTOR inhibition has shown promise in estrogen receptor (ER)–positive breast cancer, but new agents and combinations with a better therapeutic index are urgently needed. Taselisib is a potent, selective, beta-isoform–sparing PI3 kinase inhibitor.Patients and Methods:30 patients with ER-positive, metastatic breast cancer who had failed prior endocrine therapy were treated with escalating doses of taselisib (2 or 4 mg in an intermittent or continuous schedule) combined with tamoxifen 20 mg once daily in this phase 1b study using a “rolling six” design.Results:Taselisib combined with tamoxifen was generally well tolerated, with treatment-emergent adverse events as expected for this class of drugs, including diarrhea (13 patients, 43%), mucositis (10 patients, 33%), and hyperglycemia (8 patients, 27%). No dose-limiting toxicities were observed. Objective responses were seen in 6 of 25 patients with RECIST-measurable disease (ORR 24%). Median time to disease progression was 3.7 months. Twelve of 30 patients (40%) had disease control for 6 months or more. Circulating tumor (ct)DNA studies using next-generation tagged amplicon sequencing identified early indications of treatment response and mechanistically relevant correlates of clinical drug resistance (e.g., mutations in KRAS, ERBB2) in some patients.Conclusions:Taselisib can be safely combined with tamoxifen at the recommended phase 2 dose of 4 mg given once daily on a continuous schedule. Preliminary evidence of antitumor activity was seen in both PIK3CA mutant and wild-type cancers. The randomized phase 2 part of POSEIDON (testing tamoxifen plus taselisib or placebo) is currently recruiting.

Supplementary Figure 1. Participant Flow Diagram

Figure S1. Flowchart of study selection process with ICIs treatment. Figure S2. Flowchart of study selection process with TAs treatment. Figure S3. Overall Survival comparing HPD with non-HPD in patients with progression disease as best response in the ICIs and TAs cohorts ( RECIST 1.1 progression disease Landmark Analysis). Figure S4. Overall Survival in second line (a) and third (b) setting HPD vs non-HPD progressors by RECIST criteria in ICIs cohort. Figure S5. Concordance between RECIST and TGR criteria in ICIs cohort. Table S1. Computed tomography (CT) acquisition protocol parameters. Table S2. Clinical variables in patients treated with TAs. Table S3. Multivariate model in patients with progression disease as best response in ICIs group (using TGR).