More than half of breast cancers express low levels of HER2. In a phase 3 trial, the antibody–drug conjugate trastuzumab deruxtecan resulted in longer survival than the physician’s choice of ...chemotherapy among patients with HER2-low breast cancer.
Prion diseases are caused by the accumulation of an aberrantly folded isoform of the prion protein, designated PrPSc. In a cell-based assay, quinacrine inhibits the conversion of normal host prion ...protein (PrPC) to PrPSc at a half-maximal concentration of 300 nM. While these data suggest that quinacrine may be beneficial in the treatment of prion disease, its penetration into brain tissue has not been extensively studied. If quinacrine penetrates brain tissue in concentrations exceeding that demonstrated for in vitro inhibition of PrPSc, it may be useful in the treatment of prion disease.
Oral quinacrine at doses of 37.5 mg/kg/D and 75 mg/kg/D was administered to mice for 4 consecutive weeks. Plasma and tissue (brain, liver, spleen) samples were taken over 8 weeks: 4 weeks with treatment, and 4 weeks after treatment ended.
Quinacrine was demonstrated to penetrate rapidly into brain tissue, achieving concentrations up to 1500 ng/g, which is several-fold greater than that demonstrated to inhibit formation of PrPSc in cell culture. Particularly extensive distribution was observed in spleen (maximum of 100 microg/g) and liver (maximum of 400 microg/g) tissue.
The documented extensive brain tissue penetration is encouraging suggesting quinacrine might be useful in the treatment of prion disease. However, further clarification of the distribution of both intracellular and extracellular unbound quinacrine is needed. The relative importance of free quinacrine in these compartments upon the conversion of normal host prion protein (PrPC) to PrPSc will be critical toward its potential benefit.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
LBA3
Background: About 55% of mBC typically categorized as HER2 negative, express low levels of HER2 (IHC 1+ or IHC 2+/ISH− by ASCO/CAP 2018 guidelines) with poor outcomes in later lines (Tarantino ...2020). T-DXd has shown promising efficacy in HER2-low mBC in a phase 1 study (NCT02564900; Modi 2020). This is the primary report from DESTINY-Breast04 (NCT03734029), the first randomized, multicenter, open-label, phase 3 study comparing efficacy and safety of T-DXd vs TPC in pts with HER2-low mBC treated with 1-2 prior lines of chemotherapy in the metastatic setting. Methods: 557 pts with centrally confirmed HER2-low mBC were randomly assigned 2:1 to T-DXd 5.4 mg/kg or TPC (capecitabine, eribulin, gemcitabine, paclitaxel, or nab-paclitaxel). The primary endpoint was progression-free survival (PFS) determined by blinded independent central review (BICR) in pts with hormone receptor–positive (HR+) mBC. Key secondary endpoints (hierarchically tested after the primary endpoint) include PFS by BICR in the full analysis set (FAS; HR+/−) and overall survival (OS) in pts with HR+ mBC and in FAS. Other endpoints were objective response rate, duration of response, safety, and an exploratory analysis of pts with HR− mBC. Results: As of Jan 11, 2022, 373 and 184 pts (88.7% and 88.6% HR+ mBC) were assigned to T-DXd and TPC, respectively. Median follow-up was 18.4 months (mo; 95% CI, 17.9-19.1). Median treatment duration was 8.2 mo (range, 0.2-33.3) with T-DXd and 3.5 mo (range, 0.3-17.6) with TPC. Efficacy results are in the Table. 52.6% of pts with T-DXd vs. 67.4% of pts with TPC had grade (G) ≥ 3 treatment-emergent adverse events (TEAEs). With T-DXd, 45 pts (12.1%; 10.0% G1/2, 1.3% G3/4, 0.8% G5) had independently adjudicated drug-related interstitial lung disease ILD/pneumonitis vs. 1 pt (0.6% G1) with TPC. Conclusions: DESTINY-Breast04 is the first phase 3 trial of a HER2-directed therapy in pts with HER2-low mBC to show a statistically significant and clinically meaningful benefit in PFS and OS compared to standard-of-care treatment, regardless of HR status, with a generally manageable safety profile. Funding: Daiichi Sankyo, Inc., and AstraZeneca. Clinical trial information: NCT03734029. Table: see text
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Background: Treatment options are limited for patients with advanced melanoma who have progressed on checkpoint inhibitors and targeted therapies such as BRAF/MEK inhibitors (if ...BRAF-V600E mutated). Adoptive cell therapy utilizing tumor-infiltrating lymphocytes (TIL) has shown antitumor efficacy with durable long-term responses in heavily pretreated melanoma patients. Safety and efficacy of lifileucel (LN-144), a centrally manufactured autologous TIL therapy are presented. Methods: C-144-01 is a global Phase 2 open-label, multicenter study of the efficacy and safety of lifileucel in patients with unresectable metastatic melanoma. We report on Cohort 2 (N = 55) patients who received cryopreserved lifileucel. Tumors resected at local institutions were processed in central GMP facilities for TIL production in a 22-day process. Final TIL infusion product was cryopreserved and shipped to sites. Patients received one week of cyclophosphamide/fludarabine preconditioning lymphodepletion, a single lifileucel infusion, followed by up to 6 doses of IL-2. Results: In 55 patients with Stage IIIC/IV unresectable melanoma, 3.1 mean prior therapies (anti-PD1 100%; anti-CTLA-4 80%; BRAF/MEK inhibitor 24%), high baseline tumor burden (110 mm mean target lesion sum of diameters), ORR was 38% (2 CR, 18 PR, 1 uPR). Of 21 responders, 4 have progressed to date with median follow up of 7.4 months. Overall disease control was 76%. Improved responses in some patients were observed with longer follow up. Most (54) patients progressed on prior anti-PD1 and those with PD-L1 negative status (TPS < 5%) were among responders. Mean cells infused was 28 x10
9
. Median IL-2 doses administered was 6.0. Adverse events resolved to baseline, 2 weeks post TIL infusion, a potentially important benefit of one-time TIL therapy. Conclusions: Lifileucel treatment results in 38% ORR in heavily pretreated metastatic melanoma patients with high baseline disease burden who received prior anti-PD1 and BRAF/MEK inhibitor if BRAF mutated. Based on these data, a new Cohort 4 in C-144-01 has been initiated to support lifileucel registration. Clinical trial information: NCT02360579.
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TPS473
Background: Gem therapy improves outcomes in pts with resected PC. However, disease recurrence is common, prompting a need for improved regimens. nab-P + Gem was superior to Gem ...alone in MPACT, a phase III trial of pts with metastatic PC (mPC) for all endpoints, including overall survival (OS; median, 8.7 vs 6.6 months; hazard ratio HR 0.72; P < 0.001). Toxicities were manageable and consistent with prior studies. The APACT trial will compare adjuvant nab-P + Gem vs Gem alone in pts with resected PC. Methods: Pts (≈ 800) with confirmed PC (R0 or R1 resection); stage T1 - 3, N0 - 1, M0; Eastern Cooperative Oncology Group performance status ≤ 1; adequate organ function; and CA19-9 < 100 U/mL within 14 days of randomization are eligible. Pts with mixed-origin tumors; present or previous mPC; any other malignancy within 5 years of randomization; HIV or hepatitis B or C infection; or prior neoadjuvant treatment or radiotherapy for PC are ineligible. Randomization should occur once pts adequately recover from surgery but ≤ 12 weeks after surgery. Pts will receive 6 cycles of either nab-P 125 mg/m
2
plus Gem 1000 mg/m
2
or Gem 1000 mg/m
2
on days 1, 8, and 15 of a 28-day cycle. Stratification factors are resection (R0 vs R1) and nodal (LN+ vs LN−) status and geographic region (North America vs Europe vs Australia vs Asia Pacific). Pts with > 2 dose reductions will be discontinued. The primary endpoint is independently assessed disease-free survival (DFS). Secondary endpoints are OS and safety. Quality of life and correlation of tumor heterogeneity with clinical outcome are exploratory outcomes. At least 489 DFS events from 800 pts will allow 90% power to detect an HR for DFS of 0.74 at a 2-sided significance level of 0.05. Interim analyses, 1 for safety (after 100 pts are treated for ≥ 2 cycles) and 2 for efficacy (the first for futility and the second for futility and superiority), will be performed. As of July 2015, > 400 pts were enrolled, and 80% of all activated study sites (n = 141) randomized ≥ 1 pt. Of the 674 screened pts, ≈ 25% were ineligible, mainly due to postsurgical disease recurrence identified at screening. Pt enrollment is ongoing. ClinicalTrials.gov: NCT01964430. Clinical trial information: NCT01964430.
Abstract
Background In DESTINY-Breast04, the HER2-targeted antibody drug conjugate trastuzumab deruxtecan (T-DXd) demonstrated significant survival benefit vs treatment of physician’s choice (TPC) in ...patients (pts) with HER2-low unresectable or metastatic breast cancer (mBC) (Modi et al. N Engl J Med 2022). These results emphasize the importance of accurately identifying HER2 expression in breast tumor tissue. Here, we describe concordance between previously determined (historical) HER2 scores and central HER2 scores, and tumor sample characteristics for pts with mBC screened and enrolled in DESTINY-Breast04. Methods DESTINY-Breast04 was a randomized, open-label, phase 3 study in pts with centrally determined HER2-low (immunohistochemistry IHC 1+ or IHC 2+ with negative in situ hybridization ISH) mBC who had previously received 1-2 lines of chemotherapy. Pts were randomized 2:1 to T-DXd or TPC. HER2 scores were determined via central testing of tumor specimens by the investigational Ventana PATHWAY 4B5 IHC assay, using the 2018 American Society of Clinical Oncology/College of American Pathologists (ASCO/CAP) testing guidelines HER2 scoring algorithm, and Ventana INFORM HER2 dual ISH assay (as applicable). Results 1340 pts identified as having HER2-low mBC per historical data submitted tumor samples for central HER2-low testing. Of those, 557 pts met all eligibility criteria and were enrolled in DESTINY-Breast04. The proportion of samples from metastatic vs primary tumors was 59% vs 41% for all submitted tumor samples and 65% vs 35% for enrolled patients. Of those with available data, most were biopsy specimens (995 74% vs 344 26% resection/excisions) and were submitted as archived formalin-fixed, paraffin-embedded tissue (1183 88% vs 157 12% freshly collected samples); historical testing dates ranged from 2000-2020. Of samples with data on the historical HER2 IHC test used (31%), most were scored using local Ventana 4B5 (63%) or Agilent HercepTest (32%) assays. Tumor distribution characteristics were similar between screened and enrolled pts. For samples with historical and central HER2 results (N = 1108), 849/1108 (77%) were centrally scored as HER2-low. Of the samples that were not centrally scored as HER2-low, 88% were scored as HER2 IHC 0. Historical and central HER2 score concordance was assessed by sample region of origin (North America, Europe, China, or Asia without China) and collection date (2013 or earlier, 2104-2018, or 2019 or after) and scoring agreement was associated with these factors. Efficacy of T-DXd vs TPC for pts in DESTINY-Breast04 was consistent across all tumor sample characteristics (primary vs metastatic, specimen type, archival vs fresh, and tissue collection date). Conclusions Despite the lack of prior clinical utility and training in distinguishing HER2 IHC 0 from HER2-low (IHC 1+, 2+/ISH–), evolving guidelines since historical HER2 status provision, differences in local testing methods, and differences in key sample characteristics (primary vs metastatic; archived vs fresh; widely variable sample biopsy and testing dates), there was a 77% agreement between historical and central HER2-low status using the Ventana PATHWAY 4B5 IHC assay and Ventana INFORM HER2 Dual ISH assay. This rate is comparable to the reported initial concordance rates for HER2 overexpression IHC testing (range 74-82%; Roche J. Natl Cancer Inst 2002, Perez. J Clin Oncol 2006). Moreover, consistent benefit of T-DXd vs TPC was generally seen across patient groups with various tumor sample characteristics in DESTINY-Breast04. Determination of HER2-low status using the Ventana PATHWAY 4B5 IHC assay (and ISH when applicable) demonstrated the ability of the test, analyzed by pathologists using current ASCO/CAP guidelines, to identify pts who benefit from T-DXd. Funding This study was funded by Daiichi Sankyo and AstraZeneca.
Citation Format: Aleix Prat, Shanu Modi, Junji Tsurutani, David Cameron, Nadia Harbeck, Charo Garrido, Maha Karnoub, Ching Hsu, Wenquin Feng, Lotus Yung, Yibin Wang, Dhiraj Gambhire, Shirin K. Ford, Patrik Vitazka, Naoto T. Ueno. HER2-18 Determination of HER2-low status in tumors of patients with unresectable and/or metastatic breast cancer in DESTINY-Breast04 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 HER2-18.
Abstract
Background: DESTINY-Breast04 demonstrated that the HER2 targeting antibody–drug conjugate trastuzumab deruxtecan (T-DXd) significantly prolonged progression-free survival (PFS) and overall ...survival (OS) vs treatment of physician’s choice (TPC) in patients (pts) with HER2-low (immunohistochemistry IHC 1+ or IHC 2+/in situ hybridization negative) metastatic breast cancer (mBC) in pts in the hormone receptor−positive (HR+) cohort and all pts (HR+ and HR-; median PFS, 9.9 vs 5.1 months mo, hazard ratio: 0.50; median OS, 23.4 vs 16.8 mo, hazard ratio: 0.64; both P < 0.0001; Modi et al. N Engl J Med 2022). Objective response rate (ORR) with T-DXd was ≥50% across cohorts. These subgroup analyses examine pt history and disease characteristics that may correlate with response to therapy.
Methods: N = 557 pts with centrally confirmed HER2-low mBC were randomized 2:1 to T-DXd or TPC. Randomization was stratified by HER2 status (IHC 1+ vs 2+), 1 vs 2 prior lines of chemotherapy, and HR+ (with vs without prior treatment with cyclin-dependent kinase 4/6 inhibitor CDK4/6i) vs HR−. With the exception of the PFS and OS analyses by prior CDK4/6i use, all other described efficacy analyses were assessed post-hoc.
Results: Benefit of T-DXd vs TPC was consistent in pts with or without prior CDK4/6i use (Table 1). Pts with high disease burden (ie, ≥3 metastatic sites) also benefited from T-DXd vs TPC (Table 2). There was a small subgroup (n = 22) among all pts (HR+ n = 18 and HR− disease n = 4) with rapid progression prior to enrollment (disease progression within 6 mo of concluding a prior course of chemotherapy in early breast cancer). T-DXd showed responses in 7/14 (50%) pts in this subgroup vs 0/8 with TPC; this subgroup also had prolonged median PFS with T-DXd vs TPC (Table 3). Efficacy data for HER2 IHC 1+ vs 2+ and prior chemotherapy subgroups will be presented. Median OS was not reached for many subgroups (insufficient events in each group data not shown); however, subgroups in general showed OS benefit consistent with the primary analysis. With T-DXd, rates of interstitial lung disease/pneumonitis were similar in pts with/without prior CDK4/6i use.
Conclusions: T-DXd treatment for HER2-low mBC in the phase 3 study DESTINY-Breast04 showed consistent efficacy independent of disease burden, prior CDK4/6i treatment, or rapid progression status. ILD is an important identified risk and requires proactive monitoring and management. These data continue to support the use of T-DXd as the new standard of care across subgroups of pts with HER2-low mBC.
Editorial Acknowledgment
Under guidance of the authors, assistance in medical writing and editorial support was provided by Eileen McIver, PhD, and Soniya Patel, PhD, of ApotheCom, and was funded by Daiichi Sankyo.
Funding
This study was funded by Daiichi Sankyo and AstraZeneca.
Table 1. Efficacy by Prior CDK4/6i Treatment in Pts With HER2-Low Breast Cancer, HR+ Cohort.
Table 2. Efficacy by Disease Burdena in Pts With HER2-Low Breast Cancer, ITT.
Table 3. Efficacy by Rapid Progressor Statusa in Pts With HER2-Low Breast Cancer, ITT.
Citation Format: Nadia Harbeck, Shanu Modi, William Jacot, Toshinari Yamashita, Joo Hyuk Sohn, Maria Vidal, Junji Tsurutani, Naoto T. Ueno, Aleix Prat, Naoki Niikura, Binghe Xu, Hope Rugo, Konstantinos Papazisis, Javier Cortés, Ian Krop, Dhiraj Gambhire, Lotus Yung, Yibin Wang, Jasmeet Singh, David Cameron. Trastuzumab deruxtecan vs treatment of physician’s choice in patients with HER2-low unresectable and/or metastatic breast cancer: Subgroup analyses from DESTINY-Breast04 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 P1-11-01.
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