EGF105084, a phase II study of lapatinib for brain metastases in patients (pts) with HER2+ breast cancer following trastuzumab (H) based systemic therapy and cranial radiotherapy (RT)

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 1012-1012 ◽  
Author(s):  
N. U. Lin ◽  
V. Dieras ◽  
D. Paul ◽  
D. Lossignol ◽  
C. Christodoulou ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Brain Metastases ◽  
Phase Ii ◽  
Systemic Therapy ◽  
Preliminary Data ◽  
Brain Lesion ◽  
Stage Iv ◽  
Cranial Radiotherapy ◽  
Cns Disease ◽  
Her2 Breast Cancer

1012 Background: CNS disease is a major problem among pts treated with H for stage IV HER2+ breast cancer with a reported incidence of 28–43%. This study was designed to characterize further the activity reported with lapatinib in an initial phase II trial in women with HER2+ disease metastatic to brain (Lin et al ASCO ‘06). Methods: Eligible pts had HER2+ breast cancer, prior H therapy and cranial RT, ECOG PS 0–2, and radiographic evidence of progressive brain metastases with at least one measurable (LD = 10mm) brain lesion. Pts received lapatinib 750 mg PO BID. Brain MRIs were obtained at 3.0 mm slices without gaps in the axial dimension. The primary endpoint was CNS response as defined by a = 50% volumetric (vol) reduction of CNS lesions in the absence of: new lesions, need for increased dose of steroids, progressive neurological signs/symptoms (NSS), or progressive extra-CNS disease. CNS disease progression was defined as either a = 40% vol increase from nadir, increase in steroid requirements, or progression of NSS. Results: The study exceeded its accrual goal of 220 pts in < 1 year; 238 pts were enrolled from Jan-Nov 06. Preliminary data from the initial 104 pts have undergone independent radiology review. 8 pts (7.7%) met vol criteria for partial response with a median absolute vol reduction of CNS disease of 3.6 cm3 (range 0.4 to 29.7 cm3). Exploratory analysis revealed that 17 of the initial 104 pts (16.3%) experienced a = 20% vol reduction of CNS disease with a median absolute vol reduction of 3.3cm3. The median time to vol progression in these 17 pts was 16 wks (range 12 -24 wks). Analysis of efficacy and tolerability based upon protocol defined criteria from all 238 pts will be presented. Conclusions: Preliminary data from this large multicenter trial provides evidence that lapatinib has activity based on vol reductions in pts with progressive HER2+ CNS disease following prior H-based systemic therapy and cranial RT. Definitive conclusions will be based on the entire database. Additional studies are warranted incorporating lapatinib in combination with other therapies and/or in a less refractory setting to optimize its use in HER2+ CNS disease. [Table: see text]

Effect of type and timing of systemic therapy on risk of radiation necrosis in patients with HER2+ breast cancer brain metastases.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e14002-e14002
Author(s):  
Christine Park ◽  
Evan Buckley ◽  
Amanda E.D. Van Swearingen ◽  
Will Giles ◽  
James Emmett Herndon ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Brain Metastases ◽  
Systemic Therapy ◽  
Radiation Necrosis ◽  
Treatment Modalities ◽  
Conformity Index ◽  
Her2 Breast Cancer ◽  
Breast Cancer Brain Metastasis ◽  
The Impact ◽  
Systemic Therapies

e14002 Background: It is estimated that 30% of patients with metastatic human epidermal growth factor receptor 2-positive (HER2+) breast cancer will develop brain metastases. Current standard of care options for HER2+ breast cancer brain metastasis (BCBrM) includes radiation therapy (stereotactic radiosurgery [SRS] or whole brain radiation), brain permeable systemic therapies, and in select cases, neurosurgical resection. A multimodal approach combining these different treatment modalities has improved the overall survival and functional outcomes of patients with BCBrM. Some HER2-directed systemic therapies, however, may increase the risk of radiation necrosis (RN), a longer-term consequence of SRS. This study explores the impact of timing and type of systemic therapies on the development of RN in patients treated with SRS for HER2+ BCBrM. Methods: This was a single-institution, retrospective study including patients ≥18 years of age with HER2+ BCBrM who received SRS between 2013 and 2018 at Duke University with at least 12-month post-SRS follow-up. Presence of RN was determined at one-year post-SRS. Demographics, radiotherapy parameters (total dose, fractions, clinical target volume [CTV], gross tumor volume [GTV], conformity index [CI], volume receiving 12 gray [V12Gy]), and timing (during [within 4 weeks of SRS] vs. not during SRS) and type of systemic therapy (HER2-directed therapy, mitosis inhibitors, DNA synthesis inhibitors, others) were evaluated. Results: Among 46 patients with HER2+ BCBrM who received SRS, 28 (60.9%) developed RN and 18 (39.1%) did not. Age at time of SRS did not differ between those who developed RN and those who did not (mean 53.3 vs 50.4 years, respectively). There was a higher percentage of African Americans in the RN group (28.6% vs 11.1%, p = 0.3). There were no significant differences between the measured radiotherapy parameters—including dose, fraction, CTV, GTV, CI, V12Gy—between the two groups (all p > 0.05). Receipt of any type of systemic therapy during SRS did not differ between patients who did or did not develop RN (60.7% vs 55.6%, p = 0.97). However, patients who developed RN more commonly received more than one line of HER2-directed therapy independent of SRS timing compared to those who did not develop RN (75.0% vs 44.4%, p = 0.08). In fact, a significantly higher proportion of those who developed RN received more than one line of HER2-directed therapy during SRS compared to those did not develop RN (35.7% vs 5.6%, p<0.05). Conclusions: Patients with HER2 BCBrM who receive multiple lines of HER2-directed therapy during SRS for BCBrM may be at higher risk of RN. This data supports a practice of holding HER2-directed therapy during SRS if medically acceptable. Further investigation of next generation HER2-directed therapies in a larger cohort of patients should be investigated to help guide best practice to minimize RN.

Effects of lapatinib and cranial radiotherapy in a case of brain metastases from HER2+breast cancer

2013 ◽  
Vol 18 ◽  
pp. S173 ◽  
Author(s):  
E. Capelo Medina ◽  
J. Cabrera Rodríguez ◽  
A. Corbacho Campos ◽  
A. Torres García ◽  
J. Muñoz García ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Brain Metastases ◽  
Cranial Radiotherapy ◽  
Her2 Breast Cancer

Phase II trial of lapatinib for brain metastases in patients with HER2+ breast cancer

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 503-503 ◽  
Author(s):  
N. U. Lin ◽  
L. A. Carey ◽  
M. C. Liu ◽  
J. Younger ◽  
S. E. Come ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Brain Metastases ◽  
Primary Endpoint ◽  
Objective Response ◽  
Metastatic Breast ◽  
Sufficient Evidence ◽  
Radiation Toxicity ◽  
Cns Disease ◽  
Her2 Breast Cancer ◽  
Grade 3

503 Background: One-third of women with HER2+ metastatic breast cancer develop central nervous system (CNS) metastases. This study evaluated the safety and efficacy of lapatinib, an oral inhibitor of EGFR and HER2, in patients with HER2+ brain metastases. Methods: Eligible patients (pts) had HER2+ breast cancer, new or progressive brain metastases, and at least one measurable (LD ≥1.0cm) lesion. Pts received lapatinib 750 mg PO BID. Tumor response was assessed by MRI every 8 wks. FDG-PET scans were performed at baseline, and repeated at wks 1 and 8. The primary endpoint was objective response (CR+PR) in the brain by RECIST. Secondary endpoints included safety, quality-of-life (QOL), and PET changes. Sample size was calculated using a 2-stage design to distinguish objective response of 5% (H0) vs 20% (HA); ≥ 4 objective responses were required to reject the null hypothesis. Results: 39 pts were enrolled, mean age 52 yrs (range 31–76). All pts developed CNS disease on trastuzumab; 38 progressed after prior radiation. Toxicity data are available for 38 pts; the most common AEs were diarrhea (grade 3, 21%), fatigue (grade 3, 16%), and rash (grade 3, 5%). Three pts remain on active treatment. Two pts achieved a PR by RECIST, and remained on study for 158 and 347 days. An additional pt achieved >30% decrease in LD of her CNS lesion but, upon central radiology review, did not meet RECIST criteria for measurable disease and was excluded from analysis of the primary endpoint. Five additional pts achieved SD≥16 wks. Median time to treatment failure was 3.2 mo (95% CI 2.3 to 3.8). Preliminary volumetric analysis of 20/39 pts demonstrates 5 pts with ≥30% volumetric decline in CNS lesions, and an additional 3 pts with 15–30% volumetric decline. Analyses of QOL and correlation of PET with clinical outcomes will be presented. Conclusion: Lapatinib is well-tolerated in this population. Although the study failed to demonstrate the hypothesized level of activity as assessed by RECIST, there is sufficient evidence of clinical effect, albeit preliminary, to suggest that lapatinib can penetrate the CNS. Further investigation of lapatinib in HER2+ CNS disease is warranted and ongoing. Acknowledgements: AVON PFP award; NCI-SPORE in Breast Cancer at DF/HCC(CA89393), UNC(CA58223), Georgetown; ASCO YIA. [Table: see text]

Impact of extracranial disease status on survival after initial central nervous system (CNS) involvement and radiation therapy in HER2+ breast cancer brain metastases (BCBM).

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 1041-1041
Author(s):  
Laura Noteware ◽  
Luis Ramirez ◽  
Nicole Dalal ◽  
James Emmett Herndon ◽  
Scott R. Floyd ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Metastatic Disease ◽  
Systemic Therapy ◽  
Local Therapy ◽  
Progression Free Survival ◽  
Disease Status ◽  
Cns Involvement ◽  
Cns Disease ◽  
Her2 Breast Cancer ◽  
Extracranial Disease

1041 Background: BCBMs are very common in metastatic HER2+ breast cancer. CNS-directed local therapy is the gold standard for treatment, followed by systemic HER2-targeted therapies. In patients with HER2+ BCBM and stable extracranial disease (ECD), consensus guidelines recommend continuing current systemic therapy after local therapy. Our goal was to determine the implications of ECD status at time of HER2+ BCBM first CNS involvement on outcomes including intracranial progression-free survival (PFS1) and overall survival (OS). Methods: Retrospective analysis was performed on data extracted from 77 patients with HER2+ BCBM who received CNS radiation at Duke between 2006 and 2020 following initial documentation of CNS involvement. Demographics, dates of metastatic and intracranial diagnosis, ECD status at first CNS involvement, systemic therapy, and outcomes were collected. The primary endpoint was PFS1 defined as the time from first CNS radiation to the subsequent documentation of intracranial progression (RANO-BM). OS was defined as time from first CNS radiation and first metastatic disease to date of death or last known alive. ECD status was defined by RECIST1.1 from systemic staging scans within 30 days of first CNS involvement. Results: In this patient cohort of HER2+ BCBMs undergoing CNS radiation at first CNS involvement, >50% of patients had extracranial disease control: no ECD (25%) or stable/responding disease (31%). 52% of patients’ tumors were ER+. Median age was 50 years (range 27 – 75). Most patients (58%) developed first CNS involvement during adjuvant or first/second line metastatic therapy. For first CNS radiation, 49% received SRS and 48% WBRT. All patients with no ECD presented with isolated CNS disease as first metastatic presentation. Median OS in this cohort from initial metastatic disease to death was markedly worse for patients with no ECD (25.3m, 95% CI: 16.8 to 35.3) compared to those with progressive or stable/responding ECD (48.8m, 95% CI: 28.1 to 65; and 52.9 months, 95% CI: 43.7 to 73.3, respectively; p=0.03). Median OS from first CNS involvement to death was not statistically different amongst groups. This analysis did not detect median PFS1 differences based on ECD after first CNS radiation: progressive ECD (6.3m), no ECD (8.7m), or stable/responding ECD (10.6m) (p=0.13), though clinically meaningful differences were observed. Conclusions: Patients with isolated HER2+ BCBM with no ECD at the time of their initial CNS involvement (25% of population) have substantially worse OS compared to patients who present with ECD and develop CNS metastases later in their disease course. This population with isolated CNS disease at metastatic presentation deserves investigation of novel treatment algorithms, including earlier introduction of brain penetrable HER2-targeted agents.

scholarly journals CTNI-05. NRG ONCOLOGY / RTOG 1119: PHASE II RANDOMIZED STUDY OF WHOLE BRAIN RADIOTHERAPY / STEREOTACTIC RADIOSURGERY WITH CONCURRENT LAPATINIB IN PATIENTS WITH BRAIN METASTASES FROM HER2-POSITIVE BREAST CANCER

2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii42-ii42
Author(s):  
In Ah Kim ◽  
Kathryn Winter ◽  
Paul Sperduto ◽  
Jennifer De Los Santos ◽  
David Peereboom ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Brain Metastases ◽  
Stereotactic Radiosurgery ◽  
Phase Ii ◽  
Response Rate ◽  
Whole Brain Radiotherapy ◽  
Specific Response ◽  
Whole Brain ◽  
Brain Radiotherapy ◽  
Her2 Breast Cancer

Abstract Trastuzumab/pertuzumab improved outcomes for patients (pts) with HER2+ breast cancer. Increased survival coupled with limited blood-brain barrier (BBB) penetration of these agents apparently contributes to increased incidence of brain metastases (BM). Lapatinib (L) crosses the BBB and demonstrates activity against BM. Based upon pre/early clinical data, it’s hypothesized that L + whole brain radiotherapy (WBRT) or Stereotactic Radiosurgery (SRS) would improve intracranial control compared to WBRT/SRS (RT) alone. This randomized phase II trial included HER2+ breast cancer pts with ≥ 1 measurable, unirradiated parenchymal BM. Pts were randomized 1:1 to WBRT (37.5 Gy/3 weeks) or SRS +/- concurrent L (1000 mg dailyx6 weeks), andwere stratified by graded prognostic assessment (GPA), use of non-CNS penetrating anti-HER2 therapies, and previous SRS/resection. The primary endpoint was intracranial complete response (CR) rate 12weeks (wk) after RT. Secondary endpoints included objective response rate (ORR), lesion-specific response rate, CNS progression-free survival, and overall survival. 114 of 143 pts were evaluable for 12-wk CR (52 RT, 62 RT+L). Rate of grade 3 and 4 adverse events were 8% and 0% for RT and 29% and 6% for RT+L. 92% and 90% pts received concurrent and adjuvant L per protocol/acceptable variation. There were no significant differences in 12 or 4wk CR rates (p=0.97 and p=0.77); 5.8% and 0% at 12wk and 3.6% and 1.5% at 4wk for RT and RT+L, respectively. The ORR at 4 wk was 42% and 56% (p=0.059, RECIST), 40% and 58% (p=0.027, WHO) in the RT and RT+L, respectively. Although the addition of lapatinib to WBRT/SRS did not improve the 12wk CR rate, it showed meaningful clinical benefit by demonstrating a trend toward improvement of 4 wk ORR. Results of ongoing central review of MRIs using RECIST1.1, WHO and RANO-BM criteria including secondary endpointswill be reported. Support: NCI grants U10CA180868, U10CA180822, UG1CA189867, and Novartis

Phase I/II study of T-DM1 alone versus T-DM1 and metronomic temozolomide in secondary prevention of HER2-positive breast cancer brain metastases following stereotactic radiosurgery.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. TPS2572-TPS2572
Author(s):  
Alexandra Dos Santos Zimmer ◽  
Seth M. Steinberg ◽  
DeeDee Kay Smart ◽  
Mark R. Gilbert ◽  
Terri Armstrong ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Clinical Trial ◽  
Secondary Prevention ◽  
Brain Metastases ◽  
Phase I ◽  
Phase Ii ◽  
Brain Mri ◽  
Her2 Positive ◽  
Her2 Breast Cancer ◽  
Patient Reported

TPS2572 Background: We demonstrated that low doses of temozolomide (TMZ) administered in a prophylactic, metronomic fashion significantly prevented development of brain metastases in murine models of breast cancer. Based on these findings, we developed a secondary-prevention clinical trial. Methods: Phase I is a standard 3+3 design: T-DM1 3.6mg/kg IV every 21 days plus TMZ 30, 40 or 50 mg/m2 daily, to identify the maximum tolerated dose (MTD) of the combination, and is completing accrual, with 9 patients accrued, currently on the third and last dose level. Phase II will randomize patients to T-DM1 3.6mg/kg versus T-DM1 3.6mg/kg plus TMZ at recommended phase 2 dose (RP2D), to evaluate if addition of TMZ improves the recurrence-free incidence from distant new brain metastases at one year from 50% to 65%. Patients will undergo radiology guided lumbar puncture at baseline and after 6 weeks of treatment (C3D1) for correlative studies, brain MRI, systemic restaging CTs, and questionnaires for evaluation of symptoms and quality of life. Eligibility: HER2+ breast cancer with brain metastases (up to 10 lesions), treated with SRS and/or resection ≤12 weeks before enrollment, no leptomeningeal metastases, no previous WBRT, ECOG ≤2 and adequate organ and marrow function. Biomarkers, including cell free DNA from CSF, serum and tumor block, exosomal DNA, serum markers for neuroinflammation, and patient reported outcomes, will be analyzed in an exploratory fashion. Target accrual: up to 18 patients in phase I and 98 in phase II. Clinical trial information: NCT03190967 .

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