Ira Gore

Neratinib after trastuzumab-based adjuvant therapy in patients with HER2-positive breast cancer (ExteNET): a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial

BACKGROUND Neratinib, an irreversible tyrosine-kinase inhibitor of HER1, HER2, and HER4, has clinical activity in patients with HER2-positive metastatic breast cancer. We aimed to investigate the efficacy and safety of 12 months of neratinib after trastuzumab-based adjuvant therapy in patients with early-stage HER2-positive breast cancer. METHODS We did this multicentre, randomised, double-blind, placebo-controlled, phase 3 trial at 495 centres in Europe, Asia, Australia, New Zealand, and North and South America. Eligible women (aged ≥18 years, or ≥20 years in Japan) had stage 1-3 HER2-positive breast cancer and had completed neoadjuvant and adjuvant trastuzumab therapy up to 2 years before randomisation. Inclusion criteria were amended on Feb 25, 2010, to include patients with stage 2-3 HER2-positive breast cancer who had completed trastuzumab therapy up to 1 year previously. Patients were randomly assigned (1:1) to receive oral neratinib 240 mg per day or matching placebo. The randomisation sequence was generated with permuted blocks stratified by hormone receptor status (hormone receptor-positive [oestrogen or progesterone receptor-positive or both] vs hormone receptor-negative [oestrogen and progesterone receptor-negative]), nodal status (0, 1-3, or ≥4), and trastuzumab adjuvant regimen (sequentially vs concurrently with chemotherapy), then implemented centrally via an interactive voice and web-response system. Patients, investigators, and trial sponsors were masked to treatment allocation. The primary outcome was invasive disease-free survival, as defined in the original protocol, at 2 years after randomisation. Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00878709. FINDINGS Between July 9, 2009, and Oct 24, 2011, we randomly assigned 2840 women to receive neratinib (n=1420) or placebo (n=1420). Median follow-up time was 24 months (IQR 20-25) in the neratinib group and 24 months (22-25) in the placebo group. At 2 year follow-up, 70 invasive disease-free survival events had occurred in patients in the neratinib group versus 109 events in those in the placebo group (stratified hazard ratio 0·67, 95% CI 0·50-0·91; p=0·0091). The 2-year invasive disease-free survival rate was 93·9% (95% CI 92·4-95·2) in the neratinib group and 91·6% (90·0-93·0) in the placebo group. The most common grade 3-4 adverse events in patients in the neratinib group were diarrhoea (grade 3, n=561 [40%] and grade 4, n=1 [<1%] vs grade 3, n=23 [2%] in the placebo group), vomiting (grade 3, n=47 [3%] vs n=5 [<1%]), and nausea (grade 3, n=26 [2%] vs n=2 [<1%]). QT prolongation occurred in 49 (3%) patients given neratinib and 93 (7%) patients given placebo, and decreases in left ventricular ejection fraction (≥grade 2) in 19 (1%) and 15 (1%) patients, respectively. We recorded serious adverse events in 103 (7%) patients in the neratinib group and 85 (6%) patients in the placebo group. Seven (<1%) deaths (four patients in the neratinib group and three patients in the placebo group) unrelated to disease progression occurred after study drug discontinuation. The causes of death in the neratinib group were unknown (n=2), a second primary brain tumour (n=1), and acute myeloid leukaemia (n=1), and in the placebo group were a brain haemorrhage (n=1), myocardial infarction (n=1), and gastric cancer (n=1). None of the deaths were attributed to study treatment in either group. INTERPRETATION Neratinib for 12 months significantly improved 2-year invasive disease-free survival when given after chemotherapy and trastuzumab-based adjuvant therapy to women with HER2-positive breast cancer. Longer follow-up is needed to ensure that the improvement in breast cancer outcome is maintained. FUNDING Wyeth, Pfizer, Puma Biotechnology.

Adjuvant docetaxel and cyclophosphamide plus trastuzumab in patients with HER2-amplified early stage breast cancer: a single-group, open-label, phase 2 study.

BACKGROUND Previous results suggest that docetaxel plus cyclophosphamide improves disease-free survival (DFS) and overall survival compared with doxorubicin plus cyclophosphamide in early stage breast cancer. We assessed the addition of 1 year of trastuzumab to a non-anthracycline regimen, docetaxel plus cyclophosphamide, in patients with HER2-amplified early stage breast cancer and examined whether this regimen was equally effective in patients with TOP2A-amplified and TOP2A-non-amplified disease. METHODS This was an open-label, single-group, phase 2 study. Eligible patients were aged 18-75 years; had Eastern Cooperative Oncology Group performance status of 1 or less; HER2-amplified early stage breast cancer; operable, histologically confirmed, invasive carcinoma of the breast; adequate tumour specimen available for FISH analysis of TOP2A status; and adequate haematological, renal, hepatic, and cardiac function. Patients received four 21-day cycles of intravenous docetaxel 75 mg/m(2), plus intravenous cyclophosphamide 600 mg/m(2), plus intravenous trastuzumab 4 mg/kg (loading dose) on day 1 and 2 mg/kg on days 1, 8, and 15 during chemotherapy, followed by trastuzumab 6 mg/kg every three weeks for the remainder of 1 year. The primary endpoint was 2-year DFS in TOP2A-amplified and TOP2A-non-amplified patients; the primary analysis was done by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00493649. FINDINGS 493 patients were enrolled between June 15, 2007, and Aug 5, 2009. After a median follow-up of 36·1 months (IQR 35·5-36·7), 2-year DFS was 97·8% (95% CI 94·2-99·2) and 2-year overall survival was 99·5% (95% CI 96·2-99·9) for the 190 patients with TOP2A-amplified disease; 2-year DFS was 97·9% (95% CI 94·9-99·1) and 2-year overall survival was 98·8% (95% CI 96·2-99·6) for the 248 patients with TOP2A-non-amplified disease; 55 patients were not assessable for TOP2A status. In the 486 patients who received at least one dose of study drug, the most common adverse events of any grade were fatigue (284 patients, 58·4%), neutropenia (250, 51·4%), and nausea (217, 44·7%). The most common grade 3-4 toxic effects were neutropenia (229, 47·1%), febrile neutropenia (30, 6·2%), fatigue (21, 4·3%), and diarrhoea (16, 3·3%). Cardiac dysfunction occurred in 29 (6·0%) patients (12 [2·5%] grade 1, 15 [3·1%] grade 2, and two [0·4%] grade 3). 23 patients had at least one study-related serious adverse event. 16 patients stopped trastuzumab because of cardiac dysfunction. INTERPRETATION A short, four-cycle regimen of docetaxel and cyclophosphamide combined with trastuzumab could be an option for adjuvant treatment of women with lower risk HER2-amplified early breast cancer, irrespective of TOP2A status. FUNDING Sanofi.

Comparative Severity of Atherosclerosis in Costa Rica, Guatemala, and New Orleans

The present study is concerned with the comparative severity of aortic atherosclerosis in specimens obtained from 941 necropsies performed in low-income Costa Ricans, Guatemalans, and New Orleans whites. The findings indicate geographic differences in the severity of atherosclerosis after the age of 30 years. The dietary habits, serum cholesterol, and lipoprotein patterns of similar populations are compared with the present pathologic findings.

Arteriosclerotic aneurysms of the abdominal aorta: A review

Summary Since the middle of the 20th century, atherosclerosis has displaced syphilis as the most common cause of aortic aneurysm. Arteriosclerotic aneurysms occur with increasing frequency after the age of 50, reaching a peak incidence of 14% in males in the ninth decade. Males predominate in a 6:1 ratio, due to the earlier onset of aortic atherosclerosis in this sex. Blacks are affected less than half as frequently as whites. Although arteriosclerotic aneurysms are a consequence of atherosclerosis of the abdominal aorta, there is some evidence that hypertension and cigarette smoking may play an augmenting role. The development of an aneurysm of the abdominal aorta appears related to impaired nutrition to the media, the chief supporting layer, as a result of atherosclerotic thickening of the intima. The abdominal aorta is particularly subject to hemodynamic stress from the presence of a standing shock wave, the effect of collision of the normal pulse wave colliding with a reflection of the preceding pulse wave from the bifurcation. The pathologic aspects of atherosclerosis have been reviewed and its pathogenesis summarized as disturbances of the normal transmural movement of plasma constituents. A diagnosis of abdominal aneurysm is made by the finding of a well-defined pulsating mass in the epigastrium, usually projecting to the left. Expansile pulsation is particularly characteristic. Rupture of an aneurysm is suggested by the triad of excruciating abdominal pain, shock, and presence of an enlarging abdominal mass, but may simulate gastrointestinal, urinary tract, or other disease. Following rupture the mass may be fixed and tender, and an additional mass may develop in the left lower quadrant. Rupture is most common into the retroperitoneal tissues on the left side, less frequently the peritoneal cavity is involved, and only occasionally rupture occurs into the duodenum or the vena cava. Hemorrhagic discoloration of the skin overlying the hematoma is a sign occasionally encountered 3 or more days after rupture. Plain roentgenograms are often helpful in diagnosis, and may reveal a rim of calcification corresponding to the walls of the aneurysm. Ultrasonic aortography is a useful method for determining not only the diameter of an aneurysm but also for detecting enlargement. Autopsy studies indicate that about 28% of aneurysms rupture during the patients lifetime. Small stable aneurysms seldom produce symptoms or rupture. Deep-seated pain, referrable to the aneurysm, should be regarded as evidence of enlargement. When rupture occurs, pain may become excruciating and is followed by shock in about half the cases. Treatment by aneurysmectomy with replacement by a homograft was developed in the early 1950s but was soon succeeded by use of the more durable synthetic prostheses. Tabulation of a number of reported series indicates an overall mortality from elective surgery of 16%, although the mortality has in recent years to less than 4% in an umber of surgical centers. Corresponding figures for the overall mortality of ruptured aneurysms, 54.5%, has been reduced to 32%–34%. Surgery is recommended for the symptomatic or expanding aneurysm. Rupture is an absolute indication for emergency surgery. Surgical indications for surgery on the small stable aneurysms are not clear; the decision must take into account the age of the patient, the mortality from surgery, the likelihood of rupture if the aneurysm is left alone, the presence of associated disease, and the useful life of the patient.

Coronary atherosclerosis and myocardial infarction in Kyushu, Japan, and Boston, Massachusetts.

Abstract Necropsy examinations of 352 consecutive autopsies in Kyushu and 350 similar autopsies in Boston disclose a considerable difference in the severity of coronary atherosclerosis in Japan and in the United States. As shown by quantitative appraisal, the onset of intimal disease occurs approximately two age decades later in Japan and progresses thereafter at a much slower rate. Similarly, myocardial infarction was found to be seven times more frequent in the U.S. series.

Congenital Aneurysms of the Coronary Arteries with Report of a Case

A case is presented of congenital aneurysm of a coronary artery in a patient with angina pectoris and myocardial infarction. Etiologies other than coronary atheroselerosis should be considered in young patients with clinical coronary disease; they include syphilitic ostial stenosis, coronary embolization, pulmonary origin of a coronary artery, and necrotizing arteritis in addition to aneurysm of a coronary artery. In this instance the aneurysm caused a shadow that was seen by x-ray but was not identified during life.

Dissecting aneurysm of the aorta

IRST CLEARLY DESCRIBED more than 200 yr ago, ~ dissecting aneurysm may be defined as a deformity of the aorta resulting from an intramural hemorrhage. Its extension along the length of the aorta for variable distances is the characteristic which gives the lesion its name. Commonly, dissection extends into one or more of the primary branches of the aorta. Infrequently, isolated dissecting aneurysms arise outside of the aorta and have been observed in cerebral, 2 temporal, 3 coronary, 4 hepatic, 5 renal, 6 and other arteries. Currently, varying with the special interests of individual hospitals, dissecting aneurysms comprise as many as 23~o of aortic aneurysms, second only to the atherosclerotic variety. 7 According to Hirst and associates, 8 they are found in about one of every 10,000 general hospital admissions and once in every 363 autopsies. The peak incidence involves the years 40-69, although no age group is exempt. There is a two- to threefold prediliction for males but after the age of 80, the sex ratio is reversed. When allowance is made for differences in the prevalence of hypertension, no racial prediliction has been observed. Clinical Features In little more than a generation, the clinical recognition of dissecting aneurysm, once an untreatable rarity, has become commonplace and an urgent requirement of effective management. 8 Sudden onset of excruciating, sharp, tearing, persistent chest pain is most frequent. Subsequent axial or peripheral migration of pain is distinctive, especially if associated with pulse and/or pressure differences in the extremities and/or other evidences of transient or stable arterial obstruction. Hypertension is most commonly present. Should external rupture from the dissection channel supervene, signs and symptoms of massive hemorrhage, varying with the site, will be added to those already present and indeed may become predominant.

Randomized Phase II Trial of Parsatuzumab (Anti‐EGFL7) or Placebo in Combination with FOLFOX and Bevacizumab for First‐Line Metastatic Colorectal Cancer

Abstract Lessons Learned. These negative phase II results for parsatuzumab highlight the challenges of developing an agent intended to enhance the efficacy of vascular endothelial growth factor inhibition without the benefit of validated pharmacodynamic biomarkers or strong predictive biomarker hypotheses. Any further clinical development of anti‐EGFL7 is likely to require new mechanistic insights and biomarker development for antiangiogenic agents. Background. EGFL7 (epidermal growth factor‐like domain 7) is a tumor‐enriched vascular extracellular matrix protein that supports endothelial cell survival. This phase II trial evaluated the efficacy of parsatuzumab (also known as MEGF0444A), a humanized anti‐EGFL7 IgG1 monoclonal antibody, in combination with modified FOLFOX6 (mFOLFOX6) (folinic acid, 5‐fluorouracil, and oxaliplatin) bevacizumab in patients with previously untreated metastatic colorectal cancer (mCRC). Methods. One‐hundred twenty‐seven patients were randomly assigned to parsatuzumab, 400 mg, or placebo, in combination with mFOLFOX6 plus bevacizumab, 5 mg/kg. Treatment cycles were repeated every 2 weeks until disease progression or unacceptable toxicity for a maximum of 24 months, with the exception of oxaliplatin, which was administered for up to 8 cycles. Results. The progression‐free survival (PFS) hazard ratio was 1.17 (95% confidence interval [CI], 0.71–1.93; p = .548). The median PFS was 12 months for the experimental arm versus 11.9 months for the control arm. The hazard ratio for overall survival was 0.97 (95% CI, 0.46–2.1; p = .943). The overall response rate was 59% in the parsatuzumab arm and 64% in the placebo arm. The adverse event profile was similar in both arms. Conclusions. There was no evidence of efficacy for the addition of parsatuzumab to the combination of bevacizumab and chemotherapy for first‐line mCRC.

Abstract P2-11-03: Incidence and severity of diarrhea with neratinib + intensive loperamide prophylaxis in patients (pts) with HER2+ early-stage breast cancer (EBC): Interim analysis from the multicenter, open-label, phase II control trial

Background: Neratinib (Puma Biotechnology Inc) is an irreversible pan-HER inhibitor in late-phase development for the treatment of early-stage and metastatic HER2+ BC. Diarrhea, the main toxicity of neratinib, requires active management with loperamide prophylaxis given early in the course of treatment. CONTROL (PUMA-NER-6201) is an international, open-label, phase II study investigating the efficacy of loperamide prophylaxis in the prevention of neratinib-associated diarrhea. CONTROL has recently been expanded to include prophylaxis with loperamide + budesonide, which targets inflammation identified in a preclinical model of neratinib induced diarrhea. Methods: Pts with HER2+ early-stage BC who had completed trastuzumab-based adjuvant therapy were eligible. All pts were to receive oral neratinib 240 mg/day for 1 year + structured loperamide prophylaxis on d1–56 (2 cycles). Adverse events were graded according to NCI-CTCAE, v4.0. Primary endpoint: incidence of grade ≥3 diarrhea. A protocol defined interim analysis (data cut-off July 2016) was performed when ∼120 pts had completed ≥2 cycles of neratinib + loperamide prophylaxis. A preliminary analysis of the loperamide + budesonide cohort was also performed at this time. Clinicaltrials.gov: NCT02400476. Results: For the interim analysis, 133 pts received neratinib + loperamide prophylaxis. A further 16 (of 40 planned) pts received neratinib + loperamide prophylaxis (2 cycles) + budesonide (1 cycle). Key results are shown in the table. Incidence of grade ≥3 diarrhea was 27.1% with loperamide prophylaxis and 12.5% with loperamide + budesonide prophylaxis vs 39.9% without protocol-mandated loperamide prophylaxis (ExteNET). Grade 2 diarrhea also decreased (20.3%, 18.8% vs 32.5%, respectively). Grade 3 diarrhea events were uncommon after cycle 1 in all CONTROL cohorts. Conclusions: A structured loperamide prophylactic regimen for 2 cycles is associated with a lower incidence and severity of neratinib associated diarrhea, with notably less grade 2/3 diarrhea compared to ExteNET events. There appears to be some adaptation to the effects of neratinib, as higher-grade diarrhea occurs early and does not typically recur. Preliminary data suggest that adding budesonide may further improve outcomes; enrollment into the budesonide cohort continues. Citation Format: Barcenas C, Olek E, Hunt D, Tripathy D, Ibrahim E, Wilkinson M, Hurvitz S, Iannotti N, Kellum A, Manalo Y, Wong S, Hansen V, Alvarez R, Chan A, Gore I, Kendall D, Wade J, Ruiz R, Fang P, Bryce R, Moran S. Incidence and severity of diarrhea with neratinib + intensive loperamide prophylaxis in patients (pts) with HER2+ early-stage breast cancer (EBC): Interim analysis from the multicenter, open-label, phase II control trial [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P2-11-03.