MBC Pts Research Articles

Efficacy, safety and tolerability of dual monoclonal antibody therapy with pertuzumab + trastuzumab in HER2+ metastatic breast cancer patients previously treated with trastuzumab.

Abstract Abstract #3138 Pertuzumab (P), a humanized monoclonal antibody, is a first-in-class HER heterodimer inhibitor that binds to the HER2 dimerization domain, inhibiting the interaction of HER2 with other HER family members. Xenograft studies demonstrated a synergistic effect of P with trastuzumab (T) in combating HER2-amplified breast cancer, and two clinical P+T PhII studies were undertaken in HER2+ MBC.
 The first Ph II study evaluated the efficacy and safety of P+T in HER2+ MBC patients (pts) who progressed during prior T therapy (Gelmon et al, ASCO 2008).
 Pts received T at either 4mg/kg loading dose (LD) followed by 2mg/kg qw or 8mg/kg LD followed by 6mg/kg q3w and P 840mg LD followed by 420mg q3w; 21/66 pts remain on therapy. Of the 16/66 pts (24%) who responded to therapy, there were 5 CRs, 11 PRs, and an additional 17 pts with SD for ≥6mos, for a total of 33/66 (50%) receiving clinical benefit. Most frequent events include diarrhea (64%), fatigue (33%), nausea (27%) and rash (26%). Three pts experienced Gr3 AEs that resolved for therapy to continue, and no Gr4 AEs were noted. There were no symptomatic declines in left ventricular ejection fraction (LVEF). No pts withdrew for treatment or cardiac-related AEs.
 The second Ph II study evaluated P+T in HER2+ MBC previously treated with T (Portera et al, Clin Can Res 2008). Pts in this study progressed on T-based regimens and had a baseline LVEF ≥55%. Pts received T 8mg/kg LD followed by 6mg/kg q3w and P 840mg LD followed by 420mg q3w. Of the 11 pts, 2 (18%) achieved PR and 3 pts had SD ≥18wks. Gr1-3 left ventricular systolic dysfunction (LVSD) was seen in 5/11 (45%) pts; 1 had symptomatic CHF. All 5 pts had previously received at least 240 mg/m2 doxorubicin, and LVSD resolved in 3/5 (60%) pts following therapy. Other AEs were mild- moderate and were not treatment limiting.
 These studies have shown that the combination of P+T is well tolerated and active in HER2+ MBC pts who have progressed on T-based therapies. No dose limiting toxicities have been identified to date, and further data as well as biomarker analyses are ongoing.
 This is a promising biologic combination therapy targeting HER2 disease that shows activity while avoiding typical chemotherapy side effects.
 Additional studies examining this combination include the currently enrolling Ph III Cleopatra study (Clinical Evaluation of P and T), a 1st line HER2+ MBC trial that will randomize 800 pts to docetaxel (D) & T +/- P. The primary endpoint compares progression-free survival (PFS) between pts based on tumor assessments by independent review facility (IRF). Pts will receive D 75mg/m2 q3w, T 8mg/kg LD followed by 6mg/kg q3w, and P 840mg LD followed by 420mg q3w or placebo. Extensive biomarker data will be collected to test markers that may correlate with treatment success. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 3138.

Peripheral-blood gene expression profiling in bladder cancer (BC) patients (pts)

5076 Background: There is a compelling need for biomarkers in the diagnosis and surveillance of bladder cancer (BC). In a pilot study, we previously reported that gene expression profile signature in circulating blood cells (CBC) can distinguish BC pts from other genitourinary cancers and from healthy controls. Here, we take our hypothesis-generating study to the hypothesis-testing level in a larger independent cohort of pts that: 1) includes more stringent control subjects, i.e., bladder pathology other than cancer; and 2) seeks to develop a gene-signature from CBC that can distinguish the presence and extent of BC. Methods: 85 pts (28 superficial BC (sBC), 27 metastatic BC (mBC), and 30 pts with benign bladder pathology) were studied. RNA from CBC was isolated and purified total RNA was labeled and hybridized onto Illumina Human-6 v2 Expression BeadChips (48,000 transcript probes/sample). Expression data were log base 2 transformed and within-array standardized. Unsupervised hierarchical clustering of 4438 high variance genes was used to group samples. T-tests were used to compare the 3 groups of pts. The Benjamini-Hochberg method was used to adjust the resulting p-values for multiple comparisons. Genes were selected based on adjusted p-value (≤ 0.05) and fold change (≥1.5). Results: Clustering led to almost complete separation of BC and benign pts and partial separation of sBC and mBC pts. A subset of 600 genes (230 significantly over-expressed genes and 370 under-expressed genes) were strikingly different between mBC pts compared to benign pts. The top-ranking overexpressed genes include genes related to inflammatory responses such as: peptidoglycan recognition protein 1 (p=2.9×10−8), CD177 molecule (p=5.4×10−8) and haptoglobin (p=5.6×10−7). Top-ranking underexpressed genes included genes related to cell cycle regulation and molecular chaperones such as: CDC like kinase 1 (p=1.7×10−9), Purinergic receptor P2Y (p=1.7×10−9), and Chaperonin Subunit 6a (p=2.3×10−9). Conclusions: Our study reveals a distinct blood-based gene expression signature that differentiates between metastatic BC (pts) and those with benign bladder pathology conditions. Efforts are ongoing to validate a smaller set of high-ranking genes as a BC signature that can be used as a diagnostic/prognostic tool. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Bristol-Myers Squibb, GPC Biotech Bristol-Myers Squibb, Eli Lilly, Genentech™ BioOncology, Pfizer

Kinetics of CEA and CA15–3 correlate with response in patients undergoing chemotherapy for metastatic breast cancer

1087 Background: The aim of this retrospective analysis was to determine the correlation between tumor marker kinetic (TMK) like CEA and/ or CA 15–3 and imaging during of MBC pts. Methods: TMK (CEA, AxSYM, Abbott; CA 15–3, Elecsys, Roche) were evaluated in MBC pts at the beginning of palliative chemotherapy (pre-treatment value = A), after 20–30 days (1st intermediate value = B), after 40–60 days (2nd intermediate value = C) and at the time of staging with imaging techniques (D). Response to treatment was assessed by UICC criteria. Two criteria for progressive and two for non-progressive disease based on TMK were established. The 1st criterion for progression required that the increase from A to C had to be >25 %, and the increase per day from A to C had to be greater than the increase from A to B. The 2nd criterion for progression required that D should be >25% than A and an increase of C to D was required. The 1st criterion for non-progressive disease required that the decrease from A to C had to be > 25% and C < B. The 2nd criterion for non-progressive disease required D <25% than B and D < C. Results: 54 (70%) pts showed a correlation of TMK and imaging results. In 10 (13%) pts no correlation was obtained, and in 13 (17%) pts no biochemical statement was possible because of divergent TMK. Using our criteria a sensitivity of 70.2 % was reached. Conclusion: We could show a correlation between TMK and imaging results. After validation in a prospective trial using our criteria in clinical practice could improve therapeutic monitoring and reduce radiation exposure in pts with MBC. No significant financial relationships to disclose.

Phase I trial of alvespimycin (KOS-1022; 17-DMAG) and trastuzumab (T)

1115 Background: Alvespimycin (A) inhibits the activity of Hsp90, resulting in degradation of client proteins, such as the HER2 receptor. In vivo, Hsp90 inhibition induces rapid degradation of HER2 with loss of pAKT, cyclin D2 and tumor growth inhibition. Methods: Pts receive standard weekly doses of T followed by A in escalating doses via IV doses over 1 hr. Define the recommended dose (RP2D), toxicity and signs of activity of T+A in pts with solid tumors. PK: assessed after the 1st and 4th infusion. PBLs: purified to investigate changes in intracellular signaling proteins by immunoblot. The RP2D will produce DLT in no more than 1/6 evaluable pts. Results: 21 pts enrolled in 3 cohorts (60, 80 and 100 mg/m2). Median age 53 yrs, range 31–75; median KPS 90; prior regimens not including hormonal therapy: median 6, range 1–13; prior T-regimens for MBC pts: median 3, range 0–9. Diagnoses: HER2+ MBC (n=18), ovarian (n=3). DLT was observed at the highest dose, consisting of 1 pt with hypoxia and ↓LVEF; an additional pt at this dose had Grade 3 ↑AST, however ↑hepatic metastases and ascites were observed. Drug-related toxicity: diarrhea (60%), fatigue, headache (both 45%), nausea, arthralgias (both 40%), dry eye and pain in extremity (both 25%); all Grade 1–2 severity except 1 episode of Gr3 fatigue and Gr3 diarrhea. PK (n=18): t½ 17.7 hr (32%CV); Clearance 18.1 L/hr (46%CV); Vz 438L (42%CV); no change upon weekly dosing. AUCinf/Cmax (100 mg/m2): 14268 ng*hr/mL (60%CV) and 2233 ng/mL (23.5%CV). HER2+ MBC activity: 1 pt (13 prior regimens; 3x T and 1x lapatanib) with evaluable disease showed near complete resolution of lung metastases by CT/PET with significant improvement in dyspnea; 3 pts with HER2+ MBC with SD (4, 5 and 7+ months). Ovarian CA activity: 1 pt (HER2 unknown; 13 prior regimens; 11+ months on-study) with evaluable disease showed near complete resolution of ascites and pleural effusion at end of Cycle 2 with ↓83% CA125. Dose-dependent increase in Hsp70 in PBLs; at 80 and 100 mg/m2, Hsp70 induction was maintained prior to successive weekly doses. Conclusions: Combination of T+A has signs of activity in H-refractory HER2+ MBC and refractory ovarian cancer. Definition of RP2D dose is pending. Toxicity has been manageable. No significant financial relationships to disclose.

Preliminary results of a multicenter phase II trial of vinflunine (with trastuzumab in HER2+ pts) as first-line treatment in metastatic breast cancer

1043 Background: Vinflunine (VFL) is a new and innovative microtubule inhibitor of the vinca alkaloid class that achieves high intracellular concentrations. By inhibition of tubulin polymerization, cell proliferation is arrested leading to apoptotic death. Demonstrating anti- angiogenic and vascular disrupting activities, VFL has demonstrated significant efficacy as 2nd line chemotherapy in MBC (M. Campone, BJC 2006). This trial was designed to evaluate the response rate and safety of VFL as 1st line therapy in MBC as well as its activity in combination with trastuzumab in HER2+ MBC pts. Methods: Eligibility: 0 prior regimens for MBC, > 6 mo from adjuvant therapy, RECIST measurable disease, ECOG PS 0–2, adequate organ function, < G2 neuropathy. Treatment: 320 mg/m2 IV over 20 minutes q3 weeks; 280 mg/m2 with trastuzumab 6 mg/kg q3 weeks in HER2+ pts. Response evaluations q9 weeks; treatment continued until progression or toxicity. A total of 96 pts will be enrolled, 48 pts per each of 2 cohorts, HER2- and HER2+. Results: 18 pts are enrolled, 13 pts evaluable for toxicity and 12 pts for response. 3 pts received VFL monotherapy and 10 pts were treated with VFL + trastuzumab. Median age: 59 years (43–78). ECOG PS 0: 9 pts, 1: 3 pts, 2: 1 pt. Prior adjuvant chemo: 7 pts (54%), with 5 prior anthracyclines and 6 prior taxanes. 2 pts received adjuvant hormonal therapy only. 4 pts presented with de novo stage IV HER2+ MBC. Metastatic disease sites: liver: 6 pts, lung: 7 pts, bone: 5 pts, lymph nodes: 6 pts. 46% had 3 or more sites of organ involvement. Median of 3 cycles (range:1 - 11) was delivered. 7 pts (58%, all HER2+) had a PR and 4 pts (33%) achieved SD. Only 1 pt progressed. Heme toxicity: G3/4 neutropenia: 2 pts (16%); no febrile neutropenia was noted. G3 non-heme toxicity consisted of N/V: 2 pts and myalgia, 2 pts. There were no G4 events. 4 pts were hospitalized (vomiting: 2, cerebro-vascular accident: 1, back pain: 1 pt). 92% of pts remain free of progression at 6 months. Median TTP has not been reached. Conclusions: Vinflunine is a promising new drug with a high level of activity as first line MBC therapy, especially in combination with trastuzumab. VFL is well tolerated in this patient population with a manageable toxicity profile. Accrual to this trial continues. [Table: see text]

Cardiotoxicity of weekly trastuzumab (T) plus epirubicin (E) and paclitaxel (P) for HER2-positive locally advanced (LA) and/or metastatic (M) breast cancer (BC): A feasibility phase II study

11509 Background: The introduction of T for patients (pts) overexpressing HER-2 changed the natural history of BC. The adjunction of T to anthracyclines and taxanes for both LABC and MBC provided a significant incidence of unexpected cardiotoxicity. Given the low cardiac toxicity in our previous experience with weekly ET in unselected MBC pts, a feasibility phase II study aimed to cardiotoxicity was planned. Methods: Pts affected by untreated LABC/MBC overexpressing HER-2 by FISH/CISH amplification or 3-positive Dako- Test, underwent weekly T (4–2 mg/kg/week), day 1, and E (25 mg/m2/week) plus P (80 mg/m2/week), day 2, plus G-CSF support, for 16/24 consecutive weeks in absence of progression or toxicity, in LA/M pts, respectively. Pts with significant cardiac disease/L-FEV<50% were excluded. Primary endpoint was the rate of pts with L-FEV reduction >10% after 12 weeks. An optimal 2-stage Simon design was applied. With a power of 90% at a 5% significance level, assuming a toxicity rate of 30% as unacceptable, and less than 10% as acceptable, an initial group of 15 pts was required; with 11 pts with no toxicity, a second step with further 21 pts (total 36) was planned. Non-cardiac toxicity and activity were evaluated as secondary end-points. Results: From May 2004 to November 2006, 15 pts entered the study. Patient characteristics: median age=47 (range 37–69); LABC/MBC=4/11; positive hormonal receptor 8/7; menopausal pre/post=7/8; PS 0/1=14/1; number of met sites 1/2/3=7/6/2. Median baseline- and post-week-12-L-FEV was 69% (range 64–77) and 65% (range 61–76), respectively. With a median number of courses of 13 (range 8–24), 3 pts had a >10% L-FEV reduction (20%), with an overall median L-FEV reduction of 5.2%. No EKG alteration or specific symptoms were registered. With a 17-months median follow-up, 13 pts were evaluable for response. Eight response (61.5%, 95% CI 9- 87) were documented, with a median response duration of 9 months. No grade 3–4 toxicity were registered, with the exception of severe alopecia. Conclusions: The weekly administration of T plus E and P is extremely tolerable, also with regard to L-FEV reduction. The low L- FEV reduction rate allowed entering the second step of the study. No significant financial relationships to disclose.

Metronomic chemotherapy with capecitabine and oral cyclophosphamide in combination with bevacizumab in metastatic breast cancer (mbc): Evidence of activity of an antiangiogenic treatment

11501 Background: Metronomic chemotherapy has shown efficacy in patients (pts) with MBC. Laboratory and clinical studies suggest that the combination with a specific antiangiogenic drug may be particularly effective. Methods: We evaluated the activity and biological effects of low dose continuous oral Capecitabine (500 mg PO TID) and Cyclophosphamide (50 mg PO QD) plus Bevacizumab (10 mg/Kg Q 2 weeks) in a two stage phase II trial in MBC pts, who received =3 lines of chemotherapy for advanced disease. Planned sample size is 46 pts. Results: To date, 26 patients have been enrolled on the study and 23 are evaluable. Pts characteristics: 1/2/=3 sites of metastatic disease 6/9/11 pts; dominant sites of disease soft tissues/bone/viscera 1/11/22; previous treatment for MBC: endocrine/chemo/trastuzumab 13/21/1 pts (=2 lines 25). Results: there were 1 CRs (4.3%), 10 PRs (43.5%), 6 SD (26.1%), and 6 PD (26.1%), for an overall response rate of 48% (exact 95% CI 27–69%). Median progression free survival was 6 months (+). Grade 3 side effects: 6 hypertension , 1 leucopenia , 2 neutropenia , 2 transaminitis (both with liver metastases). No patient was withdrawn from the study due to side effects, and hypertension was manageable with adequate therapy. Data on median circulating endothelial cells (CECs) will be available. Conclusions: Metronomic chemotherapy with capecitabine and cyclophosphamide in combination with bevacizumab has clinical activity and low toxicity in advanced breast cancer. No significant financial relationships to disclose.

Clinical significance of brain metastases occurrence in HER2 overexpressing metastatic breast cancer patients treated with trastuzumab

10593 Background: Recent data report that HER2 overexpressing metastatic breast cancer patients (HER+ MBC pts) treated with trastuzumab (T) have a high rate of Brain metastasis (BM). This study aimed to evaluate the prognostic significance of BM occurrence and the related clinical outcome in a specific patient population. Methods: All the HER+MBC patients treated with trastuzumab (with or without chemotherapy) between 09/1999 and 12/2004 were included in this study. Results: A total of forty three patients were enrolled into the study cohort. The median follow-up was 48 months (range, 11–166). Fifteen patients (35%) developped BM. The median interval from the the first MBC event to BM was 18 months (range, 1–65). In multivariate analysis; younger age was the only factor associated with BM occurrence (46 versus 57 years; p = 0.01). Patients with BM tend to have a longer median duration of response to T than patients without BM (16 months versus 13 months; p = 0.1). At the time of BM appearance, 6 of the 15 patients (40%) were still responding or had achieved extracranial stable disease while receiving trastuzumab. Twelve out of 15 (80%) pts received a whole-brain radiation therapy, and 8 pts continued to receive trastuzumab until extracranial disease progression. The median overall survival for patients diagnosed with BM was 10 months (range, 2–42). At three-year, there was no significant difference in overall survival rates between the two groups. The 3-YS was 63.5% and 66.7% for pts with or without BM, respectively; (p = 0.7). Conclusions: The BM occurrence in HER2+ MBC pts treated with Trastuzumab is not linked to tumour resistance, but likely related to the T inability to cross the blood-brain barrier. There is no impaired survival for these pts treated with effective and appropriate therapy. [Table: see text]

RegistHER: Baseline characteristics of a cohort of HER2-positive metastatic breast cancer (MBC) patients

20095 Background: HER2 is amplified in 25% of breast cancers and is associated with poor survival. registHER captures the natural history, treatment patterns and outcomes in 1000 newly-diagnosed HER2-positive MBC patients (pts) throughout the U.S. This observational study recruits pts in both academic and community centers. Methods: This ongoing prospective cohort study collects clinical, pathologic and treatment data at enrollment, quarterly until death, loss to follow-up or 3 years after the last enrollment. We describe baseline pt and clinical characteristics in registHER compared with HER2-positive MBC pts in the phase III pivotal trial (Slamon DJ, et al. N Engl J Med. 2001;344:783–792). Results: Between December 2003 and September 2005, 813 eligible pts were enrolled at 280 study sites. Most pts were seen at community-based (76%) vs academic (18%) clinics; a few pts did not fall into either category (6%). A comparison of baseline characteristics is shown below. Conclusions: registHER pts tended to have a shorter disease-free interval and more estrogen receptor positive disease than pts in the pivotal trial. Reasons for these differences could reflect trial referral and/or diagnostic testing differences. Fewer registHER patients were white, but other characteristics were similar between the two groups. These findings support the hypothesis that observational studies describe a broad patient population which may not exactly duplicate clinical trials. Within registHER, there was some variation between academic vs community clinics (eg. nodal status and adjuvant therapy). Treatment pattern analyses are ongoing. [Table: see text] [Table: see text]

A comparative study on capecitabine (Cape) pharmacokinetics (PK) in elderly or younger patients with metastatic breast (MBC) or colo-rectal cancer (CRC)

12003 Background: Cape is an efficient oral prodrug of 5FU in MBC and CRC. Unexpected severe toxicity in older patients (pts) was reported after standard dose of 2500mg/sm/day. About 70% of drug and metabolites are excreted with the urine and a 25% reduction of the dose is recommended if the pt has a creatinine clearance (CrCl) <50ml/min. However no prospective study has been done on Cape PK in the elderly pts. Methods: Between Oct 2004 and Nov 2005, 21 pts with MBC or CRC and age ≥70yrs or ≤60yrs who received Cape (1000 mg/sm bid for 14 days every 21 days) entered the study after giving signed informed consent. CrCl was calculated according to the Cockcroft-Gault method. Patient characteristics: 15 elderly pts (median 78 range71–84yrs), 6 younger pts (median 50.5 range 43–57yrs); 9 (42.9%) males and 12 (57.1%) females; median KPS 90 (range 70–100); 8 MBC pts (38%), 13 CRC pts (62%). Blood samples were taken on the first day of treatment at time 0 and at 0.25,0.5,1,2,3,4,5,6,8 hrs after the first drug administration and on 4th, 8th, 12th and 14th days in the morning. Plasma levels of Cape, 5DFUR, 5DFCR and 5FU were determined by a validated HPLC method and UV detection. Results: At present PK data after the first administration of Cape are available for 13 pts (9 elderly; 4 younger). The mean Cape and 5DFCR AUC0–8hr are higher in older patients (Cape 6653±2564.8 vs. 4427±2714.5; P=0.09; 5DFCR 8635±5197.1 vs. 6292±3813.6; P=0.26), while no evident differences are present for 5DFUR and 5FU. The same results are obtained both in pts with CrCl < and ≥ 50 ml/min. The ratios of DFUR_AUC to Cape_AUC and 5FU_AUC to Cape_AUC are conversely higher in younger than in older pts (mean: 2.2 vs 1.62). A large interindividual variability in the concentration/time curves is present for Cape and metabolites. Cape dose reduction because of G3 toxicity (2 hand-foot syndrome, 1 stomatitis) was performed in 3 elderly pts. Drug systemic exposure was higher in 2 of these pts independently of CrCl. Conclusions: The preliminary results of this PK study suggest that elderly patients treated with Cape at 1000 mg/sm/bid are more drug-exposed than younger patients, independently of renal function. PK analysis is ongoing for the remaining patients. No significant financial relationships to disclose.

Phase I trial of KOS-953, a heat shock protein 90 inhibitor, and trastuzumab (T)

501 Background: KOS-953 (17-AAG in Cremophor) is a potent Hsp90 inhibitor that in vivo induces rapid degradation of Her2, loss of pAKT and tumor growth inhibition in a Her2+ breast cancer xenograft. Objectives: Define the phase 2 dose of KOS-953 + T. Define toxicity and PK of KOS-953, its active metabolite and T. Assess changes in intracellular signaling proteins (such as Hsp70) in leucocytes. Describe antitumor activity. Methods: Eligible pts with advanced solid tumors (Her2 + was not required) received standard weekly doses of T followed by IV KOS-953 in escalating doses over 2 hrs. Results: 25 pts enrolled in 4 cohorts (225, 300, 375 and 450 mg/m2; 4, 3, 8 and 10 patients per cohort), receiving a total of 94 cycles (median 3, range <1 - 12+). Demographics: 21 female (17 with Her2+ metastatic breast cancer ‘MBC‘, 1 Her2 status unknown); median age/KPS 66 yrs/90; # prior T-containing regimens for MBC pts (n=18) equaled 2 (range 0–5). DLT was observed at the 3rd and 4th cohort (1 pt each): 2-week dose delay for recovery from Grade 4 fatigue/Grade 2 nausea & anorexia at 375 mg/m2; delayed recovery of platelets at 450 mg/m2. Drug-related Grade 3 toxicity: emesis, increased ALT and hypersensitivity (n=2); Grade 4 drug-induced thrombocytopenia in a pt with Hashimoto’s disease after 7 cycles. In general the drug was well tolerated. Grade 1 or 2 toxicities included fatigue, nausea, diarrhea, emesis, headache, rash/pruritus, increased AST/ALT and anorexia. Most toxicities (except headache) were not dose dependent. PK of parent (n=21): t½ 3.0 ± 2.1 h; clearance 31.8 ± 12.8 L/h; Vz 164 ± 101 L. Metabolite: Tmax 30–60 min after end-of-infusion with similar AUC and longer t½ of 6.1 ± 1.7 h. PK of T showed no changes compared to previous reports. Among 17 pts with Her2 + MBC s/p multiple regimens of T: PR= 1, MR = 3, 5 pts with SD (5, 7+, 9 and 12+ months). Pts with PR and MRs had confirmed progression of disease prior to study on T-containing regimen. Pharmacodynamic testing showed reactive induction of Hsp70/72 in leucocytes at all dose levels. Conclusions: KOS-953 added to T is active in refractory Her2 + MBC with no change in PK compared to single-agent therapy. The phase 2 dose of KOS-953 is 450 mg/m2; enrollment to the phase 2 trial of this combination in Her2+ MBC is on-going. [Table: see text]

The combination of trastuzumab and vinorelbine as a atractive regimen in overexpressing metastatic breast cancer patients

3212 Background: Trastuzumab (T) and vinorelbine (V) combination has previously shown as a interesting regimen for Her-2 positive metastatic breast cancer (mbc) patients(pts). It is retrospective analysis of the efficacy and safety T/V combination in Her-2 positive mbc treated in two polish centers. Methods: Between February 2002 and May 2004, 45 women were treated with weekly combination of T and V. Median age 50 (range 35–73), median of metastatic sites 2, median of visceral metastases -1. In all pts overexpression Her-2 3+ (39) or FISH positive (6) were confirmed. 14 pts had not received any chemotherapy for metastatic disease (subgroup A), 12 pts were previously treated by 1 line of chemotherapy for mbc (subgroup B), 19 pts by 2 or more line of chth (subgroupC). In 18pts antracycline because of mbc were used. In 24 cases V was administrated as first combination with T, in 21 as second or third (after combination of docetaxel or cisplatin).T and V were administrated weekly (V-30mg/m2 in 19 pts, 25mg/m2 - 26 pts). Pts were assessed for toxicites and reassessed for response every 8 weeks until progression. Results: The overall response was obtained in 17 pts (38%): in subgroup A-5pts, B-4pts, C-8pts. Median time of treatment duration in responders was 23 weeks. There was no significant differences of results in subroups A,B,C. SD was observed in 22pts. We noted 2 cases of PD during treatment. In the median follow-up 29 weeks (r 2–119) PD was noted in22 pts with mTTP 20 weeks (r 3–111).15pts are still receiving treatment. The regimen was well tolerated. WHO 3–4 grade(G) neutropenia was observed in 17 pts (with 2 cases of infections G3), G3 anaemia in 1pt. There was one case of severe cardiotoxicity in our group -congestive heart failure G3 after 9 weeks therapy, required end of treatment with Herceptin. Toxicites (main hematologic) required vinorelbine dose reduction from 30mg/m2 to 25mg/m2 in 89 cycles (11%) and from 25mg/m2 to 20mg/m2 in 48 cycles (6%).There were 71cycles (9%) of V omitted from 823 planed. Conclusions: This analysis confirm that combination of vinorelbine and trastuzumab is active and well tolerated regimen in Her-2 positive mbc pts, even pretreated by one or more line systemic therapy. No significant financial relationships to disclose.

Phase II trial of gemcitabine plus trastuzumab in minimally pretreated HER2 overexpressing metastatic breast cancer

704 Background: Gemcitabine is an exciting novel deoxcytidine analog demonstrating synergism, when combined with trastuzumab, in human breast cancer cell lines. Trastuzumab plus chemotherapy, has yielded superior ORR, TTP, as well as survival as compared to chemotherapy alone in HER2+ tumors. This study evaluates the clinical activity of gemcitabine administered with trastuzumab in minimally pretreated HER2 amplified MBC. Methods: Eligibility: Pts with HER2 3+ or FISH + tumors, 0–1 prior MBC regimens, bidimensional disease, doxorubicin < 360 mg/m2, and LVEF ≥ 50%. Treatment consisted of gemcitabine 1000 mg/m2 days 1, 8, 15, q28 days in conjunction with 4 mg/kg trastuzumab D1 and then 2 mg/kg for 8 consecutive weeks followed by D1, 8, 15 administration of a q28d schedule with gemcitabine, both continuing until disease progression or toxicity. Results: 40 pts were enrolled between 7–5–01 & 11–19–04 with 33 evaluable for response. Median age is 57. 28 pts were HER2 3+ and 6 FISH+. Sites of metastatic disease included 13 lung, 19 liver, 16 bone, 17 soft tissue; the majority of pts had ≥ 2 metastatic sites of disease. 21 pts had prior adjuvant therapy, 21 pts prior doxorubicin & 26 pts prior taxanes. 19 pts had no prior MBC therapy, 17 pts-1 line, 3 pts ≥ 2 lines of MBC therapy. Clinical benefit rate of 66% was noted with 3 CRs, 8 PRs and 11 with SD. 11 pts progressed and 4 are unevaluable. A median of 3.5 cycles were delivered (range 1 - 14). G 3/4 heme toxicity was notable for neutropenia in 21 pts- accompanied by fever in only 1 pt, thrombocytopenia-5, and anemia-1pt. G 3/4 non-heme toxicity consisted of fatigue-5, pulmonary-4, nausea-4, vomiting-3, and edema-2 pts. Cardiac dysfunction was noted in 1 pt. Median survival was 18.8 mo with a median PFS of 3.9 mo. Conclusion: Gemcitabine plus trastuzumab is safe and well tolerated in minimally pretreated HER2+ MBC pts, the majority of whom were anthracycline and taxane pretreated. This preliminary analysis supports the suggestion of enhanced anti-tumor activity between gemcitabine and trastuzumab, with the preliminary median survival surpassing that expected for either agent alone at this juncture of treatment. Final data to be presented. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Genentech, Lilly Oncology Genentech, Lilly Oncology Genentech, Lilly Oncology

Gemcitabine plus docetaxel (GD) versus capecitabine plus docetaxel (CD) for anthracycline-pretreated metastatic breast cancer (MBC) patients (pts): Results of a European phase III study

581 Background: CD has shown to have higher efficacy when compared with D alone in MBC. GD has shown to be efficacious and safe in MBC even in anthracycline-pretreated pts; gemcitabine was recently approved in this setting. This study compared GD with CD as first- or second-line treatment in MBC pts pretreated with an anthracycline. Primary objective was progression-free survival (PFS); secondary objectives were overall response rate (ORR), time to treatment failure (TtTF), overall survival (OS), toxicity, and quality of life (QOL). Methods: Pts with histologically confirmed MBC who relapsed after an anthracycline-based regimen either in neoadjuvant or first-line metastatic disease were randomized to GD (G 1000 mg/m2 d1,8; D 75 mg/m2 d1) or CD (C 2500 mg/m2 d1–14; D 75 mg/m2 d1) q21 days; neoadjuvant pretreatment with taxanes was allowed if completed >6 months before entry. Results: Between October 2002 and March 2004, 305 pts were randomized; 295 pts were included in this analysis (150 GD, 145 CD). Arms ...

Delayed antiemetic treatment for weekly chemotherapy: Overview of 275 patients enrolled in 6 phase II trials of vhemotherapy in metastatic breast vancer

8057 Background: Although weekly administration is a frequent way to administer chemotherapy, current guidelines for the prevention and control of both acute and delayed emesis do not consider such schedule. In this analysis, we retrospectly review the delayed nausea and vomiting pattern of 6 different weekly schedules in 1st line-2nd line chemotherapy for MBC patients (pts). Patients: We gathered 6 databases from 1990 to 2003, comprising of 275 patients participating in phase II trials in MBC pts using weekly chemotherapy. The trials evaluated activity and tolerability of weekly epirubicin (25 mg/m2/wk) with either lonidamine (450 mg/d) (EL, 51 pts), vinorelbine (25 mg/m2/wk) (EN, 52 pts) and paclitaxel (80 mg/m2/wk) (ET, 53 pts), in 1st line, and weekly vinorelbine (N, 25 mg/m2/wk, 40 pts), weekly docetaxel (D, 35 mg/m2/wk, 28 pts), and weekly paclitaxel (80 mg/m2/wk) plus 5-fluorouracil (300 mg/m2/wk) (TF, 51 pts) in 2d line, for 24 weeks. We considered epirubicin-based as moderately emetogenic chemotherapy (MEC), and non- epirubicin-based therapy as low emetogenic chemotherapy (LEC). For acute emesis, pts received dexamethasone 8 mg plus anti-5HT3 day 1 i.v. No antiemetic prophylaxis was given for delayed emesis. Nausea/vomiting grade 1–4 were compared (MEC vs LEC; polychemotherapy vs monochemotherapy). Results: In overall 275 pts, only 1 patient (0.4%) showed delayed G3 nausea/vomiting. No grade 4 was observed. Grade 1 and 2 were observed in 27.2% and 14.2% of the pts. MEC (156 pts) was administered as 1st line treatment, while LEC (119 pts) as 2nd line. Conclusions: In our series of pts, moderate delayed emesis (Grade 2) is not significantly different when comparing weekly MEC versus LEC. Acute antiemetic medication covers delayed emesis well for weekly MEC and LEC. Our results suggest that no prophylactic corticosteroids are needed for delayed emesis, when weekly MEC or LEC are administered. No significant financial relationships to disclose.

Humoral immune-response to naturally occurring STn in metastatic breast cancer patients (MBC pts) treated with STn-KLH vaccine

2547 Background: Theratope is an investigational therapeutic cancer vaccine consisting of a synthetic form of STn conjugated to KLH. Phase III study results showed a trend for increased survival in MBC pts concurrently treated with Theratope (T) and hormone therapy (HT) (38.2mo (T) vs. 30.7mo (control, C), Cox P= 0.07). Methods: MBC pts with no evidence of disease or non-progressive disease following any first-line chemotherapy were eligible for a randomized, controlled, double-blind, multicenter study. Study arms were adjuvant plus T or adjuvant plus KLH (C). All pts received a single IV dose of cyclophosphamide (300mg/m2) 72 hr before vaccine. Primary endpoints were overall survival (OS) and time to progression. Secondary endpoints were humoral (IgG) responses to the KLH (carrier), STn (synthetic monomeric form), and OSM (naturally occurring clustered STn) antigens in MBC pts +/- HT treated with T. IgG was measured using ELISA assays for STn, OSM, and KLH at week-12 of vaccine therapy. Median OS was prospectively assessed as a function of IgG titers. Results: Of a planned accrual of 950 pts, 1030 were enrolled and 1028 randomized to recive adjuvant + T(n=523) or C (n=505). As of September 2003, median duration of follow-up was 22.2 mo. Median titer of anti-OSM IgG was 320 in the T group and 0 in the C group. Median OS was significantly greater in T treated pts who received concurrent HT and who had IgG titers of anti-OSM equal to or higher than the median titer (41.1 vs. 25.4 mo, log-rank p=0.01) (see Table). OS was not influenced by anti-STn or anti-KLH titers, indicating that only titers of the naturally occurring clustered STn antigen are predictive of increased OS. Conclusions: Experimental vaccine trials suggest that the ability to mount an immune response is associated with favorable clinical outcomes. Our data from this large, prospective trial indicate that the magnitude of the immune response to the relevant and specific antigen is most predictive of a favorable clinical outcome. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Biomira, Inc.; EMD Pharmaceuticals Biomira, Inc. Biomira, Inc.; EMD Pharmaceuticals Biomira, Inc.; Merck KGaA

Humoral immune-response to naturally occurring STn in metastatic breast cancer patients (MBC pts) treated with STn-KLH vaccine

2547 Background: Theratope is an investigational therapeutic cancer vaccine consisting of a synthetic form of STn conjugated to KLH. Phase III study results showed a trend for increased survival in MBC pts concurrently treated with Theratope (T) and hormone therapy (HT) (38.2mo (T) vs. 30.7mo (control, C), Cox P= 0.07). Methods: MBC pts with no evidence of disease or non-progressive disease following any first-line chemotherapy were eligible for a randomized, controlled, double-blind, multicenter study. Study arms were adjuvant plus T or adjuvant plus KLH (C). All pts received a single IV dose of cyclophosphamide (300mg/m2) 72 hr before vaccine. Primary endpoints were overall survival (OS) and time to progression. Secondary endpoints were humoral (IgG) responses to the KLH (carrier), STn (synthetic monomeric form), and OSM (naturally occurring clustered STn) antigens in MBC pts +/- HT treated with T. IgG was measured using ELISA assays for STn, OSM, and KLH at week-12 of vaccine therapy. Median OS was prospectively assessed as a function of IgG titers. Results: Of a planned accrual of 950 pts, 1030 were enrolled and 1028 randomized to recive adjuvant + T(n=523) or C (n=505). As of September 2003, median duration of follow-up was 22.2 mo. Median titer of anti-OSM IgG was 320 in the T group and 0 in the C group. Median OS was significantly greater in T treated pts who received concurrent HT and who had IgG titers of anti-OSM equal to or higher than the median titer (41.1 vs. 25.4 mo, log-rank p=0.01) (see Table). OS was not influenced by anti-STn or anti-KLH titers, indicating that only titers of the naturally occurring clustered STn antigen are predictive of increased OS. Conclusions: Experimental vaccine trials suggest that the ability to mount an immune response is associated with favorable clinical outcomes. Our data from this large, prospective trial indicate that the magnitude of the immune response to the relevant and specific antigen is most predictive of a favorable clinical outcome. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Biomira, Inc.; EMD Pharmaceuticals Biomira, Inc. Biomira, Inc.; EMD Pharmaceuticals Biomira, Inc.; Merck KGaA

Patient benefit from trastuzumab plus a taxane regardless of estrogen receptor (ER) status or prior adjuvant therapy for HER2+ metastatic breast cancer (MBC)

674 Background: Trastuzumab (Herceptin, H) is a humanized monoclonal antibody which showed a significant survival benefit in a randomized trial comparing chemotherapy plus H vs. chemotherapy alone in first-line treatment of HER2+ MBC. The effect of prior adjuvant therapy and ER status on response to H/chemotherapy is not well characterized. We performed subset analyses to determine whether patients (pts) responded differently to H/taxane therapy depending on ER status and prior adjuvant therapy. Methods: Pts had previously untreated HER2+ MBC (prior hormonal therapy allowed), normal left ventricular ejection fraction (LVEF), and measurable or evaluable disease. All pts received H (4 mg/kg load -> 2mg/kg q week) with either paclitaxel or docetaxel at standard doses. LVEF was measured at baseline, at week 16 of therapy and as indicated thereafter. Results: 401 pts have been enrolled. Baseline characteristics: median age 56, performance status 0–1 (90%), estrogen receptor (ER)+ (49%), ER- (49%), postmenopausal (55%). 352 pts were evaluable for best response within 6 months of starting combination therapy. The objective response rates (ORR) and clinical benefit rates (CBR) are shown below with 95% confidence intervals for the overall population and for subsets. Both taxane/H regimens were well tolerated. The median LVEF was 63% at baseline and 60% at week 16. 8 patients experienced clinical CHF (2%); 5/8 had significant pre-existing cardiac disease or risk factors. There was one case of fatal neutropenic sepsis. Conclusions: HER2+ MBC pts derive equal benefit from therapy with H plus a taxane regardless of ER status or prior adjuvant chemotherapy or hormonal therapy. There was a low incidence of clinical CHF. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Genentech, Inc. Genentech, Inc. Genentech, Inc.

Long-term follow-up of patients concomitantly treated with hormone therapy in a prospective controlled randomized multicenter clinical study comparing STn-KLH vaccine with KLH control in stage IV breast cancer following first-line chemotherapy

2603 Background: Theratope (T) is an investigational therapeutic cancer vaccine consisting of a synthetic form of the tumor-associated antigen Sialyl Tn (STn) conjugated to the carrier protein keyhole limpet hemocyanin (KLH). This abstract reports a survival follow-up of the phase III trial with emphasis on the subgroup concomitantly treated with hormone therapy. Methods: Metastatic breast cancer patients (MBC pts) who had no evidence of disease or non-progressive disease following any first-line chemotherapy were randomized 1:1 to receive adjuvant plus T or control (C) (adjuvant plus KLH). All pts received a single IV infusion of cyclophosphamide before vaccine. Primary endpoints were time to disease progression (TTP) and overall survival (OS). Pts were stratified by disease status and concomitant hormone therapy (HT). Results: 1028 pts were randomized: 34% received concurrent HT (n = 350). The concomitant treatment in the two treatment arms on hormone therapy (n = 180 T, n = 170 C) consisted mainly of SERMs (43% vs. 39%) and AIs (47% vs. 52%). OS and TTP analyses were performed (table). Conclusions: In pts not concomitantly treated with hormones no difference between T and C was demonstrated. However, HT combined with T indicates a favorable trend based on the current database. Currently, not enough events have been reached to calculate median overall survival for the Theratope arms combined with all hormone modalities, AIs, and SERMs. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Biomira, Inc.; EMD Pharmaceuticals Biomira, Inc. Biomira, Inc.

Evaluation of vinorelbine (N) and trastuzumab (H) as first-line therapy for patients (pts) with HER2- positive metastatic breast cancer (HER2+ MBC): Impact on clinical response and cardiac function

636 Background: Combination therapy of vinorelbine (N) and trastuzumab (H) has recently been shown to be an active and safe regimen for HER2 positive MBC patients (Burstein JCO 01, 19;2722–2730). Here we report results of a multinational phase II trial. Methods: HER2 positive MBC pts (IHC 3+ or FISH + by centralised testing), with measurable disease, KPS = 70%, no prior H or N were treated with N : 30mg/m2/week and H: 4 mg/kg on day1 as loading dose and then 2mg/kg /w. Patients were reassessed every 8 w. All pts were evaluated for the left ventricular ejection fraction (LVEF) at the baseline and every 6 months and more often if needed. Either ultrasonography or MUGA scan were used. Results: Between October 2000 and June 2002, 69 patients were included in the study, median age: 53 years (30–74), prior neo/adjuvant chemotherapy: 65.2%, prior hormonal therapy: 49.3%, visceral metastasis: 75.4%. Sixty-six patients were evaluable for response and 68 pts for toxicity. The overall response rate was 61%, disease control (CR+PR+SD = 24 weeks) was 79%. The median duration of response was 11.7 months, and median progression-free survival was 10 months. Median survival has not yet been reached. The regimen was well tolerated, WHO grade 3–4 neutropenia (44.6% of cy) with 2 episodes of febrile neuropenia, H infusion reactions grade 3 (1.5 % of pts), grade 3: asthenia (8.8 % of pts), neuropathy (4 % of pts) and infection (6 % of pts). No severe nausea, vomiting or alopecia have been reported. The median LVEF at baseline was 64%. At week 28, forty-one of 68 pts (60 %) were rescreened for LVEF; the median LVEF was unchanged at 58%. Four pts experienced a decline of LVEF below 50%. This decline of LVEF was asymptomatic in 3 out of 4 pts and resolved after discontinuation of H for one cycle. Subsequently treatment was reintroduced for these 3 pts without further complications. One pt came off study due to grade 3 symptomatic cardiac dysfunction that resolved with therapy. Conclusion: Our results indicate that N + H is one of the most active treatment regimens for pts with HER2 positive MBC and demonstrates to be safe regimen. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Roche; Aventis; Lilly; Pierre Fabre