Annual Meeting Proceedings Part 1 - American Society of Clinical ...

1016 Poster Discussion Session (Board #8), Mon, 1:15 PM-5:15 PM and
4:45 PM-5:45 PM
Tesetaxel: Activity of an oral taxane as first-line treatment in metastatic
breast cancer. Presenting Author: Andrew David Seidman, Memorial
Sloan-Kettering Cancer Center, New York, NY
Background: Tesetaxel, unlike standard taxanes (docetaxel, paclitaxel), is
not a substrate for Pgp, a major cause of taxane resistance in tumor models.
In a DU4475 breast cancer xenograft that overexpresses Pgp, tesetaxel
induced a 94% reduction in tumor size, markedly exceeding the activity of
docetaxel (46%) and paclitaxel (26%). Tesetaxel is associated with
substantially less neuropathy preclinically than equi-myelotoxic doses of
docetaxel. In clinical studies to date, tesetaxel is not associated with
hypersensitivity reactions (0% incidence in � 450 patients [pts]), thus
eliminating the need for premedication and extended observation. In a prior
study, tesetaxel (27-35 mg/m2 Q3 wks) achieved a 38% partial response
(PR) rate as 2nd-line therapy in pts with metastatic breast cancer (MBC)
who had progressed after multidrug anthracycline-containing regimens. To
extend these data, we initiated a phase 2 study of tesetaxel as 1st-line therapy in women with MBC. Methods: Eligibility included MBC; HER2-;
ECOG PS 0-1; and adequate organ function. Adjuvant chemotherapy
(including taxanes) was allowed. Tesetaxel was administered orally without
anti-allergic premedication at a starting dose of 27 mg/m2 once every 3
wks. Overall response rate (ORR; RECIST) was the primary endpoint.
Results: All 45 pts have been accrued. Median age is 58 y (range 36-80);
median time from diagnosis, 4.0 y (range 0-21); triple negative status, 8
pts at diagnosis, 14 at time of metastasis. Metastatic sites are lung (22
pts), lymph nodes (22), liver (24), and bone (21). Prior treatment includes
anti-estrogen therapy (32 pts), adjuvant chemotherapy (31), prior taxane
(25), and radiotherapy (28). ORR in 24 pts evaluable for response is 50%
(1 CR [4%], 11 PR [46%]); 5 responding pts had prior taxane therapy.
Neutropenia is the most common � Grade 3 adverse event with 50% of
casesobservedafterdoseescalationto35mg/m2 ;febrileneutropeniaandGrade
3 peripheral neuropathy occurred in 2 pts each. There were no hypersensitivity
reactions. Conclusions: Tesetaxel is highly active in 1st-line MBC and
overcomes multiple limitations of standard taxanes. Updated ORR and PFS
for all pts will be presented. Weekly dosing will be evaluated in a new cohort
of pts.
1018 Poster Discussion Session (Board #10), Mon, 1:15 PM-5:15 PM and
4:45 PM-5:45 PM
Everolimus with paclitaxel plus bevacizumab as first-line therapy for
HER2-negative metastatic breast cancer (MBC): A randomized, doubleblind,
placebo-controlled phase II trial of the Sarah Cannon Research
Institute (SCRI). Presenting Author: Denise Aysel Yardley, SCRI/Tennessee
Oncology, PLLC, Nashville, TN
Background: Constitutive activation of mTOR and amplified PI3K/Akt/
mTOR signaling are common in MBC, and increase as treatment-resistance
is acquired. Everolimus (E), an mTOR inhibitor, has single agent activity,
combines well with paclitaxel (P) and bevacizumab (B), and prolonged PFS
when added to AI therapy in BOLERO-2. In this randomized phase II trial, E
was added to P/B as first-line treatment of HER2-negative MBC. Methods:
Women with untreated HER2-negative MBC were randomized (1:1) to P
90mg/m2 IV (days 1, 8, and 15) and B10mg/kg IV (days 1 and 15) q28
days with E 10mg PO (Arm 1) or placebo PO (Arm 2) daily. Response
assessment was performed q8 weeks until progression or intolerable
toxicity. Primary endpoint was PFS. Secondary endpoints: safety, overall
response rate, response duration, overall survival. 110 pts allowed detection
of improvement in median PFS from 11 to 16 months with 70% power.
Results: Between 8/2009 and 6/2011, 112 pts were randomized (Arm
1�55; Arm 2�57). Median age: 58 years (range: 25-79). 88% were ER�
or PR�. Pts received a median 5 treatment cycles (range: �1- 26�); 18
(16%) pts remain on treatment (Arm1, 9; Arm 2, 9). Median PFS were 8.8
months (Arm 1) and 7.1 months (Arm 2) (95% CIs 7.4-9.6; 5.5-9.1
months, p�0.79, HR 0.94). Complete responses were observed in 5%
[Arm1, 4 (7%); Arm 2, 2 (4%)] with partial responses in 49% [Arm1, 29
(53%); Arm 2, 26 (46%)]. Responses rates in taxane pretreated pts Arm 1
22%, Arm 2 12%. Hematologic toxicity was similar in both arms; grade 3
mucositis occurred in 13% of E pts. Dose reductions (47% vs 25%) and
interruptions (42% vs 26%) were more frequent with E due to mucositis
and rash. Treatment discontinuation rates were similar. Conclusions: The
addition of E did not result in a significant improvement in the efficacy of
weekly paclitaxel/bevacizumab in the first-line treatment of HER2-negative
MBC although response rates and median PFS were better with E. Possible
explanation for these results may include lower dose intensity in the E arm,
treatment of less resistant pts, or intrinsic differences in E activity when
added to antiestrogen vs chemotherapy.
Breast Cancer—Triple-Negative/Cytotoxics/Local Therapy
1017 Poster Discussion Session (Board #9), Mon, 1:15 PM-5:15 PM and
4:45 PM-5:45 PM
Final analysis of phase II study of EZN-2208 (PEG-SN38) in metastatic
breast cancer (MBC). Presenting Author: Cynthia R. C. Osborne, Baylor
Sammons Cancer Center, Texas Oncology PA, US Oncology, Dallas, TX
Background: EZN-2208 is a water-soluble PEGylated conjugate of SN38.
EZN-2208 results in prolonged exposure of tumors to SN38 via preferential
accumulation of EZN-2208 in the tumor and prolonged release of SN38.
These data represent the final analysis of our study evaluating EZN-2208 in
MBC. Methods: EZN-2208 9 mg/m2 (SN38 equivalents) was delivered as a
60-minute IV infusion, weekly for 3 wks in 4-wk cycles. The primary
objective was to determine the overall response rate (RR) in female patients
with metastatic breast cancer (MBC) who had received prior adjuvant or
metastatic therapy with either 1) anthracycline and taxane (AT) or 2)
anthracycline, taxane, and capecitabine (ATX). Secondary objectives included
evaluation of RR based on tumor receptor status, duration of
response, progression-free survival (PFS), overall survival (OS), and safety.
Results: Patients with MBC (n�164) were treated with a median (range) of
3.3 (0.3-22) cycles of EZN-2208. The objective response rate (RR) was
20% for AT and 9% for ATX. The clinical benefit rate (CBR�%CR � %PR
� %SD �6 months) was 41% and 27% in patients in the AT and ATX
cohorts, respectively. The RR and CBR among ER� patients were 11%
(10/91 pts) and 41.8% (38/91 pts). In patients who progressed during or
within 30 days of prior platinum-containing regimens (Platinum Progressors),
the CBR was 20% (8/40 pts). Among triple negative breast cancer
(TNBC) patients, the RR and CBR were 22.5% (11/49 pts) and 36.7%
(18/49 pts). For TNBC, Platinum Progressors, the CBR was 26.1% (6/23
pts). Overall, most common reported drug-related adverse events were
diarrhea, nausea and neutropenia. Conclusions: EZN-2208 has notable
activity in patients with previously treated MBC and appears to be an active
agent for treatment of TNBC. Patients with TNBC, who had been previously
treated with a platinum-based regimen, also derive clinical benefit from
EZN-2208. The safety profile of EZN-2208 is acceptable with good
tolerability in most patients. Further evaluation of EZN-2208 in MBC in
general and TNBC in particular is warranted.
1019 Poster Discussion Session (Board #11), Mon, 1:15 PM-5:15 PM and
4:45 PM-5:45 PM
Metformin in early breast cancer (BC): A prospective, open-label, neoadjuvant
“window of opportunity” study. Presenting Author: Saroj Niraula,
Division of Medical Oncology and Hematology, Princess Margaret Hospital
and University of Toronto, Toronto, ON, Canada
Background: There is growing evidence that metformin may exert anticancer
effects through indirect (insulin-mediated) or direct (insulinindependent)
mechanisms. Here, we report final results of a neo-adjuvant
“window-of-opportunity” study of metformin in women with operable BC.
Methods: Newly diagnosed, untreated, non-diabetic BC patients received
metformin 500 mg tid after diagnostic core-biopsy until definitive surgery(no
other treatment). Clinical [weight, symptoms, European Organization
for Research and Treatment of Cancer Quality of Life Questionnaire
(EORTC-QLQ-C-30)] and biologic characteristics [insulin, glucose, homeostatic
model assessment (HOMA), C-reactive protein (CRP), leptin] were
compared pre- and post-metformin as were Terminal deoxynucleotidyl
transferase-mediated dUTP nick end labeling (TUNEL, an apoptotic
marker) and Ki67 (primary end-point) scored blinded by manual count of
positive nuclear-staining. The planned sample-size of 40 patients gave
90% power to detect a 5.5 percentage point change in Ki67. Results:
Thirty-nine patients were enrolled and mean age was 51 years; metformin
was given for 18 days (median), range 13-40 days. Twenty patients had T1
and 19 T2/T3 tumors; 16 tumors were grade III; 24 were N0; 32 ER/PR
positive, 5 HER-2 positive. Grade 1-2 self-limiting diarrhea, anorexia and
abdominal distention occurred in 50%, 41% and 32%. EORTC QLQ scores
were stable in all function domains and overall scores. Main study
outcomes are tabulated here. Conclusions: Short-term preoperative metformin
was well-tolerated and resulted in clinical and cellular effects in
keeping with beneficial anti-cancer effects as demonstrated by improved
insulin resistance (HOMA), decreased proliferation (ki67) and increased
apoptosis (TUNEL).
Variable (units)
Pre-metformin
mean (SD)
53s
Mean change
(SD) p change
Weight (kg) 70.3 (12.3) -1.2 (1.4) �0.0001
BMI (kg/m 2 ) 26.9 (4.6) -0.5 (0.5) �0.0001
CRP (mg/L) 2.0 (2.7) -0.2 (2.6) 0.35
Glucose (mmol/L) 5.30 (0.56 -0.14 (0.43) 0.045
Insulin (pmol/L) 43.4 (23.9) -4.7 (18.1) 0.069
HOMA 1.47 (0.95) -0.21 (0.75) 0.047
Leptin (ng/ml) 16.5 (13.0) -1.3 (7.2) 0.15
TUNEL 0.56 (0.58) 0.49 (1.00) 0.0037
Ki67 36.5 (24.8) -3.0 (9.8) 0.016
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