Dose-dense (DD) doxorubicin and cyclophosphamide (AC) followed by weekly paclitaxel (P) with trastuzumab (T) and lapatinib (L) in HER2/neu-positive breast cancer is not feasible due to excessive diarrhea: updated results.

Abstract

#2108 Background: DD q 2 weekly (w) AC → P + T x 1 year (y) has an acceptable safely profile w/ congestive heart failure (CHF) rate of 1/70 pts (Dang, JCO 2008). Lapatinib (L) is effective in HER2 (+) BC. We conducted a pilot study of dd AC → w P + T + L to determine its feasibility and cardiac safety.
 Methods: Enrolled pts had HER2 (+) BC; LVEF > 50%. Rx consisted of AC at 60/600 mg/m2 x 4 q 2 w (w/ pegfilgrastim 6 mg day 2) → P at 80 mg/m2 x 12 q w + T x 1 y; L (1000 mg daily beginning w/ P + T and continued x 1 y). MUGA is obtained at baseline and at months (mo) 2, 6, 9, and 18. Rx is considered feasible if 1) > 80% pts can complete the PTL phase without a dose delay or reduction and 2) the cardiac event rate (CHF or cardiac death) is < 4%. Pts can remain on-Rx w/ one dose reduction of L (1000 mg → 750 mg) for a G 3 event or < G 3 toxicity (unacceptable).
 Results: From March 2007 to April 2008, we enrolled 95 pts. Median (med) age was 45 years (range, 28-73). At a med follow-up of 7 months, 90 are evaluable. Of the 90 pts, 34 (37%) withdrew from study during the PTL phase; 29 for a 2nd event of G 3 or unacceptable < G 3 toxicities (15 G 3 diarrhea, 4 G 1/2 diarrhea, 1 G 3 rash, 2 G 2 rash, 1 G 3 dyspnea and also had G 3 diarrhea, 1 G 3 ↑QTc also had G 3 diarrhea, 1 G 3 ↑ALT also had G 3 diarrhea, 1 G 3 paronychia, 1 G 3 pneumonitis, 1 asymptomatic LVEF ↓, 1 myocarditis) and 5 for other reasons (2 personal reason, 1 PCP pneumonia, 1 progression, 1 P hypersensitivity). Overall, 25/90 (27%) pts had G 3 diarrhea and 31/90 (34%) pts required a dose reduction of lapatinib. Med LVEF at baseline is 67% (N=95), at mo 2 is 68% (N=90), at mo 6 is 65% (N=53), and mo 9 is 65% (N=28). To date there are no patient drop-outs due to significant LVEF declines after dd AC; one patient dropped during PTL out due to an asymptomatic LVEF decline.
 Discussion: L at 1000 mg/day is not feasible combined w/ weekly P and T by protocol stipulation (> 20% pts required L dose reduction) primarily due to excessive G 3 diarrhea. These results have led to the modification of Design 2 (Arm D) of ALTTO. We will report updated results. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 2108.

Dose-Dense Adjuvant Doxorubicin and Cyclophosphamide Is Not Associated With Frequent Short-Term Changes in Left Ventricular Ejection Fraction

“…The LVEF by multigated radionuclide angiography (MUGA) scan had to be at or above 55% for trial 1 (ddAC followed by PT). 13 The minimal enrollment LVEF was subsequently lowered to Ն 50% for trial 2 (ddAC followed by weekly PT plus lapatinib) 14 and trial 3 the B-containing study (B and ddAC followed by B and nab-P). 17 Patients who received B were also required to have a normal serum creatinine or a creatinine clearance Ն 60 mL/min by the Cockroft-Gault formula.…”

“…Therefore, at 1 year, the respective CHF rates for trials 1, 2, and 3 were 1.4%, 3%, and 0% (median follow-up of 28, 12, and 18 months). 13,14 In addition, one (1.3%, 95% CI, 0.03% to 6.8%) of 80 patients in trial 3 developed CHF at month 15 (3 months after completing therapy). 17…”

“…8,11 Based on these results, we conducted a second trial which differed only in the substitution of a weekly schedule for paclitaxel administration and the addition of lapatinib (ddAC followed by weekly P with T and lapatinib). 14 For patients with HER2-normal breast cancer, bevacizumab (B) (Avastin, Genentech, San Francisco, CA), a humanized monoclonal antibody to vascular endothelial growth factor (VEGF) with proven efficacy in combination with chemotherapy for metastatic breast cancer, 15 is being tested in the adjuvant setting. In preparation, B was evaluated with ddAC followed by P in the Eastern Cooperative Oncology Group (ECOG) study 2104 and the incidence of symptomatic CHF with ddAC followed by P with B was 2%.…”

HER2 breast cancer therapies: a review

“…Heat shock protein 90 (HSP90) inhibitor inhibits HSP90's stabilizing effect on client proteins [73][74][75] Facilitates Her2 degradation 76,77…”

HER2 breast cancer therapies: a review

“…An unexpected toxicity of grade 3 diarrhea seen with the concurrent paclitaxel/trastuzumab/ lapatinib combination was observed in a pilot study of this combination following dose-dense AC, where lapatinib was given at a dose of 1000 mg daily. This combination was not feasible with 34% of patients requiring a lapatinib dosereduction, predominantly due to grade 3 diarrhea 73 . These findings led to a modification of the lapatinib dose on the corresponding arm of ALTTO trial (design 2, arm D).…”