ATLANTAHerceptin combined with interleukin 2 (IL-2) is an
active, well-tolerated regimen that has produced a clinical response
in 4 of 25 breast cancer patients, said Gini Fleming, MD,
assistant professor of clinical medicine, Hematology/Oncology
Section, University of Chicago Pritzker School of Medicine.
In vitro studies have shown that Herceptin (trastuzumab), a humanized
anti-HER2 monoclonal antibody, participates in antibody-dependent
cellular cytotoxicity, Dr. Fleming said at the 35th annual meeting of
the American Society of Clinical Oncology (ASCO) on behalf of the
Cancer and Leukemia Group B (CALGB). Natural killer cells may express
Fc-gamma receptors and also participate in antibody-dependent
cellular cytotoxicity, she said.
Since 10% of natural killer cells naturally express a high-affinity
receptor and an intermediate-affinity receptor for IL-2, low doses of
the agent can expand the number of natural killer cells via the
high-affinity receptor. Higher doses of IL-2 may also engage
intermediate-affinity receptors and stimulate cytotoxicity, Dr.
For this phase I study to determine Herceptin toxicity when given
with IL-2, the CALGB chose low-dose plus pulsed intermediate-dose
IL-2. A phase I study in 1998 showed this schedule to result in in
vivo expansion and potential activation of natural killer cells.
Patients received daily, low-dose IL-2 plus intermediate-dose pulses
of IL-2 for 3 days every 2 weeks given subcutaneously. Herceptin was
given intravenously every 2 weeks prior to the IL-2 pulses, with
Herceptin doses escalated in successive cohorts of at least six
The study included 25 breast cancer patients ; all were heavily
pretreated, and all had tumors receptive to Herceptin treatment. Four
additional subjects with HER2-overexpressing tumors of the lung,
ovary, or head/neck were included as well.
The starting Herceptin doses for four groups of patients were 1, 2,
4, and 8 mg/kg. The protocol required that the sixth patient in a
group must have been on the groups dose level for at least 30
days before the group moved to the next dose level. The number of
treatment cycles ranged from 1 to 14, with a median of 4 per patient.
Patients had a median of three prior chemotherapy regimens, and 11
had been transplanted.
Dr. Fleming reported that partial or complete responses occurred with
the higher doses; the most effective Herceptin doses were 4 or 8
mg/kg every 2 weeks. None of the non-breast-cancer subjects responded
to the regimen, she said.
The initial planned dosages of IL-2 were 1.25 million IU/m²/d
plus intermediate doses of 15 million IU/m² for 3 days every 2
weeks. Side effects, however, forced most of the first 18
patients to drop out or take reduced doses, Dr. Fleming said.
Starting IL-2 Doses Reduced
As a consequence, researchers amended the starting low IL-2 dose to 1
million IU/m² and the intermediate dose to 12 million IU/m².
Among 12 patients treated at those doses, IL-2 toxicities from the
intermediate dose caused study removal or dose reduction for three
patients: one each had hypoxia, rigors, or nausea/vomiting. With the
low dose, one patient had neutropenia. Dr. Fleming attributed all
hematologic toxicities primarily to low-dose IL-2.
Researchers measured in vitro cytotoxicity by analyzing patients
plasma, target cell lines, and peripheral blood mononuclear cells.
The only treatment-limiting toxicity attributed to Herceptin was one
incident of neck pain and dyspnea at the 4 mg dose, Dr. Fleming
noted. In the final dosing regimen, dyspnea occurred sporadically.
Dr. Fleming observed that it may be likely to occur in patients with
lung tumor involvement.
Summarizing the results, Dr. Fleming stated: This regimen can
produce an increase in the percentage of peripheral blood mononuclear
cells, which are natural killer cells.