Edatrexate Plus Paclitaxel in Metastatic Breast Cancer

abstract & commentary

Synopsis: Based on preclinical data suggesting synergistic activity, edatrexate was combined with a 3-h paclitaxel infusion in patients with advanced metastatic breast cancer in a phase I study involving escalating doses of edatrexate. A maximum tolerated dose for edatrexate in the combination was determined to be 350 mg/m2. In addition to myelosuppression, diarrhea, stomatitis, nausea and vomiting, and myalgias were the major toxicities. In 23 patients, four complete and seven partial responses were noted (overall response rate 48%). This combination is active even in patients who have previously received methotrexate.

Source: D’Andrea G, et al. Clin Cancer Res 1999; 5:275-279.

In recent years, a number of important studies have identified the features of methotrexate action that make it effective as an antitumor agent. These studies have led to the development of methotrexate congeners that appear to be more effective than methotrexate. For example, edatrexate (10-ethyl-10-deaza-aminopterin) has a higher affinity for the one-carbon-reduced folate transporter than does methotrexate and is more readily polyglutamated by the folylpolyglutamate sythetase in tumors than is methotrexate. Therefore, greater concentrations of edatrexate polyglutamates accumulate in tumors and lower levels of these polyglutamates accumulate in normal proliferative cells than do methotrexate polyglutamates and the result is a higher therapeutic index.1

Paclitaxel is known to be highly active in the treatment of breast cancer and a number of other malignancies.2 Investigation of potential interactions between paclitaxel and edatrexate in preclinical models suggested impressive synergy when edatrexate was administered before paclitaxel but antagonism if the order of administration was reversed3. Therefore, D’Andrea and colleagues at Memorial Sloan-Kettering Cancer Center undertook a phase I dose-escalation study in patients with metastatic breast cancer.

Thirty-five women were entered into the study. All had metastatic breast cancer with only one prior regimen for the treatment of their metastatic breast cancer with no history of prior taxane use. Prior methotrexate exposure as a component of adjuvant therapy was permitted. Patients were treated as outpatients every three weeks. Edatrexate was given as a one hour infusion on day 1 and paclitaxel was given at 175 mg/m2 by three-hour infusion on day 2. The edatrexate doses were escalated from 180 mg/m2 to 210, 240, 270, 300, 350, and 400 mg/m2 in separate cohorts.

All 35 patients were assessable for toxicity and 23 patients had measureable disease and were assessable for tumor response. The median number of cycles of therapy given was four (range 2-33). The maximum tolerated dose of edatrexate was 350 mg/m2 when given on this schedule with 175 mg/m2 of paclitaxel. At the maximum tolerated dose, one patient experienced grade 3 diarrhea, but no other grade 3 nonhematologic toxicities were encountered. By contrast, two patients at the 400 mg/m2 dose level experienced grade 4 stomatitis. Thus, gastrointestinal tract toxicity is dose-limiting for this combination. Other toxicities included myalgias and neurosensory complaints.

Encouraging antitumor efficacy was noted. Of the 23 patients evaluable for response, four (17%) achieved a complete response and seven (30%) achieved a partial response. None of these eleven responders had prior therapy for metastatic disease; two had only hormonal therapy for their metastatic disease and nine had received adjuvant chemotherapy, including six who had taken methotrexate.

Commentary

Resistance to methotrexate is usually mediated by mechanisms involving reduced folate transport or intracellular metabolism. These mechanisms usually do not affect sensitivity to tubulin-binding agents such as paclitaxel. Similarly, paclitaxel resistance mechanisms, while not completely defined, generally do not lead to methotrexate resistance. Thus, the combination of the two agents could be effective clinically.

This phase I study of paclitaxel with the super-methotrexate edatrexate provides substantial encouragement based upon the modest toxicity and high level of activity (48% response rate) in metastatic breast cancer. The responders were mainly patients with minimal prior treatment; nevertheless, it is clear that additional exploration of the combination in phase II and possibly phase III studies is warranted.

It is difficult to understand why the activity of this combination would be sequence-dependent. It remains to be determined whether this in vitro sequence dependence will be clinically apparent and if so, whether the mechanism can be defined and used to predict other synergistic interactions.

References

1. Sirotnak FM. NCI Monogr 1987;5:27-35.

2. D’Andrea GM, Seidman AD. Semin Oncol 1997;24(suppl 13):S13-27;S13-44.

3. Chou T-C, et al. Cancer Chemother Pharmacol 1996;37:222-228.