Is the gefitinib plus trastuzumab combination feasible in breast cancer patients?

We have previously demonstrated that combined treatment of breast cancer cells that co-express epidermal growth factor receptor (EGFR) and ErbB-2 with the EGFR tyrosine kinase inhibitor (TKI) gefitinib plus trastuzumab results in a synergistic antitumor effect [1Go]. Similar findings have been obtained by independent research groups [2Go]. Following these results, a phase I/II clinical trial of trastuzumab plus gefitinib in breast cancer patients with ErbB-2 expressing tumors has been completed [3Go]. In the phase I study, patients were treated with trastuzumab (2 mg/kg/week) plus gefitinib at two dose levels, 250 and 500 mg/day. At the highest dose, two out of three patients developed grade 3 diarrhoea. Therefore, the phase II study was conducted using gefitinib 250 mg/day. Few responses were observed and only in previously untreated patients (two of 28), and time to progression appeared shorter than that previously reported with trastuzumab alone. These results led the investigators to conclude that further use of combinations of trastuzumab plus EGFR-TKIs is not justified.

We believe that the results of the phase II study could have been flawed by the dose of gefitinib, 250 mg/day, lower than the 500 mg/day usually considered as full dose. In fact, equivalence of the 250 and 500 mg doses has been suggested by phase II trials of gefitinib in non-small-cell lung cancer, a disease where the majority of patients responding to gefitinib carry a mutation of the EGFR-TK domain associated with increased sensitivity to gefitinib. Since EGFR mutations have not been found in breast cancer, the 250 mg dose could be too low to be active. This dose was chosen because of the unexpected toxicity observed at the 500 mg level. However, a phase I trial of the EGFR-TKI erlotinib plus standard-dose trastuzumab in women with ErbB-2-positive metastatic breast cancer yielded different results. Trastuzumab could be combined with 150 mg/day of erlotinib, which is the maximum tolerated dose of the drug, without significant diarrhoea, and two partial responses were observed [4Go]. Therefore, the full daily dose of erolotinib was chosen for a phase II trial of this combination in breast cancer. Finally, grade 3 diarrhoea occurred in 10% of trastuzumab-resistant breast cancer patients treated with the dual EGFR/ErbB-2 inhibitor lapatinib, a frequency similar to that observed with pure EGFR-TKIs [5Go]. These findings suggest that the contemporary blockade of EGFR and ErbB-2 does not result in increased intestinal toxicity, and that chance could have played a relevant role in the toxicity observed by Arteaga et al. [3Go].

In conclusion, we believe that based on preliminary results obtained with either erlotinib plus trastuzumab or lapatinib [4Go, 5Go], the contemporary targeting of EGFR and ErbB-2 might result in enhanced antitumor activity in breast cancer patients with acceptable toxicity. In this respect, the study of trastuzumab plus gefitinib at 500 mg/day should not be halted following a single phase I trial. However, a major drawback of studies of EGFR-TKIs in breast cancer is the absolute lack of criteria to select patients that are likely to respond to these agents. Therefore, identification of such criteria is mandatory to improve the efficacy of this approach.

N. Normanno1,*, M. Campiglio2, F. Perrone3, A. De Luca1 and S. Menard2

1 Cell Biology and Preclinical Models Unit and 3 Clinical Trials Unit, INT-Fondazione Pascale, 80131 Naples; 2 Molecular Targeting Unit, Istituto Tumori Milano, 20133 Milan, Italy

* E-mail: nicnorm{at}yahoo.com

Acknowledgements

N. Normanno, F. Perrone and S. Menard are supported by grants from the Associazione Italiana per la Ricerca sul Cancro (AIRC) and from Ministero della Salute, Ricerca Finalizzata FSN'04.

References

1. Normanno N, Campiglio M, De Luca A et al. Cooperative inhibitory effect of ZD1839 (‘Iressa’) in combination with trastuzumab (‘Herceptin’) on human breast cancer cell growth. Ann Oncol 2002; 13: 65–72.[Free Full Text]

2. Moulder SL, Yakes FM, Muthuswamy SK et al. Epidermal growth factor receptor (HER1) tyrosine kinase inhibitor ZD1839 (Iressa) inhibits HER2/neu (erbB2)-overexpressing breast cancer cells in vitro and in vivo. Cancer Res 2001; 61: 8887–8895.[Abstract/Free Full Text]

3. Arteaga CL, O'Neil A, Moulder SL et al. ECOG1100: a phase I–II study of combined blockade of the erbB receptor network with trastuzmab and gefitinib (‘Iressa’) in patients (pts) with HER2-overexpressing metastatic breast cancer. Breast Cancer Res Treat 2004; 88 Suppl 1: S15–S16 (Abstr 25).[CrossRef]

4. Britten CD, Pegram M, Rosen P et al. Targeting ErbB receptor interactions: A phase I trial of trastuzumab and erlotinib in metastatic HER2+ breast cancer. Proc Am Soc Clin Oncol 2004; 23: 206 (Abstr 3045).

5. Blackwell KL, Kaplan EH, Franco SX et al. A phase II, open-label, multicenter study of GW572016 in patients with trastuzumab-refractory metastatic breast cancer. Proc Am Soc Clin Oncol 2004; 23: 196 (Abstr 3006).





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