Intermittent versus continuous erlotinib with concomitant modified “XELOX” (q3W) in first‐line treatment of metastatic colorectal cancer

Abstract

BACKGROUND: This study evaluated the activity of 2 schedules of erlotinib in combination with chemotherapy, and the prognostic significance of serum amphiregulin (AREG) and transforming growth factor alpha (TGFa) in metastatic colorectal cancer. METHODS: A total of 60 untreated patients were randomized to a "continuous" (CON; erlotinib 100 mg daily) or an "intermittent" (INT; erlotinib 150 mg on alternate day on day 2 to 14, then 150 mg daily on days 15 to 21) schedule of erlotinib with a modified XELOX (capecitabine plus oxaliplatin) regimen. Serum levels of AREG and TGFa were determined serially. RESULTS: Baseline characteristics were similar between the 2 arms. Of the 58 patients evaluated for response, there was a nonsignificant trend toward a slightly higher overall response rate in the INT arm (66.7%) versus the CON arm (56.7%). At a median follow-up of 2.8 years, the median overall survival was 18.8 months (95% confidence interval 5 11.3-22.9 months) and 20.7 months (95% confidence interval 5 12.5-31 months, P 5.19) for the CON and INT arm, respectively. KRAS mutation did not predict drug response. The 2 arms did not differ significantly in toxicity. Baseline serum TGFa was an independent predictor of progression-free survival, whereas a drop in serum TGFa and AREG levels following 3 to 4 cycles of treatment were associated with shorter progression-free survival and overall survival, respectively. CONCLUSIONS: The intermittent erlotinib schedule was associated with a higher response rate, although this is not statistically significant. Serum TGFa and AREG levels have prognostic significance in erlotinib-treated patients with colorectal cancer, and further studies are warranted. Cancer 2013;119:4145-53. V C 2013 American Cancer Society.KEYWORDS: erlotinib, oxaliplatin, capecitabine, amphiregulin, transforming growth factor alpha. INTRODUCTIONThe development of epidermal growth factor receptor tyrosine kinase inhibitors (EGFR TKI) in the treatment of metastatic colorectal cancer (mCRC) has taken a new turn with the recent reports on the DREAM 1 and the DUX studies, 2 which showed that erlotinib may play a role when combined with either bevacizumab 1 or cetuximab 2 in the palliative treatment of mCRC. Studies in preclinical models of CRC have demonstrated an additive to synergistic effect on growth inhibition when an EGFR TKI is combined with chemotherapy. 3 Furthermore, this inhibitory effect could be scheduledependent in CRC cells, such that synergism could be better observed when chemotherapy was administered before the EGFR TKI rather than concomitantly, whereas antagonism maybe observed if EGFR TKI is given before the cytotoxic agent. 4,5 Drug scheduling may also be important when combining EGFR TKI and cytotoxic agents, as shown in lung cancer models, where an intermittent schedule of EGFR TKI was more effective in controlling tumor growth than a continuous schedule. 6 Despite the number of clinical reports on the activity of combining EGFR TKI and chemotherapy in mCRC, none of them have evaluated the ...

PHD3 Controls Lung Cancer Metastasis and Resistance to EGFR Inhibitors through TGFα

“…S6). These results show that increased TGFα levels underlie the enhanced resistance to therapeutic EGFR inhibition conferred by PHD3 loss and are in line with previous studies showing that EGFR ligands are capable of activating EGFR tyrosine kinase activity and signaling even in the presence of erlotinib (41) and that higher TGFα levels in erlotinib-treated patients with metastatic cancer correlate with worse prognosis (42).…”

Targeting HER2 in colorectal cancer: The landscape of amplification and short variant mutations in ERBB2 and ERBB3

“…Various levels of success have been achieved targeting ERBB2 amplification in CRC, and use of both antibody and small molecule treatments has been described . To our knowledge, tyrosine kinase inhibitors such as afatinib and lapatinib have yielded limited clinical efficacy as monotherapies in patients with mCRC, suggesting antibody therapeutics or combination therapies may be more beneficial in this tumor type . In one report of a widely disseminated, ERBB2 ‐amplified mCRC, various combinations of trastuzumab, trastuzumab‐DM1 and pertuzumab achieved prolonged patient response and disease control …”

“…31,36,46,[63][64][65] To our knowledge, tyrosine kinase inhibitors such as afatinib and lapatinib have yielded limited clinical efficacy as monotherapies in patients with mCRC, suggesting antibody therapeutics or combination therapies may be more beneficial in this tumor type. [66][67][68] In one report of a widely disseminated, ERBB2-amplified mCRC, various combinations of trastuzumab, trastuzumab-DM1 and pertuzumab achieved prolonged patient response and disease control. 69 Two effective therapeutic options have emerged in the management of ERBB2-amplified colorectal cancers.…”

Amphiregulin enhances cell migration and resistance to doxorubicin in chondrosarcoma cells through the MAPK pathway

“…Similarly, another study found that high levels of AR in serum correlated with poor progression‐free survival after first‐line trastuzumab plus taxane therapy in patients with HER2‐positive metastatic breast cancer . However, these findings are contradicted by a study suggesting that increased serum AR levels were associated with prolonged progression‐free survival and overall survival in erlotinib‐treated patients with colorectal cancer . AR serves as a serological biomarker for evaluation of prognosis and therapeutic response in several different types of cancer; however, the clinical significance of AR in the serum of patients with chondrosarcoma remains unclear.…”

“…30 However, these findings are contradicted by a study suggesting that increased serum AR levels were associated with prolonged progression-free survival and overall survival in erlotinib-treated patients with colorectal cancer. 53 Numerous studies in different types of cancer cells have showed that AR plays an important role in promoting drug resistance. In human breast cancer cells, AR expression is significantly associated with resistance to cisplatin 39 and trastuzumab.…”