Benoit Samson

Bevacizumab with or without erlotinib as maintenance therapy in patients with metastatic colorectal cancer (GERCOR DREAM; OPTIMOX3): a randomised, open-label, phase 3 trial

BACKGROUND The combination of an anti-VEGF or an anti-EGFR-targeted monoclonal antibody with chemotherapy has shown clinical activity in patients with metastatic colorectal cancer. However, combining both anti-VEGF and anti-EGFR antibodies with chemotherapy in first-line treatment resulted in adverse outcomes. We assessed whether the combination of erlotinib, an EGFR tyrosine kinase inhibitor, with bevacizumab could increase the efficacy of maintenance therapy in patients with unresectable metastatic colorectal cancer. METHODS This randomised, open-label, phase 3 study was undertaken in 49 centres in France, Austria, and Canada. Eligible patients were aged 18-80 years with histologically confirmed, unresectable metastatic colorectal cancer, WHO performance status 0-2, had received no previous therapy for metastatic disease, and had adequate organ function. Patients without disease progression after bevacizumab-based induction therapy were randomly assigned (1:1) by a minimisation technique to bevacizumab (7·5 mg/kg every 3 weeks) or bevacizumab plus erlotinib (150 mg once daily) as maintenance therapy until progression. All patients were stratified by centre, baseline performance status, age, and number of metastatic sites. The primary endpoint was progression-free survival on maintenance therapy analysed by intention to treat. We report the final analysis. This trial is registered with ClinicalTrials.gov, number NCT00265824. FINDINGS Between Jan 1, 2007, and Oct 13, 2011, 700 eligible patients were enrolled; following induction treatment, patients without disease progression were randomly assigned to bevacizumab (n=228) or bevacizumab plus erlotinib (n=224). At the final analysis, median follow-up was 51·0 months (IQR 36·0-60·0) in the bevacizumab group and 48·3 months (31·5-61·0) in the bevacizumab plus erlotinib group. In the primary analysis (after 231 progression-free survival events), median progression-free survival from randomisation was 5·1 months (95% CI 4·1-5·9) in the bevacizumab plus erlotinib group compared with 6·0 months (4·6-7·9) in the bevacizumab group (stratified hazard ratio [HR] 0·79 [95% CI 0·60-1·06]; p=0·11; unstratified HR 0·76 [0·59-0·99]; p=0·043). In the final analysis, median progression-free survival from randomisation was 5·4 months (95% CI 4·3-6·2) in the bevacizumab plus erlotinib group compared with 4·9 months (4·1-5·7) in the bevacizumab group (stratified HR 0·81 [95% CI 0·66-1·01], p=0·059; unstratified HR 0·78 [0·68-0·96], p=0·019). At the final analysis, median overall survival from maintenance was 24·9 months (95% CI 21·4-28·9) in the bevacizumab plus erlotinib group and 22·1 months (19·6-26·7) in the bevacizumab group (stratified HR 0·79 [95% CI 0·63-0·99], p=0·036; unstratified HR 0·79 [0·64-0·98], p=0·035). The most frequent grade 3-4 adverse events were skin rash (47 [21%] of 220 patients in the bevacizumab plus erlotinib group vs none of 224 patients in the bevacizumab alone group), diarrhoea (21 [10%] vs two [<1%]), and asthenia (12 [5%] vs two [<1%]). INTERPRETATION Maintenance bevacizumab plus erlotinib might be a new non-chemotherapy-based maintenance option for the first-line treatment of patients with unresectable metastatic colorectal cancer after bevacizumab-based induction therapy. FUNDING GERCOR and F Hoffmann-La Roche.

Bevacizumab (Bev) with or without erlotinib as maintenance therapy, following induction first-line chemotherapy plus Bev, in patients (pts) with metastatic colorectal cancer (mCRC): Efficacy and safety results of the International GERCOR DREAM phase III trial.

LBA3500^ Background: Therapy targeting VEGF or EGFR demonstrated clinical activity in combination with chemotherapy (CT) in mCRC but monoclonal antibodies cannot be associated. The DREAM trial compares a maintenance therapy (MT) with bev +/- EGFR tyrosine kinase inhibitor erlotinib (E) after a first-line Bev-based induction therapy (IT) in pts with mCRC. METHODS Pts with previously untreated and unresectable mCRC were eligible. After a Bev-based IT with FOLFOX or XELOX or FOLFIRI, pts without disease progression were randomized to MT between Bev alone (Bev 7.5 mg/kg q3w; arm A) or Bev+E (B 7.5 mg/kg q3w, E 150 mg/day continuously; arm B). Pts were treated until progression or unacceptable toxicity. The primary endpoint was PFS on MT. RESULTS The study enrolled 700 pts from 01/2007 to 11/2011 in 3 countries (France, Canada, Austria). 446 (63.7%) pts were randomized for MT (arm A, N=224; arm B, N=222). Among the 446 randomized pts, IT regimen was FOLFOX-Bev in 265 pts (59.4%), XELOX-Bev in 135 pts (30.3%), and FOLFIRI-Bev in 46 pts (10.3%). Baseline characteristics of randomized pts were (arm A/B): ECOG PS 0, 60% in both arms; normal LDH level 47%/49%; normal alkaline phosphatase level 48%/50%; synchronous metastasis 83%/82%. The median no of MT cycles was 6 in both arms. With a median follow-up of 31.0 months, 327 PFS events were observed. Median MT-PFS were 4.6 m in arm A vs 5.8 m in arm B (HR 0.73 [95%CI: 0.59-0.91], P=.005). Median PFS from inclusion were 9.2 m vs 10.2 m. During MT, in arm A vs arm B, grade 3-4 diarrhea (<1% vs 9%) and grade 3 skin toxicity (0% vs 19%) were the main differences in toxicity. Severe adverse events from randomization related to B or E were 6 in arm A and 7 in arm B. Overall survival is not mature. CONCLUSIONS The addition of erlotinib to bevacizumab after induction therapy significantly improves the duration of maintenance PFS, following induction with first-line chemotherapy plus bevacizumab, in patients with unresectable metastatic colorectal cancer.

Activity and Safety of the Antiestrogen EM-800, the Orally Active Precursor of Acolbifene, in Tamoxifen-Resistant Breast Cancer

PURPOSE To determine the efficacy and safety of EM-800 (SCH-57050), the precursor of acolbifene, a new, highly potent, orally active, pure antiestrogen in the mammary gland and endometrium, for the treatment of tamoxifen-resistant breast cancer. PATIENTS AND METHODS Forty-three post menopausal/ovariectomized women with breast cancer who had received tamoxifen, either for metastatic disease or as adjuvant to surgery for > or = 1 year, and had relapsed were treated in a prospective, multicenter, phase II study with EM-800 (20 mg/d [n = 21] or 40 mg/d [n = 22] orally). Results Thirty-seven patients had estrogen receptor (ER)-positive tumors (>10 fmol/mg; mean, 146 fmol/mg cytosolic protein), three patients had ER-negative/progesterone receptor-positive tumors, and three patients had undetermined ER status. The objective response rate to EM-800 was 12%, with one complete response and four partial responses. Ten patients (23%) had stable disease for > or = 3 months, and 7 patients (16%) had stable disease for > or = 6 months. With a median follow-up of 29 months, median duration of response was 8 months (range, 7 to 71+ months). Treatment with EM-800 was well tolerated. No significant adverse events related to the study drug were observed clinically or biochemically. CONCLUSION EM-800 produced responses in a significant proportion of patients with tamoxifen-resistant breast cancer, thus showing that this highly potent, selective estrogen receptor modulator, which lacks estrogenic activity in the mammary gland and endometrium, has incomplete cross-resistance with tamoxifen, thus suggesting additional benefits in the treatment of breast cancer.

497OBEVACIZUMAB-ERLOTINIB AS MAINTENANCE THERAPY IN METASTATIC COLORECTAL CANCER. FINAL RESULTS OF THE GERCOR DREAM STUDY

ABSTRACT Aim: VEGF or EGFR targeted monoclonal antibodies with chemotherapy demonstrated clinical activity in metastatic colorectal cancer (mCRC). Yet, combining these monoclonal antibodies in mCRC achieved adverse outcomes. However, erlotinib (E), an EGFR tyrosine kinase inhibitor, combined with bevacizumab (B) as maintenance (m) therapy after B-based induction therapy (IT) improved progression-free survival (PFS) (Tournigand, ASCO 2012). We report here the final results of the DREAM study. Methods: DREAM is a phase III trial in patients with unresectable mCRC. Pts without progression or surgery after a B-based IT were randomised to B (7.5 mg/kg q3w) or B (same dose) plus E (150 mg/d) as maintenance therapy until progression after stratification by centre, baseline ECOG status, ALP, LDH, induction chemotherapy (XELOX2-B vs mFOLFOX7-B or FOLFIRI-B), KRAS status, age, number of metastatic sites and tumour response (RR). Primary endpoint was mPFS from randomisation. Secondary endpoints were overall survival (OS), PFS from registration (r), response according to KRAS status, adverse events, curative resection, chemotherapy-free interval (CFI), and HR-QoL. Results: Among 701 registered pts, 452 were randomised for maintenance (B, 228; BE, 224). Median follow-up was 50 months. B arm vs BE arm, medians were: mPFS 4.9 vs 5.9 months (HR 0.77, CI 0.62-0.94; p = 0.012), rPFS 9.3 vs 10.2 months (HR 0.76, 95%CI 0.63-0.93; p = 0.007), mOS 22.0 vs 25.0 months (HR 0.80, CI 0.63-0.98; p = 0.034), rOS 26.9 vs 30.5 months (HR 0.80, CI 0.64-0.99; p = 0.040). All subgroups, including KRAS, had a benefit in OS. RR from baseline maintenance were B vs BE arm: all patients 11.5% vs 22.5% (OR 0.45, CI 0.25-0.79; p = 0.003), KRAS WT 15.4% vs 24% (OR 0.58, CI 0.27-1.19; p = 0.133), KRAS mut 8.3% vs 19.7% (OR 0.37, CI 0.12-1.04; p = 0.041). Patients in the B arm vs BE arm experienced less grade 3/4 diarrhea (0.9% vs 9.3%) and skin rash (0% vs 21.4%). Median time on therapy was 110 days in arm BE. Conclusions: Combination of erlotinib and bevacizumab as maintenance therapy significantly prolonged PFS and OS in patients with unresectable mCRC. The combination of anti-VEGF mab and EGFR tyrosine kinase inhibitor is active, even in mutated KRAS patients. Disclosure: B. Chibaudel: Roche, Sanofi; C. Tournigand: Roche, Sanofi; F. Bonnetain: Roche, Nestle, Merck; T. Andre: Roche; A. De Gramont: Roche, Sanofi. All other authors have declared no conflicts of interest.