Gastrointestinal Malignancies - OncoFacts from Annual Meeting 2010 (COIN trial, fluoropyrimidine-oxaliplatin, cetuximab, XELOX-bevacizumab, European Organisation for Research and Treatment of Cancer, CLOCC trial, FOLFOX, trial N0147, KRAS mutations, - 100004

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Gastrointestinal Malignancies - OncoFacts from Annual Meeting 2010 (COIN trial, fluoropyrimidine-oxaliplatin, cetuximab, XELOX-bevacizumab, European Organisation for Research and Treatment of Cancer, CLOCC trial, FOLFOX, trial N0147, KRAS mutations,

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Description: Abstracts 3502 and 3525
Investigators from the UK Medical Research Council (MRC) presented results of their COIN trial in which 2500 patients with advanced colorectal cancer were randomized to continuous fluoropyrimidine-oxaliplatin with or without cetuximab (arms A & B) vs intermittent fluoropyrimidine-oxaliplatin (arm C). Sixty-six percent received CapeOx and 34% received FOLFOX. In the comparison of the 2 continuous arms (A & B), the authors sought to identify potential clinical and biologic factors that predicted for benefit from the addition of cetuximab. KRAS, BRAF, and NRAS mutation status were examined. The cetuximab arm had more toxicity with significantly increased amounts of diarrhea, skin rash, hand-foot syndrome, anemia, and lethargy. In the KRAS wild-type (WT) group progression-free survival (PFS) was 8.6 months in both arms. Overall survival (OS) was 17+ months in both arms, but was much shorter than has been reported in US trials with chemo-cetuximab where OS was in the range of 20 months – 24 months. In the KRAS WT group, the overall response rate (ORR) in the cetuximab arm was 64% versus 57% in the chemo alone arm. The ORR did not differ among the patients with KRAS mutation. In the group with KRAS mutation, PFS and OS were worse in the cetuximab arm. In examination of pre-defined subsets, the greatest likelihood of clinical benefit from the addition of cetuximab to chemotherapy was seen in patients who received FOLFOX as opposed to CapeOx, those with limited metastatic disease, and those who were KRAS WT.

In abstract 3525, the COIN investigators presented the data for the comparison of arm A (continuous chemotherapy without cetuximab) versus arm C (intermittent chemotherapy). The intermittent arm was considerably less toxic. Patients spent a median of 15 weeks on treatment compared to 25 weeks in the continuous therapy arm. Quality of life was much better on the intermittent arm. Overall survival was 14.3 months on the intermittent arm versus 15.6 months on the continuous arm, and some of that loss in OS may have been due to reluctance on the part of some patients on intermittent therapy to restart treatment in a timely manner.

Abstract 3501
Josep Taberno presented the results of the Spanish Group MACRO trial. Four hundred eighty patients with metastatic colorectal cancer were randomized to receive 6 cycles of XELOX-bevacizumab followed by continuation treatment with XELOX-bevacizumab versus 6 cycles of XELOX-bevacizumab followed by single-agent bevacizumab until disease progression. The primary endpoint was PFS with the objective being to show non-inferiority for the single-agent bevacizumab arm. Progression-free survival curves remained together for the initial 6 months of XELOX-bevacizumab treatment. Then the curves diverged in favor of continuation XELOX-bevacizumab coming back together at approximately 18 months post-randomization. The hazard ratio (HR) for PFS was 1.11, which did not meet the criteria for non-inferiority. There was some criticism of this trial suggesting that an observation alone arm or a fluoropyrimidine-bevacizumab arm might have been of value. Overall survival was no different and adverse event profiles were also not significantly different.

Abstract 3526
The European Organisation for Research and Treatment of Cancer (EORTC) presented the results of the randomized phase II CLOCC trial in which patients with liver only unresectable metastatic colorectal cancer were randomized to FOLFOX versus FOLFOX plus radio frequency ablation (RFA). After October, 2005 bevacizumab was added to FOLFOX in both arms. In 90% of patients, the RFA procedure was carried out during open laparotomy. The primary endpoint of this randomized trial of 119 patients was to demonstrate a 30-month OS of >38% for the RFA plus chemotherapy arm. Requirements were that patients had <10 liver lesions, none of which was >4cm in size. Progression-free survival, a secondary endpoint, was 17 months for the RFA-chemotherapy arm and 10 months for the chemotherapy only arm. Three-year PFS was 28% versus 11% for the chemo only arm. Thirty-month survival was 64% for the RFA-chemo arm and 59% for the chemo only arm, which was not statistically different. The primary benefit from RFA may have been due to reduction of tumor bulk and thereby delayed progression to symptomatic disease.

Abstracts CRA3507 and 3508
Steve Alberts presented the results of the North Central Cancer Treatment Group (NCCTG) Intergroup phase III trial N0147 in patients with KRAS WT stage III colon cancer. Rich Goldberg subsequently presented the results in the patients with KRAS mutations. The trial randomized patients with resected stage III colon cancer to mFOLFOX6 with or without cetuximab. The trial was initially open to all patients regardless of KRAS status, but after June, 2008 only patients with KRAS WT were randomized. A total of 2600 patients were enrolled. Included for analysis were 1847 patients who were KRAS WT. The primary endpoint for the KRAS WT patients was 3-year disease-free survival (DFS). Disease-free survival was 72.3% for the mFOLFOX6-cetuximab arm and 75.8% for the mFOLFOX6 alone arm with a HR = 1.2. A subset analysis of patients >70 years of age revealed an inferior 3-year DFS of 66.1% for the mFOLFOX6-cetuximab arm with an 80.9% 3-year DFS for the mFOLFOX6 alone arm for a HR = 1.79 and P-value = .03. Many older patients stopped treatment early because of toxicity, especially on the chemotherapy-cetuximab arm.

Overall survival was also not statistically different but marginally favored the mFOLFOX6 arm with a HR = 1.3. Subgroup analysis showed that no subgroup benefited from the addition of cetuximab in this adjuvant trial. In the analysis of the 717 patients who were initially randomized and then determined to have KRAS mutant tumors, 3-year DFS rates were somewhat lower than those of the patients with KRAS WT. But once again, there was no evidence of benefit from the addition of cetuximab in the patients with KRAS mutations. The HR of 1.2 for DFS and 1.5 for OS suggest marginally worse survival with the addition of cetuximab. From a prognostic standpoint among patients treated with mFOLFOX6, patients with KRAS WT overall did better than patients with KRAS mutation with 3-year disease-free survival (DFS) of 75.8% versus 67.2% for a HR = 0.7 and a P-value of .04.

Abstract LBA4007
In gastric cancer, phase II data has suggested that the addition of bevacizumab to chemotherapy may prolong survival in patients with advanced disease. The AVAGAST trial is an international study comparing capecitabine-cisplatin-bevaciz​umab (XPB) with capecitabine-cisplatin (XP) plus placebo. Seven hundred seventy four patients with inoperable, locally advanced, or metastatic gastric or gastroesophageal junction adenocarcinoma were enrolled. Forty-nine percent of the patients were from Asia, 32% from Europe, and 19% from the Americas. The primary endpoint was an improvement in OS from 10 months to 12.8 months. Ninety-five percent of patients had a performance status of 0-1.The primary endpoint was not met with OS being 12.1 months in the XPB arm and 10.1 months in the XP-placebo arm for a HR = 0.87 and P = .1002.

However, there were geographic differences in the OS results that are interesting.
OS XPB XP-placebo HR
Asian 13.9 mos 12.1 mos 0.97
Europe 11.1 mos 8.6 mos 0.85
Americas 11.5 mos 6.8 mos 0.63

The OS of only 6.8 months among the American patients treated with XP-placebo is surprisingly short compared to past studies. Progression-free survival was better in the XPB arm at 6.7 months versus 5.3 months (P = .0037). The objective response rate was also significantly better with XPB at 46% versus 37% with P = .03. Biomarker analysis is ongoing, but it seems unlikely that these studies will explain the geographically heterogeneous results.

Abstract 4010
The PRODIGE 4/ACCORD 11 trial randomized 342 previously untreated patients with metastatic pancreatic cancer to single-agent gemcitabine given in the standard fashion versus FOLFIRINOX, which consisted of oxaliplatin on day 1, irinotecan, leucovorin and bolus 5-FU on day 2 followed by a 46-hour infusion of 5-FU repeated every 14 days. Eligible patients were <75 years old with performance status of 0-1 and measureable disease. The primary objective of OS was increased from 6.8 months to 11.1 months with a HR = 0.57 and a P<.0001. The secondary endpoints of PFS (6.4 months vs 3.3 months) and ORR (31% vs 9.4%) were also better with FOLFIRINOX. Grade 3-4 febrile neutropenia, peripheral neuropathy, vomiting, fatigue, and diarrhea were also significantly more frequent in the FOLFIRINOX arm. The authors stated that use of FOLFIRINOX required vigilant patient selection, education, monitoring, and active management. Whether or not this represents a new standard of care is controversial and debatable.

References
1. Maughan TS, Adams R, Smith CG, et al. Identification of potentially responsive subsets when cetuximab is added to oxaliplatin-fluoropyrimidine chemotherapy (CT) in first-line advanced colorectal cancer (aCRC): Mature results of the MRC COIN trial. J Clin Oncol. 2010;28(15s). Abstract 3502.

2. Adams R, Wilson RH, Seymour MT, et al. Intermittent versus continuous oxaliplatin-fluoropyrimidine (Ox-Fp) chemotherapy (CT) in first-line treatment of patients (pts) with advanced colorectal cancer (aCRC): Predictive factors (PF), quality of life (QL), and final efficacy results from the MRC COIN trial. J Clin Oncol. 2010;28(15s). Abstract 3525.

3. Tabernero J, Aranda E, Gomez A, et al. Phase III study of first-line XELOX plus bevacizumab (BEV) for 6 cycles followed by XELOX plus BEV or single-agent (s/a) BEV as maintenance therapy in patients (pts) with metastatic colorectal cancer (mCRC): The MACRO Trial (Spanish Cooperative Group for the Treatment of Digestive Tumors [TTD]). J Clin Oncol. 2010;28(15s). Abstract 3501.

4. Ruers T, Punt CJ, van Coevorden F, et al. Final results of the EORTC intergroup randomized study 40004 (CLOCC) evaluating the benefit of radiofrequency ablation (RFA) combined with chemotherapy for unresectable colorectal liver metastases (CRC LM). J Clin Oncol. 2010;28(15s). Abstract 3526.

5. Alberts SR, Sargent J, Smyrk TC, et al. Adjuvant mFOLFOX6 with or without cetuxiumab (Cmab) in KRAS wild-type (WT) patients (pts) with resected stage III colon cancer (CC): Results from NCCTG Intergroup Phase III Trial N0147. J Clin Oncol. 2010;28(15s). Abstract CRA3507.

6. Goldberg RM, Sargent DJ, Thibodeau SN, et al. Adjuvant mFOLFOX6 plus or minus cetuximab (Cmab) in patients (pts) with KRAS mutant (m) resected stage III colon cancer (CC): NCCTG Intergroup Phase III Trial N0147. J Clin Oncol. 2010;28(15s). Abstract 3508.

7. Kang Y, Ohtsu A, Van Cutsem E, et al. AVAGAST: A randomized, double-blind, placebo-controlled, phase III study of first-line capecitabine and cisplatin plus bevacizumab or placebo in patients with advanced gastric cancer (AGC). J Clin Oncol. 2010;28(15s). Abstract LBA4007.

8. Conroy T, Desseigne F, Ychou M, et al. Randomized phase III trial comparing FOLFIRINOX (F: 5FU/leucovorin [LV], irinotecan [I], and oxaliplatin [O]) versus gemcitabine (G) as first-line treatment for metastatic pancreatic adenocarcinoma (MPA): Preplanned interim analysis results of the PRODIGE 4/ACCORD 11 trial. J Clin Oncol. 2010;28(15s). Abstract 4010.
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Posted on : 07/14/10
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