Advances in gastroesophageal adenocarcinoma, pancreatic cancer highlight GI symposium
David H. Ilson
The 2013 Gastrointestinal Cancers Symposium, the 10th annual international meeting organized by gastroenterologists, surgeons, and medical and radiation oncologists, convened from Jan. 24-26 in San Francisco.
Each meeting day focused on specific diseases. The program included a mixture of didactic and state-of-the science lectures, as well as oral and poster presentations of novel clinical research that covered the broad spectrum of esophagogastric, pancreatic, hepatobiliary and colorectal cancers.
Targeted therapies shared the spotlight with chemotherapy trials during the oral and poster presentations for the esophageal and gastric cancer meeting day.
Investigators from the United Kingdom presented results of two large phase 3 trials designed to evaluate EGFR-targeted agents in esophageal and gastroesophageal junction cancers.
Crosby and colleagues presented results of the SCOPE 1 trial, a phase 3 trial of definitive chemoradiotherapy with capecitabine and cisplatin with or without cetuximab (Erbitux; Bristol-Myers Squibb, Eli Lilly) in esophageal cancer.
Most of the 238 patients recruited had squamous tumors (73%). Most cancers were located in the mid or distal esophagus with either stage II (37%) or stage III (63%) disease.
The addition of cetuximab resulted in higher rates of nonhematologic toxicity (78% vs. 62.8%; P=.004) and a lower rate of completion of therapy (75% vs. 86% for radiotherapy; P=.027).
More importantly, treatment with cetuximab during radiotherapy resulted in inferior failure-free survival at 24 weeks (66% vs. 77%), inferior median OS (22 months vs. 25 months, P=.043) and inferior 2-year survival (41% vs. 56%).
Dutton and colleagues presented results of the COG trial, which evaluated gefitinib (Iressa, AstraZeneca) 500 mg daily vs. placebo in 450 patients with metastatic esophageal and gastroesophageal junction adenocarcinoma that progressed on first-line chemotherapy.
An earlier report of this trial indicated that gefitinib failed to improve OS, the primary trial endpoint, whereas PFS was marginally improved by a median of 7 days.
Dutton and colleagues reported data from the quality-of-life analysis. Gefitinib improved symptoms of odynophagia and social function at the cost of higher rates of diarrheal toxicity.
The results of these two large negative trials of EGFR-targeted therapy in locally advanced and metastatic disease add to other recently reported negative trial results of EGFR-targeted agents in esophagogastric cancers.
With the equally negative results from the recently reported phase 3 evaluation of chemotherapy combined with either panitumumab (Vectibix, Amgen) or cetuximab in two European trials, it is unlikely there will be further large-scale study of currently available EGFR-targeted agents in esophagogastric cancers.
Ramucirumab for advanced disease
In contrast to these negative results, Fuchs and colleagues reported positive results from the REGARD trial, which evaluated the VEGF receptor-2 targeted agent ramucirumab (IMC-1121B, ImClone Systems), a humanized monoclonal antibody that blocks ligand binding to the VEFG receptor-2.
The double blind, placebo-controlled trial included 355 patients whose disease progressed on initial chemotherapy for advanced disease. All patients received best supportive care. Researchers assigned 238 patients to ramucirumab 8 mg/kg IV once every 2 weeks, and the other 117 patients received placebo.
Researchers reported higher median OS (5.2 months vs. 3.8 months; HR=0.776; P=.0473) and PFS (2.1 months vs. 1.3 months; HR=0.483; P<.0001) among patients assigned to ramucirumab. The disease control rate was 49% for patients who received ramucirumab vs. 23% for those who received best supportive care alone (P<.00001).
Antitumor responses were rarely seen in either treatment arm (3.4% for ramucirumab vs. 2.6% for placebo). Toxicity for ramucirumab nearly mirrored that seen for placebo, with rare observation of grade 3 or 4 hypertension (7.2%).
Given the positive effects on PFS and OS, as well as improvement in disease control and the relative absence of toxicity, ramucirumab likely will become a new therapeutic option in gastroesophageal adenocarcinoma after progression on initial chemotherapy.
Yung-Jue Bang, MD, PhD, of the Seoul National University Hospital and Seoul National University College of Medicine, presented data on a novel HER-2 targeted agent evaluated in the TyTAN trial.
Researchers enrolled 261 patients with HER-2–positive gastric cancer who had progressive disease on initial chemotherapy. The patients were randomly assigned to paclitaxel 80 mg/m2 weekly on days 1, 8 and 15, followed by 1 week off, with or without the dual tyrosine kinase inhibitor lapatinib (Tykerb, GlaxoSmithKline) 1,500 mg daily.
Researchers reported median OS of 11 months for patients who received paclitaxel plus lapatinib vs. 8.9 months for patients who received paclitaxel alone (HR=0.84; P=.2088). The difference was not statistically significant.
In a pre-planned analysis of immunohistochemistry 3+ patients, however, OS was significantly improved (14 months vs. 7.6 months; HR=0.59; P=.0176), indicating a potential benefit for lapatinib in patients with strong HER-2 overexpression.
Metastatic gastric cancer
Studies conducted in Japan and the United Kingdom evaluated chemotherapy treatments for patients with metastatic gastric cancer.
Higuchi and colleagues presented data from a noninferiority phase 3 trial that compared first-line use of oxaliplatin plus S-1 vs. S-1 plus cisplatin in 680 patients in Japan with advanced gastric disease.
Patients were assigned to receive either oxaliplatin 100 mg/m2 with S-1 40 mg/m2 twice daily for 14 days every 3 weeks, or S-1 40 mg/m2 twice daily for 21 days plus cisplatin 60 mg/m2 on day 8 every 5 weeks.
The researchers reported equivalent response rates for oxaliplatin (56%) and cisplatin (52%), as well as similar PFS (5.5 months vs. 5.4 months), with the HR meeting the criteria for noninferiority.
The results reinforce results from other phase 3 trials, supporting the substitution of oxaliplatin for cisplatin in the treatment of esophagogastric cancer.
Ford and colleagues presented results of the COUGAR-02 trial, which addressed second-line chemotherapy. Patients received either docetaxel 75 mg/m2 every 3 weeks or best supportive care.
Of the 168 patients treated, the disease site was the stomach in 46% and gastroesophageal junction in 54%.
Docetaxel treatment was associated with improved median OS (5.2 months vs. 3.6 months; HR=0.67; P=.01).
Data from this and other recent phase 3 trials support the modest but measurable efficacy of second-line chemotherapy in esophagogastric cancer, and they establish taxane monotherapy as a care standard.
‘Landmark advance’ for pancreatic cancer
Data from potentially practice-changing trials were presented in the pancreaticobiliary cancers session.
Von Hoff and colleagues presented results from the MPACT trial, a phase 3 trial designed to compare weekly gemcitabine 1,000 mg/m2 with or without the addition of nab-paclitaxel (Abraxane, Abraxis BioScience).
The investigation included 861 patients. Standard gemcitabine was administered weekly for 7 weeks, then weekly for 3 weeks on and 1 week off. Nab-paclitaxel 125 mg/m2 was combined with weekly gemcitabine for 3 weeks on and 1 week off.
Nab-paclitaxel was associated with significantly improved median OS (8.5 months vs. 6.7 months; HR=0.72; P=.000015), a higher rate of 1-year survival (35% vs. 22%; P=.0002), improved PFS (5.5 months vs. 3.7 months; HR=0.69; P=.000024) and a significant improvement in response rate (23% vs. 7%).
Researchers reported higher rates of some grade 3 or 4 toxicities among patients assigned to the nab-paclitaxel arm, including neutropenia (38% vs. 27%), fatigue (17% vs. 7%) and neuropathy (17% vs. 1%).
The results of this trial represent a landmark advance in the treatment of pancreatic cancer. For the first time, a chemotherapy doublet combination has improved outcome in pancreatic cancer compared with gemcitabine monotherapy.
The MPACT trial validates taxanes as an active and important class of agents in this disease. Although nab-paclitaxel likely will gain acceptance as a new therapy option in pancreatic cancer, the results of the MPACT trial still fall short of the response and survival improvements achieved with the three-drug regimen FOLFIRINOX. Given the complexity and toxicity of FOLFIRINOX and the potential need for selection of patients with high functional status for such therapy, nab-paclitaxel plus gemcitabine likely will represent an alternative combination regimen that can be offered to patients with advanced pancreatic cancer.
S-1 vs. gemcitabine
Uesaka and colleagues presented results of JASPAC-01, another provocative trial in the adjuvant setting of resected pancreatic cancer.
In a noninferiority trial design, investigators compared standard adjuvant therapy with gemcitabine 1,000 mg/m2 weekly, 3 weeks on and 1 week off for 6 months, with S-1 40 mg to 60 mg twice daily for 4 weeks repeated every 6 weeks for four courses.
Of the 385 patients enrolled, the HR for OS for S-1 vs. gemcitabine was 0.56 (P<.0001 for noninferiority and P<.001 for superiority).
Two-year survival was 53% for patients assigned to gemcitabine and 70% for those assigned to S-1. Results from this study are consistent with trials in the West that indicate adjuvant 5-FU–based chemotherapy is as effective as gemcitabine in the adjuvant treatment of resected pancreatic cancer.
The potential superior outcome of S-1 compared with gemcitabine in this Japanese trial was surprising, and it may establish a new care standard in Japan.
Capecitabine for locally advanced pancreatic cancer
In the chemoradiotherapy-based treatment of locally advanced pancreatic cancer, Mukherjee and colleagues presented results from the SCALOP trial, which compared capecitabine vs. gemcitabine as radiosensitizing chemotherapy during combined modality therapy.
The trial, conducted in the United Kingdom, included 114 patients with inoperable, locally advanced pancreatic cancer.
All patients received induction chemotherapy with three cycles of gemcitabine 1,000 mg/m2 weekly for 3 weeks on and 1 week off, plus capecitabine 830 mg/m2 twice daily for 21 days. Patients then received 50.4 Gy of radiotherapy in 28 daily fractions combined with either gemcitabine 300 mg/m2 weekly or capecitabine 830 mg/m2 twice daily administered on weekdays during radiotherapy.
Patients in the gemcitabine arm experienced higher rates of grade 3 or 4 hematologic toxicity (18.4 vs 0%; P=.007) and nonhematologic toxicity (26.3% vs. 11.1%; P=.095). OS was superior in the capecitabine arm (15.2 months vs. 13.4 months; HR=0.50; P=.025).
The results favor the use of capecitabine over gemcitabine combined with concurrent radiotherapy in the treatment of locally advanced pancreatic cancer.
Bevacizumab for colorectal cancer
Two trials compared first-line chemotherapy with or without bevacizumab (Avastin, Genentech) in patients with colorectal cancer.
In the AVEX trial, Cunningham and colleagues evaluated the contribution of bevacizumab to capecitabine monotherapy in the treatment of patients with metastatic colorectal cancer aged 70 years or older.
All 280 patients received capecitabine 1,000 mg/m2 twice daily for 14 days every 3 weeks. Half of the patients also received bevacizumab 7.5 mg/kg on day 1.
The addition of bevacizumab was associated with significantly improved PFS (9.1 months vs. 5.1 months; HR=0.53; P<.001). OS was superior in the bevacizumab arm (20.7 months vs. 16.8 months; HR=0.79; P=.182), but the difference was not statistically significant. Bevacizumab also was associated with increased response rates (19.3% vs. 10%), and no new toxicity signals for bevacizumab were observed.
The results indicate a benefit for the use of bevacizumab combined with monochemotherapy in an elderly population.
Loupakis and colleagues reported results from the TRIBE trial, which compared combination chemotherapy with bevacizumab with either FOLFIRI or FOLFOXIRI.
Among the 508 patients treated, FOLFOXIRI significantly improved PFS compared with FOLFIRI (11.9 months vs. 9.5 months; HR=0.72; P=.001) and led to an increase in antitumor response rate (64% vs. 53%; P=.015).
OS data had not matured at the time of the presentation. Toxicities significantly increased by twofold or greater with FOLFOXIRI compared with FOLFIRI, including grade 3 or 4 diarrhea (19% vs. 11%), stomatitis (9% vs. 4%) and neutropenia (50% vs. 20%).
The results validate a high degree of activity for FOLFOXIRI combined with bevacizumab. OS data are awaited to direct the potential appropriate utilization of triplet chemotherapy in advanced colorectal cancer.
Adjuvant chemotherapy for stage II colon cancer
Kumar and colleagues from British Columbia, Canada, reported the results of a trial that evaluated adjuvant chemotherapy in stage II colon cancer as a function of high- and low-risk stage II disease.
Of the 1,697 patients studied, 73% were high risk and 27% were low risk. In this retrospective study, 363 high-risk patients and 61 low-risk patients received adjuvant chemotherapy. A 5-year OS benefit for adjuvant chemotherapy vs. no treatment was limited to the high-risk group (75% vs. 68%; P<.01), and improvements in 3-year RFS, 5-year DFS and OS were limited to high-risk patients with T4 tumors. Trends toward an adverse effect of adjuvant chemotherapy were observed in low-risk stage II patients.
These data add to literature supporting the potential application of adjuvant chemotherapy in colon cancer to only high-risk stage II patients.
The following were presented at the Gastrointestinal Cancers Symposium; Jan. 24-26, 2013; San Francisco:
Bang YJ. Abstract #11.
Crosby T. Abstract #LBA3.
Cunningham D. Abstract #337.
Dutton SJ. Abstract #6.
Ford H. Abstract #LBA4.
Fuchs CS. Abstract #LBA5.
Higuchi K. Abstract #60.
Kumar A. Abstract #338.
Loupakis F. Abstract #336.
Mukherjee S. Abstract #230.
Uesaka K. Abstract #145.
Von Hoff DD. Abstract #LBA148.
For more information:
David H. Ilson, MD, PhD, is a medical oncologist with Memorial Sloan-Kettering Cancer Center’s Gastrointestinal Oncology Service, a professor of medicine at Weill Cornell Medical College and a HemOnc Today Editorial Board member. He can be reached at Memorial Sloan-Kettering Cancer Center, 1275 York Ave., New York, NY 10065; email: email@example.com.
Disclosure: Ilson reports no relevant financial disclosures.