By Richard L. Schilsky, MD, FASCO, Chief Medical Officer of ASCO. I’ve been a regular attendee of the Gastrointestinal Cancers Symposium since it began 11 years ago. This year’s meeting was among the very best with record attendance, superb educational talks and keynote lectures, multidisciplinary panels discussing real-world clinical problems, and an array of important research studies presented in oral abstract and poster sessions. If you followed my Twitter feed from the meeting (@rschilsky), you saw what struck me as some of the meeting highlights.
It has been years since we’ve made meaningful progress in gastric cancer, but it’s now becoming clear that this disease can be prevented and more effectively treated. Individuals from high-risk families can now be screened for germline mutations in the E-cadherin gene, and mutation carriers can be considered for prophylactic gastrectomy. The majority of gastric cancers worldwide are caused by H. pylori infection, and global measures to eradicate this infection coupled with endoscopic surveillance in endemic regions have potential to dramatically reduce the incidence and mortality of gastric cancer. Treatment for metastatic gastric cancer was stagnant for many years until the recent demonstration that trastuzumab added to chemotherapy improves the survival of patients with HER-2 overexpressing gastric cancer.
At the GI Symposium this year, we heard the first presentation of the results of the RAINBOW trial, a global, randomized, double-blind, placebo-controlled trial of ramucirumab in 665 patients with advanced gastric or gastroesophageal junction adenocarcinoma who progressed on first-line platinum/fluoropyrimidine-based combination therapy. The addition of ramucirumab, an anti-VEGF receptor monoclonal antibody, to paclitaxel significantly prolonged the overall survival (OS) from a median of 7.36 to 9.63 months (HR 0.807, 95% CI [0.678-0.962]; p = 0.0169).
This year we also began to see glimmers of hope in pancreatic cancer. Findings from a randomized phase II trial of a dual immunotherapy approach in patients with metastatic pancreatic adenocarcinoma using GVAX pancreas—an irradiated, whole-cell tumor vaccine—and CRS-207—live-attenuated Listeria monocytogenes modified to express mesothelin to stimulate innate and adaptive immunity showed that patients who received cyclophosphamide/GVAX alone attained a median OS of 3.4 months compared with 6.0 months for those who received CRS-207 in addition to cyclophosphamide/GVAX (HR 0.4477; p = 0.0057). Notably, patients who received at least three doses of immunotherapy in the combination arm achieved a median OS of 9.7 months. These positive findings met the early stopping rule for efficacy, and the study was halted to allow patients in the GVAX-alone arm to cross over to receive CRS-207 as well. An updated analysis of survival in the randomized phase III MPACT trial that first ushered in use of the nab-paclitaxel/gemcitabine regimen in metastatic adenocarcinoma of the pancreas continues to show a sustained improvement in OS with the addition of nab-paclitaxel to gemcitabine, as compared with gemcitabine alone. Median OS remains significantly greater in the combination arm at 8.7 months versus 6.6 months for the gemcitabine-alone arm (HR 0.72, 95% CI [0.620-0.825]; p < 0.0001) with some long-term survivors noted.
To me, the most important new information presented at the meeting related to the impact of RAS mutations on the effectiveness of anti-EGFR antibodies in patients with colorectal cancer. While activating mutations in KRAS exon 2, present in approximately 40% to 50% of mCRC tumors, have been known for some time to blunt the response to EGFR-targeted agents in mCRC, new data point to a longer list of mutations within the RAS gene family that are also associated with lack of treatment effectiveness. Data from several trials show that activating mutations in exons 2, 3, and 4 of both KRAS and NRAS predict a lack of response to panitumumab in the second-line setting corroborating similar recent findings from the PRIME and PEAK trials regarding panitumumab efficacy in the first-line setting. Similar results for cetuximab in the first-line setting were also reported based on a reanalysis of data from the FIRE-3, OPUS, and CRYSTAL studies. It seems that as many as 25% to 40% of patients considered to be KRAS wild-type with conventional mutation screening harbor these additional mutations that confer resistance to anti-EGFR antibodies. The practical implication is that RAS mutation testing must be greatly expanded to optimize treatment with cetuximab and panitumumab.
In patients with locally advanced rectal cancer, updated results from the randomized phase III GCR-3 trial conducted in Spain continue to tip the balance in favor of induction chemotherapy followed by chemoradiotherapy and then surgery versus the standard approach of chemoradiotherapy followed by surgery and then adjuvant chemotherapy. Pathologic complete response rates, locoregional recurrence, distant recurrence, disease-free survival, and OS all proved similar between the two approaches out to five years, although there was less acute toxicity and better compliance to the chemotherapy component of the regimens with the induction approach versus the standard approach.
Mature results from the phase III National Surgical Adjuvant Breast and Bowel Project (NSABP) R-04 trial provide conclusive answers to two important questions about neoadjuvant therapy for stage II/III rectal cancer. First, given the identical outcomes between patients treated with oral capecitabine versus continuous intravenous infusion of 5-flurouracil, the findings support use of capecitabine as a new standard of care in combination with pelvic radiotherapy prior to surgery. Second, the addition of oxaliplatin to the neoadjuvant regimen is not indicated, given that oxaliplatin conferred no improvements in outcome but did significantly increase toxicity.
This year’s GI Symposium again highlighted the critical elements of progress in GI cancer, i.e., understanding cancer etiology, identifying high-risk populations, early detection and treatment, defining molecular drivers of disease and developing new, targeted treatments, harnessing the immune system to fight cancer, and using molecular profiles to guide treatment.
Note: For information about progress against cancer and ASCO’s 50th anniversary, please visit ASCO’s CancerProgress.Net.
Richard L. Schilsky, MD, FASCO, is the Chief Medical Officer (CMO) of ASCO. He assumed this newly created position with the Society in February of 2013. Formerly, Chief of Hematology/Oncology in the Department of Medicine and Deputy Director of the University of Chicago Comprehensive Cancer Center, he is a highly respected leader in the field of clinical oncology, who specializes in new drug development and treatment of gastrointestinal cancers. Dr. Schilsky is a Past President of ASCO, having served in the role during 2008-2009, and also a Past Chair of one of the National Cancer Institute’s Cooperative Groups, Cancer and Leukemia Group B (CALGB).