May 03, 2017
By Kara Nyberg, PhD
The 2017 Gastrointestinal (GI) Cancers Symposium concludes another year of enlightening discourse, instructive education, and fruitful interaction among the 3,500 attendees—a number that signifies “an outstanding reflection of the quality of this meeting,” according to William M. Grady MD, of the Fred Hutchinson Cancer Research Center, and the 2017 GI Cancers Symposium chair.
Read on for a snapshot of the top research presented at the meeting that exemplified the theme for 2017: “Multidisciplinary Precision Care: Progress and Innovation.”
Therapeutic Innovation Advancing Precision Care
Several presentations described the exploration of new therapeutic avenues intended to enhance outcomes in select patients with GI malignancies.
Two notable studies investigated novel applications of existing diagnostic and therapeutic tools:
- Karyn A. Goodman, MD, MS, of the University of Colorado School of Medicine, presented the phase II CALGB 80803 trial in resectable esophageal adenocarcinoma. This trial demonstrated that using PET imaging following initial induction chemotherapy to assess early response can maximize pathologic complete response rates by signaling the need to switch from ineffective to alternative chemotherapy during preoperative chemoradiation (Abstract 1).
- Results of a small randomized phase II feasibility study suggest that stereotactic body radiation therapy may be an alternative bridging option to transarterial chemoembolization for patients with locally advanced hepatocellular carcinoma (HCC) awaiting a liver transplant based on comparable efficacy and safety, with the added convenience of outpatient administration (Abstract 223).
Three studies underscored the potential of immunotherapy, specifically with the PD-1 inhibitor nivolumab, in cancers of the stomach, liver, and colorectum:
- Findings from the ONO-4538-12 (ATTRACTION-2) trial establish nivolumab as the first immunotherapy in phase III analyses to significantly improve overall survival (OS; p < 0.0001), progression-free survival (PFS; p < 0.0001), and overall response rate (ORR; p < 0.0001) in patients with advanced gastric or gastroesophageal junction cancer, fulfilling a dire need for individuals who have failed standard second- or later-line chemotherapy (Abstract 2).
- Interim results of the large phase I/II CheckMate 040 study indicate that nivolumab is both active and well tolerated when given as first- or second-line monotherapy to patients with advanced HCC (Abstract 226), prompting the large phase III CheckMate 459 trial comparing nivolumab versus sorafenib in the first-line setting.
- Updated data for single-agent nivolumab within the phase II CheckMate 142 study conducted in heavily pretreated patients with metastatic colorectal cancer (mCRC) featuring high microsatellite instability or DNA mismatch repair deficiency showed that nivolumab yielded such marked improvements in objective responses, disease control, long-term survival, and patient quality of life (Abstract 519). Single-agent nivolumab should be considered a new standard of care for these individuals, according to the study investigators.
Targeted therapies also demonstrated promise in difficult-to-treat patient populations with limited treatment options:
- Jennifer A. Chan, MD, MPH, of the Dana-Farber Cancer Institute, presented data from a small prospective phase II trial that suggested that cabozantinib confers marked clinical benefit in patients with progressive, well-differentiated neuroendocrine tumors—lesions that historically are very difficult to treat given their chemoresistant nature (Abstract 228).
- Interim results of the phase II SWOG 1406 trial revealed that the addition of vemurafenib to cetuximab and irinotecan significantly prolonged PFS (p = 0.0002) and the disease control rate (p = 0.001) in patients with BRAFV600E-mutated mCRC, illustrating the benefit of inhibiting both BRAF and EGFR within the MAPK pathway to staunch tumor growth (Abstract 520).
And yet, with successes come failures. Although study findings sometimes do not provide the answers expected or desired, these results still offer up valuable information reinforcing current standards of care and lending insight into how to restructure future endeavors, as illustrated by the following:
- Despite an attempt to demonstrate that adjuvant chemotherapy prolongs relapse-free survival (RFS) in patients with localized biliary tract cancer following resection, the results of the prospective phase III PRODIGE 12–ACCORD 18 trial turned out negative, showing no statistical difference between gemcitabine plus oxaliplatin and surveillance with regard to RFS or patient quality of life (Abstract 225).
- The addition of the mTOR inhibitor everolimus (RAD001) to paclitaxel failed to significantly improve OS, PFS, or ORR compared with paclitaxel alone among patients with gastric cancer who progressed after fluoropyrimidine/platinum-based therapy within the large randomized, double-blind, multicenter, phase III RADPAC trial (Abstract 4). Biomarker studies might help identify patient subgroups that could benefit.
- In a systematic review of 148 phase II trials of investigational first-line therapies conducted in more than 7,500 patients with locally advanced or metastatic pancreatic cancer published between 1978 and 2015, 55.4% were reported as successful by investigators but only 14.9% advanced to phase III trials. The high attrition may be explained, in part, by the failure to conform with National Cancer Institute recommendations for the adequate design of pilot trials to inform future study (Abstract 227).
New Insight Into Offering Precision Care
A key tenet of precision care relies on the ability to identify the specific patients for whom a given treatment will work best. Two studies took a closer look at existing therapies in an effort to meet this aim:
- Investigators dug back into the Adenoma Prevention With Celecoxib tissue archives and identified two biomarkers—cyclooxygenase-2 (COX-2) and 15-prostaglandin dehydrogenase (15-PGDH)—that distinguish those individuals at high risk for colorectal adenomas who stand to derive the greatest benefit from celecoxib chemoprevention of colorectal cancer (Abstract 524).
- A pooled analysis of the phase III REGARD and RAINBOW trials of second-line ramucirumab in patients with advanced gastric or gastroesophageal junction cancer revealed benefits with the antiangiogenic agent for OS, PFS, and global health status, along with comparable safety, across all age groups analyzed, supporting use of ramucirumab in the young (≤ 45 years), old (≥ 70 years), and all those in between (46 to 69 years; Abstract 3).
Precision care also requires a solid understanding of the disease in question to identify appropriate therapies. To begin to tease apart the marked heterogeneity of colorectal cancer, recent efforts have focused on the “sidedness” of disease. New analyses are building on this work, both in metastatic and earlier-stage disease:
- Multiplatform profiling of a large bank of right- and left-sided primary tumors reveals a continuum of molecular alterations when moving from the right colon—the cecum and ascending colon—to the left colon—the splenic flexure, descending colon, and sigmoid colon—and on to the rectum, suggesting that clinical trials should stratify patients based on the location of the primary tumor as well as molecular features (Abstract 522).
- Results of a retrospective cohort analysis suggest that right-sided tumors may display worse outcomes compared with left-sided tumors in select patients with stage II disease based on two prognostic markers, the 12-gene Oncotype DX score and CDX2 tumor expression, both associated with disease recurrence (Abstract 523).