You can use regorafenib first, since patients have less tolerance as time goes by [ie, use the less tolerable agent while patients are healthier], or you can use TAS-102 first, because patients may not get another shot for treatment if their disease is progressing after infusional therapies— Thomas J. George, Jr, MD, FACP
Although new gastrointestinal cancers are on the rise, advancements in their treatment, as well as the upcoming results of perioperative trials, could prove to be “clinical practice game-changers,” declared Thomas J. George, Jr, MD, FACP, at the 2016 Community Oncology Conference in Orlando, Florida.1 New agents in refractory gastroesophageal, pancreatic, and colorectal cancers have emerged, he added, and moving them into first-line treatment has become a priority. Dr. George is Director of the Gastrointestinal Oncology Program and Research Director of the Joint Oncology Program at the University of Florida, Gainesville.
Gastric Cancer: VEGF Inhibitors and Immunotherapy
Anti-VEGF (vascular epithelial growth factor) therapy has demonstrated activity in advanced gastric cancer, leading to U.S. Food and Drug Administration (FDA) approval of ramucirumab (Cyramza) alone or in combination with paclitaxel in previously treated metastatic esophagogastric cancers in the REGARD and RAINBOW trials.2,3 In the REGARD trial, which included 355 patients previously treated for advanced gastric or gastroesophageal junction adenocarcinoma, there was a survival benefit with ramucirumab vs placebo (median overall survival of 5.2 months vs 3.8 months).2 Similarly, in the RAINBOW trial of 665 patients, also with previously treated advanced gastric or gastroesophageal junction adenocarcinoma, the combination of ramucirumab and paclitaxel significantly increased overall survival vs paclitaxel with placebo.3
“These data are a very nice demonstration of stepwise interval improvement in the care of our patients for metastatic second-line therapy,” reflected Dr. George.
The RAINFALL trial (capecitabine [or fluorouracil [5-FU]], and cisplatin with or without ramucirumab) is currently ongoing, with the aim of moving ramucirumab up to first-line therapy for metastatic esophagogastric cancers, and results should be out in the next 2 years. “We’re all anxiously awaiting this, because it could be a new option for a lot of our patients. It has the potential to change the standard of care in our practices,” he said.
Immunotherapy is gaining relevancy in gastrointestinal cancers, but only for specific cohorts. Single-agent pembrolizumab (Keytruda) produced a “wow factor” in a pilot study in MSI-H colorectal cancer and was granted breakthrough status by the FDA.
In the KEYNOTE-012 trial,4 Bang et al found that pembrolizumab demonstrated promising antitumor activity in advanced gastric cancer, although it was restricted to programmed cell death ligand 1 (PD-L1)-expressing tumors. Studies with pembrolizumab in larger populations are underway, particularly in gastric, microsatellite instability–high colorectal cancer, and mismatch-repair deficiency metastatic colorectal cancer. And as a result, personalized treatment decisions will continue to be refined by patient selection, noted Dr. George.
Immunotherapy is not quite ready yet for prime time in the treatment of gastric cancers, Dr. George admitted. However, he predicted, if ongoing studies find immune checkpoint inhibitors to be effective in patients with esophagogastric adenocarcinoma, “immunotherapy could become a part of our standard practice.”
Pancreatic Cancer: Triplet Therapy
In pancreatic cancer, “what we’re still dealing with is gemcitabine/5-FU–based therapy as our backbone,” said Dr. George. Current systemic therapy options for pancreatic cancer include gemcitabine, gemcitabine and erlotinib, gemcitabine and nanoparticle albumin bound (nab)-paclitaxel (Abraxane), or FOLFIRINOX (5-FU/leucovorin/irinotecan/oxaliplatin).
Over 20 years, he noted, median survival has improved from approximately 5.6 months in the 1990s to 11.1 months with triplet therapy. “We are seeing incremental increases and stepwise progression of overall survival in this patient population,” stated Dr. George. He also added that median survival is not the whole story, since 1-year overall survival is increasing as well. “Our first-line therapies are actually quite effective,” he noted.
Most patients with pancreatic cancer will only see one line of treatment, but for those who are fit, Dr. George recommends several options after first-line therapy. He suggested that clinicians enroll such patients in a clinical trial; try agents that they did not use the first time (ie, if 5-FU–based therapy was used, switch over to gemcitabine-based and vice versa); or use nanoliposomal irinotecan (MM-398) with 5-FU/leucovorin, which demonstrated improvement in median survival over 5-FU and leucovorin (6.1 vs 4.2 months) and doubling of progression-free survival (3.1 vs 1.5 months) in the NAPOLI-1 trial.5
Several multicenter adjuvant trials are on the horizon, stated Dr. George. “Within the next year or two, we may see major results from at least two of these randomized controlled trials in the adjuvant setting, and this may then change what we need to do in the adjuvant setting, which subsequently changes everything else thereafter if they relapse.”
Unfortunately, monotherapy immunomodulator pancreatic cancer studies have been negative, suggesting that combinations of these agents may be required. “Pancreatic cancer has been a very tough nut to crack, and the immunomodulators are proving that to be true as well,” admitted Dr. George.
Colorectal Cancer: Regorafenib or TAS-102
The typical patient with metastatic colorectal cancer will now have multiple options after the first- and second-line therapies. Fit patients have the following palliative options: enrollment in a clinical trial or treatment with regorafenib (Stivarga) or TAS-102 (trifluridine and tipiracil [Lonsurf]).
TAS-102 was approved by the FDA in 2015 for use in patients with refractory colorectal cancer. The randomized phase III trial of TAS-102 on which this approval was based showed a statistically significant improvement in median and progression-free survival over placebo.6 The median overall survival improved from 5.3 months with placebo to 7.1 months with TAS-102, and the hazard ratio for death in the TAS-102 group vs the placebo group was 0.68 (P < .001).6
There are currently no head-to-head comparisons with regorafenib and TAS-102, but Dr. George called their activity “equitable and almost superimposable,” although TAS-102 showed better tolerability. In choosing between these two agents, he suggested, “You can use regorafenib first, since patients have less tolerance as time goes by [ie, use the less tolerable agent while patients are healthier], or you can use TAS-102 first, because patients may not get another shot for treatment if their disease is progressing after infusional therapies.” ■
Disclosure: Dr. George has received institutional research funding from Bayer, Bristol-Myers Squibb, Celgene, and NewLink Genetics and is a consultant for Bayer and NewLink Genetics.
1. George TJ: Concept to practice: New advances in the treatment of gastrointestinal cancers. 2016 Community Oncology Conference. Presented April 14, 2016.
2. Fuchs CS, Tomasek J, Yong CJ, et al: Ramucirumab monotherapy for previously treated advanced gastric or gastro-oesophageal junction adenocarcinoma (REGARD): An international randomized, multicentre, placebo-controlled, phase 3 trial. Lancet 383:31-39, 2014.
3. Wilke H, Muro K, Van Cutsem E, et al: Ramucirumab plus paclitaxel versus placebo plus paclitaxel in patients with previously treated advanced gastric or gastro-eosphageal junction adenocarcinoma (RAINBOW): A double-blind, randomized phase 3 trial. Lancet Oncol 15:1224-1235, 2014.
4. Bang Y-J, Chung H-C, Shankaran V, et al: Relationship between PD-L1 expression and clinical outcomes in patients with advanced gastric cancer treated with the anti-PD-1 monoclonal antibody pembrolizumab (MK-3475) in KEYNOTE-012. 2015 ASCO Annual Meeting. Abstract 4001.
5. Wang-Gillam A, Li CP, Bodoky G, et al: Nanoliposomal irinotecan with fluorouracil and folinic acid in metastatic pancreatic cancer after previous gemcitabine-based therapy (NAPOLI-1): A global, randomized, open-label, phase 3 trial. Lancet 387:545-557, 2016.