Future Looks Bright for GI Cancers, Experts Agree

John L. Marshall, MD

John L. Marshall, MD

Gastrointestinal (GI) cancers are among the most common and most fatal oncologic malignancies on the planet, according to John L. Marshall, MD. “Every oncologist faces these diagnoses on a weekly—daily— basis, and so it’s critical that they have a very solid understanding of the optimum management for these patients, and there are significant developments in each of these medical areas,” Marshall said. “It’s really imperative that doctors have a very high level of understanding.”

Practitioners received insight into treating patients across the GI field—colorectal cancer (CRC), hepatocellular carcinoma (HCC), pancreatic cancer, neuroendocrine tumors (NETs), gastric cancer, and sarcomas—during the GI cancers track at the 2016 Chemotherapy Foundation Symposium.

“The key thing in GI cancer today, is understanding the molecular subgroups and better patient selection for different kinds of therapies,” said Howard S. Hochster, MD. That kind of knowledge and skill is emerging now in colon cancer “with the whole left-sided/right-sided story and MSI [microsatellite instability]-high tumors,” and the same will happen with gastric cancer and the different biologic subsets of that disease, he said. “Those are the kinds of areas where we will see greater progress by understanding biology and finding the right patients and the right treatment.”

Marshall is chief of the Division of Hematology and Oncology at Medstar Georgetown University Hospital and director of the Otto J. Ruesch Center for the Cure of Gastrointestinal Cancers. Hochster is professor of Medical Oncology and associate director for Clinical Sciences at Yale Cancer Center. He also serves as clinical program leader of the Gastrointestinal Cancers Program, Smilow Cancer Hospital. Both men are serving as moderators and presenting during the GI track today.

A key update in the colorectal cancer (CRC) landscape over the past year was presented at the 2016 ASCO annual meeting, with the discussion of a retrospective analysis of the phase III 80405 trial of irinotecan/5-FU/ leucovorin (FOLFIRI) or oxaliplatin/5-FU/leucovorin (mFOLFOX6) with bevacizumab or cetuximab for patients with KRAS wild-type untreated metastatic adenocarcinoma of the colon or rectum (mCRC). Survival outcomes in patients with mCRC were found to be significantly longer with tumors originating on the left versus the right side of the colon.¹

In Marshall’s lecture, “Where Are We With Liver- Directed Therapy in Metastatic CRC?” he plans to review the history and current evidence for the use of liver-directed therapies in mCRC, as well as the need to partner with interventional radiology teams as part of a multidisciplinary approach to treating patients.

For example, during the 2016 World Congress on GI Cancer, researchers showed that selective internal radiation therapy with SIR-Spheres Y-90 resin microspheres added to standard frontline chemotherapy led to a significant increase in hepatic depth of response in patients with mCRC, according to an analysis of the phase III SIRFLOX study.²

“There has been a great deal of innovation in terms of liver-specific management for metastatic colon cancer,” said Marshall. “We have gone from when we were simply embolizing tumors to now delivering smarter technologies, the most recent of which is radioembolization where injections of radioactive materials are given.” Not only is the treatment safe and well tolerated, but there are early signs of significant clinical improvement, he said.

Marshall speculated that over the next couple of years, additional data may be reported supporting the use of liver-directed therapy in early lines of therapy as opposed to salvage treatment.

Homing in on CRC, Marshall explained that there hasn’t been much change in the adjuvant setting in terms of standard of care, but what is recognized among researchers is that colon cancer is comprised of more than 1 disease. “We are increasingly getting away from a one-size-fits-all kind of management, and it’s increasingly complex,” said Marshall. “Therefore, it is very important for the practicing oncologist to be up-todate on the latest information.”

More can’t-miss presentations during this track included a lecture by Alan P. Venook, MD, titled, “Key Considerations in the Selection of Frontline Therapy in Metastatic CRC,” which provided a deeper understanding of not only molecular profiles of colon cancer, but also the nature of left- and right-sided colon tumors.

Tanios Bekaii-Saab, MD, also discussed “Optimizing Sequencing Beyond Disease Progression in CRC,” a presentation that addressed a challenge many practicing oncologists are facing.

“We’ve made some progress in frontline metastatic disease but, quite honestly, the real progress that has been made is in subsequent lines of therapy,” said Marshall. “We now have 11 approved drugs for metastatic colon cancer—more are on the way— and so, in order to optimize benefit and survival, we all need to be very good chess players.” He said Bekaii-Saab would discuss different options to optimize results in treatment.

In addition, broad molecular profiling is expected to have an impact that will shift the paradigm of CRC, especially with HER2-targeted agents that could show efficacy in the rare subset of patients. However, there are additional new targetable mutations for which researchers hope to have matching therapies.

The Tough Cancer to Crack

Another focus of the GI sessions was pancreatic cancer, specifically Hochster’s lecture, “Practice Patterns in Pancreatic Cancer—From Neoadjuvant to Metastatic Disease.” Here, he plans to discuss ongoing studies investigating PEGPH20, a pegylated version of rHuPH20, as well as a combination trial of FOLFIRINOX and gemcitabine/nanoparticle albumin-bound (nab)- paclitaxel (Abraxane), which is being looked at in preoperative settings. “I think that is a question that everybody wants the answer to—Is one really better than the other?” he asked.

Yet, many challenges remain in treating pancreatic cancer, Hochster said, adding that future research should focus on developing therapies targetable to KRAS mutations. “Pancreatic cancer remains the toughest nut to crack in the GI cancer area and maybe all of oncology,” said Hochster. “Everything that has really worked in colon cancer has been tried in pancreatic cancer, and it hasn’t helped very much. We tried all of the anti-VEGF drugs, the anti-EGFR drugs, and various TKIs, and we haven’t seen any of them pad much benefit on overall survival in pancreatic cancer.

“The biggest advance has been with combination chemotherapy instead of just single-agent gemcitabine. The hope, at the moment, is to move some of those into the earlier stages where we may be able to get better responses earlier on. The role for targeted therapy or genomic-based therapy is questionable: almost all [patients with] pancreatic cancer have a KRAS mutation, and there is no real effective therapy for tumors with KRAS mutations on a targeted level, and so that has limited the approach that has worked so well in lung cancer, for example. Also, it seems like [pancreatic cancer] is not a kind of tumor that responds all that well to inhibition of checkpoint blockade, so those drugs don’t seem to do very well either.”

Taking a look at the overall theme of his lecture, Hochster said he hopes to inform attendees about the progress being made with combination regimens and by moving intensive chemotherapy regimens into earlier lines of therapy.

The Game-Changing Landscape

Treatment management of NETs also was covered in this track, with a talk by Jonathan R. Strosberg, MD, titled, “Are We Making Progress in the Management of Neuroendocrine Tumors?” which can be expected to include mention of Lutathera (lutetium Lu 177 dotatate). “That is going to be a new approval and new treatment algorithm for patients with metastatic neuroendocrine tumors,” Hochster said. “We already have a relative explosion of effective therapies beyond just octreotide for these patients, and we look forward to Strosberg’s review of that.”

David H. Ilson, MD, PhD, talked about new approaches in gastric cancer, and Manish A. Shah, MD, discussed immunotherapy in GI cancers, with close attention to early immune therapy data in that space. A. Ruth He, MD, PhD, provided insight on new developments in HCC. Two sessions were dedicated to sarcoma: “Overcoming ‘Nihilism’ in the Management of Soft Tissue Sarcoma,” by George D. Demetri, MD, and, “Expert Perspectives on Emerging Strategies for Soft- Tissue Sarcomas,” by Katherine A. Thorton, MD. “The two talks on sarcomas were very interesting also,” Hochster said. “That was an added dessert.”

Hochster has been moderating the GI session at CFS for 20 years, and he says that the symposium is among best of its kind in the country. “They get very key investigators to give very short presentations on their area, and everything is really the latest advances in every disease presented over 3 days,” said Hochster. “You can learn about every disease site in a very concise, intense way by sitting in one room. That’s why the Chemotherapy Foundation Symposium™ is really great and really unlike anything else.”

Hits and Misses With Immunotherapy

In the next year or two, practitioners can anticipate pivotal findings from ongoing studies with immunotherapy agents for patients—not just with CRC but also in other GI cancers, Marshall explained. This was recently observed in a phase Ib trial looking at the combination of atezolizumab (Tecentriq) with cobimetinib (Cotellic), which demonstrated signs of clinical activity in patients with MSI-stable CRC.³

“We recognize that MSI-high colon cancers are responding to immunotherapy,” he said. “What’s new since then is, out of the blue, a very surprising data set where, in MSIstable colon cancers, a combination of a MET inhibitor with a PD-L1 inhibitor demonstrated clinical benefit in those patients. We once thought immunotherapy was not going to be an effective approach in colon cancer, [but] we now recognize that there is hot emergence of this.”

Further steps to take with immunotherapy include the approval of checkpoint inhibitors for MSI-high patients, where Marshall stressed that work needs to be done. “Quite honestly, we are trying everything because we don’t have a sense of what’s going to work and what’s not going to work,” he said. “We also don’t have a solid biomarker predictor of benefit so the reality is we are trying everything.”

Beyond CRC is the work that lies ahead in HCC with investigational approaches, including immunotherapy. In gastric cancer, Marshall said the opportunity might be there, but molecular profiling and better characterization will be important next steps to improving outcomes there. Studies are looking at immunotherapy in pancreatic cancer, too, says Hochster. However, there is a lack of a consensus that there is a signal there. “The one that is the most advanced is PEGPH20—that’s not exactly a targeted therapy—but it is being limited in the phase III trial to the patients with a high expression of hyaluronan acid,” Hochster concluded.

References

Venook AP, Niedzwiecki D, Innocenti F, et al. Impact of primary (1º) tumor location on overall survival (OS) and progression-free survival (PFS) in patients (pts) with metastatic colorectal cancer (mCRC): analysis of CALGB/SWOG 80405 (Alliance).J Clin Oncol.2016 (suppl; abstr 3504).

Heinemann V, van Hazel GA, Sharma NK, et al. Evaluation of depth of response within a volumetric model in patients with metastatic colorectal cancer: results of the SIRFLOX study. Presented at: 2016 World Congress on GI Cancer; June 28 - July 2, 2016; Barcelona, Spain. Abstract O-014.

Bendell JC, Kim TW, Goh BC, et al. Clinical activity and safety of cobimetinib (cobi) and atezolizumab in colorectal cancer (CRC).J Clin Oncol.2016;34 (suppl; abstr 3502).