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School of Gastrointestinal Oncology

A number of novel therapies are currently being explored as second-line treatments for patients with advanced hepatocellular carcinoma (HCC), including a host of targeted therapies and various immune checkpoint inhibitors, according to Ghassan Abou-Alfa, MD, at the 

“Almost 15 years ago, there was very little interest in the disease, now there is a plethora of clinical trials that are readily available in the first-, second-, and third-line setting,” explained Abou-Alfa, a medical oncologist at Memorial Sloan Kettering Cancer Center. “I highly encourage the physicians and their patients to seek clinical trials in those settings, because short of sorafenib there is nothing called 'standard of care.' There is diversity in regard to the targets, this is going to give a wealth of information.”

Sorafenib was approved based on the phase III SHARP trial,

 which randomized 602 patients to the multikinase inhibitor (n = 299) or placebo (n = 303). Median overall survival (OS) with sorafenib was 10.7 months compared with 7.9 months with placebo, representing the first and only systemic therapy to improve survival in a phase III study for patients with HCC. In the trial, there was a 31% reduction in the risk of death with sorafenib (HR, 0.69; 95% CI, 0.55-0.87; 

Following this demonstration of success, a number of studies were commenced in an attempt to build upon these results, including an investigation of adjuvant sorafenib for patients with HCC. Unfortunately, this study failed to show a benefit for sorafenib versus placebo.

 1114 patients were randomized to sorafenib (n = 556) or placebo (n = 558) following ablation or resection. At the final analysis, the median recurrence-free survival (RFS) was 33.3 months with sorafenib versus 33.7 months with placebo (HR, 0.94; 95% CI, 0.780-1.134; 

 =. 26). Median OS was not yet assessable from the study (HR, 0.995; 95% CI, 0.761-1.300; 

 sorafenib (n = 154) or placebo (n = 153) was added to transarterial chemoembolization (TACE) for patients with intermediate-stage HCC. Results were similar between the two arms for OS (HR, 0.898; 95% CI, 0.606-1.33) and for time to progression (TTP; HR, 0.797; 95% CI, 0.588-1.080).

In further attempts to expand upon the use of sorafenib, studies have assessed combination approaches. In the phase III CALGB-80802 study

 patients with advanced HCC received frontline sorafenib alone (n = 173) or in combination with doxorubicin (n = 173). Median OS with the combination was 8.9 months compared with 10.5 months with single-agent sorafenib (HR, 1.06; 95% CI, 0.8-1.4).

“There is not a role for adjuvant sorafenib, and there is no role for peri-TACE sorafenib,” said Abou-Alfa. “The role of sorafenib in the local regional setting was unfortunately negative, we didn't prove that additional sorafenib adds anything in that regard.”

Now, with sorafenib solidified as the frontline therapy for advanced HCC, phase III studies are exploring a host of second-line treatments, including the multikinase inhibitors cabozantinib (NCT01908426) and regorafenib (NCT01774344), the MET inhibitor tivantinib (NCT01755767), and the VEGFR2 inhibitor ramucirumab (NCT02435433). Additionally, phase II studies are looking at immune-based approaches in the second-line setting.

“Work in the second-line setting is multi-faceted—immunotherapeutics are under evaluation and the molecular understanding of HCC is underway,” said Abou-Alfa.

PD-L1 is expressed in 45% to 100% of patients with HCC. This expression is demonstrated on the tumor itself and the microenvironment, in Kupffer cells and tumor associated monocytes. Murine models and early clinical studies have shown promising efficacy for PD-L1 blockade. Additionally, evidence suggests that CTLA-4 blockade could also be an effective option.

 the CTLA-4 inhibitor tremelimumab showed signs of activity in 20 patients with HCC and chronic hepatitis C. The partial response rate was 17.6% with the immunotherapy and the disease control rate (DCR) was 76%. TTP was 6.5 months and a virologic response was indicated. However, grade 3 AST and ALT increases were seen in 45% of patients.

Adding to the early success seen with immunotherapy, the anti—PD-1 agent nivolumab (Opdivo) showed an objective response rate of 19%, which consisted of 2 complete responses for patients with pretreated advanced HCC.

 Stable disease was experienced by 48% of patients, for a DCR of 67%. These responses were observed regardless of hepatitis infection status.

“There are studies looking at anti—PD-L1 and anti–CTLA-4 and the combinations of the agents in a randomized, second-line setting,” said Abou-Alfa. “There is one other aspect that needs to be looked into, and that is the localized setting. This is an environment that is very poor inflammatory in nature, and probably adding an anti–PD-L1 in this setting would be of value.”

A phase II study is currently exploring the PD-L1 inhibitor durvalumab and tremelimumab alone or in combination for patients with unresectable HCC following prior sorafenib. The trial plans to enroll 120 patients, with an estimated completion date of April 2018 (NCT02519348).

A phase III study is also comparing nivolumab with sorafenib as a frontline therapy for patients with advanced HCC. This trial plans to enroll 726 patients with dual primary endpoints of OS and TTP. The primary completion date is July 2017 (NCT02576509).

			Llovet JM, Ricci S, Mazzaferro V, et al. Sorafenib in Advanced Hepatocellular Carcinoma.

			Bruix J, Takayama T, Mazzaferro V, et al. Adjuvant sorafenib for hepatocellular carcinoma after resection or ablation (STORM): a phase 3, randomised, double-blind, placebo-controlled trial. 

			Lencioni R, Llovet JM, Han G, et al. Sorafenib or placebo in combination with transarterial chemoembolization (TACE) with doxorubicin-eluting beads (DEBDOX) for intermediate-stage hepatocellular carcinoma (HCC): Phase II, randomized, double-blind SPACE trial. 

			Abou-Alfa GK, Niedzwieski D, Knox JJ, et al. Phase III randomized study of sorafenib plus doxorubicin versus sorafenib in patients with advanced hepatocellular carcinoma (HCC): CALGB 80802 (Alliance). 

			Sangro B, Gomez-Martin C, de la Mata M, et al. A clinical trial of CTLA-4 blockade with tremelimumab in patients with hepatocellular carcinoma and chronic hepatitis C. 

			El-Khoueiry AB, Melero I, Crocenzi TS, et al. Phase I/II Safety and Antitumor Activity of Nivolumab in Patients with Advanced Hepatocellular Carcinoma (HCC): CA209-040. 

View more from the 2016 School of Gastrointestinal Oncology

A number of novel therapies are currently being explored as second-line treatments for patients with advanced hepatocellular carcinoma, including a host of targeted therapies and various immune checkpoint inhibitors.

Novel Agents on Horizon for Advanced HCC

Immunotherapy approaches are showing early signs of activity against a range of gastrointestinal (GI) cancers, defying the skeptical view that these tumors would not respond to the emerging agents succeeding in other malignancies.

That was part of the message that Christopher R. Heery, MD, an immunotherapy research leader at the National Cancer Institute (NCI), delivered during a presentation at the 1st Annual School of Gastrointestinal Oncology™ that Physicians’ Education Resource (PER) hosted in New York City on April 23.

Antibodies aimed at the CTLA-4 or PD-1/PD-L1 immune checkpoints have generated responses in gastric, pancreatic, colorectal (CRC), and hepatocellular carcinoma, said Heery, who is director of the Clinical Trials Group at the NCI’s Laboratory of Tumor Immunology and Biology.

The responses, however, have been lower than in other tumor types, and Heery emphasized that more research is needed to understand the underlying biology of GI cancers. Studies thus far suggest that immune responses can be primed or induced, and several trials into combinations of checkpoint blockade agents and vaccines are getting underway.

“For most cancers, we can’t just do checkpoint inhibition,” said Heery. “We’ll need something else to generate T-cell responses. We’ll need more studies to understand what are the mechanisms of a given tumor that need to be targeted to make this all happen.”

Heery said recent research into agents targeting PD-1/PD-L1 in gastric cancer and in CRC tumors with mismatch-repair (MMR) deficiency have shown the potential for checkpoint blockade strategies.

In a phase I study, durvalumab (MEDI4736) elicited a 7% response rate (2 of 28 patients), according to an interim analysis.

In a phase Ib study, pembrolizumab (Keytruda) monotherapy generated a 30.8% overall response rate among 39 patients with PD-L1—expressing recurrent or metastatic adenocarcinoma of the stomach or gastroesophageal junction.

 PD-L1 expression was considered positive if ≥1% of tumor cells or any part of the tumor stroma stained positive on archived tumor samples using a prototype immunohistochemistry assay.

Another milestone for immunotherapy in GI cancers came in 2015 when researchers demonstrated a 40% response rate after pembrolizumab treatment among 10 patients with heavily pretreated CRC who harbored genetic defects in DNA MMR pathways.

 There were no responses among patients whose tumors were MMR proficient.

Among 17 participants with noncolorectal MMR-deficient GI cancers who received pembrolizumab, the objective response rate was 47%, according to updated results of that study presented during the 2016 Gastrointestinal Cancers Symposium.

 These included patients with ampullary, pancreatic, biliary, small bowel, and gastric cancers. Four participants achieved a complete response.

MMR-deficient tumors harbor thousands of mutations that may produce neoantigens that can be recognized and targeted by T cells, leading to the hypothesis that immune augmentation with PD-1/PD-L1 blockade could be highly effective in MMR-deficient tumors.

Another useful immune-related marker is the level of tumor-infiltrating lymphocytes (TILs), which can be measured at diagnosis and is predictive of outcomes in colorectal cancer, Heery said. In 2006, Galon et al posited that in situ analysis of CD3 TILs was a better predictor of survival than standard histopathological methods.

Heery said the research showed that a higher density of TILs correlated with a lower risk of recurrence almost independent of the stage at diagnosis.

The success of therapies aimed at immune checkpoints has established that these agents act on T cells, Heery said.

“Immune checkpoint inhibitors require underlying T-cell activation,” he said. “If there aren’t T cells trying to kill the tumor, using a checkpoint inhibitor is essentially a waste of time.”

Only a minority of tumors have natural T cells including 50% of melanomas, 20% to 30% of renal cell carcinomas, and 10% to 20% of lung cancer and CRC, according to Heery.

Yet, although CRCs are in a similar range as lung cancers for the prevalence of natural T cells, the checkpoint blockade agents have been less successful in CRC than they have been in lung cancer.

“At baseline, a lot of patients with colon cancer have dense T-cell infiltrate but in metastatic disease that number seems to go down significantly,” said Heery, adding that more research is needed to understand the dynamics.

At the same time, Heery said that immune responses could be induced in patients with GI cancers but that a change in tactics would be needed. He said anticancer vaccines typically are evaluated in patients who have received multiple lines of therapy but that in fact “vaccines work best with minimal disease.”

Combinations of checkpoint blockade agents with vaccines and/or standard therapies such as chemotherapy, targeted therapies, or radiation are under consideration.

Heery said 1 trial scheduled to get underway at Georgetown University is a small phase I/II study of durvalumab combined with the PANVAC pox viral vaccine, capecitabine, and bevacizumab. Another study would investigate avelumab, which also targets PD-L1, in combination with FOLFOX-A (FOLFOX plus bevacizumab) and a carcinoembryonic antigen (CEA)—based vaccine.

“What we’re going to need to do is understand on a per-patient basis what the inhibitory factors within that tumor are,” said Heery. “If we can tip the balance so that we activate more T cells and get them into the tumor, we might be able to overcome this lack of immune cells in the tumor.”

“The goal is to take a T-cell poor tumor and drive it to have T-cell infiltrates,” Heery noted.

Segal NH, Hamid O, Hwu W, et al. A phase I multi-arm dose-expansion study of the anti-programmed cell death-ligand-1 (PD-L1) antibody MEDI4736: Preliminary data. 

. 2014;25(suppl 4): iv361-iv372. 10.1093/annonc/mdu342.

Muro K, Bang Y, Shankaran V, et al. A phase 1b study of pembrolizumab (Pembro; MK-3475) in patients (Pts) with advanced gastric cancer. Presented at: ESMO 2014 Congress; September 26-30, 2014; Madrid, Spain. LBA15.

Le DT, Uram JN, Wang H, et al. PD-1 blockade in tumors with mismatch-repair deficiency. 

Le DT, Uram JN, Wang H, et al. PD-1 blockade in mismatch repair deficient non-colorectal gastrointestinal cancers.

Galon J, Costes A, Sanchez-Cabo F, et al. Type, density, and location of immune cells within human colorectal tumors predict clinical outcome.

Immunotherapy approaches are showing early signs of activity against a range of gastrointestinal cancers, defying the skeptical view that these tumors would not respond to the emerging agents succeeding in other malignancies.

Immunotherapy Doubts Fading in GI Cancers

Douglas B. Evans, MD, FACS, Chair, Professor, Donald C. Ausman Family Foundation Professor of Surgery, Medical College of Wisconsin, discusses how to appropriately sequence therapies for pancreatic cancer.

A combination of chemotherapy, surgery, and radiation has been shown to be better than surgery alone, says Evans. However, it is unclear in which sequence to deliver these treatments. This is especially challenging because much of the pancreatic cancer patient population is older, has medical comorbidities, and variable social support, says Evans.

Evans has been interested in neadjuvant treatment sequencing for many years, and now that there are improved systemic therapies, there is more interest in this approach, he says.

Dr. Douglas Evans on Neadjuvant Therapy for Pancreas Cancer

The treatment of patients with liver cancer requires a multidisciplinary approach, explains Michael Choti, MD, professor and chair of the Department of Surgery at UT Southwestern Medical Center.

“Cancer of the liver, often metastatic to the liver, is often an area that is associated with more complex management,” says Choti. “Liver cancer often involves working with the medical oncologist, surgeon, radiation oncologist, and experts in imaging, gastroenterology, and interventional radiology in order to provide the patient with the best treatment.”

There have been significant advancements in liver cancer, especially involving personalized medicine, biomarkers, and imaging, Choti adds. Treatment options have also expanded as new systemic therapies and surgical techniques are introduced.

: What advancements are occurring in the management of liver cancer?

School of Gastrointestinal Oncology, hosted by Physicians’ Education Resource (PER) on April 23, 2016, in New York City, Choti explained the impact of these advancements and how building on them will require all oncology professionals to work as a team.

: Globally, we have a better understanding of personalized medicine and biomarkers to identify which patients may be better candidates for therapy that is directed at one specific organ, such as the liver. If we can understand prognostic biomarkers, we can define which patients may benefit from, for example, surgical therapy of liver metastasis. That could be very advantageous.

We are clearly making advances in that area. We are on our way to identifying better predictive biomarkers, which could tell us which patients may do better or worse with liver-directed therapy.

Significant changes are happening in how we treat patients with liver cancer. As a surgical oncologist, we are certainly increasing and improving therapies, techniques, minimally invasive surgery, and other approaches to treat patients safely and more aggressively for local or metastatic liver cancer.

What role could PD-1 agents play in the treatment landscape of liver cancer?

How do you decide which patients should receive specific therapies?

We are also seeing advancements in the area of imaging, liver-directed therapies and, of course, the systemic therapies are improving. These, along with immunotherapy, not only offer better long-term outcomes for patients, but they also increase the opportunity to reduce residual disease in the liver.

This is a new class of agents that may offer the ability to treat patients who, in the past, have not been candidates for systemic therapies.

The biology of GI cancer can vary not just based on the site of origin, but also based on genetics and other patterns that will predict how patients will respond. The decision of how which patients will receive which therapy is often multifactorial. It is based on a team decision, multidisciplinary tumor boards, and looking at the biology of patterns.

We do this to determine not only which type of chemotherapy a patient should receive, but also whether to offer local therapy or surgical therapy for metastatic disease. With localized GI cancer, surgical therapy is still the mainstay of curative therapy for patients. Even with the development of new agents and new therapies, these agents are largely used in patients with advanced, incurable forms of cancer.

How is it determined whether patients have resectable versus nonresectable disease?

Additionally, surgical therapy for patients with local disease is still the standard. There is an increasing ability to offer local or surgical therapies—even in patients with more advanced disease who are responding better to new systemic therapies.

This is a very important topic. The reason it is an important topic is because it’s complicated—it’s not just something that is easy to define. It requires sophisticated quality of imaging, sophisticated discussion, and expertise in the surgeon and the radiologist.

There was a study that surveyed medical oncologists on whether they could determine resectable versus nonresectable disease. It is very clear that there is a major discordance between a community medical oncologist’s ability to look at either the radiologic report or the scan itself to determine if their patient is a candidate for surgery or not.

In conclusion, it is difficult for medical oncologists to determine if a patient has resectable disease; often, it requires a multidisciplinary team and their expertise in order to offer patients the best treatment.

Michael Choti, MD, explains the impact of advancements in the treatment of patients with liver cancer and how building on them will require all oncology professionals to work as a team.   


Multidisciplinary Treatment a Growing Need in Liver Cancer

Cancer care is shifting from a consumption to a value-based model, and precision oncology should play a vital role in that process by helping to deliver more effective therapies with more manageable pricing profiles, according to an internationally prominent leader in the colon and gastrointestinal (GI) cancer fields.

John L. Marshall, MD, chief of the Division of Hematology/Oncology at Georgetown University Hospital, described a broad vision for developing new therapies and providing improved care as part of a value-based equation in an opening address at the 1st Annual School of Gastrointestinal Oncology™ that Physicians’ Education Resource (PER) hosted in New York City on April 23.

Marshall, who co-chaired the meeting, said medical centers are marketing precision medicine oncology offerings but they are not truly practicing it. “Nobody really is,” he said. “We have a few bits and pieces.”

“To move the bar, we have to get away from trial-and-error empirical medicine and we have to embrace the idea that cancers are complex and different, and begin using this concept of precision medicine,” Marshall said.

In putting the need for change into context, Marshall struck a note of urgency. He said GI cancers collectively are the most common and most fatal malignancies worldwide and constitute “a major health problem.”

He said the worldwide incidence and mortality rates from GI cancers are projected to rise from nearly 4 million cases and less than 3 million deaths in 2008 to more than 6 million cases and more than 4 million deaths by 2030.1,2 These projections include statistics for cancers of the pancreas, liver, esophagus, and stomach, as well as colorectal cancer.

However, just as patients in the United States struggle with the costs of cancer care, people throughout the world are in worse straits. Marshall said only about 1 in 7 people worldwide has access to cancer care.

“Cancer care is a luxury item—it requires multidisciplinary care, it requires pathology, MRI scanners, CyberKnives&mdash;we need a proton beam center,” he said. “We need high-tech surgery, we need drugs, we need supportive care.”

Although researchers and clinicians have made progress against GI cancers, Marshall said fundamental changes are needed in the process for testing molecularly targeted therapies in clinical trials and in approaches to treating patients in daily practice.

“Over 95% of the patients today are treated on pathway, on guidelines,” said Marshall. “That’s good, but that also means those patients are not contributing to the future. They’re getting today’s standard, and so we’re accepting today’s standard as an OK place to be.”

Using colon cancer as an example, Marshall said there are no clear answers as to why therapies that help patients with metastatic disease do not work well in adjuvant settings. “I think these are actually different biologic diseases,” he said, referring to stage III and IV cancers. “We’ve begun to reshape our thinking about colorectal cancer.”

Notably, he said that the clinical utility of microsatellite instability (MSI) status was correlated with patient responses to fluorouracil-based adjuvant chemotherapy for patients with stage II or III colon cancer in 2003, but that it took more than a decade to become more widely integrated in clinical practice.3

As it stands now, molecular testing in colorectal cancer consists of determining whether a tumor sample contains mutations in RAS family (KRAS or NRAS); BRAF mutation testing if the tumor is RAS wild-type; and MSI, a molecular signature commonly caused by the loss of DNA mismatch-repair function.3

Several gene profiling assays also are commercially available but these are helpful for classifying patients into risk levels and do not help clinicians sort out which patients would benefit from chemotherapy and which patients would not, Marshall said.

Looking forward, Marshall believes the future lies in broad molecular tumor profiling, which offers the potential to analyze patients individually on a more detailed level. For instance, Marshall said that clinicians could determine not only which cell-signaling pathway was activated in a given cancer, but also which components of that circuit were operative for a particular patient.

“It’s this level of granularity that we may need to get to in order to really understand precision medicine,” he said.

Marshall, however, noted that the accuracy and success of molecular profiling depends heavily upon the quality of the tumor sample. The more time that elapses during surgery before a tumor samples are fixed, the greater the likelihood that messenger RNA and proteins will change.

Marshall noted that new collaborations are forming to advance precision oncology. He cited the American Society of Clinical Oncology’s TAPUR study and the National Cancer Institute’s MATCH study as examples of molecularly focused attempts to streamline the development of targeted therapies.

He is serving as chair of the Caris Centers of Excellence for Precision Medicine Network, which brings together several leading cancer centers to study the utility of molecular testing in diagnostics and treatment. Cancer types under study include GI, genitourinary, breast, lung, sarcoma, melanoma, and familial cancers.

In one study as part of a Caris project, researchers found that multiplatform molecular profiling of the tumors of 1180 patients increased overall survival (OS) in 53% of cases, Marshall said. Patients who received treatment through a molecularly matched profile saw a 9-month improvement in OS and received less chemotherapy. “They lived longer and they got less treatment when we used this broad profiling project,” Marshall said.

Another collaborative project involves the GI Cancer Alliance Network, which is seeking to develop a global alliance of “Smart” Cancer Centers where patients will undergo molecular profiling and the data will be shared to help analyze new treatment options. The network includes centers in the United States, Europe, South America, Asia, and Australia.

“We’ve got to partner on a much larger scale,” Marshall said. “We know cancer care is global and development is global. We have to do this at a price point that the rest of the world can actually afford.”

			Bray F, Jemal A, Grey N, et al. Global cancer transitions according to the Human Development Index (2008-2030): a population-based study. Lancet Oncol. 2012;13(8):790-801.

			American Cancer Society. Global Cancer Facts & Figures 3rd Edition. Atlanta: American Cancer Society; 2015.

			Ribic CM, Sargent DJ, Moore MJ, et al. Tumor microsatellite-instability status as a predictor of benefit from fluorouracil-based adjuvant chemotherapy for colon cancer. N Engl J Med. 2003;349(3):247-257.

Cancer care is shifting from a consumption to a value-based model, and precision oncology should play a vital role in that process by helping to deliver more effective therapies with more manageable pricing profiles.

Precision Medicine Vital to Value-Based GI Cancer Care

Given the numerous available treatment options, the most important issue in frontline colorectal cancer (CRC) care is clarifying the goals of therapy, according to Wells Messersmith, MD.

“If the patient might be cured…then I would go ‘all-in’ with cytotoxics [FOLFOXIRI], because we’re going to try and shrink [the tumor] and we’re going to get really high response rates [with that regimen],” Messersmith, director of the Gastrointestinal Medical Oncology Program at the University of Colorado Cancer Center, said in a presentation at the

School of Gastrointestinal Oncology meeting.

Messersmith said he would also focus on achieving a high response with an “all-in” cytoxic backbone (FOLFOXIRI) combined with a targeted agent in highly symptomatic patients, because the high response might improve the patient’s quality of life by providing symptom relief.

In other patients—elderly patients, or asymptomatic/unresectable individuals&mdash;frontline “response is irrelevant,” said Messersmith, because “you’re not going to cure the patient, you’re just trying to keep things at bay.” With these patients, he said he uses a 5-FU plus bevacizumab (Avastin) approach.

Chemotherapy Regimen With Highest Response

At the meeting, Messersmith discussed several topics in frontline CRC care, including responses with FOLFOXIRI, comparing EGFR and VEGFR targeted therapies, and emerging treatment approaches.

The chemotherapy backbone with the highest demonstrated response rate in frontline CRC has been FOLFOXIRI in the phase III TRIBE trial.

 The study randomized 508 patients with metastatic CRC to receive either FOLFOXIRI plus bevacizumab (n = 252) or FOLFIRI plus bevacizumab (n = 256) for up to 12 cycles over 6 months.

The response rate was 65% with FOLFOXIRI plus bevacizumab versus 53% with FOLFIRI (

 = .006). The FOLFOXIRI combination had a median overall survival (OS) rate of 29.8 months compared with 25.8 months for the FOLFIRI arm (HR, 0.80; CI, 0.65-0.98; 

 = .030). The median progression-free survival (PFS) was 12.3 months versus 9.7 months, respectively (HR, 0.77; CI, 0.65-0.93; 

In the study, the FOLFOXIRI regimen increased the incidence of grade 3/4 diarrhea, stomatitis, febrile neutropenia, and neutropenia compared with the FOLFIRI regimen.

Messersmith said the phase II STEAM trial

 “basically confirmed the response rate in the TRIBE study.” The STEAM trial randomized patients to FOLFOXIRI and concurrent bevacizumab (cFOLFOXIRI), FOLFOXIRI and sequential bevacizumab (sFOLFOXIRI), or FOLFOX plus bevacizumab. Overall response rate for the 3 arms was 60.2%, 62%, and 47%, respectively. The median PFS was 11.7 months with cFOLFOXIRI, 10.7 months with sFOLFOXIRI, and 9.3 months with FOLFOX.

Messersmith described the inconsistent results between the FIRE-3 and CALGB/SWOG 80405 trials, which compared VEGF and EGFR inhibitors in the frontline setting for patients with 

 frontline cetuximab (Erbitux) plus FOLFIRI improved OS by 3.7 months versus bevacizumab plus FOLFIRI in patients with 

 wild-type metastatic CRC. However, no advantage was observed with either the primary endpoint of objective response rate or the secondary endpoint of PFS. Based on these data, many European physicians will use an EGFR inhibitor in the frontline setting for 

 frontline therapy with bevacizumab or cetuximab combined with either FOLFOX or FOLFIRI yielded a comparable survival benefit of approximately 29 months in patients with 

Messersmith said, in his view, both drugs remain valid options in the first-line setting.

Messersmith described key emerging issues in CRC treatment, including immunotherapy, that may eventually impact the frontline-line paradigm. As with most solid tumors, PD-1 inhibitors are being explored in CRC. In November 2015, the FDA granted a breakthrough therapy designation to the anti—PD-1 agent pembrolizumab (Keytruda) as a potential therapy for patients with microsatellite instability-high (MSI-H) metastatic CRC.

The designation was based on findings from an ongoing phase II study, which demonstrated high response rates with pembrolizumab in patients with heavily pretreated CRC with mismatch repair deficiency, a condition that causes MSI. Given this emerging potential for immunotherapy, Messersmith stressed the importance of MSI testing in patients with CRC.

Another key topic Messersmith repeatedly mentioned was tumor location. He said prognosis and outcomes for patients may be impacted by whether they have left- or right-sided tumors. Studies of this phenomenon are ongoing, and data on this topic will be presented at the upcoming 2016 ASCO Annual Meeting, according to Messersmith.

Cremolini C, Loupakis F, Masi G, et al. FOLFOXIRI plus bevacizumab (BEV) versus FOLFIRI plus BEV as first-line treatment of metastatic colorectal cancer: updated survival results of the phase III TRIBE trial by the GONO Group. Presented at: 2015 Gastrointestinal Cancers Symposium; January 15-17, 2015; San Francisco, CA. Abstract 657.

Bendell JC, Tan BR, Reeves JA, et al. Overall response rate (ORR) in STEAM, a randomized, open-label, phase 2 trial of sequential and concurrent FOLFOXIRI-bevacizumab (BEV) vs FOLFOX-BEV for the first-line (1L) treatment (tx) of patients (pts) with metastatic colorectal cancer (mCRC). 

Heinemann V, von Weikersthal LF, Decker T, et al. Randomized comparison of FOLFIRI plus cetuximab versus FOLFIRI plus bevacizumab as first-line treatment of KRAS-wildtype metastatic colorectal cancer: German AIO study KRK-0306 (FIRE-3). 

Venook AP, Niedzwiecki D, Lenz HJ, et al. CALGB/SWOG 80405: Phase III trial of irinotecan/5-FU/leucovorin (FOLFIRI) or oxaliplatin/5-FU/leucovorin (mFOLFOX6) with bevacizumab (BV) or cetuximab (CET) for patients (pts) with KRAS wild-type (wt) untreated metastatic adenocarcinoma of the colon or rectum (MCRC). 

Given the numerous available treatment options, the most important issue in frontline colorectal cancer care is clarifying the goals of therapy.

Numerous Frontline CRC Options Allow Individualized Approach

Tanios Bekaii-Saab, MD, professor of Medicine, Mayo Clinic, discusses 2 new agents, regorafenib and TAS-102, for the treatment of patients with colorectal cancer.

Phase III studies have shown that both agents improved outcomes when compared with placebo in refractory settings, Bekaii-Saab explains.

Currently, there is only sequencing data for patients to receive regorafenib first followed by TAS-102; therefore, that is how the agents are used together. However, Bekaii-Saab emphasizes that there are certain instances where one therapy should be used versus the other.

Tanios Bekaii-Saab, MD, professor of Medicine, Mayo Clinic, discusses about 2 agents, regorafenib and TAS-102, for the treatment of patients with treat colorectal cancer.

Dr. Bekaii-Saab on Active Agents for the Treatment of Colorectal Cancer

The management of patients with gastrointestinal (GI) cancers requires a multidisciplinary approach, particularly in an era of molecular discoveries that are likely to segment care into more precisely defined subtypes, according to John L. Marshall, MD.

That’s why Marshall, chief of the Division of Hematology/Oncology at Georgetown University Hospital, has designed the first-ever Physicians’ Education Resource (PER) conference on GI malignancies to reflect the collaborative nature of treating patients with these cancers.

School of Gastrointestinal Oncology™, which took place April 23 at the Grand Hyatt New York in New York City, featured several general sessions and three tracks for medical oncology, surgery and radiation, and multidisciplinary management. Marshall co-chaired the meeting with Michael A. Choti, MD, MBA, FACS, professor and chair of the Department of Surgery at UT Southwestern Medical Center in Dallas.

“GI cancer is a multidisciplinary team sport,” said Marshall, who also is director of the Otto J. Ruesch Center for the Cure of Gastrointestinal Cancers. “We all work together, and we need each other to optimize outcomes for patients. We created a curriculum that both hits the major research elements everybody has to know across all the subspecialties, but then also allows for smaller-group learning around the very specific subspecialties.”

before the conference, Marshall discussed the changes underway in the field of GI malignancies.

: What major trends do you see emerging now and within the next 5 years?

 During the last decade or so, there has been significant progress in medical therapies for GI cancers, so we’ve moved the bar in that way for metastatic disease. I think the progress that we’ll make going forward is using molecular profiling to identify new targets; new pathways that will move the field even more rapidly. That’s why we’re emphasizing the impact of molecular testing and molecular profiling.

We know that immunotherapy is touching every cancer and GI cancer is no exception.

But what's really happening is a lot of progress in what I’ll call local regional therapy, whether it’s surgery for metastatic disease, radioembolization, or novel techniques in radiation. As patients are living longer—using colon cancer as the model&mdash;we’re recognizing that a lot of patients benefit from more efficient local regional approaches to managing metastatic disease.

As scans have gotten better, and surgeons and radiation oncologists and interventional radiologists have gotten better, we have additional tools—surgical-based tools and local tools&mdash; to treat the cancer.

Are there new molecular targets on the near horizon in colorectal cancer?

We know HER2 is not common but it happens at a regular enough interval that HER2-directed therapies have some value, and there are clinical trials to support that. But, frankly, when you go beyond that, there are many lower-level expressions [of potential targets].

Instead of going into any specific marker, I think it’s more important to think about broad profiling and understanding how to optimize our treatment. We need markers that bring value to what we’re doing.

Your question comes from more of a drug discovery/new therapy angle. I think it’s going to be equally important for us to use molecular testing to decide whom not to give treatment to and to use alternative kinds of therapies that aren’t necessarily on a pathway.

At this point, the molecular tests with clinical utility seem to involve 

, and microsatellite instability (MSI) or mismatch repair (MMR). Are there any others that can be translated into practice now?

That is not the way I would say it. These are the only ones that are being used. We’re not sure whichever ones might be useful. So right now standard tests are indeed the ones you listed, but the whole point of what we’re trying to do is move the bar.

How are we going to do that? One strategy is to pick this off as individual targets. The other strategy is to do it as more of a broad profile, and at least my bias is that the broad profile will help.

What do you think the molecular profiling landscape might look like 5 years from now?

We’re at this critical juncture where we believe it’s going to be helpful, but we have to prove its value to patients. There are several efforts going forward to try and do that. My guess is that, given the costs of molecular profiling getting lower and lower, that we will be doing broad profiling on every patient with every cancer and that it will be worth it.

Even if we only find a few rare things, there is an overall value to cancer care in cost, and patient outcomes will improve as a result. That’s my hypothesis. It’s my hope that that’s where that will be 5 years from now.

Will the ability to categorize colon cancer into molecular subtypes result in viewing the malignancy as many different tumor types or subtypes?

It’s already been published that there are probably at least 4 subtypes in colon. That’s a first stake in the ground as we go forward. I think we’ll learn to refine that and then use those molecular subtypes or classifications to help us sort patients and sort therapies. So, yes, absolutely, I think that’s where this is going.

Nobody is doing it in clinical practice, let’s put it that way. We’re not at a point where we are sending off molecular testing, categorizing patients according to these subcategories, and then making different therapy decisions based on those broad categories.

We’re still using the individual markers to make those decisions. So it’s not a standard, something I would recommend to every oncologist, and we’re not doing that routinely at our academic centers either.

What do you think is the potential for immunotherapy in GI malignancies?

Immunotherapy is reaching every field, every tumor type, and GI is no exception. We have defined a relatively small subgroup of patients with colon cancer through the MSI genetic abnormality that predicts for an improved response to checkpoint inhibitors.

But that’s a relatively small number. In gastric cancer, for example, in an unenriched patient population, we’ve seen response rates in the 20% to 30% range with single-agent checkpoints. It’s very promising, and I would expect we would see relatively quick approvals and acceptance of using checkpoint inhibitors in those subgroups.

It’s exciting. If there’s going to be a lot of resources put into it, my guess is that in the end, we will again have a subset of patients who benefit, hopefully larger than the subset that we have now.

And it may be used in combinations with other immunomodulatory drugs including vaccines and other checkpoint inhibitors but also maybe in combination with chemotherapy and other traditional approaches. Again, very dramatic positive success in GI cancers in certain subgroups, and our challenge going forward is extending that to others.

Is there anything particularly promising on its way for pancreatic cancer?

Because we’ve had some success in the chemotherapy world, there’s been some renewed energy. There are interesting approaches, including stem cell approaches, stromal approaches, and other immunotherapies, as well. The frustration there is that we still haven’t made significant strides beyond the more recent chemotherapy improvements. More attention is being spent, there are some early leads on small clinical trials, and I hope that those things are supported as more studies are done.

In the area of liver cancer, is there excitement about radiotherapy techniques making an impact in early disease?

They’re certainly being utilized but that’s been fairly true for a while. I think I have yet to really see something emerge as a major game changer other than what we had over the last several years. I think as the techniques have improved and the experience of the physicians has improved and patient selection has gotten better, I think that’s where we’re seeing our improved outcomes.

John L. Marshall, MD, discusses how the management of patients with gastrointestinal cancers requires a multidisciplinary approach.

Treating GI Cancers Is a “Team Sport,” Conference Leader Says

Dr. Christopher Heery, medical oncologist, National Cancer Institute, discusses the progress that has been made in the treatment of patients with neuroendocrine tumors (NETs).

Over the past few years, research has demonstrated that agents used to control the symptoms of NETs could also be used to control disease. Also, Heery says, the combination of radionuclides and other experimental agents may become the backbone of future therapy.

Select subgroups of patients with NETs could also experience positive outcomes with agents such as everolimus (Afinitor) and sunitinib (Sutent).

Dr. Christopher Heery, medical oncologist, National Cancer Institute, discusses the progress that has been made in the treatment of patients with neuroendocrine tumors. 


School of Gastrointestinal Oncology | Conference