Despite Skepticism, Immunotherapy Has Early Promise in GI Cancer

Growing Treatment Paradigm in CRC

John L. Marshall, MD

Precision oncology should play a vital role in the shift toward value-based medicine by helping to deliver more effective therapies with more manageable pricing profiles, according to John L. Marshall, MD, at the1st Annual School of Gastrointestinal Oncology™ hosted by Physicians’ Education Resource (PER).

In an opening address at the meeting, 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. Marshall, who co-chaired the meeting, said medical centers are marketing precision 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.

Prevalence of GI Cancers

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.^1,2These 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—we need a proton beam center,” he said. “We need high-tech surgery, we need drugs, we need supportive care.”

Molecular Testing in GI Cancers

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 inRASfamily (KRASorNRAS);BRAFmutation testing if the tumor isRASwild-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 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.

Innovative Initiatives

Marshall noted that new collaborations are forming to advance precision oncology. He cited the ASCO’s TAPUR study and the NCI’s MATCH study as examples of molecularly focused attempts to streamline the development of targeted therapies.

Marshal is also 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.”

References:

1. 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.
2. American Cancer Society. Global Cancer Facts & Figures 3rd Edition. Atlanta: American Cancer Society; 2015.
3. 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.