Gregory L. Beatty, MD, PhD
Immunotherapy has shown promise in select patients with gastrointestinal (GI) malignancies, but challenges remain in immune recognition and optimal sequencing, says Gregory L. Beatty, MD, PhD.
Cancers that form in the GI tract often avoid immune recognition, but patients who have mismatch repair-deficient (dMMR) cancers have larger mutational loads, making it easier for the immune system to recognize those tumors. The PD-1 inhibitor pembrolizumab (Keytruda) is approved by the FDA for the treatment of patients with unresectable or metastatic, microsatellite instability-high (MSI-H) or dMMR solid tumors that have progressed after prior treatment, which includes patients with MSI-H or dMMR colorectal cancer (CRC) who have progressed on a fluoropyrimidine, oxaliplatin, and irinotecan.
More recently, the FDA granted a priority review to a supplemental biologics license application for the combination of nivolumab (Opdivo) and ipilimumab (Yervoy) for the treatment of adult patients with MSI-H or dMMR metastatic CRC following progression on a fluoropyrimidine, oxaliplatin, and irinotecan. This was based on findings from the phase II CheckMate-142 trial, where the investigator-assessed overall response rate in the cohort treated with the combination was 55% (95% CI, 45.2%-63.8%) at a median follow-up of 13.4 months, with 31% of patients having stable disease. The disease control rate for ≥12 weeks was 80%.
Nivolumab monotherapy was approved by the FDA in August 2017 for the treatment of adult and pediatric patients with MSI-H or dMMR mCRC that has progressed following treatment with a fluoropyrimidine, oxaliplatin, and irinotecan.
However, the majority of patients with GI malignancies still do not respond to immunotherapy, says Beatty, specifically those with pancreatic and gastroesophageal cancers.
Beatty, assistant professor of medicine, director of Translation Research, Pancreatic Cancer Research Center, University of Pennsylvania Perelman School of Medicine, discussed the promise for immunotherapy in GI cancers during a presentation at the 2018 OncLive®
State of the Science Summit™ on Gastrointestinal Cancers. In an interview during the meeting, he shared insight on the challenges with sequencing immunotherapies in light of recent advancements in the field.
OncLive: Can you provide an overview of your presentation?
There is a lot of promise for immunotherapy in GI malignancies, but there have been a lot of challenges. Part of that has emerged because the gut is where 70% of the immune system resides. One of the key challenges for the immune system is deciding whether to activate or to remain tolerant. There are a lot of pathogens that are in the gut, for which the immune system must [attack] on a daily basis. Many cancers in the GI tract have found ways in which to use that tolerance mechanisms to evade immune recognition. That creates a challenge for utilizing immune therapy. There are subsets of patients that appear to respond to immunotherapy, and those are ones who have dMMR [cancer]. Those tumors usually have larger numbers of mutations, so those tumors look more nonself, which alerts the immune system to attack. There, checkpoint therapies that target PD-1/PD-L1 have been quite successful.
Most patients with GI malignancies do not respond. The majority of [patients with] pancreatic cancer do not respond to immunotherapy. In CRC, [tumors] that do not have dMMR usually do not respond. For gastroesophageal cancer, the majority still do not respond.
Finding ways in which to condition tumors for improved responses to immune therapy is the next step. It is not just combinations of those therapies, but strategically sequencing therapies to change a tumor that is resistant to one that is sensitive. Whether it is sensitive to immune therapy or cytotoxic therapies, inflammation in the immune system is a key player in defining that balance.
Were there any updates at the 2018 AACR Annual Meeting of immunotherapy in GI malignancies?
There are 2 new players in the field, so to speak: epigenetic therapies and rational ways to use targeted therapies. Here I presented some work using a MEK inhibitor, which seems to condition tumors to be more immunogenic, so they are more visible to the immune system because they upregulate MHC expression, which is important for T cells to recognize. However, the MEK inhibitors also seem to improve T-cell responses by improving the function of those T cells—not necessarily their ability to expand in the priming setting, but their ability to act in the effector setting.