Role of Immunotherapies Emerging in Gastric/GEJ Cancers

Andrew Ko, MD

Data presented at the 2018 Gastrointestinal Cancers Symposium showcased the efficacy of targeted agents and immunotherapy in select settings of gastric/gastroesophageal junction (GEJ) cancers, yet ongoing studies could further define the role of immunotherapy, explained Andrew Ko, MD.

For example, the randomized, double-blind, phase III CheckMate-577 trial may prove that patients may derive benefit from the PD-1 monoclonal antibody nivolumab (Opdivo) in the adjuvant setting. The trial is investigating nivolumab’s use as an adjuvant treatment following chemoradiation and surgery for patients with resectable esophageal and GEJ cancers (NCT02743494).

However, Ko cautions against administering immune therapies to patients without corresponding predictive biomarkers. For example, the FDA approved pembrolizumab (Keytruda) for the treatment of patients with PD-L1—positive recurrent or advanced gastric or GEJ adenocarcinoma who have received 2 or more lines of chemotherapy including fluoropyrimidine- and platinum-containing chemotherapy, and, if appropriate, HER2/ neu-targeted therapy, in September 2017.

OncLive: What highlights have we seen in the past year in gastric/GEJ cancers?

In an interview during the 2018 OncLive^® State of the Science Summit™ on Gastrointestinal Cancers, Ko, professor in the Department of Medicine at the University of California, San Francisco (UCSF) Helen Diller Family Comprehensive Cancer Center, discussed how the approval of pembrolizumab has impacted patients with positive PD-L1 expression and how clinical trials that have reshaped the standard of care in patients with gastric and GEJ cancers.Ko: There are a number of developments that have been practice changing. In terms of novel therapies, the approval of pembrolizumab in the fall of 2017 has changed the way we treat advanced disease. This is specific to the subset of patients with gastric/GEJ cancers with positive PD-L1 expression. There is biomarker selection criteria we use as a basis for which drugs can and should be used.

Pembrolizumab is currently approved for patients who have progressed on a platinum- and fluoropyrimidine-based regimen. Positive PD-L1 expression is determined by a combined positive score, which looks at PD-L1—positive expression, tumor cells, and immune cells. Those patients are candidates for immunotherapy. Pembrolizumab is associated with toxicities that are on par with what we would expect with this class of checkpoint inhibitors.

What clinical trials are looking at immunotherapy agents beyond pembrolizumab?

What ongoing trials could have results that have potential to change practice?

In the setting of perioperative management, we know that giving periodical epirubicin, cisplatin, and 5- fluorouracil (5-FU; ECF) is inferior to the combination of 5-FU, docetaxel, oxaliplatin, and fluorouracil/leucovorin (FLOT). MAGIC, a large German study that reported out this past year, showed that the FLOT regimen resulted in a significant improvement compared with the previous ECF standard. The standard of care for patients with resectable gastric and GEJ cancers is now FLOT. Patients receive 4 cycles prior to surgery and 4 cycles after surgery.While immune checkpoint inhibitors, specifically PD-1 inhibitors, are the furthest along in development, there are studies looking at combination immunotherapy regimens. Nivolumab has been looked at and is approved in Asia as a monotherapy for gastric/GEJ cancers. Some data presented at the 2018 Gastrointestinal Cancers Symposium showed that the combination of nivolumab plus the CTLA-4 monoclonal antibody ipilimumab (Yervoy) may be associated with even higher rates of response. There are a whole host of other immunotherapy agents, including IDO inhibitors that are in early clinical development. These also show promise as part of combination regimens.The greatest interest is in immunotherapy agents. As we eagerly anticipate the impact of a number of these drugs, an important take-home message is to be a bit more circumspective. Don’t automatically assume that these agents can and should be moved to earlier settings. There are a number of studies that are looking at moving these targeted agents to first-line treatment and in the perioperative setting. In the adjuvant setting, there is a very exciting study called CheckMate-577 in which nivolumab is being looked at as an adjuvant treatment following chemoradiation and surgery for resectable esophageal and GEJ cancers.

What are some of the biggest challenges in gastric/GEJ cancers that should be addressed in the next few years?

We need to figure out what to do with patients who have undergone surgery but were found to have residual pathologic disease at the time of resection. CheckMate-577 might reveal that the use of some of these novel agents, such as immunotherapy, may at some point find their place in earlier settings where we will see a higher proportion of patients cured. Until we get those results, I would be hesitant to use them in these contexts.We are still seeing an increased incidence of upper gastrointestinal cancers, specifically GEJ cancers in Western countries. In patients in whom cure is still possible, those who are potential operative candidates, developing strategies in which we can improve cure rates with the use of adjuvant or neoadjuvant therapy may be particularly impactful.

As co-chair of this meeting, can you speak to the importance of holding events such as the State of the Science Summit™ on Gastrointestinal Cancers?

If we are going to look at immunotherapies, we need to look at developing the accompanying biomarkers. We know that PD-L1 is a biomarker used for immunotherapy agents, but only 16% of PD-L1—positive patients show an objective response. There are still a majority of patients who are nonresponders; we need new agents for those patients. We need to understand which subsets of patients are most likely to respond.This State of the Science Summit™ gave our faculty at the UCSF Helen Diller Family Comprehensive Cancer Center the opportunity to share what’s going on in the field and discuss advancements, some of which our faculty were instrumental in developing and leading. It’s a good place to exchange and communicate ideas and get the word out to our referring providers, colleagues, and collaborators.

It’s also a nice way to put faces to names, whether it’s patients for clinical trial considerations, community oncologists who we seek second opinions from, or referring providers. It’s really nice to get to know one another in a forum that affords that opportunity in a friendly and collegial environment.