Immunotherapy Active in Advanced GISTs

Arun S. Singh, MD

In a heavily pretreated patient population with gastrointestinal stromal tumors (GIST), durable responses and disease control were observed with single-agent and combination immunotherapy, according to results of a phase II randomized trial presented at the 2018 Gastrointestinal Cancers Symposium.

Since most patients with advanced GISTs become resistant to traditional tyrosine kinase inhibitors (TKIs), novel treatments are needed to push the development of this field forward, explained lead study investigator Arun S. Singh, MD. The ongoing parallel phase II trial examined the role of single-agent nivolumab (Opdivo) versus nivolumab plus ipilimumab (Yervoy). Currently, 14 patients have been enrolled on the study and 8 remain on treatment. Stable disease (SD) was the best response in 3 of 7 patients treated with nivolumab monotherapy and 1 partial response and 2 patients with SD were reported for the nivolumab/ipilimumab arm.

“Most people have the idea that you should only use TKIs for GIST. A very important finding that we had is that the immune system can be used to control GIST,” said Singh, of the Department of Medicine at University of California, Los Angeles. “Going forward, we hope that if these trials are successful…[they will] lead to the use of immunotherapy in GIST.”

OncLive: What was the rationale behind conducting this trial?

What was the design of this trial?

What were the significant findings?

Do these findings suggest a future for immunotherapy in patients with GISTs?

Are there any next steps following this trial?

Are there any significant challenges that you would like to see addressed in the next 5 to 10 years for the treatment of GIST?

In an interview with OncLive, Singh discussed the developing role of immunotherapy in patients with GISTs, particularly the randomized phase II trial investigating nivolumab as a single agent and in combination with ipilimumab.Singh: GIST is a rare group of tumors that could start anywhere in the gastrointestinal tract. The 2 most common locations are in the stomach and the small intestine. Traditionally, they are treated with surgery and more advanced or metastatic GISTs are treated with TKIs. There are 3 drugs that are FDA approved for GISTs, including imatinib (Gleevec), sunitinib (Sutent), and regorafenib (Stivarga). However, there are new exciting compounds currently in clinical trials. Our study is one of the few studies focused on immunotherapy in patients with GISTs.This is a parallel design trial. A way to think of this trial is as 2 individual trials ongoing at the same time. While it is a randomized trial, the 2 arms are not actually compared to each other. We are looking for how well a patient responds to nivolumab alone, as well as how they respond to nivolumab in combination with ipilimumab.The group of patients in this trial have advanced disease. The median number of previous therapies that were received was 4. That is quite a lot of treatment for these patients. So far, we have seen that one-third of patients received clinically meaningful benefit from this therapy. We have had 5 patients who have been on therapy for more than 6 months, which is outstanding in this heavily pretreated advanced GIST cohort of patients. At this point, they do suggest that immunotherapy has a role in GIST. We still have another 20 patients to put onto the trial, so we are going to find out more information going forward. We will get a better sense of how many patients respond and how long they are responding, so we can plan future trials with novel immunotherapy combinations and study immunotherapy in conjunction with TKIs, which will be the future direction of these studies. We have seen one-third of patients receive benefit, not just in terms of disease shrinkage but a prolonged disease control, which is important for the group. The real question is why those patients are receiving benefit. In a separate ongoing study, we are looking at predictive biomarkers—trying to identify who is responding, why they are responding, or reasons why patients do not respond to immunotherapy. There are several challenges that remain for GIST. It is one of these diseases that has been molecularly characterized. However, that has not told us everything because while we have found drugs that worked well, we are not curing patients. While there are some patients who get prolonged disease control and eradication, once you stop TKIs in patients with advanced disease, the disease comes back.

Better drugs are needed and there are some in clinical trials that look promising. Immunotherapy is another way forward. Most of the drugs that are out there now are TKIs that work inside the cell. Immunotherapy is a way of attacking from the outside by eliciting an immune response. You get the microenvironment and the body’s immune system to help to eradicate GIST.

For the regular management of GIST, there are several prognosticators that have been established. Something that we struggle with is whether patients receive small biopsies because we are not often able to do molecular sequencing of their tumors. We cannot count the mitoses…Those are important predictors of response and how patients will do on therapy.

Unfortunately, you cannot just do large biopsies in everyone because they are often prohibited due to risk. Patients can be frail, so we need to figure out other markers of how this disease is going to behave and other surrogates for mitosis.

Singh AS, Chmielowski B, Hecht JR, et al. A randomized phase 2 study of nivolumab monotherapy versus nivolumab combined with ipilimumab in patients with metastatic or unresectable gastrointestinal stromal tumor (GIST). In: Proceedings from the 2018 Gastrointestinal Cancers Symposium; January 18-20, 2018; San Francisco, California. Abstract 55.