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Immunotherapies, Stemness Inhibitors Among Advances in Gastroesophageal Cancers

Gina Columbus @ginacolumbusonc
Published: Thursday, Mar 02, 2017

However, there appears to be some interesting data that the combination of PD-1 inhibitors with chemotherapy may not only have a benefit locally, but there may potentially be an abscopal effect where it not only controls the local disease, but also prevents any disseminated or metastatic disease in the future.

We are currently running a phase Ib study led by Dr Harry Yoon in Mayo Clinic in Rochester, Minnesota, and Mayo Clinic in Arizona will also be participating. Here, we are studying the combination of carboplatin/paclitaxel with pembrolizumab (Keytruda) in combination with radiation therapy.

The other area that seems to have a lot of interest in the neoadjuvant setting is PET-CT as a way to identify patients who are actually responders to chemotherapy and radiation.

The initial results of the CALGB 80803 (Alliance) trial were also presented at the 2017 GI Cancers Symposium. The results were very preliminary, but it showed that in patients who do not have a PET-CT response—which they identified as a less than 30% response in FDG avidity—was switched to a different type of chemotherapy. Patients were initially randomized to FOLFOX or carboplatin/paclitaxel and, based on the PET-CT response, they would either continue current therapy or switch to alternate therapy.

It showed that this would be a viable way to treat gastroesophageal cancer. However, the results were preliminary and, as the data matures, we’ll be able to identify whether or not this is a viable treatment strategy in this disease. 

Can you hone in on the synergy behind those types of combinations?

That’s a good question. Some of the data suggest that when you treat with chemotherapy and radiation, we increase tumor-specific antigens or epitopes by combining with PD-1/PD-L1. This will allow the immune system to recognize these antigens as being formed. It could have not only a local control, but also have a systemic control, act as a guardian, and stop the cancer from spreading. 

What are the future directions of this field?

With immunotherapy, one area of interest is the combination of multiple different agents. There has already been some early data in the phase Ib setting with the combination of multiple different immunotherapy agents. The data look very promising and this is an area that will continue to be developed. While it’s a small sample, it looks like the response rates are greater than 30% in this patient population with the combination of different immunotherapy agents. 

Another area that seems to be a very hot topic across all GI malignancies is the JAK/STAT pathway.

There is a lot of interest in an agent called BBI-608, which is currently under investigation in multiple phase III studies in other GI malignancies, which is looking at attacking the stem cells of cancer cells—which tend to be the most indolent and treatment resistant of all cancer cells.

In terms of gastric cancer, the BRIGHTER study looked at the combination of paclitaxel with BBI-608 so, hopefully as data matures, that will give us some further insight as to whether or not this is a relevant treatment strategy in this disease.

Can you explain the mechanism of action of BBI-608?

Mainly, it attacks the STAT pathway and inhibits the pathway from where the underlying root of these cancer stem cells that tends to be resistant to chemotherapy. It looks like there might be some synergistic effects when you combine it with chemotherapy. The early phase Ib data showed that, in patients who never received any prior taxol therapy, the response rate was up to 31%. It looks like a viable treatment strategy—not only attacking the stem cells, but also the other cancer cells.

What other data out of the 2017 GI Cancers Symposium were practice changing?

The main thing was in immunotherapy. When we saw the initial phase Ib data from the KEYNOTE-012 study [of pembrolizumab in advanced gastric cancer], that looked like it was really promising. While this phase III data was mainly in East Asia, it kind of validated all of the information that we knew about PD-1 being a relevant treatment strategy across all patients with gastric cancer.
Becerra C, Stephenson J, Jonker DJ, et al. Phase Ib/II study of cancer stem cell (CSC) inhibitor BBI608 combined with paclitaxel in advanced gastric and gastroesophageal junction (GEJ) adenocarcinoma. J Clin Oncol. 2015;33(suppl; abstr 4069).

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