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Other Immunotherapy Approaches in Gastric/GEJ Cancers

Insights From: Yelena Y. Janjigian, MD, Memorial Sloan Kettering Cancer Center; Alan P. Venook, MD, University of California San Francisco; Zev A. Wainberg, MD, UCLA School of Medicine
Published: Tuesday, Jan 30, 2018



Transcript: 

Alan P. Venook, MD: The JAVELIN trial is actually timely, as we just got negative results in the avelumab trial about 2 days ago. This was as a second-line treatment. I believe it was about 700 patients randomized to the checkpoint inhibitor versus physician’s choice of therapy. It did not reach its anticipated benefit level, so that did not work in those patients. Those are tough studies to do. As I’ve said, patients who’ve had prior therapy come in all shapes and sizes. It’s very hard to know if you’re getting equal patients on each arm. That drug is still being tested in the first line. I believe that study is still underway, or at least it may have been accrued, but we’re awaiting results. So, that’s a question we haven’t answered yet.

The other new therapies in gastric cancer, other than combination HER2 treatments—pertuzumab plus trastuzumab, for example. That’s being studied and really hasn’t been very exciting so far. TDM1 [trastuzumab emtansine] from the treatment for breast cancer would be nice if it worked in HER2-positive gastric cancer. I think those are rare beings, and I don’t know what role that has.

I think fundamentally, one of the most exciting things is that there’s a new stem cell, a so-called stemness, inhibitor. It’s a new drug that has been out in a variety of studies, this stemness inhibitor, and it appears to work well in combination with chemotherapy in terms of effectiveness for advanced disease. The question, of course, with cancer ultimately is, if you can’t eradicate the stem cells, if the stem cells continue to exist, we think they are aware of where more cells come from. They repopulate the cancers. That’s a promising therapy, but that’s very early going. And other than that, I’m not sure there’s anything new or exciting. Of course, all of the other checkpoint inhibitors out there—atezolizumab, etc—are being tested one way or another in gastric cancer, and we’ll await those results as well.

Zev A. Wainberg, MD: Virtually, every checkpoint inhibitor is being studied right now in gastric and gastroesophageal junction adenocarcinomas, and that’s because there’s proof of principle now that these drugs work. So, there’s interest in investigating the other checkpoint inhibitors, whether they’re single-agent drugs or second-generation checkpoint inhibitors, either in combination with the existing PD-1 inhibitors or in combination with chemotherapy. There’s also a host of new drug development focused on combining immunotherapy with targeted therapy, such as, in the case of gastric and GEJ cancer, HER2 inhibitors such as trastuzumab, pertuzumab, or some of the other HER2 inhibitors. And in particular in gastric and GEJ cancer, there’s also an interest in combining them with VEGF inhibitors such as ramucirumab, which is already approved for gastric cancer. If we can identify a good group of patients who would benefit particularly from these combination strategies, many oncologists would prefer this to chemotherapy.

Our expectation is that in the next 5 years, we’re going to be subdividing gastric and GEJ cancers even more, whereby it’s not just going to be HER2 gets HER2 inhibitors plus chemotherapy, but it will also be PD-L1 or perhaps PD-L1 plus something else, checkpoint inhibitors plus chemotherapy or checkpoint inhibitors with other targeted therapies. So, this is a big, exciting area right now, and a lot of different targets are being looked at.

There are also other immunotherapy strategies that are combining agents with other checkpoint inhibitors, such as blocking PD-1 and blocking CTLA4. This is the subject of a number of clinical trials that are blocking PD-1 plus other immune targets such as TIGIT, which is another checkpoint, or B7-H3, which is another checkpoint. There are many different combinations of immunotherapy out there that make sense scientifically. Whether they’ll manifest as improvements in the clinic is a whole different story. One of the clear early indications is that a lot of these combinations of immunotherapy drugs do add considerable toxicity, so that’s obviously needs to be considered. If the toxicity outweighs the efficacy benefit, then it’s not going to make it very far in clinical development.

Alan P. Venook, MD: To my knowledge, therapeutic vaccines have not shown much effect and don’t have a role yet in gastric or GE junction cancer. There aren’t many examples where vaccines do have a role. Obviously, I think programming T cells is a little different in passive vaccines, which are passively putting in active white cells. That is a different question. But to my knowledge, there is no role for vaccines right now. All the vaccines that have been used to goose the immune system, Aduro’s listeria vaccine for example, have not been shown to be effective in gastric cancer, at least so far.

Transcript Edited for Clarity 
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Transcript: 

Alan P. Venook, MD: The JAVELIN trial is actually timely, as we just got negative results in the avelumab trial about 2 days ago. This was as a second-line treatment. I believe it was about 700 patients randomized to the checkpoint inhibitor versus physician’s choice of therapy. It did not reach its anticipated benefit level, so that did not work in those patients. Those are tough studies to do. As I’ve said, patients who’ve had prior therapy come in all shapes and sizes. It’s very hard to know if you’re getting equal patients on each arm. That drug is still being tested in the first line. I believe that study is still underway, or at least it may have been accrued, but we’re awaiting results. So, that’s a question we haven’t answered yet.

The other new therapies in gastric cancer, other than combination HER2 treatments—pertuzumab plus trastuzumab, for example. That’s being studied and really hasn’t been very exciting so far. TDM1 [trastuzumab emtansine] from the treatment for breast cancer would be nice if it worked in HER2-positive gastric cancer. I think those are rare beings, and I don’t know what role that has.

I think fundamentally, one of the most exciting things is that there’s a new stem cell, a so-called stemness, inhibitor. It’s a new drug that has been out in a variety of studies, this stemness inhibitor, and it appears to work well in combination with chemotherapy in terms of effectiveness for advanced disease. The question, of course, with cancer ultimately is, if you can’t eradicate the stem cells, if the stem cells continue to exist, we think they are aware of where more cells come from. They repopulate the cancers. That’s a promising therapy, but that’s very early going. And other than that, I’m not sure there’s anything new or exciting. Of course, all of the other checkpoint inhibitors out there—atezolizumab, etc—are being tested one way or another in gastric cancer, and we’ll await those results as well.

Zev A. Wainberg, MD: Virtually, every checkpoint inhibitor is being studied right now in gastric and gastroesophageal junction adenocarcinomas, and that’s because there’s proof of principle now that these drugs work. So, there’s interest in investigating the other checkpoint inhibitors, whether they’re single-agent drugs or second-generation checkpoint inhibitors, either in combination with the existing PD-1 inhibitors or in combination with chemotherapy. There’s also a host of new drug development focused on combining immunotherapy with targeted therapy, such as, in the case of gastric and GEJ cancer, HER2 inhibitors such as trastuzumab, pertuzumab, or some of the other HER2 inhibitors. And in particular in gastric and GEJ cancer, there’s also an interest in combining them with VEGF inhibitors such as ramucirumab, which is already approved for gastric cancer. If we can identify a good group of patients who would benefit particularly from these combination strategies, many oncologists would prefer this to chemotherapy.

Our expectation is that in the next 5 years, we’re going to be subdividing gastric and GEJ cancers even more, whereby it’s not just going to be HER2 gets HER2 inhibitors plus chemotherapy, but it will also be PD-L1 or perhaps PD-L1 plus something else, checkpoint inhibitors plus chemotherapy or checkpoint inhibitors with other targeted therapies. So, this is a big, exciting area right now, and a lot of different targets are being looked at.

There are also other immunotherapy strategies that are combining agents with other checkpoint inhibitors, such as blocking PD-1 and blocking CTLA4. This is the subject of a number of clinical trials that are blocking PD-1 plus other immune targets such as TIGIT, which is another checkpoint, or B7-H3, which is another checkpoint. There are many different combinations of immunotherapy out there that make sense scientifically. Whether they’ll manifest as improvements in the clinic is a whole different story. One of the clear early indications is that a lot of these combinations of immunotherapy drugs do add considerable toxicity, so that’s obviously needs to be considered. If the toxicity outweighs the efficacy benefit, then it’s not going to make it very far in clinical development.

Alan P. Venook, MD: To my knowledge, therapeutic vaccines have not shown much effect and don’t have a role yet in gastric or GE junction cancer. There aren’t many examples where vaccines do have a role. Obviously, I think programming T cells is a little different in passive vaccines, which are passively putting in active white cells. That is a different question. But to my knowledge, there is no role for vaccines right now. All the vaccines that have been used to goose the immune system, Aduro’s listeria vaccine for example, have not been shown to be effective in gastric cancer, at least so far.

Transcript Edited for Clarity 
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