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Gastric/GEJ Cancers: Non-Immunotherapeutic Advancements

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: I’m hard pressed to come up with exciting new combinations that really are worth pursuing in gastric GE junction cancer. I did mention FLOT, which is 5FU, leucovorin, oxaliplatin, and docetaxel. There is a study comparing that to the conventional MAGIC trial of neoadjuvant epirubicin-based combination therapy in patients with gastric cancer. The results were superior with FLOT. I find it to be exceedingly toxic, and I’m not much of a fan of that combination. I’d say that’s probably as close as we’ve come to a new combination. Some other combinations have come and gone, combinations more aggressive than FOLFOX or ECX [epirubicin, cisplatin, and capecitabine]. I think the issue is not so much getting an effect, but getting a durable effect and leaving your patients in good enough shape to have a decent quality of life when they’ve had the effect.

There’s an oral taxane in studies that is interesting. This has the advantage of being oral. As a taxane, we know that class of drugs has activity in gastric and GE junction cancer. I think it’s being studied. We don’t yet know what the results are. The appeal for an oral chemotherapy is self-evident, because you can avoid some of the complications related to IV use. On the other hand, I worry a lot about the absorption and how effective it might be in a patient with gastric cancer, for example, where their gut may not work very well. I’m not sure that’s necessarily an area I would be pursuing. And again, regarding other therapies, I just am not aware of anything that holds extreme promise. Some things have come and gone, and we’re struggling to look for targets that are actionable, not just from mutations that we can find.

Yelena Y. Janjigian, MD: HER2 remains one of the most validated biomarkers in metastatic gastric cancer. Trastuzumab was the first biologic agent FDA approved in this disease in 2009, and it really highlighted the importance of HER2 in the biology and growth of metastatic gastric cancer. The ToGA study showed that, in combination with chemotherapy, trastuzumab improved survival, response rate, and progression-free survival in this disease. And unfortunately, beyond trastuzumab, we have not been able to improve the bar and raise it further in both the first-line setting and in the second-line setting in HER2-positive disease.

Recently, the readout of the JACOB study with the combination of trastuzumab, pertuzumab, and chemotherapy did not show improved outcome, or a statistically significant improved outcome, compared to trastuzumab chemotherapy. There was definitely a trend, and there was very noticeable survival difference between the curves, but this difference was not statistically significant. Ultimately, this was a negative study.

Why does that occur? We’re trying to lump a lot of these HER2 strategies together and learn from the breast cancer data. But what we’re realizing is that HER2-positive gastric cancer is very distinct from HER2-positive breast cancer. The TCG shows us that there are a lot of co-alterations in EGFR and KRAS. With those tumors that are HER2 positive but RAS driven, there are data from our institution showing that those tumors are not HER2 sensitive. Therefore, you can imagine the large study that was trending positive.

But if there is 15% to 20% of a population where you wouldn’t have changed their outcome with HER2-directed therapies, these are the patients who are “diluting the overall benefit,” and this ultimately leads to a negative study. The next generation of these HER2 drug studies need to stratify by level of HER2 and concurrent alterations to really find a subpopulation that is truly HER2 driven, otherwise we will be disappointed over and over again with these strategies that would have ultimately—if made successful in a smaller subpopulation—given us more options for truly HER2-positive patients.

Next-generation strategies are really exploring combinations of these agents, both with HER2 and immune checkpoint inhibitors in this strategy, and these HER2-directed bispecific antibodies are really under high development and will be important to watch out for. But right now, we’ve all really taken a pause, and we need to regroup on the HER2 strategy in metastatic gastric cancer. The take-home point is that it’s still a very important biomarker to test for, and trastuzumab needs to be used in the first-line setting. But beyond that, we are still under development in clinical trials.

In the preoperative setting, there are several trials looking at HER2-directed agents and locally advanced disease. With agents like pertuzumab and even trastuzumab, some of these studies have completed both in the United States and Europe, and we’re looking to see the data to determine whether those agents can be used in nonmetastatic disease.  

Transcript Edited for Clarity 
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Transcript: 

Alan P. Venook, MD: I’m hard pressed to come up with exciting new combinations that really are worth pursuing in gastric GE junction cancer. I did mention FLOT, which is 5FU, leucovorin, oxaliplatin, and docetaxel. There is a study comparing that to the conventional MAGIC trial of neoadjuvant epirubicin-based combination therapy in patients with gastric cancer. The results were superior with FLOT. I find it to be exceedingly toxic, and I’m not much of a fan of that combination. I’d say that’s probably as close as we’ve come to a new combination. Some other combinations have come and gone, combinations more aggressive than FOLFOX or ECX [epirubicin, cisplatin, and capecitabine]. I think the issue is not so much getting an effect, but getting a durable effect and leaving your patients in good enough shape to have a decent quality of life when they’ve had the effect.

There’s an oral taxane in studies that is interesting. This has the advantage of being oral. As a taxane, we know that class of drugs has activity in gastric and GE junction cancer. I think it’s being studied. We don’t yet know what the results are. The appeal for an oral chemotherapy is self-evident, because you can avoid some of the complications related to IV use. On the other hand, I worry a lot about the absorption and how effective it might be in a patient with gastric cancer, for example, where their gut may not work very well. I’m not sure that’s necessarily an area I would be pursuing. And again, regarding other therapies, I just am not aware of anything that holds extreme promise. Some things have come and gone, and we’re struggling to look for targets that are actionable, not just from mutations that we can find.

Yelena Y. Janjigian, MD: HER2 remains one of the most validated biomarkers in metastatic gastric cancer. Trastuzumab was the first biologic agent FDA approved in this disease in 2009, and it really highlighted the importance of HER2 in the biology and growth of metastatic gastric cancer. The ToGA study showed that, in combination with chemotherapy, trastuzumab improved survival, response rate, and progression-free survival in this disease. And unfortunately, beyond trastuzumab, we have not been able to improve the bar and raise it further in both the first-line setting and in the second-line setting in HER2-positive disease.

Recently, the readout of the JACOB study with the combination of trastuzumab, pertuzumab, and chemotherapy did not show improved outcome, or a statistically significant improved outcome, compared to trastuzumab chemotherapy. There was definitely a trend, and there was very noticeable survival difference between the curves, but this difference was not statistically significant. Ultimately, this was a negative study.

Why does that occur? We’re trying to lump a lot of these HER2 strategies together and learn from the breast cancer data. But what we’re realizing is that HER2-positive gastric cancer is very distinct from HER2-positive breast cancer. The TCG shows us that there are a lot of co-alterations in EGFR and KRAS. With those tumors that are HER2 positive but RAS driven, there are data from our institution showing that those tumors are not HER2 sensitive. Therefore, you can imagine the large study that was trending positive.

But if there is 15% to 20% of a population where you wouldn’t have changed their outcome with HER2-directed therapies, these are the patients who are “diluting the overall benefit,” and this ultimately leads to a negative study. The next generation of these HER2 drug studies need to stratify by level of HER2 and concurrent alterations to really find a subpopulation that is truly HER2 driven, otherwise we will be disappointed over and over again with these strategies that would have ultimately—if made successful in a smaller subpopulation—given us more options for truly HER2-positive patients.

Next-generation strategies are really exploring combinations of these agents, both with HER2 and immune checkpoint inhibitors in this strategy, and these HER2-directed bispecific antibodies are really under high development and will be important to watch out for. But right now, we’ve all really taken a pause, and we need to regroup on the HER2 strategy in metastatic gastric cancer. The take-home point is that it’s still a very important biomarker to test for, and trastuzumab needs to be used in the first-line setting. But beyond that, we are still under development in clinical trials.

In the preoperative setting, there are several trials looking at HER2-directed agents and locally advanced disease. With agents like pertuzumab and even trastuzumab, some of these studies have completed both in the United States and Europe, and we’re looking to see the data to determine whether those agents can be used in nonmetastatic disease.  

Transcript Edited for Clarity 
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