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Gastric/GEJ Cancer: Immunotherapeutic Strategies

Insights From: David Ilson, MD PhD, Memorial Sloan Kettering Cancer Center; Minaxi Jhawer, MD, Englewood Hospital and Medical Center
Published: Friday, Aug 10, 2018



Transcript: 

Minaxi Jhawer, MD: With the explosion of immunotherapy across all diseases, we see that it clearly has a role in gastric and GE [gastroesophageal] junction cancer. Patients who have MSI [microsatellite instability]–high or PD-L1 overexpressing tumors benefit the most from pembrolizumab. Patients who do not overexpress PD-L1 have a bare response of probably 4 %to 5%. It’s not 0%, but at the same time, the response is really higher in the ones who are overexpressing. That’s why we do send off the full next-generation sequencing panel to understand the biology of the tumor and then target the therapies. What’s also interesting is that patients who have EBV [Epstein-Barr virus]–positive and overexpressing tumors actually have high PD-L1. So, that might be an interesting biomarker. For now, it’s not something we routinely test, but it might evolve to be.

David Ilson, MD, PhD: In the realm of tissue testing and genomic profiling, the biomarkers that we study in addition to HER2 are MSI and PD-L1. We now know that anti–PD-1 drugs do have a significant signal of activity in refractory gastric cancer. For pembrolizumab, we had a recent publication of a large expansion cohort from a trial called KEYNOTE-059, where 259 patients with chemotherapy-refractory GE junction or gastric cancer were treated with pembrolizumab as a salvage option. Most patients had received 2 or 3 previous lines of chemotherapy. All patients were tested for PD-L1 positivity, and about 60% tested PD-L1 positive, with a threshold of 1% positive staining.

This study showed a significant signal of activity in PD-L1–positive patients, with a response rate of about 13% to 14%, and the duration of response was more than a year in these patients. PD-L1–negative patients on this trial only had about a 5% response rate, and the median duration of response was only about 6 to 8 months. The other issue that was looked at in this trial was MSI-high patients, and 7 MSI-high patients on this trial had a response rate of nearly 60%, with quite durable and ongoing responses. Based on this large expansion cohort, regulatory approval was achieved for pembrolizumab for either PD-L1–positive or MSI-high chemotherapy-refractory gastric cancers. We now have an approved indication for this drug. You can argue to do the testing early, but basically, once patients are resistant to 2 or 3 lines of chemotherapy, pembrolizumab should be considered as a standard option for salvage.

The other positive study we should talk about is nivolumab versus best supportive care. The KEYNOTE-059 trial was a large expansion cohort. It wasn’t a randomized trial, but the trial of nivolumab, the ONO-4538-12 trial, took chemotherapy-refractory gastric cancer and randomized patients to best supportive care versus nivolumab. The data actually look quite similar to pembrolizumab from the phase II trial, with a response rate of about 11% to 12% and an improvement in 1-year survival [of] up to 27% compared to 11% for supportive care. Based on those data, nivolumab is now approved in Asia for chemotherapy-refractory gastric cancer. I think that data are now being reviewed in the United States.

Interestingly, that trial was agnostic of PD-L1 expression. They did not require PD-L1 expression, and in their early analysis, it didn’t seem that PD-L1 expression clearly correlated with response. One trial that we’re waiting for the results of, that has been reported in a press release, is the second-line trial comparing pembrolizumab to paclitaxel. That was a negative trial. Pembrolizumab did not best chemotherapy alone as second-line treatment. That was a disappointing result. Another trial that was reported in a press release was a trial of avelumab, which is an anti–PD-L1 drug, versus physician's-choice chemotherapy in refractory disease. That also did not show a superior outcome. So, 2 randomized trials of immunotherapy in later-line treatment versus chemotherapy alone were negative studies.

What we’re awaiting now are first-line trials of immunotherapy combined with chemotherapy. There are trials of pembrolizumab plus a 5-FU [fluorouracil] platinum, nivolumab plus FOLFOX [folinic acid/fluorouracil/oxaliplatin] being compared to chemotherapy alone. In the nivolumab arm, there’s a third arm of ipilimumab and nivolumab, pure immunotherapy, up front. Those are going to be very interesting trials to see whether adding immunotherapy as part of initial chemotherapy improves outcomes and whether or not there’s a potential advantage for immunotherapy agents alone versus chemotherapy as first-line treatment. That being said, this should not be done outside of a clinical trial. We have to await the results of these studies, and there is a sobering reminder that the 2 negative trials of immunotherapy plus chemotherapy indicate that immunotherapy drugs alone may not be better than chemotherapy agents in later lines.

Transcript Edited for Clarity 
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Transcript: 

Minaxi Jhawer, MD: With the explosion of immunotherapy across all diseases, we see that it clearly has a role in gastric and GE [gastroesophageal] junction cancer. Patients who have MSI [microsatellite instability]–high or PD-L1 overexpressing tumors benefit the most from pembrolizumab. Patients who do not overexpress PD-L1 have a bare response of probably 4 %to 5%. It’s not 0%, but at the same time, the response is really higher in the ones who are overexpressing. That’s why we do send off the full next-generation sequencing panel to understand the biology of the tumor and then target the therapies. What’s also interesting is that patients who have EBV [Epstein-Barr virus]–positive and overexpressing tumors actually have high PD-L1. So, that might be an interesting biomarker. For now, it’s not something we routinely test, but it might evolve to be.

David Ilson, MD, PhD: In the realm of tissue testing and genomic profiling, the biomarkers that we study in addition to HER2 are MSI and PD-L1. We now know that anti–PD-1 drugs do have a significant signal of activity in refractory gastric cancer. For pembrolizumab, we had a recent publication of a large expansion cohort from a trial called KEYNOTE-059, where 259 patients with chemotherapy-refractory GE junction or gastric cancer were treated with pembrolizumab as a salvage option. Most patients had received 2 or 3 previous lines of chemotherapy. All patients were tested for PD-L1 positivity, and about 60% tested PD-L1 positive, with a threshold of 1% positive staining.

This study showed a significant signal of activity in PD-L1–positive patients, with a response rate of about 13% to 14%, and the duration of response was more than a year in these patients. PD-L1–negative patients on this trial only had about a 5% response rate, and the median duration of response was only about 6 to 8 months. The other issue that was looked at in this trial was MSI-high patients, and 7 MSI-high patients on this trial had a response rate of nearly 60%, with quite durable and ongoing responses. Based on this large expansion cohort, regulatory approval was achieved for pembrolizumab for either PD-L1–positive or MSI-high chemotherapy-refractory gastric cancers. We now have an approved indication for this drug. You can argue to do the testing early, but basically, once patients are resistant to 2 or 3 lines of chemotherapy, pembrolizumab should be considered as a standard option for salvage.

The other positive study we should talk about is nivolumab versus best supportive care. The KEYNOTE-059 trial was a large expansion cohort. It wasn’t a randomized trial, but the trial of nivolumab, the ONO-4538-12 trial, took chemotherapy-refractory gastric cancer and randomized patients to best supportive care versus nivolumab. The data actually look quite similar to pembrolizumab from the phase II trial, with a response rate of about 11% to 12% and an improvement in 1-year survival [of] up to 27% compared to 11% for supportive care. Based on those data, nivolumab is now approved in Asia for chemotherapy-refractory gastric cancer. I think that data are now being reviewed in the United States.

Interestingly, that trial was agnostic of PD-L1 expression. They did not require PD-L1 expression, and in their early analysis, it didn’t seem that PD-L1 expression clearly correlated with response. One trial that we’re waiting for the results of, that has been reported in a press release, is the second-line trial comparing pembrolizumab to paclitaxel. That was a negative trial. Pembrolizumab did not best chemotherapy alone as second-line treatment. That was a disappointing result. Another trial that was reported in a press release was a trial of avelumab, which is an anti–PD-L1 drug, versus physician's-choice chemotherapy in refractory disease. That also did not show a superior outcome. So, 2 randomized trials of immunotherapy in later-line treatment versus chemotherapy alone were negative studies.

What we’re awaiting now are first-line trials of immunotherapy combined with chemotherapy. There are trials of pembrolizumab plus a 5-FU [fluorouracil] platinum, nivolumab plus FOLFOX [folinic acid/fluorouracil/oxaliplatin] being compared to chemotherapy alone. In the nivolumab arm, there’s a third arm of ipilimumab and nivolumab, pure immunotherapy, up front. Those are going to be very interesting trials to see whether adding immunotherapy as part of initial chemotherapy improves outcomes and whether or not there’s a potential advantage for immunotherapy agents alone versus chemotherapy as first-line treatment. That being said, this should not be done outside of a clinical trial. We have to await the results of these studies, and there is a sobering reminder that the 2 negative trials of immunotherapy plus chemotherapy indicate that immunotherapy drugs alone may not be better than chemotherapy agents in later lines.

Transcript Edited for Clarity 
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