PD-L1 inhibitors initially show positive results in advanced gastric cancer

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Immunotherapy and cancer treatment

In recent years, the popularity of immunotherapy in the field of oncology is continuing to rise. Lancet Oncol published the preliminary results of the Keynote-012 study evaluating the efficacy of the PD-L1 inhibitor pembrolizumab in patients with advanced gastric cancer on May 3, which attracted a lot of attention. Professor Elizabeth C Smyth of the Royal Marsden Hospital in England interpreted the study, which can bring us some thoughts and inspirations.
The prognosis of advanced gastric cancer is poor, and less than 10-15% of metastatic patients can survive for more than 2 years. Trastuzumab and ramoluzumab for second-line treatment of HER2-positive gastric cancer patients can slightly improve overall survival. Because there are many examples of failures of therapeutic drugs in the field of gastric cancer, it seems that these drugs have achieved little success. In this challenging current status of advanced gastric cancer treatment, the Keynote-012 study conducted by Professor Kei Muro and colleagues initially showed positive results, indicating that PD-L1 inhibitors have potential therapeutic value in advanced gastric cancer.

The results of the Keynote-012 study are surprising

In the Keynote-012 study, PD-L1-positive patients with advanced gastric cancer received the anti-PD-1 antibody pembrolizumab until disease progression or intolerable adverse events. The study screened a total of 162 patients with advanced gastric cancer, of which 65 (40%) were positive for PD-L1 expression, and finally 39 (24%) patients were enrolled in this international multicenter Phase 1B study. Excitingly, 17 of the 32 patients (53%) experienced tumor regression; 8 of 36 (22%) patients with evaluable efficacy had confirmed partial remission. This remission rate is consistent with the results of immunotherapy trials in other cancers, with a median response time of 40 weeks, and 4 of 36 patients (11%) with disease remission did not show disease progression as of the reporting time. As expected, 9 patients (23%) experienced immune-related adverse events. No patients discontinued treatment due to immune-related adverse events. Compared with 11% to 30% of patients in the second-line chemotherapy trial, the results were very surprising. In view of the fact that the survival results of recent international gastric cancer clinical trials are affected by regional differences, Kei Muro and colleagues further proved that the survival of Asian and non-Asian patients in the Keynote-012 trial is similar.

Can the expression of PD-L1 predict the efficacy of immunotherapy?

Keynote-012 test screening uses immunohistochemistry to detect the expression of PD-L1. Patients with tumor cells, immune cells or these two cell masses need to express at least 1% of PD-L1 to be eligible for the trial. The author then reassessed the status of PD-L1 using different assays. The results of the second assay indicate that the expression of PD-L1 in immune cells, not tumor cells, is associated with the efficacy of pembrolizumab in gastric cancer. Secondly, 8 of 35 biopsy specimens that could be evaluated had a negative PD-L1 result. These results demonstrate the complexity of PD-L1 analysis in general, especially the evaluation of biomarkers for gastric cancer. This deviation may be due to dynamic changes in PD-L1 expression after treatment, differences in evaluation methods, and heterogeneity of gastric cancer. Therefore, it is unclear whether in the past clinical trials without biomarker screening, some patients with seemingly PD-L1 negative patients who received anti-PD1 drug treatment for disease remission were related to the heterogeneity of biomarker expression , Or whether there is a real correlation between biomarkers and efficacy. Further research is needed

The best method for evaluating PD-L1 expression and whether it is a true and effective predictive biomarker in gastric cancer immunotherapy. The authors also report the preliminary results of interferon gamma gene expression as a biomarker for primary tissue lesion independent prediction. If this result is verified, it may help to avoid some immunohistochemistry-related problems in the future.
Issues that need further thinking

Of course, a small sample test like Keynote-012 inevitably has some problems. First, it is unclear whether there is an interaction between the chemotherapy received in the past and the efficacy of pembrolizumab. Although some responding patients had only received first-line or less chemotherapy prior to pembrolizumab, most (63%) responding patients had received second-line or more anti-tumor therapy. Moreover, Keynote-012 is a small sample of initial clinical trials and cannot be included in most patients with advanced gastric cancer with short survival, which may make immunotherapy-related relatively slow response rates and occasional falsehoods.

The results of progress are hardly convincing. Several ongoing clinical trials are trying to determine the optimal immunotherapy time window for gastric cancer patients. Second, although in theory, patients with gastric cancer with unstable microsomes should be more suitable for immunotherapy, and
In the Keynote-012 trial, only half of the patients with microsatellite instability treated with pembrolizumab responded. This subtype of gastric cancer accounts for 22% of the total gastric cancer patients and is worthy of further study. Finally, the parameters that evaluate the positive results of this gastric cancer immunotherapy clinical trial also need to be carefully considered. The proportion of patients who experienced disease remission in the Keynote-012 trial was smaller than that in the RAINBOW trial with paclitaxel and combined ramolizumab. In fact, the Keynote-012 test is negative from a purely statistical definition. Patients who responded to treatment did not show significant improvement in progression-free survival and overall survival. In the future, ongoing clinical trials also need to pay attention to these issues.
Clinical trials related to anti-CTLA-4 and anti-PD-1 treatments have been very successful in melanoma. In comparison, the results of the Keynote-012 trial seem to be slightly optimistic. However, the annual mortality rate of gastric cancer worldwide is three times that of malignant melanoma, so the results of this study are still very important. For most gastric cancer patients who lack effective treatments, the current findings are an exciting first step towards achieving long-term remission of the disease.In recent years, the popularity of immunotherapy in the field of oncology is continuing to rise.Lancet Oncol published the preliminary results of the Keynote-012 study evaluating the efficacy of the PD-L1 inhibitor pembrolizumab in patients with advanced gastric cancer on May 3, which attracted a lot of attention.Professor Elizabeth C Smyth of the Royal Marsden Hospital in England interpreted the study, which can bring us some thoughts and inspirations.

The prognosis of advanced gastric cancer is poor, and less than 10-15% of metastatic patients can survive for more than 2 years. Trastuzumab and ramoluzumab for second-line treatment of HER2-positive gastric cancer patients can slightly improve overall survival. Because there are many examples of failures of therapeutic drugs in the field of gastric cancer, it seems that these drugs have achieved little success. In this challenging current status of advanced gastric cancer treatment, the Keynote-012 study conducted by Professor Kei Muro and colleagues initially showed positive results, indicating that PD-L1 inhibitors have potential therapeutic value in advanced gastric cancer.
The results of the Keynote-012 study are surprising
In the Keynote-012 study, PD-L1-positive patients with advanced gastric cancer received the anti-PD-1 antibody pembrolizumab until disease progression or intolerable adverse events. The study screened a total of 162 patients with advanced gastric cancer, of which 65 (40%) were positive for PD-L1 expression, and finally 39 (24%) patients were enrolled in this international multicenter Phase 1B study. Excitingly, 17 of the 32 patients (53%) experienced tumor regression; 8 of 36 (22%) patients with evaluable efficacy had confirmed partial remission. This remission rate is consistent with the results of immunotherapy trials in other cancers, with a median response time of 40 weeks, and 4 of 36 patients (11%) with disease remission did not show disease progression as of the reporting time. As expected, 9 patients (23%) experienced immune-related adverse events. No patients discontinued treatment due to immune-related adverse events. Compared with 11% to 30% of patients in the second-line chemotherapy trial, the results were very surprising. In view of the fact that the survival results of recent international gastric cancer clinical trials are affected by regional differences, Kei Muro and colleagues further proved that the survival of Asian and non-Asian patients in the Keynote-012 trial is similar.

Can the expression of PD-L1 predict the efficacy of immunotherapy?

Keynote-012 test screening uses immunohistochemistry to detect the expression of PD-L1. Patients with tumor cells, immune cells or these two cell masses need to express at least 1% of PD-L1 to be eligible for the trial. The author then reassessed the status of PD-L1 using different assays. The results of the second assay indicate that the expression of PD-L1 in immune cells, not tumor cells, is associated with the efficacy of pembrolizumab in gastric cancer. Secondly, 8 of 35 biopsy specimens that could be evaluated had a negative PD-L1 result. These results demonstrate the complexity of PD-L1 analysis in general, especially the evaluation of biomarkers for gastric cancer. This deviation may be due to dynamic changes in PD-L1 expression after treatment, differences in evaluation methods, and heterogeneity of gastric cancer. Therefore, it is unclear whether in the past clinical trials without biomarker screening, some patients with seemingly PD-L1 negative patients who received anti-PD1 drug treatment for disease remission were related to the heterogeneity of biomarker expression , Or whether there is a real correlation between biomarkers and efficacy. Further research is needed

The best method for evaluating PD-L1 expression and whether it is a true and effective predictive biomarker in gastric cancer immunotherapy. The authors also report the preliminary results of interferon gamma gene expression as a biomarker for primary tissue lesion independent prediction. If this result is verified, it may help to avoid some immunohistochemistry-related problems in the future.

Issues that need further thinking

Of course, a small sample test like Keynote-012 inevitably has some problems. First, it is unclear whether there is an interaction between the chemotherapy received in the past and the efficacy of pembrolizumab. Although some responding patients had only received first-line or less chemotherapy prior to pembrolizumab, most (63%) responding patients had received second-line or more anti-tumor therapy. Moreover, Keynote-012 is a small sample of initial clinical trials and cannot be included in most patients with advanced gastric cancer with short survival, which may make immunotherapy-related relatively slow response rates and occasional falsehoods.

The results of progress are hardly convincing. Several ongoing clinical trials are trying to determine the optimal immunotherapy time window for gastric cancer patients. Second, although in theory, patients with gastric cancer with unstable microsomes should be more suitable for immunotherapy, and
In the Keynote-012 trial, only half of the patients with microsatellite instability treated with pembrolizumab responded. This subtype of gastric cancer accounts for 22% of the total gastric cancer patients and is worthy of further study. Finally, the parameters that evaluate the positive results of this gastric cancer immunotherapy clinical trial also need to be carefully considered. The proportion of patients who experienced disease remission in the Keynote-012 trial was smaller than that in the RAINBOW trial with paclitaxel and combined ramolizumab. In fact, the Keynote-012 test is negative from a purely statistical definition. Patients who responded to treatment did not show significant improvement in progression-free survival and overall survival. In the future, ongoing clinical trials also need to pay attention to these issues.
Clinical trials related to anti-CTLA-4 and anti-PD-1 treatments have been very successful in melanoma. In comparison, the results of the Keynote-012 trial seem to be slightly optimistic. However, the annual mortality rate of gastric cancer worldwide is three times that of malignant melanoma, so the results of this study are still very important. For most gastric cancer patients who lack effective treatments, the current findings are an exciting first step towards achieving long-term remission of the disease.

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