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Advancements in Chemotherapy & PD-1 Inhibitor Therapies

Insights From: Vicky Makker, MD, Memorial Sloan Kettering Cancer Center
Published: Tuesday, Apr 30, 2019



Transcript:

Vicky Makker, MD:
With regards to the treatment of advanced endometrial cancers, or those that are recurrent, the current recommendations and preferred regimens are multiagent combination chemotherapy agents. The options here include carboplatin and paclitaxel; carboplatin and docetaxel; cisplatin and doxorubicin; cisplatin, doxorubicin, and paclitaxel; carboplatin, paclitaxel, bevacizumab; and finally carboplatin, paclitaxel, and trastuzumab.

For the majority of advanced endometrial cancer patients who will require systemic treatment, the preferred regimen is carboplatin and paclitaxel chemotherapy. The data that have led to this are from Gynecologic Oncology Group [GOG] study 209, in which patients with stage III or stage IV endometrial cancers who had measurable or nonmeasurable disease, and also patients with recurrent or advanced endometrial cancers were randomized to either carboplatin and paclitaxel or cisplatin, doxorubicin, and paclitaxel.

This trial showed us, and at the moment it’s just presented in abstract form, that paclitaxel and carboplatin is noninferior to the 3-drug regimen with regards to progression-free survival and overall survival. So it really has become the accepted standard for patients who require chemotherapy when they have advanced disease.

As I mentioned, approximately 25% of patients who are serous or serous-like have HER2 [human epidermal growth factor receptor 2] amplifications or overexpress HER2. So there was a randomized phase II trial recently that was presented which compared paclitaxel-carboplatin to paclitaxel, carboplatin, and trastuzumab in patients who overexpress HER2. And it showed that the median progression-free survival favored the 3-drug regimen. So the median progression-free survival was 8 versus 12.6 months and again favored the carboplatin, paclitaxel, and trastuzumab. So this is a viable option for patients who are serous or serous-like and are HER2 amplified.

Carboplatin, paclitaxel, bevacizumab can also be utilized for patients who have advanced or recurrent endometrial cancers. This is based on the results from [GOG-0086P] that showed that in the population of patients who had received carboplatin, paclitaxel, and bevacizumab, that they had an objective response rate of approximately 60%, and that the combination resulted in improved overall survival compared with the other arms in that trial. And so these are options for patients who have advanced-stage endometrial cancers.

Now, with regard to hormonal therapy, hormonal therapy is a viable option for patients who have advanced endometrial cancers. Hormone therapy really is most well utilized and appropriate in patients who have low-grade endometrioid adenocarcinomas. These are the FIGO [International Federation of Gynecology and Obstetrics] grade 1 and grade 2 endometrioid adenocarcinomas. And those who have low-volume disease.

There are a number of agents that have been studied across a myriad of trials, mainly run through the Gynecologic Oncology Group, that have shown that response rates range from 10% to 33%, and that response rates are the highest when combination approaches that combine tamoxifen alternating with progesterone agents had the highest response rates. And at the moment the options that are available with regards to hormonal therapy include tamoxifen, megestrol acetate, fulvestrant, the aromatase inhibitors, and LHRH [luteinizing hormone-releasing hormone] agonists. So all of these are options for patients in the advanced-disease patient population with regards to chemotherapy and hormonal therapy.

With the recent approval of pembrolizumab, which is a monoclonal antibody that targets PD-1 [programmed cell death protein 1], inhibits the binding of PD-1 to its ligands, PD-L1 and PD-L2. We now have in 2017 accelerated approval of this agent that was the first approval that was sited tissue agnostic in patients with pediatric and adult metastatic tumors that have progressed on frontline therapy and are also microsatellite instability high or mismatched repaired deficient. And this has really been a very important advancement in the world of endometrial cancers, for sure.

The approval resulted from a number of small, uncontrolled, multicohort, multicenter studies of 149 patients that were enrolled that had microsatellite instability high or evidence of mismatched repaired deficiency. These patients were enrolled in different dosages of pembrolizumab. They either received pembrolizumab intravenously, 200 mg every 3 weeks or 10 mg per kilogram every 2 weeks until progression, and could receive a maximum of 2 years of pembrolizumab. In these studies, collectively across all the cohorts the objective response rate was approximately 40%. The responses were comparable in the colorectal cancer patients and the other patients, and they were accrued across 14 cancer types including endometrial cancers.

So this approval now is very relevant in patients with endometrial cancers. And I think that for patients who have evidence of mismatch repair deficiency or have microsatellite instability in high endometrial cancers—which again comprise approximately 26% of the recurrent-disease patient population—this is the preferred second-line therapy for those patients.

Educational Support Provided by Eisai.

Transcript Edited for Clarity.
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Transcript:

Vicky Makker, MD:
With regards to the treatment of advanced endometrial cancers, or those that are recurrent, the current recommendations and preferred regimens are multiagent combination chemotherapy agents. The options here include carboplatin and paclitaxel; carboplatin and docetaxel; cisplatin and doxorubicin; cisplatin, doxorubicin, and paclitaxel; carboplatin, paclitaxel, bevacizumab; and finally carboplatin, paclitaxel, and trastuzumab.

For the majority of advanced endometrial cancer patients who will require systemic treatment, the preferred regimen is carboplatin and paclitaxel chemotherapy. The data that have led to this are from Gynecologic Oncology Group [GOG] study 209, in which patients with stage III or stage IV endometrial cancers who had measurable or nonmeasurable disease, and also patients with recurrent or advanced endometrial cancers were randomized to either carboplatin and paclitaxel or cisplatin, doxorubicin, and paclitaxel.

This trial showed us, and at the moment it’s just presented in abstract form, that paclitaxel and carboplatin is noninferior to the 3-drug regimen with regards to progression-free survival and overall survival. So it really has become the accepted standard for patients who require chemotherapy when they have advanced disease.

As I mentioned, approximately 25% of patients who are serous or serous-like have HER2 [human epidermal growth factor receptor 2] amplifications or overexpress HER2. So there was a randomized phase II trial recently that was presented which compared paclitaxel-carboplatin to paclitaxel, carboplatin, and trastuzumab in patients who overexpress HER2. And it showed that the median progression-free survival favored the 3-drug regimen. So the median progression-free survival was 8 versus 12.6 months and again favored the carboplatin, paclitaxel, and trastuzumab. So this is a viable option for patients who are serous or serous-like and are HER2 amplified.

Carboplatin, paclitaxel, bevacizumab can also be utilized for patients who have advanced or recurrent endometrial cancers. This is based on the results from [GOG-0086P] that showed that in the population of patients who had received carboplatin, paclitaxel, and bevacizumab, that they had an objective response rate of approximately 60%, and that the combination resulted in improved overall survival compared with the other arms in that trial. And so these are options for patients who have advanced-stage endometrial cancers.

Now, with regard to hormonal therapy, hormonal therapy is a viable option for patients who have advanced endometrial cancers. Hormone therapy really is most well utilized and appropriate in patients who have low-grade endometrioid adenocarcinomas. These are the FIGO [International Federation of Gynecology and Obstetrics] grade 1 and grade 2 endometrioid adenocarcinomas. And those who have low-volume disease.

There are a number of agents that have been studied across a myriad of trials, mainly run through the Gynecologic Oncology Group, that have shown that response rates range from 10% to 33%, and that response rates are the highest when combination approaches that combine tamoxifen alternating with progesterone agents had the highest response rates. And at the moment the options that are available with regards to hormonal therapy include tamoxifen, megestrol acetate, fulvestrant, the aromatase inhibitors, and LHRH [luteinizing hormone-releasing hormone] agonists. So all of these are options for patients in the advanced-disease patient population with regards to chemotherapy and hormonal therapy.

With the recent approval of pembrolizumab, which is a monoclonal antibody that targets PD-1 [programmed cell death protein 1], inhibits the binding of PD-1 to its ligands, PD-L1 and PD-L2. We now have in 2017 accelerated approval of this agent that was the first approval that was sited tissue agnostic in patients with pediatric and adult metastatic tumors that have progressed on frontline therapy and are also microsatellite instability high or mismatched repaired deficient. And this has really been a very important advancement in the world of endometrial cancers, for sure.

The approval resulted from a number of small, uncontrolled, multicohort, multicenter studies of 149 patients that were enrolled that had microsatellite instability high or evidence of mismatched repaired deficiency. These patients were enrolled in different dosages of pembrolizumab. They either received pembrolizumab intravenously, 200 mg every 3 weeks or 10 mg per kilogram every 2 weeks until progression, and could receive a maximum of 2 years of pembrolizumab. In these studies, collectively across all the cohorts the objective response rate was approximately 40%. The responses were comparable in the colorectal cancer patients and the other patients, and they were accrued across 14 cancer types including endometrial cancers.

So this approval now is very relevant in patients with endometrial cancers. And I think that for patients who have evidence of mismatch repair deficiency or have microsatellite instability in high endometrial cancers—which again comprise approximately 26% of the recurrent-disease patient population—this is the preferred second-line therapy for those patients.

Educational Support Provided by Eisai.

Transcript Edited for Clarity.
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