Antibody-Drug Conjugates for Endometrial Cancer

Mariana Gouveia, MD, gives an overview of the use of antibody-drug conjugates for the treatment of patients with endometrial cancer. Dr Gouveia touches on the targets of HER2, folate receptor alpha, and TROP-2 with agents such as trastuzumab deruxtecan, mirvetuximab soravtansine, sacituzumab govetican, and sacituzumab tirumotecan.

Dr Gouveia concludes, “The future for ADCs in gynecological cancer is bright, but…we must look for biomarkers and optimal management of toxicities.”

Transcript:

My name is Mariana Goveia. I am a medical oncologist at DASA Oncologia in Sao Paulo, Brazil. And it's such a pleasure being here. Thank you so much for the opportunity and the kind invitation, I'm really happy.

Can you discuss the issue of sequencing treatment for patients with endometrial cancer?

When talking about sequencing until 2023, the standard first -line treatment for primary advanced or recurrent endometrial cancer consisted of chemotherapy, the combination of carboplatin and paclitaxel. Afterwards, treatment sequencing depended on mismatch repair status. For those with mismatch repair status deficient disease, treatment was with monotherapy using an immune checkpoint inhibitor such as pembrolizumab or dostarlimab. In contrast, pembrolizumab plus lenvatinib displayed efficacy in those with mismatch repair proficient disease. This was considered the standard treatment for these patients in the second line.

The year 2023 represented a paradigm shift in the treatment of advanced endometrial cancer with 4 phase 3 trials demonstrating benefit of the addition of immunotherapy to carboplatin and paclitaxel in the first line setting. These occurred regardless of mismatch repair with a greater magnitude of benefit for deficient mismatch repair status patients. It is important to highlight that in Brazil, we have already regulatory approval for pembrolizumab, dostarlimab, and durvalumab for all comers.

As immunotherapy migrates to the first-line scenario, treatment sequencing remains a critical issue for us, given the limited options and poor prognosis in this setting. Beyond first line, isolated chemotherapy, for example, showed a poor response with an overall response rate of  15% or less. And patients were already receiving immunotherapy in first line right now. So, facing this unmet need, the therapeutic landscape is evolving rapidly and antibody-drug conjugates (ADCs) represent a promising strategy for subsequent lines, understanding this whole evolution from the therapeutic landscape.

What are the ADCs seen in the endometrial cancer space?

Nowadays, there are almost 190 ADCs in development globally. Of course, I'm not going to talk about all of them. I'm going to focus in 3 different targets: HER2, folate receptor alpha, and TROP-2 for endometrial cancer. But there are several ongoing phase 1 and 2 trials investigating other targets such as AXL, tissue factor, Claudin 6.

Regarding HER2, trastuzumab deruxtecan, T-Dd was evaluated in Destiny-PanTumor02 trial and among 40 patients with a median of 2 or higher lines, the overall response rate was 57%. But for those with 3+ expression, we observed an overall response rate of 84%, and that's really impressive. Currently in the US, for patients with unresectable or metastatic HER2-positive solid tumors, including endometrial cancer, who have received prior systemic therapy, there is agnostic approval for T-DXd. Here in Brazil, we do not have access yet.

Moving on to folate receptor alpha, mirvetuximab soravtansine was already studied in endometrial cancer with 16 patients receiving this ADC. All of them had prior treatment and the overall response rate for this medication was 37%.

Now, when talking about TROP-2, I'm going to comment on 2 different drugs, sacituzumab govitecan and sacituzumab tirumotecan. For saci govitecan, the TROPiCS-03 trial recently published in JCO, a phase 2 basket trial with 41 patients heavily pretreated with advanced endometrial cancer with a median of 3 prior lines. In this population, 85% had already received chemotherapy and immunotherapy. An overall response rate of 22% was observed, and TROP2-expression was not associated with best tumor volume change. Whereas for sacituzumab tirumotecan, there was a smaller proportion of patients who had received chemotherapy and immunotherapy and in this study for this ADC, the overall response rate was 27%, and there was a higher response in patients with a TROP2 expression of more than 200.

I talked a little bit about these three targets and 4 ADCs, but of course there are many other ADCs that are being evaluated and these are the main ones that we could comment, but we still need further data on lots of ADCs.

Are there any special considerations for prescribing ADCs to patients with endometrial cancer?

I have four special considerations on ADCs. The first one is financial burden. These drugs are extremely expensive. And we have to think about how we can improve access to these therapies. This is a critical issue. The second issue on ADCs is adverse events. Regarding TROP-2, for example, almost all drugs present a grade 3 stomatitis in 10% of the cases. Every study states that toxicities were manageable, but maybe this is not as manageable as it seems for the patients. Besides that, for T-DXd, there is a risk of pneumonitis as a potential adverse event, and these do need special monitoring. The third consideration is biomarkers. With the number of ADCs in development and the perspective of the incorporation of many of them, the development of biomarkers are crucial. They have to be evaluated and validated in the trials. At last, several studies were performed mainly or entirely in Chinese populations and they were too small. It will be important to further validate the efficacy in large clinical trials and many of them are already ongoing actually.

Is there anything else you would like to add about ADCs in this patient population?

The future for ADCs in gynecological cancer is bright, but it seems that one size does not fit all patients. We must look for biomarkers and optimal management of toxicities. For those who are interested in this field, ADCs in gynecological cancer, I strongly recommend Kathleen Moore and Toon Van Gorp discussion on ADCs in ESMO 2024. We have so much to learn about ADCs in the following years, and this is a really exciting field for us.

Source:

Gouveia MC, Martins de Silveira TH, Scaranti M. The rise of antibody-drug conjugates in advanced endometrial cancer. International Journal Gynecological Cancer. Published online: September 9, 2024. doi: 10.1136/ijgc-2024-006091.