Beyond Immunotherapy Treatment for Patients With Recurrent Metastatic Endometrial Cancer

At the 2023 ESMO Gynecological Cancers Congress in Barcelona, Spain, Mansoor Raza Mirza, MD, a clinical oncologist from Rigshospitalet in Denmark, presented data on nonimmunological achievements and the role of HER2, B53, and other molecular targets in endometrial cancer. 

Q: Can you describe the current treatment landscape for endometrial cancer, leading up to your research on molecular targets in endometrial cancer? 

Dr Mirza: Until recently we had nothing available for our patients other than chemotherapy, and the response to chemotherapy is quite pathetic. Once you have a patient who has progressed on carboplatin and paclitaxel, the monotherapy has a very bad efficacy with a median PFS [progression-free survival] of around 3.5 months, whichever chemotherapy you want to use, and we had nothing else available. The same is the case for endocrine therapy.

Q: What are some of the developments you have seen in molecular targets for endometrial cancer? 

Dr Mirza: The biggest achievement is what we have seen with TCGA [The Cancer Genome Atlas] data, and after that we can see that this is not just a type 1 and type 2 disease. This is a very heterogeneous disease. You have quite a few molecular targetable alterations, mutations, and I will give you some examples where we are moving with that.

We performed a trial to add a CDK4/6 inhibitor in ENGOT-EN3 PALEO study. It's a small, randomized phase 2 trial, which gave us clear evidence of activity of combination therapy than the single agent endocrine therapy letrozole. We were working hard to get the phase 3 trial started, and it's my pleasure to tell that now we will be starting ENGOT-en17 together with our US colleagues to look at the role of letrozole plus lerociclib, another CDK4/6 inhibitor, versus letrozole alone. If positive, that study will change our standard of care.

Another very important area is the HER2, and we know from the TCGA analysis that HER2 mutation, deletion, amplification across endometrial cancer is quite impressive. That’s why we saw, again, a smaller phase 2 randomized trial by Professor Amanda Fader [MD, Johns Hopkins Medicine, Baltimore, MD] with trastuzumab, which was positive. That has sparked the thinking that now we would be able to move further, and especially when we look at the data of trastuzumab deruxtecan (T-DXd) in breast cancer, it is obvious that we must move that drug in both HER2-low and HER2-positive tumors, so we are planning trials on that, as well.

Q: What future trials are planned for other treatment areas or targets? 

Dr Mirza: When it comes to PTEN mutations, it's a tricky subject because the toxicity of the drugs makes it difficult to plan our trial right now. We have a couple of randomized trials, one by Amit Oza [MD, Princess Margaret Cancer Center, Toronto, Ontario, Canada] performed with ridaforolimus against standard of care. Both trials have shown initial activity, and I think it would be great if we can come further with these drugs and perform a larger trial to change our standard of care.
PIK3CA is another area we must work on, and we are trying to establish a study where we would be able to give patients who are endocrine receptor–positive a hormonal therapy plus or minus a PIK3CA drug. We are still trying to develop such ideas.

Another idea which has already reached phase 3 and had results in phase 3 is in the p53 wild-type tumors. This is first-in-class drug, which is called selinexor, selective inhibitor of nuclear export. What it does is that it blocks the export team, which is responsible for the nuclear export of all the good molecules. By blocking that, you keep all the tumor-suppressive proteins like the p53, high kP, PTEN in the nucleus and you get programmed cell death.

The first phase 3 trial was the ENGOT-en5/SIENDO study, which was done in the patients with stage 4 disease, primary stage 4, or first recurrent patients who had received carboplatin paclitaxel and have a response. These patients were then randomized to receive maintenance selinexor or placebo. The trial in the whole population showed moderate efficacy. But when we looked at the molecular classification and look at the subgroup analysis of p53 wild-type patients, the hazard ratio was 0.375, which is extremely positive. We have now started a phase 3 trial only in the p53 wild-type population. It would be great to see the results of this trial, which will change our standard of care once again. Another drug is being tested in the same population, navtemadlin, in the ENGOT-en21 trial, but it's a little bit early in its development. We must do the phase 2 and then phase 3 trial, but these things are planned.

In p53-mutant population, there are signals of efficacy of V1 inhibitors in a trial performed by Joyce Liu [MD, MPH, Dana-Farber Cancer Institute, Boston, MA] on adavosertib that showed initial activity. It is a nonrandomized, single-arm trial showing a response rate of 30%, which is quite impressive, in the specific population. I think we are moving quite well with all these trials.

Another very important thing what we are looking at is the PARP inhibitors and PARP inhibitors in combination with immunotherapy. Two phase 3 trials will answer that question, the ENGOT-en6/RUBY part 2, and DUO-E trial.

Q: Any final thoughts you’d like to share?

Dr Mirza: As you may see that we are completely changing the outcome of our patient, I think the main takeaway I would have for you is please do perform molecular profiling of all your patients at the time of diagnosis, so you can plan the treatment accordingly in future. Thank you very much.

Source:

Mirza M. Beyond immunotherapy: What is the role of HER2, p53 and other molecular targets in the recurrent/metastatic endometrial cancer treatment landscape? Presented at ESMO Gynecological Cancers Congress; February 23-25, 2023; Barcelona, Spain, and virtual.

Mirza M, Bjørge L, Marmé F, et al. LBA28: A randomised double-blind placebo-controlled phase II trial of palbociclib combined with letrozole (L) in patients (pts) with oestrogen receptor-positive (ER+) advanced/recurrent endometrial cancer (EC): NSGO-PALEO / ENGOT-EN3 trial. Ann Oncol. 2020;31:S1160. doi:0.1016/j.annonc.2020.08.2258

Vergote IB, Pérez Fidalgo A, Hamilton E, et al. VP2-2022: Prospective double-blind, randomized phase III ENGOT-EN5/GOG-3055/SIENDO study of oral selinexor/placebo as maintenance therapy after first-line chemotherapy for advanced or recurrent endometrial cancer. Ann Oncol. 2022;33:P448-450. doi:10.1016/j.annonc.2022.02.223