Oncologists debate the proper treatment of a patient with a grade 2 endometrial carcinoma tumor.
David O’Malley, MD: Let’s go to our third case. This is a 64-year-old post-menopausal patient who presented with a big uterus. She’s tender, she has a bunch of blood, and she’s feeling unwell. With an 18-cm uterus, we did an exploratory laparotomy on her, and because of our visualization, we also did a full bilateral pelvic lymph node dissection.
Krishnansu Tewari, MD: Oh, wow.
David O’Malley, MD: We got 12 out. She had a 44% invasion; I hate these grade 2 tumors. Grade 2 tumors, let’s call it 54%.
Bradley Monk, MD, FACOG, FACS: The size matters; it’s a big tumor.
David O’Malley, MD: It’s a big tumor, a bunch of blood, and a lot of symptoms. Molecular testing shows mismatch repair proficient. They did checkHER2/neu [human epidermal growth factor receptor 2], though I normally wouldn’t check in a nonserous cancer. We talked to her, sat down, and guess what we recommended, Brad?
Bradley Monk, MD, FACOG, FACS: Radiation.
David O’Malley, MD: Vaginal cuff brachytherapy.
Bradley Monk, MD, FACOG, FACS: No, come on.
David O’Malley, MD: Yes, vaginal cuff brachytherapy.
Krishnansu Tewari, MD: I agree with that. The pelvic sidewall is clear.
David O’Malley, MD: She had 12 negative pelvic lymph nodes.
Bradley Monk, MD, FACOG, FACS: It’s definitely not crazy, but the way pelvic radiation is delivered today, through IMRT [intensity-modulated radiation therapy], bladder and bowel sparing, it’s almost tougher to do vaginal brachytherapy. It’s more lucrative for the radiation doctor. I don’t mean to imply that’s why they do things, though. It’s a controversy. However, the PORTEC-2 trial was randomized, so the data would support vaginal brachytherapy, and that’s fine.
Krishnansu Tewari, MD: I would have treated her the same way.
David O’Malley, MD: These grade 2 tumors drive me nuts. There are some data that show about two-thirds of them are going to act like low grades, but maybe as high as one-third are going to act like a high-grade, more aggressive tumor. Unfortunately, about 17 months later, the patient recurs—a big right pelvic sidewall recurrence—and we took out those 12 pelvic lymph nodes, but maybe we missed the sentinel.
Bradley Monk, MD, FACOG, FACS: I don’t know.
David O’Malley, MD: Seven percent will be outside the usual boundaries, which is something to keep in mind. She has a right pelvic recurrence, we give her a carboplatin with paclitaxel, and she gets a nice response, with a little disease left at that point. Brad, what are you going to do with any recent data that may help us here? Do you complete the 6 to 8 cycles of carboplatin, paclitaxel?
Bradley Monk, MD, FACOG, FACS: Both of you have been passionate advocates of maintenance PARP inhibitors in ovarian cancer. You get a response and you know that the risk of recurrence is very high. We have multiple New England Journal of Medicine papers showing maintenance, and bevacizumab in maintenance. We have addressed that same question in endometrial cancer, where you’re going to recur; you get your 6 doses, and go ahead and get maintenance therapy. There’s a study that was reported on February 8th through a press release that will be presented very soon at a scientific meeting, called SIENDO, which stands for selinexor in endometrial cancer. This is a randomized 2:1 maintenance trial, once weekly of the selinexor, 80 mg, and it improved progression-free survival. I can keep talking about it, but I know, Dave, you’ve done a deep dive here. Tell us about the results of this trial and what you think about it.
David O’Malley, MD: What’s interesting is it’s an XPO1 inhibitor. We have this novel target. We saw a hazard ratio of 0.7, so about a 30% improvement in all populations. With what we’ve reported, we’ve only seen the press release, TP53 wild type seemed to benefit the most. The observation arm was right about 3.8 months improvement in progression-free survival, so that makes sense in national history.
Bradley Monk, MD, FACOG, FACS: The results are the same whether it’s TP53 or not, right?
David O’Malley, MD: Great point. When we looked at all-comers, not quite double, it was about 5.7 versus 3.8 months. But in the TP53 wild type, there was about a 3-fold improvement in the median progression-free survival.
Krishnansu Tewari, MD: What was the hazard ratio, Dave?
David O’Malley, MD: The hazard ratio was 0.4, right?
Bradley Monk, MD, FACOG, FACS: It was 0.38.
David O’Malley, MD: Yes, 0.38, precision is important. This is another positive phase 3 trial, run through GOG Partners.
Bradley Monk, MD, FACOG, FACS: The GOG-3055 trial.
David O’Malley, MD: The GOG-3055 trial, thank you. When we’re looking at this group, we know the FDA loves biomarkers. Ultimately, what will the approval look like? Will it look like the TP53wild type, or will it be all-comers? I don’t know.
Bradley Monk, MD, FACOG, FACS: I don’t know. Think how novel this is. In the TP53 wild type, remember TP53 is known as the guardian of the genome. TP53 causes G1/S arrest and allows DNA mutations to be repaired, so that works in the nucleus. XPO is an export ofTP53. If you inhibit that, the wild-type TP53 stays in the nucleus and does its job. The wild-type functional TP53 doesn’t leak out of the genome.
Krishnansu Tewari, MD: This is so exciting; we’re going to be ordering TP53 testing on all our patients with endometrial carcinoma. Are we going to order it up front or are we ordering it later?
Bradley Monk, MD, FACOG, FACS: We’re going to need to traffic through this, but this is here to stay. I’m going to give you the medians now. This is 6 cycles in stage IV recurrent of carboplatin, paclitaxel, then maintenance, once weekly, with a low discontinuation rate. You take 1 weekly fixed dose of 80 mg, and if you’re TP53 wild type, which can be assessed by immunohistochemistry staining, you go from 3.7 to 13.7 months, a 10-month improvement in progression-free survival. Bingo. This is exciting, and the mechanism of action, a nuclear pore inhibitor, is amazing. I don’t care what mutated TP53 does. I can’t turn it back on, but I can relocate the TP53 that’s functional and keep it in the nucleus where it can maintain the integrity of the genome and help patients in the long run.
David O’Malley, MD: Your passion, I can feel it.
Bradley Monk, MD, FACOG, FACS: I love it.
David O’Malley, MD: We have another phase 3 trial that is positive. We have the KEYNOTE-775 trial, we have, what did you say?
Bradley Monk, MD, FACOG, FACS: SIENDO.
David O’Malley, MD: SIENDO stands for selinexor in endometrial cancer. I love it. It’s another phase 3 trial. We have at least 4 phase 3 trials that are going to read out within the next 1 to 2 years with regard to metastatic recurrent disease looking at immune [I/O] therapy, and does it help the backbone of carboplatin and paclitaxel? Then we have the adjuvant setting for locoregional disease. Then we have high intermediate risk, patients with MSI [microsatellite instability] high or MMR [mismatch repair] deficiency. Can we or should we add I/O therapy too to improve their outcomes? We know their recurrence rates will be 25%-plus. We’ve already talked about how hard it is it to salvage in recurrent settings.
Transcript edited for clarity.