Peer Discussion Addresses Challenges in Recurrent Endometrial Cancer Treatment

Thomas Herzog, MD (MODERATOR)

Paul & Carolyn Flory Professor, University of Cincinnati

Deputy Director, University of Cincinnati Cancer Center

Cincinnati, OH

EVENT REGION New Jersey

PARTICIPANTS Jumana Chatiwala, MD | David Gallinson, DO | Anita Gul, MD | Richards A. Afonja, MD | Seema Varma, MD | Sandeep Malik, MD | Arunabh Sekhri, MD

CASE SUMMARY

A 71-year-old postmenopausal woman presented with abnormal uterine bleeding, increasing urinary frequency, and nausea/cramping for approximately 6 months. She has 2 grown children and no known family history of cancer. Her body mass index is 39; she has had type 1 diabetes since childhood, well controlled with medication. Physical examination was notable for enlarged uterus and right lower quadrant abdominal tenderness on palpation. Her ECOG performance status was 1. A CT scan of the chest, abdomen, and pelvis showed a bulky uterus with diffusely thickened endometrium of 11 mm with no parametrial involvement or lymphadenopathy visualized. Cancer antigen 125 (CA-125) level was 38.6 U/mL.

Endometrial biopsy showed endometrial adenocarcinoma of International Federation of Gynecology and Obstetrics stage IVA, grade 3 (poorly differentiated), with histopathology indicating multiple microscopic metastatic deposits of omental adenocarcinoma. Her disease was mismatch repair (MMR) proficient, microsatellite stable (MSS), estrogen receptor (ER) negative, HER2 negative, and NTRK negative. Germline testing showed no pathogenic variants.

Carboplatin/paclitaxel chemotherapy was initiated; treatment was well tolerated other than grade 1 peripheral neuropathy and vomiting. Four months after initiation, she had no evidence of disease on PET scan, with complete resolution of symptoms.

Twelve months post chemotherapy, rising CA-125 level was documented. A CT scan of the abdomen and pelvis showed multiple peritoneal implants. PET scan showed intense fluorodeoxyglucose F 18–avid lesions in lungs, peritoneum, and para-aortic lymph nodes. Interventional radiology biopsy revealed recurrent endometrial cancer.

DISCUSSION QUESTIONS

• What diagnostic testing do you use for a patient who presents with endometrial cancer?
• Should every patient with endometrial cancer undergo molecular testing?
• When should testing be ordered?

HERZOG: What [molecular] testing do you use, if any, for endometrial cancer?

CHATIWALA: I use Caris [Molecular Testing].

HERZOG: So you’re getting everything. You’re getting the NGS [next-generation sequencing], and you’re getting the IHC [immunohistochemistry], with the HER2 and MMR.

CHATIWALA: We do MMR and Caris. We used to do Foundation [Medicine] but then all the patients were getting billed. Yes, I will do MMR. I use Caris and I’ve also used NeoGenomics.

GALLINSON: The data for efficacy of HER2 is not based on an NGS finding. It’s based on the IHC.¹ So I’m going to do that separately.

HERZOG: Yes, Caris does that [as IHC]. [For those who use Caris], I know what you’re testing for, [which is] pretty much everything, because they’ll do the ER, and they’ll do everything for you with the IHC on that side of the platform, and then the NGS. They’re also doing proteomics and everything else. When do you send? Most of you are seeing patients at advanced stage or recurrent disease.

CHATIWALA: We still do MMR and HER2 in the advanced stage.

HERZOG: You bring up a critical point: What’s the 1 thing everyone needs testing-wise? What’s the bare minimum?

CHATIWALA: [At least getting] MMR.

HERZOG: Yes, that’s the bare minimum. Because what are you looking for?

GALLINSON: Lynch syndrome.

HERZOG: Yes…and it gets lost in ovarian cancer sometimes. Everyone’s talking about doing all these tests and fusions, and you see patients who aren’t even getting tested for BRCA, which is an opportunity to do cascade testing and save lives [of patients’ family members] and do other testing and risk prevention in the patient for breast cancer and everything else. You absolutely need to make sure that that happens. Most of you are probably testing them when they come to your office, because they’re in that scenario already.

GUL: I send a NGS panel right at the beginning. We don’t use Caris. Our vendor is a lab in New Jersey.

HERZOG: So you use an outside vendor. I imagine for most of you [testing] is done when they hit your door if it hasn’t already been done.

CHATIWALA: Does the CPS [combined positive score for PD-L1] matter in patients who are MMR proficient? There are patients who are MMR proficient or MSS but their CPS score will be 4 or 5.

HERZOG: There is a significant number of patients who are MMR proficient who respond [to immune checkpoint inhibitors]. There are theories that those are probably patients who happen to have high PD-L1 or high tumor mutational burden. [Investigators] are looking at that. There are small trials…[but] nothing jumps out. There are larger trials that have been more refined in terms of how they’re doing it procedurally and more rigorously, so I think we’ll have some answers on that.

HERZOG: Over half of you would repeat carboplatin and paclitaxel, then [others] do lenvatinib [Lenvima] plus pembrolizumab [Keytruda] or pembrolizumab on its own. What made you go back to chemotherapy vs doing something different? Did 1 year [without progression] make you say it had a good response and you could get some more out of that? She had grade 1 neuropathy.

AFONJA: I would opt for pembrolizumab and lenvatinib. It’s better tolerated than chemotherapy.² If you give the patient carboplatin/paclitaxel again, now they have significantly worse neuropathy. Pembrolizumab/lenvatinib is very well tolerated if the dose of lenvatinib is restricted to 10 mg. We all have issues with high blood pressure.

HERZOG: Obviously molecular signature matters to some degree. Does lenvatinib and pembrolizumab work in patients who are MMR proficient? Yes, [it does].² Then you think about efficacy, safety, prior therapy, as well as the adverse events.… Is anything else driving your decision?

GALLINSON: I went back to carboplatin/paclitaxel. I was recently advised to start a protocol to make sure you get a second carboplatin reaction. Are you premedicating them off protocol to reduce the likelihood of a carboplatin reaction after that second introduction?

HERZOG: We worry about it anytime they get more than 6 to 8 cycles…[but] we don’t do anything special. We just keep a close eye on it.

GALLINSON: In [trial] data we look at, you see [lower] incidence in the [African American] population; is that trial participation or different incidence?

HERZOG: There’s a slightly higher incidence rate in African American individuals, and interestingly, a higher number of high-risk tumors as well…and unfortunately, higher mortality.³ We think it is largely due to the more concerning biology of the tumor, but there are probably some social determinants of health that impact this as well. There are studies...they do very similarly, especially for adenocarcinomas, and there are other studies [where that is not the case].

But the fact is, we have an endometrial cancer epidemic in this country right now. When I started doing this, I think we were at 30,000 cases a year; [now] we’re at almost 65,000 cases a year of endometrial cancer.⁴ We predict by next year that the deaths from endometrial cancer will exceed those from ovarian cancer.… This is a group of patients you’re going to see more of, not less, and we are trying to figure out some of the inequalities in terms of outcomes, because that’s been a big story and endometrial cancer has been the poster child for that.

No one took carboplatin/paclitaxel, and there is more support for lenvatinib/pembrolizumab. A lot of you would do radiation therapy.

CHATIWALA: If it was confined to the lymph nodes, [I would] do local therapy, and I picked that because I have a patient who has deficient MMR and had carboplatin/paclitaxel, then 2 years after that had 1 lung nodule that was metastatic. The thoracic surgeon removed it. Two years later, she had a lung nodule on the other side…so they removed it again. Now she’s disease-free still and…when it comes up I will deal with it. That’s why I picked local therapy.

AFONJA: Do you want to give some chemotherapy as a radiosensitizer?

VARMA: Yes, there was [an option] that did say pelvic radiation with chemotherapy.

HERZOG: A couple of you chose whole pelvic radiotherapy by itself [or] whole pelvic radiotherapy with chemotherapy. What are you thinking with pembrolizumab? Is pembrolizumab likely to work by itself in a patient with MMR-proficient recurrent disease?

VARMA: Yes, it could work [if] the patient is not a candidate for radiation or aggressive [therapy].

HERZOG: I would probably go with lenvatinib/pembrolizumab, and if it’s locally confined and you could get it with radiation, that would be a consideration as well.

DISCUSSION QUESTIONS

• What data most impress you from Study 309/ KEYNOTE-775 (NCT03517449)?
• Which patients would best be served by this regimen?
• Have you prescribed lenvatinib in the treatment of endometrial cancer or other malignancies?
• At what dose do you typically initiate lenvatinib?

HERZOG: What data most impress you in terms of efficacy and safety?

MALIK: Efficacy is much better, with 30% to 40% objective responses [From the Data²].

HERZOG: [Better] than the chemotherapy, OK. Several of you have used it, so [in terms of] safety you’ve known it in your own hands.

AFONJA: I have 2 patients who presented in the [emergency department] with questionable transient ischemic attack.

HERZOG: Yes, you have to keep that blood pressure under control.

AFONJA: I reduced the dose [of lenvatinib] around 50% and it was well tolerated.

GALLINSON: [My patient] has bad osteoarthritis and the arthralgias are [a concern].

MALIK: In renal cell carcinoma, there is a [lower] dose, which is supposed to be [less] effective;⁵ does that translate [here]?

HERZOG: That’s always been the concern. Is there a threshold dose? I’ve seen oncologists use it at the extreme lowest doses and they swear they’ve had responses, but I don’t know. It’s usually in combination in our [setting]. I don’t know whether…lenvatinib at that low dose contributed to efficacy or not. What do you do in terms of starting dose? The study was conducted at 20 mg.

AFONJA: I start out at 10 mg.

HERZOG: Then do you dose escalate if they’re doing well?

AFONJA: If it’s well tolerated I try to go to [14 mg].

HERZOG: It’s 10-mg and 4-mg tablets, so you can go to 14 mg, or you can go to 18 mg, or you can drop down lower.

GALLINSON: I went from 14 mg to 10 mg in my patient with arthralgia. She’s 9 months on treatment and she’s on 4 mg, and I don’t know whether she will let me go back up. She responded [initially] and has stable disease at 9 months.

HERZOG: I’ve heard a lot of stories like that where patients have gone to even the lowest dose and they’ve still had efficacy, but is it because of the [lenvatinib] or [the pembrolizumab]? We don’t know, but it’s interesting.

GALLINSON: She is MMR proficient.

HERZOG: I haven’t seen any sign…that I would be comfortable with saying that there is clearly a threshold [where] it doesn’t work beyond this. I haven’t seen anything in endometrial cancer at this point.

CHATIWALA: In [Dr Gallinson’s] patient, have you modified the dose of pembrolizumab [to determine whether] arthralgias were contributed by pembrolizumab vs lenvatinib?

GALLINSON: She had arthralgias that got worse, but I don’t know. It’s not a wrong question.

CHATIWALA: I [read], not in patients with endometrial cancer, but [for patients receiving] pembrolizumab, it came out for patients who were [under] 100 lb to give 100 mg, not give 200 mg in patients who are having serious toxicity [such as] diarrhea, and severe arthralgias.⁶ We tried to reduce the dose; we got a good response and there are adverse events, but not so intolerable.

GALLINSON: I have a patient receiving pembrolizumab for a different disease who has severe arthralgias and needs steroids. I don’t know why this looks different but…she’s convinced she felt better with the dose reduction of the lenvatinib.

CHATIWALA: I had a patient who had diarrhea and I don’t know where she got the idea that it’s from lenvatinib. I tried to explain to her that both could give diarrhea, let’s hold one and try it.

HERZOG: This study was conducted at 20 mg [lenvatinib] along with pembrolizumab at 200 mg every 3 weeks.² Officially, it’s recommended to start at 20 mg. I’ve seen thought leaders who take care of huge numbers of patients with endometrial cancer say that’s what you should do. Then I see others who are equally as busy who say that’s not what you should do, you should start at 14 mg. You can go up, you can go down, give them 10 mg, give them 4 mg, you can go up and down from there. I tend to look at the patient, but I often start at 14 mg, and then I’ll go up to 18 mg. I don’t try to push it much further than that. Would I ever go to 20 mg? Sure, and I have, but it’s rarer for me. But that doesn’t mean it’s the right thing to do.

I got an explanation from the company as to why they went with 20 mg, and it made sense from the pharmacokinetic standpoint. It was a well thought-out process, the whole dose development and dose optimization program they had done. But in the real world, people are doing a lot of different things with that.

SEKHRI: How do you go up? Do you go up every 2 weeks?

HERZOG: I’m in no hurry to go up. I usually wait at least 3 to 4 weeks and make sure that nothing [is wrong].

DISCUSSION QUESTION

• Would your treatment approach be different if the platinum-free interval had been shorter?

GALLINSON: [In that case] I wouldn’t go from carboplatin to carboplatin/paclitaxel.

HERZOG: What would most of you use? Pembrolizumab itself or pembrolizumab/lenvatinib? Would anyone do something different? What is your breakoff? [If the interval was] 12 months, [you would be comfortable] going back. What if it were 6 months?

GALLINSON: Before using lenvatinib/pembrolizumab? Yes, sure.

CHATIWALA: It depends on how desperate you are.

DISCUSSION QUESTION

• If this patient develops disease progression on lenvatinib plus pembrolizumab, what are you likely to recommend as next-line therapy?

HERZOG: It depends on how long it’s been and how she [responded] with it. A year out, would you go back to it? You could do single-agent chemotherapy.

GALLINSON: [If the patient] just has pulmonary [nodules] and some [lymph] nodes, could you make an argument [for] hormonal therapy?

HERZOG: Unfortunately, [the case patient] was ER negative, but yes, absolutely. I use hormones frequently in these patients to give them drug holidays and so forth. With some who are ER or progesterone receptor positive, I’ve seen especially the pulmonary metastases respond well.

GALLINSON: Tamoxifen for 3 weeks [alternating with] megestrol acetate for 3 weeks, that is the investigative choice.

HERZOG: That’s what I do. There are some [beliefs that…] if you just go with one the whole time, you eventually get less receptor expression. There are some preclinical data on how that plays out. I’ve never seen serial biopsies to show that in real life.

GALLINSON: Do aromatase inhibitors work in this disease?

HERZOG: We use those as well. mTOR inhibitors are another thing to think about, especially if they have a pathogenic mutation in the PI3 kinase or PTEN pathway. Those are things we think about too.

_REFERENCES

_{1. Fader AN, Roque DM, Siegel E, et al. Randomized phase II trial of carboplatin-paclitaxel versus carboplatin-paclitaxel-trastuzumab in uterine serous carcinomas that overexpress human epidermal growth factor receptor 2/neu. J Clin Oncol. 2018;36(20):2044-2051. doi:10.1200/JCO.2017.76.5966}

_{2. Makker V, Colombo N, Casado Herráez A, et al. Lenvatinib plus pembrolizumab for advanced endometrial cancer. N Engl J Med. 2022;386(5):437-448. doi:10.1056/NEJMoa2108330}

_{3. Clarke MA, Devesa SS, Hammer A, Wentzensen N. Racial and ethnic differences in hysterectomy-corrected uterine corpus cancer mortality by stage and histologic subtype. JAMA Oncol. 2022;8(6):895-903. doi:10.1001/jamaoncol.2022.0009}

_{4. Key statistics for endometrial cancer. American Cancer Society. Updated January 12, 2023. Accessed December 8, 2023. https://tinyurl.com/mvbfcje9}

_{5. Pal SK, Puente J, Heng DYC, et al. Assessing the safety and efficacy of two starting doses of lenvatinib plus everolimus in patients with renal cell carcinoma: a randomized phase 2 trial. Eur Urol. 2022;82(3):283-292. doi:10.1016/j.eururo.2021.12.024}

_{6. Patail NK, Sher AF, Wu S. Improving tolerability of pembrolizumab with weight based dosing: a meta-analysis. J Clin Oncol. 2021;39(suppl_15):2639. doi:10.1200/JCO.2021.39.15_suppl.2639}