Paul A. DiSilvestro, MD (MODERATOR)
Director, Program in Women’s Oncology
Women & Infants Hospital of Rhode Island
Professor of Obstetrics and Gynecology
EVENT REGION Massachusetts, New Hampshire, Rhode Island
PARTICIPANT LIST Susana Campos, MD | Heather Benjamin, MD | Robert Koch, MD
In August 2021, a 64-year-old postmenopausal woman presented with abnormal uterine bleeding lasting 4 months. She had a history of arthritis, obesity (body mass index = 40), and well-controlled hypertension. Her ECOG performance status was 1. She was counseled on surgical options and scheduled for surgery. She received a diagnosis of stage IA, grade 1 endometrial cancer. Immunohistochemistry and molecular testing results showed the disease is mismatch repair deficient (dMMR), high microsatellite instability (MSI-H), and 3+ estrogen receptor positive.
In August 2022, she reported intermittent pelvic pain over the prior 4 weeks. A CT scan of the chest, abdomen, and pelvis (CT CAP) suggested relapsed/metastatic disease with involvement of 1 right external iliac lymph node. Carboplatin/ paclitaxel was administered for 6 cycles every 4 weeks. Chemotherapy was well tolerated and a complete response (CR) was recorded at the end of the regimen.
In April 2023, disease relapse was documented on routine follow-up. CT CAP showed a heterogeneously enhancing mass in the right suprarenal space, multiple bilateral pulmonary nodules, and a new right internal iliac lymph node in addition to the previously observed positive lymph node. Fine needle aspirate of the suprarenal mass confirmed metastatic endometrioid adenocarcinoma. The patient was counseled about systemic therapy options, during which she repeatedly expressed concerns about adverse events (AEs).
Through shared decision-making, immune checkpoint inhibitor (ICI) monotherapy was planned. The patient started on dostarlimab (Jemperli) with instructions to continue follow-up every 3 months.
- What factors influence your immune checkpoint inhibitor preference for a patient like this?
DISILVESTRO: When you think about teaching your residents or fellows and you say, “We have this [patient with] dMMR recurrent endometrial cancer, we want to give her an ICI, how do you decide which 1 of the 2 [treatments]?” Which factors do you think about when you pick one?
CAMPOS: I wish I had the ability to influence it, but in essence, it’s influenced by our pharmacy.
DISILVESTRO: Great point. We’re very active on the GARNET [NCT02715284] and RUBY [NCT03981796] studies— and I went to my pharmacy and said I wanted to order dostarlimab for this patient. They [said] they don’t have it on formulary. I’m [now] finally able to get it, but you’re absolutely right, Dr Campos. What do you have on formulary? [Do you have] pembrolizumab [Keytruda]?
CAMPOS: We have pembrolizumab. It’s interesting, and this may be a point that we discuss…in terms of the end points of certain studies and what the end points were and do these end points somehow influence what a formulary should have.
If you have an overall survival benefit, should that trump [another study with] no survival benefit or not? I think these are great questions that are going to come to light. We have pembrolizumab and we introduced dostarlimab. It was a very thoughtful process in terms of yes or no but, at the end of the day, are these really under our control or not?
DISILVESTRO: Any other experiences [participants] have with their pharmacies not allowing both?
BENJAMIN: We initially [only] had… pembrolizumab approved, but because there are multiple disease sites for which we’re advocating [for dostarlimab], it was hard for the administration to say no because of various malignancies, like rectal cancer, for which we needed it added to the formulary. Fortunately, we were able to [get it], but I agree, everything takes time and work, and you have to prove why it’s needed.
KOCH: This patient is incurable with pulmonary metastases. I didn’t get a good feel for what her symptomatic burden was, so that makes it a little difficult to make a choice. Given the fact that she does have incurable disease, that has to get factored into the decision-making process, and my awareness is that dostarlimab is an expensive long-term therapy. I’m not sure that it results in an improved quality of life in a patient such as this, so that’s why I [would] choose pembrolizumab.
DISILVESTRO: That’s a great point. I use dostarlimab…and that’s mainly because we participate on the trials that use dostarlimab. I can’t [dismiss] somebody who says one is more efficacious per se than the other, but for us it was the familiarity. We didn’t participate in the KEYNOTE studies. There are a lot of reasons why you might choose one or the other. The dosing and schedule [are a factor]; obviously you can go to the every-6-weeks strategy now [for pembrolizumab], and so that’s the same [for dostarlimab after 4 doses]. Formulary reimbursement, which Dr Koch brought up, is an important point.
Q:In terms of safety as a single agent, what was most notable about dostarlimab?
DISILVESTRO: If we look at the GARNET trial [NCT02715284], 99% of patients had some sort of treatment-emergent AE, with 58% having some form of grade 3 AE.1 One patient might have had multiple grade 3s, but the rate of grade 3 treatment-related AEs was about 19% in the overall population. Less than half of that was attributable to what was considered to be an immune-related treatment-related AE. No patients died, and so most of the treatment-emergent AEs were grade 1 or 2 and are manageable. About 9% of patients discontinued treatment because of this, which is about half of what we saw in the RUBY trial [NCT03981796] for dostarlimab [plus chemotherapy].2 This is a lower rate in GARNET.… You’re seeing treatment-related AEs in terms of hepatitis and of diarrhea reflecting colitis, hyperglycemia, pneumonitis— the types of AEs that we see in our [practice].
- Please share your experiences with immune-related AEs in patients receiving an ICI-based regimen for endometrial cancer.
- What are your strategies to mitigate or manage AEs?
DISILVESTRO: Do [you] wait to restart ICI therapy pending the response of the free T4 level or [would] you just start levothyroxine and press on [From the Data1,3]?
BENJAMIN: This patient was symptomatic and that would caution me to restart and initiate levothyroxine at the same time, but in some patients the call is close. It’s more of a laboratory abnormality you’re seeing. It’s not extreme, and those are the patients that I more [likely] consider concurrent levothyroxine while awaiting the normalization. But based on the symptoms, I’d prefer to wait until that normalization or at least [until] it’s improving, and the symptoms have gone away.
DISILVESTRO: Yes, and in so many of these patients we see it just from a serum panel, looking at it as a labor-atory abnormality for so many and they’re unaffected, but we do ultimately start treating them. For the group in general, from what you see in clinical trials, does your real-world experience reflect what’s been seen in these trials? Are we seeing anything unusual? Do you see things happen at a higher rate than what the trials might tell you or does that seem consistent?
CAMPOS: Everyone knows [about] the pneumonitis, the colitis, [and] the hepatitis. It’s more the subtle issues that you don’t know [about]. I had a patient with a hypercalcemia that ended up being pembrolizumab related, and we based her treatment on some case reports, but that’s what I think it emanated from. It’s not the common things that we’ve all heard about. It’s more the subtle things that maybe a laboratory result may be…abnormal and you…don’t know if that has any significance but it might, in essence, be related to a system that you haven’t given enough thought to. The part that worries me the most is that [an ICI] can do anything, and you must think when you see anything that it could be related to pembrolizumab or dostarlimab or any immune therapy not otherwise specified. The hardest part is knowing when to act or [not], and if you act, are you negating what you tried to achieve? That’s the part that becomes [challenging when] dealing with these types of agents.
DISILVESTRO: Right, and to your point, I know there are certain institutions that have teams that are there to intervene with AEs related to immune checkpoint inhibition. There are some general guidelines, [ for example, from] the American Society of Clinical Oncology4....There are very specific guidelines about how to do this and the resources are in a lot of places. The interesting thing about ICIs is there are no recommendations for dose reduction.
DISILVESTRO: People here have managed ICIs before, but we see some pretty severe [AEs]. I’ve seen some very severe colitis, which is unfortunate.
CAMPOS: In the past I’ve seen people die from toxicity from immunotherapy earlier on. These are very interesting drugs that sometimes have an unpredictable direction.
BENJAMIN: Even [with] atypical presentations—I had a patient with lung cancer who had initial chemoradiotherapy followed by immunotherapy and he had some difficulty swallowing while on the immunotherapy. I was thinking [about the] chemoradiotherapy, did a scope, and tried to figure it out, but it ended up being myasthenia gravis related to immunotherapy, and his main focal symptom [was] difficulty swallowing.
That didn’t cross my mind for a while. For weeks he was having difficulty and then it progressed to the point where he was hospitalized and unable to take oral intake. That was so atypical in this sense but [it is] something to consider [with] the wider differential [as to] when you [should] act, and when do you think it’s related to the ICI?
CAMPOS: I [suspect] immunotherapy for every [AE] until otherwise proven.
KOCH: The thing to know is the phase 1 [data] for immunotherapies to try to determine to know which doses were documented to be both effective and safe. I don’t know those data, but I would think that there are not dose-reduction guidelines because the doses that we have become accustomed to using are the doses that have been based on previous trials or studies that have been shown to be effective and safe. I would think that those are the data to look at.
DISILVESTRO: No, I think so, too. It’s an exposure issue at that safe dose, so it’s not the amount you’re getting; it’s whether you’re getting it or not, whether we can drop it down, is it efficacious? I don’t have those data, either.
1. Oaknin A, Gilbert L, Tinker AV, et al. Safety and antitumor activity of dostarlimab in patients with advanced or recurrent DNA mismatch repair deficient/ microsatellite instability-high (dMMR/MSI-H) or proficient/stable (MMRp/MSS) endometrial cancer: interim results from GARNET-a phase I, single-arm study. J Immunother Cancer. 2022;10(1):e003777. doi:10.1136/jitc-2021-003777
2. Mirza MR, Chase DM, Slomovitz BM, et al. Dostarlimab for primary advanced or recurrent endometrial cancer. N Engl J Med. 2023;388(23):2145-2158. doi:10.1056/NEJMoa2216334
3. Jemperli. Prescribing information. GlaxoSmithKline; 2023. Accessed September 19, 2023. https://tinyurl.com/ym67vkm6
4. Schneider BJ, Naidoo J, Santomasso BD, et al. Management of immune-related adverse events in patients treated with immune checkpoint inhibitor therapy: ASCO guideline update. J Clin Oncol. 2021;39(36):4073-4126. doi:10.1200/JCO.21.01440