CASE SUMMARY
A postmenopausal woman aged 64 years presented with abnormal uterine bleeding lasting 4 months. She underwent menopause at 55 years old. She is a widow, has no children, and lives alone. She had a medical history of arthritis, obesity (body mass index = 40), and hypertension well controlled with medication. Her ECOG performance score was 1.
Endometrial biopsy showed endometrioid adenocarcinoma, International Federation of Gynecology and Obstetrics (FIGO) grade 1A confined to the uterus. It was grade 1, well differentiated. Immunohistochemistry and molecular testing showed mismatch repair deficiency (dMMR), microsatellite instability-high (MSI-H), HER2-negative, NTRK-negative, and 3+ estrogen receptor (ER)-positive disease.
The patient opted for external beam radiation therapy after counseling. Ten months after completion, she reported intermittent bleeding over the prior 4 weeks. CT scan of the chest, abdomen, and pelvis suggested relapsed/metastatic disease with involvement of 1 right iliac lymph node, FIGO stage IIIC1. She received carboplatin/paclitaxel for 6 cycles and had a complete response.
Four months after chemotherapy completion, disease relapse was documented on follow-up. She had a heterogeneously enhancing mass in right suprarenal space, multiple bilateral pulmonary nodules, and a new right internal iliac lymph node (in addition to the previously observed positive lymph node). Metastatic endometrioid carcinoma was confirmed. The patient expressed concern about adverse events (AEs) of systemic therapy options.
NG: [One] reason I would think of using pembrolizumab [Keytruda] preferentially: I believe dostarlimab [Jemperli] has a loading dose required. Then, [for] pembrolizumab, you can do a longer interval, 6 weeks even from the beginning vs dostarlimab, which has the loading frequency that’s a little shorter.
POTHURI: The way that it was studied in GARNET [NCT02715284], dostarlimab was given every 3 weeks [at 500 mg] for 4 cycles, and then it was moved to [1000 mg] every 6 weeks.1 Nobody has ever looked at just starting with it every 6 weeks. With pembrolizumab, the switch [from 200 mg every 3 weeks to 400 mg every 6 weeks] was based on some retrospective data.2 It’s a good point that you bring up, because all the initial studies with pembrolizumab were done with every 3 weeks [dosing].3 They’re not done with every 6 weeks [dosing]. Yet now it’s utilized that way.
MODERATOR SIDEBAR
Targeted OncologyTM: What does the American Society of Clinical Oncology recommend for managing adverse effects (AEs) associated with immune checkpoint inhibitors (ICIs)?
POTHURI: Overall, there should be a high level of suspicion when new symptoms arise. Consult promptly with relevant specialists. I’m very quick to consult my colleagues. There’s no dose reduction for immunotherapy. You hold, but you don’t necessarily dose reduce.
In general, with grade 1 AEs, you observe and give supportive care, and you continue the ICI.5 With grade 2 AEs, you can do local or noninvasive interventions. You can hold the ICI, and then you can resume it once the toxicity resolves to grade 1. You can [give] low-dose corticosteroids, which I have had to do. And you may be able to continue treatment through that. But with the higher grades, you need to stop the ICI immediately. Sometimes, you may need to hospitalize the patient. You do need the high-dose steroids, 1.5 mg/kg to 2.0 mg/kg. Once they have a grade 3, don’t stop that steroid taper quickly. I continue them for a minimum of 4 weeks. I don’t stop, and I don’t start tapering until it’s resolved down to a grade 1 [toxicity]. The grade 4 toxicities are life-threatening and they require urgent intervention. You should permanently discontinue checkpoint therapy.
What concerns are there for endocrine toxicities?
With endocrine toxicities, the overall incidence is about 10%. You can have different symptoms, like headache, visual changes, [or] visual field changes, especially if there’s pituitary swelling. With hypothyroidism, you can have all the usual [symptoms]: cold intolerance, dry skin, constipation, weight gain, and fatigue. I’ve had a patient with adrenal insufficiency who had significant weight loss, lack of any energy, and profound fatigue, where she couldn’t even walk. Just keep that in mind, because it’s not something that we see very often, but it is real. Diabetes and diabetic ketoacidosis may also present from an endocrine standpoint.
What is recommended when it comes to managing AEs with corticosteroids? Think about the patient’s preexisting comorbid conditions before you start the steroid. Make sure you do prophylaxis for pneumocystis pneumonia if you’re using the high-dose steroids, and monitor those. Monitor for short- and long-term AEs. You may need to do gastrointestinal prophylaxis with a proton pump inhibitor or an H2 blocker, and it’s recommended if the patient is going to be on these longer-term steroids. The taper should be slow, over 4 to 6 weeks. You should see them regularly to make sure there’s not…a rebound of the immune-related AE. Then, sometimes, you may need longer tapers for a complete resolution to avoid rebound.
What factors influence your ICI [preference] for a patient like this?
WIEDER: For me, it’s mostly familiarity. Pembrolizumab is just something that I use most often, based upon the indications that it has. It is very well tolerated. It is easy to dose. [It has] good efficacy. But mostly it’s just the go-to, because of my personal experience with it.
POTHURI: Does anybody have pathways at their institution that [point toward] the ICI that they have on formulary, and that’s what they use? How many participants have dostarlimab on formulary?
WIEDER: I’m not sure.
SALMAN: No, we don’t have it. No, not in our formulary.
POTHURI: I had to advocate hard through the pharmacy committee to even get it at my institution [Perlmutter Cancer Center]. I was one of the senior authors on the GARNET trial, so it just goes to show you that [oncologists] are not aware that it’s even an option, and they don’t know if it’s at their institutions or not.
BRAUNSTEIN: Are there any advantages to dostarlimab over pembrolizumab in terms of dosing or [anything else]?
POTHURI: I can’t say that there’s any advantages in terms of the dosing. In the data, [their tolerability] look very similar [Figures 1 and 21,3], but I will tell you, anecdotally, I find that the dostarlimab is a little better tolerated, just in terms of day-to-day AEs. That’s why I like it for my patients. That is not borne out in the data, but sometimes it’s a little bit different when you’re using it in the clinic vs the numbers that you see [in the trial].
Does anybody use [dostarlimab] in a different tumor type? [Considering] the rectal cancer data? Any perceptions of the agent?
BLOKH: My perception is it’s probably going to work pretty much as any of these ICIs. You’re getting 100% [complete] response rates in rectal cancer.4 Clearly, that’s [due to] the drug. I have a feeling there are going to be very small differences in efficacy between it and the competitors.
CHEUNG: I usually use pembrolizumab in this kind of patient. Would you give it every 3 weeks or every 6 weeks?
POTHURI: What I tend to do is start at every 3 weeks, just to make sure they’re tolerating it. Then, after a couple cycles, if everything’s good, I’m more than willing to just move them to every 6 weeks. But you’re right, because the trial looked at it every 3 weeks.3
POTHURI: In your experience, how long do patients typically remain on single-agent checkpoint inhibitor for advanced dMMR, MSI-H endometrial cancer? And what is the longest a patient has remained on a checkpoint inhibitor?
MO: Some patients [can receive ICIs for] very long. I have a patient [who has received 1] for more than 3 years.
POTHURI: Do they still have disease? Is that why they’re still on it? Because I tend to come off after 2 years if they’ve had a complete response or a maximal response.
MO: I think [they have] stable disease.
POTHURI: All right, it goes to show you that they can be maintained for a long time.
POTHURI: Please share your experience with irAEs in patients receiving a checkpoint inhibitor regimen for endometrial cancer. Do you think your real-world experience reflects the data? Are there any AEs that concern you more than others?
BLOKH: I don’t treat endometrial cancer right now, but I would say, in general, single-agent ICIs are well tolerated. You can get into trouble when you start adding doublets in other diseases, like melanoma. Then you may have some more toxicity. But when I’ve given single-agent ICIs, I haven’t had much severe, high-grade toxicity.
POTHURI: I would agree with that. I find they’re very easy to use. The biggest thing is really educating patients about the irAEs so they’re recognized early, because if unrecognized, they can be fatal. Educate them about talking to you about if they have shortness of breath or a cough, even [if] it’s low, [because of concern] about pneumonitis. [Or pay attention] if they have bloody or crampy diarrhea. Because I have seen some patients get very sick when irAEs have been unrecognized, or they get recognized too late.
SALMAN: In my practice, the most troublesome AEs are these pneumonitis-like symptoms. We do periodic blood monitoring for the thyroid functions…and [manage] the diarrhea. But [for] pneumonitis in this age, is it a virus, is it COVID-19, is it pneumonia, [or] is it an irAE? It becomes a problem, and the physicians will also get nervous. Is it an AE from the ICI or is it a real infection? Then, [should patients] start the steroids or not start them, or start an antibiotic?
POTHURI: I would agree, and I tend to consult my pulmonary colleagues early on, and if there’s a question, even consider getting some tissue to look at that. But it does need to be recognized and treated early, as you point out, and it is troublesome if it’s difficult to identify or diagnose.
MELLACHERUVU: Does anybody have experience with resensitization or rechallenging with another ICI, [such as] for infusion reactions?
POTHURI: We tend to premedicate for those, and for the immune-related infusion reactions, and haven’t really needed to switch.
DAI: For immune hepatitis, when the liver enzyme goes high, often the first step I do is to hold the ICI and start the patient on steroids. I even consult a gastroenterology colleague. When the liver enzymes go down to normal, do you usually rechallenge? I often feel like when you restart it, it’s going to happen again. For the thyroid function, I feel it’s easier to manage. You can just use medication to change that. But for the hepatitis, I often just stop the treatment.
POTHURI: I would tend to agree with you. But I have tried to rechallenge, and I often leave patients on the 10-mg prednisone dose if I’m going to do that. There have been a few patients whom I have been able to successfully keep on. But, in general, you are right. It is much more difficult with the LFT [liver function test] increase than it is with things like thyroid and rash and other lesser irAEs. Are there any resources that you provide to your patients?
BRAUNSTEIN: I give them a card that says that they’re on immunotherapy [Figure 3].
POTHURI: Yes, that’s a great point. If they get admitted to the emergency department or different outside hospitals, [it’s good for providers] to know what they’re on.
REFERENCES
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. Lala M, Li TR, de Alwis DP, et al. A six-weekly dosing schedule for pembrolizumab in patients with cancer based on evaluation using modelling and simulation. Eur J Cancer. 2020;131:68-75. doi:10.1016/j.ejca.2020.02.016
3. O’Malley DM, Bariani GM, Cassier PA, et al. Pembrolizumab in patients with microsatellite instability-high advanced endometrial cancer: results from the KEYNOTE-158 study. J Clin Oncol. 2022;40(7):752-761. doi:10.1200/ JCO.21.01874
4. Cercek A, Lumish M, Sinopoli J, et al. PD-1 blockade in mismatch repair-deficient, locally advanced rectal cancer. N Engl J Med. 2022;386(25):2363-
2376. doi:10.1056/NEJMoa2201445
5. 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
