Ritu Salani, MD, MBA:
The established standard treatment for advanced or recurrent endometrial cancer is systemic CT with carboplatin and paclitaxel, based on GOG 209 showing noninferiority for platinum-doubled to doxorubicin.²³ Recently, it was demonstrated that uterine serous carcinomas, which often have a HER2 mutation, can experience a PFS benefit from the addition of trastuzumab to carboplatin and paclitaxel (HR: 0.58).²⁴ However, even with that regimen, patients often experience disease recurrence. Exploring options for therapy in advanced and recurrent endometrial cancer remains an important area of clinical study.

Ritu Salani, MD, MBA:
KEYNOTE-158 is an ongoing, single-arm, phase II basket trial of pembrolizumab in patients with solid tumors and microsatellite instability–high (MSI-H) or MMRd tumors.^25,26 Results to date have shown that patients in the MSI-H endometrial cancer cohort (N = 49) had an ORR of 57%, including 16% with complete responses (CRs), far surpassing responses with standard CT. Of note, the median duration of response (DoR) was prolonged and had not been reached at the time these data were reported.

In 2017, the FDA issued a landmark tissue/site-agnostic approval for pembrolizumab for treatment of unresectable/metastatic, MSI-H/MMRd solid tumors that had progressed after prior therapy and lacked alternative treatment options.²⁷ MSI status can be assessed by performing immunohistochemistry for inactivation of at least 1 of 4 key MMRd proteins (MLH1, MSH2, MSH6, and PMS2). It also can be assessed using next-generation sequencing. Currently, the phase III NRG-GY018 study is evaluating the addition of pembrolizumab to carboplatin plus paclitaxel in an estimated 810 patients with recurrent or stage III/IV primary endometrial cancer (NCT03914612).

Ritu Salani, MD, MBA:
The phase I GARNET study looked at the PD-1 inhibitor dostarlimab in patients with advanced or recurrent solid tumors (N = 740).²⁸ In the cohort of patients with endometrial cancer and MMRd (n = 103), there was an impressive ORR of almost 45%, with CRs in 10.7% and a long median DoR of 34.7 months. Based on these data, the FDA approved dostarlimab for MMRd recurrent or advanced endometrial cancer with progression on a platinum-containing regimen.²⁹ The ongoing phase III RUBY trial is directly comparing carboplatin plus paclitaxel with placebo or dostarlimab in patients with recurrent or primary advanced endometrial cancer (NCT03981796).

Ritu Salani, MD, MBA:
Results from the phase I GARNET trial showed significantly higher response rates in the MMRd vs the MMRp cohort (44.7% vs 13.4%). Three (2.1%) patients in the MMRp group achieved a CR vs 11 patients (10.7%) in the MMRd group. The median DoR was 34.7 months in the MMRd cohort and was not reached in the MMRp cohort.

Ritu Salani, MD, MBA:
KEYNOTE-775 is an ongoing phase III trial comparing lenvatinib plus pembrolizumab vs doxorubicin or paclitaxel in patients with advanced, recurrent, or metastatic endometrial cancer (N = 827).³⁰ The primary endpoints were PFS (by blinded independent central review) and overall survival (OS), with secondary endpoints including responses, health-related quality of life, pharmacokinetics, and safety. Of importance, patients were stratified by mismatch repair status.

Results from KEYNOTE-775 supported the 2021 FDA approval of this combination for the treatment of advanced endometrial cancer that is not MSI-H or MMRd with progression on systemic therapies.²⁷

Ritu Salani, MD, MBA:
In results presented at SGO 2021 for the patients with MMRp, the ORR was 30.3% with lenvatinib plus pembrolizumab compared with 15% for single-agent CT (P <.0001).³⁰ Correspondingly, CR, partial response, and stable disease (SD) rates were all substantially higher with the immunotherapy combination as well. In the MMRp group, the median DoR was 9.2 months vs 5.7 with CT, and the median time to response was 2.1 vs 3.5 months, respectively.

Results in the overall cohort, which included the MMRd subset, were comparable but not quite as robust.

Ritu Salani, MD, MBA:
The PFS and OS curves from KEYNOTE-775 clearly showed a trend favoring lenvatinib and pembrolizumab in all patients and in the MMRp cohort. In the MMRp group, the median PFS was 6.6 months vs 3.8 months with CT (HR: 060; P <.0001). Likewise, in this group, median OS was 17.4 months vs 12.0 months, respectively (HR: 0.68; P = .0001). As mentioned, these results led to full FDA approval of this combination in this setting.

Ritu Salani, MD, MBA:
The combined toxicity profile of lenvatinib and pembrolizumab must be a consideration when selecting therapy. Diarrhea is an issue with single-agent immunotherapy and is exacerbated with the addition of lenvatinib. In KEYNOTE-775, more than half of patients receiving the combination had diarrhea, which was grade 3 or worse in nearly 8%. This is highly disruptive for patients and affects their daily life, so patients need to be counseled on it and provided with management strategies. These can include antidiarrheal agents, steroids, and most importantly, holding the medication to allow the patients’ symptoms to recover.

Of note, the combination was associated with increased hypertension with an early onset. In total, 64% of patients had hypertension, and this was grade 3 or worse in nearly 40%. I now advise my patients taking lenvatinib and pembrolizumab to get a blood pressure cuff to monitor at home. Managing these issues early and in partnership with a patient’s primary care specialist can minimize long-term risk of hypertension and allow them to continue the therapy safely.

Hypothyroidism also was observed in 57% of patients but was grade 3 or worse in only 1.2%. Other grade 3 or worse AEs included nausea (3.4%), decreased appetite (7.9%), and vomiting (2.7%).

Ritu Salani, MD, MBA:
Colombo and colleagues³¹ presented a post hoc analysis of KEYNOTE-775 at ESMO 2021 that is really interesting.³¹ The PFS curves showed that tumors with endometrioid, serous, and clear cell histology all had improved outcomes with lenvatinib and pembrolizumab (HRs: 0.49-0.59). Physicians should feel comfortable using this regimen across these histologies.

Ritu Salani, MD, MBA:
Likewise, the post hoc analysis also showed OS improvements for the immunotherapy regimen across tumor histologies, again in the MMRp group. I was particularly struck by the difference in the clear cell histology subset, which appears to be more responsive to immunotherapy with a median OS of 19.9 months vs 8.7 months with CT (HR: 0.34), which I think is exciting and warrants further exploration.

Ritu Salani, MD, MBA:
New agents often come with challenges regarding safety profiles, such as the class effect AEs seen with immunotherapy. Of importance, rates of AEs are similar between endometrial cancer and solid tumors more generally.^26,29,32 These are typically very well tolerated, with low-grade fatigue and diarrhea being the most common. Diarrhea is one of the more challenging AEs associated with immunotherapy, particularly in patients who’ve had prior radiation therapy. Diarrhea is generally well managed by encouraging patients to notify their team, plus use of agents such as loperamide or antidiarrheals, and steroid therapy or anti-inflammatory therapy as needed.

Immune-related adverse events (irAEs) can include thyroid disorders as well as colitis and pneumonitis. I recommend that patients are evaluated with the appropriate laboratory tests, particularly for those with thyroid disorders and then partnering with an endocrine specialist or primary care physician to ensure appropriate management when these AEs occur.

Eva Y. Pan, PharmD, BCOP:
In recent years, the combination of pembrolizumab plus lenvatinib has improved the treatment of endometrial cancer. This regimen is often used in patients who are failing first-line carboplatin and paclitaxel, and its inherent toxicity means pharmacists need to ensure the patient’s healthcare team understands immunotherapy-related concerns.

It's not only important for pharmacists to educate patients about the toxicities of their treatment, including irAEs, but also for the patients to contact the team if any AEs do occur. In addition, the patient’s other healthcare professionals, specifically those who are not in oncology, should understand that the patient is receiving immunotherapy. Most clinics give immunotherapy wallet cards to patients to quickly explain to other healthcare professionals which immunotherapy they are taking and how to contact their oncology team. This card can be invaluable if the patient needs to present to urgent care or to the emergency department, as irAEs can present in any organ, and nearly any symptom could be related to an irAE. It is also important to note that irAEs should be assessed at each treatment cycle for the first 3 months.

The patient’s team should have a low threshold for starting steroids or systemic immunosuppression if an irAE is concerning. This is where pharmacists have a key role in assessing a patient’s symptoms and suggesting interventions or changes.³³

• Grade 1 irAEs: Management is mostly symptomatic. Immunotherapy can be continued, and the patient doesn’t necessarily need systemic steroids.
• Grade 2 irAEs: Consider stopping immunotherapy and systemic steroids.
• Grade 3/4 (severe) irAEs: Require stopping immunotherapy, starting systemic steroids and involving specialist to help manage symptoms/effects on the specific organ system.

Eva Y. Pan, PharmD, BCOP:
The NCCN publishes regularly updated consensus guidelines for the management of irAEs. Together with NCCN, Clinical Care Options has developed an Interactive Decision Support Tool to help healthcare professionals manage irAEs in patients receiving immune checkpoint inhibitor–based therapy, using specific patient characteristics. Enter specific patient characteristics such as organ system and toxicity grade, and receive irAE management recommendations tailored to that patient.

Eva Y. Pan, PharmD, BCOP:
Although the combination of lenvatinib and pembrolizumab is a standard of care,^27,34 we have observed in our clinic over the last few years that lenvatinib can be challenging for patients to tolerate. As seen in KEYNOTE-775, patients with endometrial cancer can experience significant fatigue, myelosuppression, as well as severe hypertension or other serious toxicities on this regimen.³⁵ It is critical to counsel patients on these toxicities as they may misunderstand the relative safety of their treatment options.

Because of the toxicity, even though the recommended starting dose for lenvatinib is 20 mg, many healthcare professionals choose to start with lower doses of 14 mg or 10 mg if patients are older, have comorbidities, or generally have a poor performance status. Nurses should be trained to support patients in adhering to their medication regimen because they may be receiving treatment for a long time.

In the initial weeks of lenvatinib treatment, specialty pharmacy staff should reach out to the patient at least twice weekly to see how they’re tolerating the drug. Checking in with patients can be very beneficial and can help patients reach out to their healthcare professional if they are experiencing AEs.

Hypertension can be very debilitating with lenvatinib, and patients often need antihypertensive medication. In our clinic, the nurses keep a binder for all patients who are actively receiving lenvatinib. When patients first start lenvatinib, they are instructed to get a blood pressure cuff (if they don’t already have one) and record their blood pressure every day for the first 2 weeks. A nurse will call them regularly to check on their blood pressure. If their blood pressure records are not concerning, the nurse may call to check in less often. However, if their blood pressure is concerning, they may need a referral to a cardiologist plus a prescription for antihypertensive medication.

Eva Y. Pan, PharmD, BCOP:
How and colleagues³⁶ at MD Anderson Cancer Center recently published a retrospective review comparing the starting dose for lenvatinib of 20 mg vs 14 mg or other lower doses in patients with recurrent endometrial cancer.³⁶ There’s been strong interest in this review because so many healthcare professionals already are starting patients at a lower dose of lenvatinib. With the caveat that this was a small study (N = 70), roughly 77% of patients started at a reduced dose.

The 20-mg dose was associated with significantly more dose reductions (P = .016), fatigue, anorexia, gastrointestinal toxicity, and more hematologic toxicity. Moreover, there was a significantly shorter time to treatment toxicity of 1.3 months with the 20-mg dose compared with 3.7 months with the reduced dose (P = .0001). Of note, there was no significant difference in response rate, PFS, or OS between the 2 dose groups. This study provides some reassurance that starting at 14 mg (or another lower dose) may be warranted. 

Ritu Salani, MD, MBA:
Now, moving on from immunotherapy. Selinexor is a selective inhibitor of the nuclear export protein XPO1 and can selectively induce apoptosis in malignant cells although sparing most normal cells. At SGO 2022, Vergote and colleagues³⁷ presented results from the ongoing phase III SIENDO study of maintenance selinexor vs placebo in patients with recurrent endometrial cancer (N = 263). In this trial, patients with stage IV or relapsed endometrial cancer and a response to first-line CT are being randomized 2:1 to receive selinexor 80 mg once weekly (or 60 mg once weekly if BMI is <20 kg/m²) vs placebo. Patients will receive treatment until disease progression, and the primary endpoint is investigator-assessed PFS.

Ritu Salani, MD, MBA:
Baseline characteristics are comparable between groups. There is a range of histologies, approximately 50% of which are endometrioid and approximately 30% of which are serous. The median age is 65 years, and nearly all patients had received a single previous regimen. Approximately 60% of patients had achieved a PR to their previous regimen, with the remainder 40% achieving CRs.

Ritu Salani, MD, MBA:
As mentioned, the primary endpoint in SIENDO was investigator-assessed PFS. Of importance, the median PFS was significantly longer in the selinexor maintenance group at 5.7 months vs 3.8 months with placebo (HR: 0.705; 1-sided P = .24). Of note, the PFS probability for patients who are at high risk for recurrence generally tends to drop off, but in this study, PFS was sustained for 1 year with selinexor in 35% of patients compared with only 26% with placebo.

Ritu Salani, MD, MBA:
Further analysis showed that the benefit of selinexor appears to be strongest with endometrioid histology, where the median PFS was 9.2 months vs 3.8 months with placebo (HR: 0.57; P = .014). By contrast, the HR in patients with serous histology was 0.85 and was not statistically significant (P = .309).

Ritu Salani, MD, MBA:
Within the subgroup of patients with endometrioid histology, those with wild-type P53 had an even more pronounced benefit from selinexor. This group had a median PFS of 13.7 months with selinexor compared with 3.7 months with placebo (HR: 0.375; 1-sided P = .0003). Further analyses are being undertaken to explore this promising early result.

Ritu Salani, MD, MBA:
If the approval of selinexor is expanded to include endometrial cancer, healthcare professionals in this space will have to learn to manage the AEs of this novel agent. In the SIENDO study, selinexor was generally well tolerated. Gastrointestinal symptoms were commonly seen, but few were grade 3/4. For example, 84% of patients had nausea, but only 10% was grade 3/4. Likewise, 52% of patients had vomiting and 37% had constipation, but only 2% or 1% were grade 3/4, respectively. Thrombocytopenia was seen in 37% of patients receiving selinexor (6% grade 3/4), and all-grade anemia and neutropenia were seen in approximately one quarter of patients each. As in other tumor types where selinexor is approved, the dosing will be critical as this drug potentially may be difficult to tolerate in some patients.

Ritu Salani, MD, MBA:
In SIENDO, there was a high rate of dose reductions and dose interruptions with selinexor, occurring in 50% of patients. However, only about 10% of patients discontinued the drug, suggesting that if safety concerns are properly managed with the appropriate interventions, patients may stay on therapy longer. Regarding quality of life, patient-reported outcomes using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 did not show statistical differences between arms.

Overall, what I find really valuable about this study, and this agent in general, is that it opens the door to maintenance therapy in endometrial cancer where there has been no clear maintenance strategy. If selinexor were to receive FDA approval in this setting, I think it would be limited to patients with endometrioid histology, quite possibly only those with wild-type P53, due to the benefit in SIENDO discussed earlier. However, this is a small study, and I’m hoping that further investigation of selinexor will clarify the potential role of this agent in patients with endometrial cancer.

I also would like to note that the dosing may be challenging in the community setting. On a clinical trial, patients are closely monitored for toxicities, and this aspect likely will need to become part of standard clinical practice with selinexor maintenance for endometrial cancer.