Second-Line Options Expand With the Use of Immunotherapy in Advanced Endometrial Cancer

As clinical use of immunotherapies begins to take hold in endometrial cancer, it is an exciting time to care for patients with this disease, according to Courtney Arn, APRN-CNP. With options such as lenvatinib (Lenvima) and pembrolizumab (Keytruda) garnering high rates of response and allowing for maintenance of quality of life, Arn noted that patients have better outlooks than ever before.

Courtney Arn, APRN-CNP

“We went a long period of time without any new advancements of gynecologic [or], specifically, endometrial cancer,” Arn said. “It is an exciting time…because there are constantly new indications, [but also] new adverse event [AE] management. So [as a nurse, it is important] to make sure that you are constantly allowing yourself to [keep] learning.”

Arn recently served as a moderator during an OncLive Peer Exchange®. This Peer Exchange was structured to put new treatment options under the nursing lens in advanced endometrial cancer. During the discussion, oncology nurse experts examined best treatment options for patients with advanced endometrial cancer with unresectable disease and how nurses can best support their patients through antihormonal therapy, chemotherapy, targeted therapies, immunotherapies, and more.

Surgery Remains Preferred Front-Line Treatment

Surgery is the preferred option whenever possible for women with endometrial cancer,¹ who are likely to receive a total hysterectomy/bilateral salpingo-oophorectomy, to remove the uterus, fallopian tubes, and ovaries. However, surgery is not always possible.¹

Kimberly A. Spickes, CNP

Kimberly A. Spickes, CNP, explained that surgery should always be considered if the patient is eligible, but for patients with pulmonary or liver metastases or a poor cardiac or pulmonary history, or who are overweight and therefore cannot tolerate anesthesia, alternative options are needed. Moreover, women who want to have children may wish to delay surgery. Radiation, either external radiation and/or vaginal brachytherapy, or chemotherapy are common choices. Carboplatin plus paclitaxel is the regimen typically used in this setting, but other drugs can be used as well.¹

Following surgery, the final pathology dictates whether the providers think further radiation or chemotherapy would be useful. Spickes noted that patients who arrive with stage IVB disease are typically started on chemotherapy right away.

Kathleen Lutz, RN, NP-BC WH

Unfortunately, advanced endometrial cancer can have a negative impact on fertility or family planning, which should be addressed with younger patients.² Kathleen Lutz, RN, NP-BC WH, noted that a large number of younger patients with endometrial cancer have arrived at her institution and often present with comorbidities. According to Lutz, the team will spend time up front to gather information using scans to determine if the cancer has spread, to see if they can avoid a systemic therapy such as chemotherapy.

Spickes noted that the process is similar where she works. “We’re seeing more and more younger women [who] want to save their fertility, so we do lots of IUDs [intrauterine devices], or even oral progesterone, depending on their preference,” she said.²

“A great option that we don’t often talk about when we’re talking about treatment for endometrial cancer is the hormonal therapy or the antihormonal therapy [such as] IUDs,” Arn said. “It’s a great option for not only patients who want to have fertility or family planning [flexibility], but also for patients who might not be a surgical candidate. Using those types of treatment options for these higher-risk patients is a really good option that sometimes we forget about or don’t mention.”²

Kimberly Halla, NP

“Some [individuals] are just not good surgical candidates,” added Kimberly Halla, NP. “We do such a good job at that surgical intervention that we forget that surgery does have its issues and it can have some serious AEs. [For] those patients who are not surgically optimized, an IUD or antihormone therapy is perfect. Then you just have to get that buy-in from those patients as well.”²

Halla added that just because a patient has an IUD, this does not mean they are immune from metastasizing disease. That is where the patient buy-in comes into play, she said. Patients interested in this option need to agree to come back for routine sampling to ensure the disease is not spreading. However, according to Halla, as the population of patients with endometrial cancer continues to be younger, having these different options available is important.

Second-Line Options Expand Beyond Chemotherapy

Unfortunately, Lutz said, most endometrial cancer recurrences occur within 3 years in the later stage. “The sites of reoccurrence are fairly evenly distributed between the vagina, the pelvis, [and] distant metastases, including lung metastases,” she said. “Symptoms of a recurrence may include vaginal bleeding, abdominal pain, pelvic pain, a new cough, and, sometimes, unexplained weight loss.” However, Lutz recalled a recent case where a patient who had early endometrial cancer and did not need adjuvant treatment came in 5 years post treatment with no symptoms, but her scans showed lung metastases. Lutz highlighted that cases such as this underscore the importance of staying on top of surveillance and follow-up.

All 4 nursing professionals agreed that the decision to rechallenge with chemotherapy is really an individual one, and thus there is no standard choice for second-line therapy. They noted that clinical trials can be an option for a patient with recurrent disease, but Spickes pointed out that where a patient lives plays a large role in whether they recommend a clinical trial or not. For example, it is not feasible for a patient who lives 3 hours away to come to the office for a clinical trial more than once a week.

Halla noted that, at her institution, when discussing rechallenge with chemotherapy, they use the following saying: “Why get off a winning horse?” What this means is, if a woman experienced a duration of response with chemotherapy that lasted 3 to 5 years, then the chemotherapy was effective to a degree, so a response with rechallenge may be anticipated. However, if a patient experiences disease recurrence quickly, such as within 1 year, then the team will often opt for a different strategy. Pembrolizumab/lenvatinib is a great option for these patients, so long as they do not have microsatellite instability–high (MSI-H) or mismatch repair–deficient (dMMR) disease, she said. For women who have dMMR tumors, pembrolizumab alone is often their choice, she said.

Data from immunotherapy trials support the drug’s use in the second-line setting. Pembrolizumab has demonstrated efficacy, both as a monotherapy in the KEYNOTE-158 trial (NCT02628067) and in combination with lenvatinib, a tyrosine kinase inhibitor, in the KEYNOTE-775 trial (NCT03517449).^3,4 Based on the findings from these trials, the FDA approved both regimens for patients with advanced endometrial cancer.

In data from cohorts D and K of KEYNOTE-158, patients with MSI-H or dMMR advanced endometrial carcinoma (n = 90) experienced an objective response rate of 46% (95% CI, 35%-56%) following treatment with pembrolizumab.³ The median follow-up time was 16.0 months (range, 0.5-62.1), at which point the complete response rate was 12% and the partial response rate was 33%. The median duration of response was not reached (range, 2.9-55.7months). The FDA approved pembrolizumab as a monotherapy on March 21, 2022.⁵

In KEYNOTE-775, which had a total of 827 participants, 697 patients with mismatch repair–proficient disease and 130 with dMMR disease were randomly assigned to receive lenvatinib plus pembrolizumab (n = 411) or chemotherapy (n = 416). The median progression-free survival was longer in the combination arm than in the monotherapy arm (6.6 vs 3.8 months), equaling an HR of 0.60 (95% CI, 0.50-0.72; P < .001). Overall survival was also improved (17.4 vs 12.0 months), with an HR for death of 0.68 (95% CI, 0.56-0.84; P < .001).⁶ The FDA granted accelerated approval to this combination on September 17, 2019, and full approval on July 21, 2021.⁶

Lutz presented a case of a patient aged 76 years who began to receive daily treatment with 14 mg of lenvatinib plus pembrolizumab after the discovery of disease progression in her lungs following surgery. After 1 year with the dual-therapy adjuvant treatment, the patient’s scans demonstrated signs of stable disease and the patient was able to interrupt her dose twice to go on vacation.

“She was able to go and enjoy her 2 vacations. Then we put her back on [treatment] and the symptoms seemed [to lessen],” Lutz said. “This is clearly a good case of where this is a perfect treatment and has given her a good quality of life for quite a long time.”

“A lot of us could probably share a success story of patients who are [receiving] lenvatinib and pembrolizumab,” Arn said. “It’s super exciting because a little over 2 years ago we didn’t have that as a treatment option, and now we’re hearing [about] patients who have been [taking] it for long periods of time and having very low-volume disease, if not a complete response, and they’re able to do those normal daily activities and go on vacations and things like that.” She noted that she also has a younger patient with children who has chosen some treatment interruptions to enjoy vacations with her family without AEs.

Arn said she likes to counsel patients by ensuring they understand that 40% of patients in the clinical trials for lenvatinib/pembrolizumab required dose interruption and that the agent was still approved. She said this helps them feel reassured that they can take some time off treatment to spend time with their family or do things that are important to them without the toxicities of treatment and without compromising their outcome.

“We really have to focus on how we can improve on that quality of life,” Halla said. “We have to individualize our care and that’s why we are [often] cautious in our starting doses. We don’t just lump everybody together at the 20-mg dose. We individualize it. Medications [such as] lenvatinib and pembrolizumab allow us to do that and have so many variations of medication dosages, and [this] allows [patients] more time at home and more time with their families. I’m so happy that these new medications and these new treatment regimens allow more time at home [for] our patients instead of [their being] in the infusion center.”

Spickes shared another success story in her practice. “I have a [woman who was treated] recently with a stage IA sarcoma that recurred 3 months after adjuvant chemotherapy. We gave her lenvatinib and pembrolizumab and she is now disease free after 13 cycles.”

“It used to be if someone progressed that quickly on their primary treatment, we had tough discussions,” Arn said. “Now we’re able to provide them not only with another option that we think could maintain their disease, but [one that can elicit a] complete response.”

AE Management in the Advanced Setting

The panelists agreed that advanced practice providers are conducting the bulk of the work in terms of teaching patients about what to expect from treatment. Lutz noted that communication methods are becoming more electronic based, and the benefit of this is that patients have several ways of communicating with their providers, including via text messages, emails, and MyChart messages. She said she always tells her patients to keep a journal with them, with instructions to write down any questions they have at home, because it is so easy to forget.

For patients undergoing rechallenge with chemotherapy, managing dehydration and fatigue represents key clinical pearls, according to the nursing professionals. In many of their institutions, patients come in every 3 weeks for assessments, and for intravenous hydration fluid as needed. With any anticancer medication, fatigue is a challenging AE to manage because it is subjective, but the panelists talk to their patients about good diet, exercise, and hydration to increase their energy levels.

Immunotherapy

In terms of immunotherapy, patients receiving combination pembrolizumab with lenvatinib and pembrolizumab should be on the lookout for hypertension, hypothyroidism, diarrhea, nausea, decreased appetite, vomiting, weight decrease, fatigue, and arthralgia.^6-8 For those receiving monotherapy with pembrolizumab, the main AEs to be aware of include pruritis, fatigue, diarrhea, arthralgia, nausea, hypothyroidism, and rash. Attention should also be drawn to immune-mediated AEs, such as hypothyroidism, hyperthyroidism, infusion reactions, colitis, and skin reactions.^7,8

In KEYNOTE-775, almost all patients experienced an AE throughout treatment. The most frequently reported AEs were hypertension for patients receiving combination therapy (64.0%), and anemia in those receiving chemotherapy (48.7%). Hypertension was also the most common serious AE with lenvatinib plus pembrolizumab, and febrile neutropenia the most common serious AE to occur with chemotherapy. The rate of grade 5 AEs was 5.7% and 4.9%, respectively.⁹

“I would say hypertension, diarrhea, and fatigue would be the most common [AEs I see],” Spickes said, regarding the combination therapy. “Sometimes the problem is you can get the diarrhea from either the pembrolizumab or from the lenvatinib, so it’s [a matter of] trying to figure out which one.”

“Just the action of taking an oral medication and putting it into your GI [gastrointestinal] system [will cause] some sort of reaction,” added Halla, who noted that some individuals find they need to take the agent with food to combat the associated nausea. “I’ve combated some of the nausea with lenvatinib combination therapy [by having] my patients take their lenvatinib at nighttime so they kind of sleep through that peak [onset] of nausea,” she said. However, she acknowledged that one difficulty with this medication is the risk of hypertension.

“I feel that I’ve really heightened my skills as a hypertension expert because I think that is the hardest thing to [convey to patients],” she said. For example, she explained, a patient aged 35 years may be resistant to understanding why they would need blood pressure medication. “They [say], ‘I don’t need high blood pressure medications….That’s an old people’s disease.’ But they come into the office at 200/100 [mm Hg], right? Talking about hypertension is [key].”

In Halla’s experience, hypothyroidism also comes into play a lot with this combination, and both lenvatinib and pembrolizumab can cause hypothyroidism. Because lenvatinib has the shorter shelf life, she said, it is easiest to hold that drug for 1 or 2 days to ascertain whether the pembrolizumab is driving the toxicity.

In KEYNOTE-158, 151 patients (64.8%) developed a treatment-related AE (TRAE) and 34 (14.6%) experienced a TRAE between grade 3 and 4. Of note, 7.5% of patients (n = 18) in this trial experienced a serious TRAE and 22 (9.4%) had to discontinue treatment because of a TRAE. Fatigue, pruritis, diarrhea, and asthenia emerged as the most common TRAEs of any grade, with an incidence rate of 14.6%, 12.9%, 12.0% and 10.7%, respectively. In contrast, the most frequently occurring grade 3 TRAEs included gamma-glutamyl transferase (n = 4, 1.7%) and pneumonitis (n = 3, 1.3%).³

“[Single-agent pembrolizumab] is definitely well tolerated,” Lutz said. “Skin toxicity over time is what we’ll see. The skin rashes, and the myalgia and arthralgias that are very tolerable.”

Dostarlimab

At the time of the Peer Exchange, the participants did not have much experience with dostarlimab-gxly (Jemperli). Since the filming of the discussion, the FDA has granted regular approval to dostarlimab for adult patients with dMMR recurrent or advanced endometrial cancer. The approval is supported by data from the phase 1 GARNET trial (NCT02715284), which demonstrated that the overall response rate in a cohort of patients with dMMR recurrent or advanced endometrial cancer (n = 141) was 45.4% (95% CI, 37.0%-54.0%) per RECIST 1.1 criteria. GARNET data also showed a complete response rate of 15.6% and a partial response rate of 29.8%.

Serious AEs reported with dostarlimab included urinary tract infection (4%), sepsis (3.3%), acute kidney injury (2.7%), and abdominal pain (2.7%). The most common all-grade events were fatigue/asthenia, anemia, rash, nausea, diarrhea, constipation, and vomiting.¹¹ Moreover, 15 patients in this trial needed to discontinue treatment. Some causes for treatment discontinuation included increased transaminases, sepsis, bronchitis, pneumonitis, rash, pruritus, pancreatitis, encephalitis, and nephritis. Dose interruptions, which occurred in 28% of patients, were mostly activated by anemia, diarrhea, asthenia, colitis, sepsis, and pneumonitis.⁸

Lutz, whose institution hosted the GARNET trial, concluded by noting that dostarlimab demonstrated promising tolerability. “I find that that’s a really good option because in our trials where we used dostarlimab, I think it was even better tolerated [than other therapies] in certain instances,” she said.

References

1. Treatment choices for endometrial cancer, by stage. American Cancer Society. Updated March 30, 2022. Accessed February 10, 2023. https://bit.ly/4035LzI
2. Hormone therapy for endometrial cancer. American Cancer Society. Updated March 27, 2019. Accessed March 16, 2023. https://bit.ly/42o6MnI
3. Marabelle A, Le DT, Ascierto PA, et al. Efficacy of pembrolizumab in patients with noncolorectal high microsatellite instability/mismatch repair–deficient cancer: results from the phase II KEYNOTE-158 study. J Clin Oncol. 2020;38(1):1-10. doi:10.1200/JCO.19.02105
4. 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
5. FDA approves Merck’s Keytruda (pembrolizumab) for patients with MSI‑H/dMMR advanced endometrial carcinoma, who have disease progression following prior systemic therapy in any setting and are not candidates for curative surgery or radiation. Merck. News release. March 21, 2022. Accessed March 21, 2023. https://bit.ly/3TFCits
6. FDA grants regular approval to pembrolizumab and lenvatinib for advanced endometrial carcinoma. FDA. Updated February 1, 2022. Accessed March 24, 2023. https://bit.ly/3kbbCjz
7. Keytruda. Prescribing information. Merck Sharp & Dohme Corp; 2022. Accessed March 24, 2023. https://bit.ly/3K7ssNI
8. Lenvima. Prescribing information. Eisai Inc; 2022. Accessed March 24, 2023. https://bit.ly/40eTVmi
9. Makker V, Colombo N, Casado Herráez A; Study 309–KEYNOTE-775 Investigators. Lenvatinib plus pembrolizumab for advanced endometrial cancer. N Engl J Med. 2022;386(5):437-448. doi:10.1056/NEJMoa2108330
10. FDA grants regular approval to dostarlimab-gxly for dMMR endometrial cancer. FDA. February 9, 2023. Accessed March 16, 2023. https://bit.ly/3JIKogm
11. Jemperli. Prescribing information. GlaxoSmithKline LLC; 2023. Accessed March 4, 2023. https://bit.ly/3FPv2p5