Salani Reviews Options for a Patient With Metastatic Endometrial Cancer

Ritu Salani, MD, MBA

Gynecologic Oncologist

UCLA Health

Los Angeles, CA

CASE SUMMARY

August 2021

• A 64-year-old postmenopausal woman presented with abnormal uterine bleeding lasting 4 months.
• She noted that she underwent menopause at 55 years of age.
• She is a widow, has no children, and lives alone.
• Medical history: arthritis, obesity (body mass index of 40), hypertension well controlled with medication
• ECOG performance status: 1
• The patient was counseled on surgical options, then scheduled for surgery.
• Diagnosis: stage IA, grade 1 endometrial cancer
• Immunohistochemistry/molecular testing results:
  • Mismatch repair deficient (dMMR)
  • Microsatellite instability high (MSI-H)
  • Estrogen receptor positive (score of 3+)

August 2022

• She reported intermittent pelvic pain over prior 4 weeks.
• Chest, abdomen, and pelvis CT scan suggested relapsed/ metastatic disease with involvement of 1 right external iliac lymph node.
• Carboplatin/paclitaxel (6 times every 4 weeks) was administered, chemotherapy was well tolerated, and a complete response (CR) was recorded at end of regimen.

April 2023

• Disease relapse was documented on routine follow-up.
• Chest, abdomen, and pelvis CT scan showed 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 cancer-positive lymph node)
• Fine-needle aspiration 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).

What immunotherapy options are available in the recurrent/metastatic endometrial cancer setting?

SALANI: In the monotherapy [for] recurrent endometrial cancer setting, we have data for both pembrolizumab [Keytruda] and dostarlimab [Jemperli]. The first data were from KEYNOTE-158 [NCT02628067], which many of us are familiar with. This was a basket trial of all solid tumors. A cohort of patients had previously [managed] MSI-H/dMMR advanced endometrial cancer. They were treated with pembrolizumab every 3 weeks for 2 years or until progression of disease or intolerable toxicities. So it’s a 2-year end point. The primary end point was objective response rate [ORR].¹

Most patients had advanced disease with metastasis. They were a heavily pretreated group, with about half [of] patients having received 1 prior line of therapy, most of the remaining having received more than 2 lines, and a handful [having] received [more] than 4 lines of therapy. [The] majority of patients received prior radiation therapy, and almost all patients had prior surgery, typical of what we’d see in an endometrial cancer cohort.¹

Based on updated 2022 data, in the 94 patients treated, ORR was approximately 50%. It was a little higher in patients who had only 1 prior line of therapy [59%] vs those who had more than 1 prior line of therapy [44%]. In patients who received prior neoadjuvant or adjuvant therapy—probably the group [at] highest risk—ORR was 40%, which is a lower rate.

These are small subgroups, so we want to be careful with our interpretation. But the takeaway is that ORR was 50%, with 16% [who had] CR, 34% with PR [partial response], and 18% with SD [stable disease]. So a lot of patients, about 70%, had some kind of clinical benefit. What I think was powerful with pembrolizumab is [that] the DOR [duration of response] beyond 4 years was 66%. These were patients who stopped therapy at 2 years, so we don’t know whether continuing therapy would have even higher rates. But these are very compelling data.¹

For the progression-free survival [PFS] and overall survival [OS] curves, some patients fall off early, but patients who respond have good responses. The median PFS was 13.1 months [95% CI, 4.3-25.7] and median OS was 65 months [95% CI, 29.5-not reached]. The survival Kaplan-Meier curves flatten out, so some durable responses [are] seen in patients.¹

Q:What data support the use of dostarlimab in the recurrent/metastatic endometrial cancer setting?

In the GARNET study [NCT02715284], the dosing schedule was 500 mg every 3 weeks for 4 cycles, and then it escalate[d] to 1000 mg every 6 weeks to progression of disease. This study was interesting because it had a dMMR/MSI-H and a MMRp/MSS [mismatch repair–proficient/microsatellite-stable] group. The patients had progressed on or after platinum doublet therapy, just like our case patient, and had 2 or [fewer] prior lines of treatment for recurrent or advanced disease, so up to 3 lines of therapy. They had no prior anti–PD-L1 therapy, and they had to have the testing done because that was one of the stratifications.²

More than half of patients had advanced-stage disease at the time of initial diagnosis. They [had a mix of] histology results because the cohorts had both dMMR and MMRp patients. They had patients with carcinomas, sarcomas, and serous carcinomas, so a decent range of different histology types. Every patient had received prior anticancer treatment; about 10% had received 3 or [more] prior lines, and about one-third of patients had this high-risk disease presentation with adjuvant or neoadjuvant therapy prior. Once again, typical with advanced endometrial cancer, 60% to 70% had received prior radiation.²

After receiving dostarlimab, the dMMR group had an ORR of 45.5%, CR [rate] of 16.1%, PR [rate] of 29.4%, and SD [rate] of 14.7%. Impressively, 83.1% of patients had responses ongoing at the time of data cutoff [median duration of follow-up, 27.6 months]. At 12 months, 93.3% of patients were still responding, and at 24 months, 83.7% [were responding]. Once again, patients may be living with the disease or may even be cured, so [there were] impressive responses in patients who responded.²

The PFS and OS [rates] for the dMMR group once again plateau with that early drop-off. Some patients don’t respond. But there were durable responses in some patients. At 36 months, 58.4% of patients survived and were still on therapy.² Not meant to be comparative, but both studies looked at the ORR as the primary end point. The GARNET study also looked at DOR. The ORRs were comparable at approximately 50%, and the median DOR was 63.2% for KEYNOTE-158, and it’s not yet been reached for GARNET, but the data are still being evaluated. These were impressive results for both agents.²

Q:What are some AEs of pembrolizumab and dostarlimab?

Patients were treated with pembrolizumab for up to 2 years, and only 7% of patients discontinued treatment. Most toxicities were not grade 3 or 4 but common ones we’ve all seen. So it was a well-characterized toxicity profile. The immune-related toxicities were a little higher, which we wouldn’t be surprised about, but still in the single digits. So it is a well-tolerated regimen.¹

Dostarlimab was given until progression of disease, so these patients potentially had a longer therapy. The grade 3 toxicities were treatment related, and the safety profile was broken up by MMR status. But the key thing is the toxicities were single digit, and 8% [of patients] came off treatment. Once the therapy was held or dose interrupted, toxicities were manageable. Grade 3 toxicities were in the single digits, and same thing with immune-related toxicities, so [there were] low toxicity rates in patients with either MMR status.²

_REFERENCES

_{1. 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}

_{2. 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}