Holloway Discusses Later-Line Treatment in Recurrent or Metastatic Endometrial Cancer

Targeted OncologyTM: What is the recommended next-line systemic therapy for this patient with recurrent/metastatic endometrial cancer?

HOLLOWAY: The NCCN [National Comprehensive Cancer Network] guidelines’ preferred regimens for recurrent or metastatic endometrial cancer are carboplatin/paclitaxel or carboplatin/paclitaxel/trastuzumab. For patients with uterine serous carcinoma, there is a role for HER2 testing, IHC, [and] next-generation sequencing, and phase 3 data indicate an improved outcome with carboplatin, paclitaxel, and trastuzumab.¹

Robert W. Holloway, MD

Medical Director,

Gynecologic Oncology Program

AdventHealth Cancer Institute

Orlando, FL

Other recommended options include carboplatin/ docetaxel, cisplatin/doxorubicin, and cisplatin/doxorubicin/paclitaxel, which [raises] the toxicity. There is carboplatin/paclitaxel/bevacizumab [Avastin]. My nurse practitioner told me they wouldn’t approve these combinations. She said only single agent was [available], which surprised me. Now I’ll have to circle back with her on that. Albumin-bound paclitaxel and topotecan [are also options]. Temsirolimus has been used with some limited success, and ifosfamide [has been used] for carcinosarcomas, which can be single agent or combined.

For biomarker-directed systemic therapy, there [are] lenvatinib [Lenvima] and pembrolizumab [Keytruda] as category 1 for non–MSI-H, non-MRD tumors and pembrolizumab for tumor mutational burden–high, MSI-H tumors as a single agent. Other regimens [such as] nivolumab [Opdivo] and dostarlimab [Jemperli] recently received the pan-tumor indication. For NTRK gene fusions, [you can use larotrectinib (Vitrakvi) or entrectinib (Rozlytrek)]. Avelumab [Bavencio] has been approved as a secondline option [for MRD/MSI-H tumors], and cabozantinib [Cabometyx] [has been approved] as well.

What data support the use of single-agent pembrolizumab as the next-line therapy in patients with recurrent or metastatic endometrial cancer?

The KEYNOTE-158 study [NCT02628067] is an ongoing, international, open-label, phase 2 study of patients with select solid tumors that have progressed on standard-ofcare therapy. Patients with previously [managed] MSI-H, MRD advanced endometrial cancers enrolled in cohorts D and K in the study. They had progression after a standard line of carboplatin plus paclitaxel and weren’t curable by other means. They received pembrolizumab once every 3 weeks. They were treated for 2 years or until progression of disease [PD] or intolerable toxicity, and then survival follow-up was done. The overall response rate [ORR] was the primary end point per RECIST version 1.1 [criteria]. The secondary end points were duration of response [DOR], progression-free survival [PFS], overall survival [OS], and safety. The median time from the first dose to data cutoff, which was January 2022, was 54.5 months, a good long-term follow-up in the study. The data are rather mature.²

The mean age in this endometrial [cancer] population was not surprising at 64 years. For ECOG PS, about 50% of them had PS of 1. Disease stage was M0 in 4% and M1 in 96%. For number of prior lines of therapy, about half of them had 1 line, but it was greater than 4 lines in about 10%. Prior adjuvant or neoadjuvant therapies were [used in] 27%, so it looks like the majority had not had neoadjuvant or adjuvant therapy. Prior radiation therapy was [noted] in 67% and prior surgery in 86%. So some of these patients did [have previous operations].

How have patients in KEYNOTE-158 responded to treatment so far?

All patients treated in the study had about a 50% response rate. Patients who had prior neoadjuvant and/or adjuvant therapy, only 10 patients, had a 40% response rate, so I don’t know [whether] that’s different. Patients who had 1 prior line of therapy had a 59% response rate. I think these numbers are relatively small to discriminate. Patients who had [more] than 1 prior line of therapy had a 44% response rate. It’s all clustering in the 40% to 50% [range], so [it’s] an extraordinarily high response rate if a patient has MSI-H disease on checkpoint inhibitors, even though they had carboplatin, paclitaxel, and/or pelvic radiotherapy before in many cases. The complete response [CR] rate was 16%, partial response [PR] rate was 34%, and stable disease [SD] [rate] was 18%.2 There’s no difference in terms of survival between PR and SD. They both are benefiting.

The median DOR was 63.2 months. The DOR at 1 year was 87%, 2 years was 71%, 3 years was 66%, and 4 years was 66%. The duration and recurrence start to flatten out. If you make it to 3 years, you’re going to have an ongoing response.

The PFS and OS plots plateau, which we’ve seen in other solid tumors [during] immunotherapy. A percentage of patients get a long-lasting DOR and benefit tremendously from the therapy. The median OS was 65.4 months [(95% CI, 29.5-not reached) and the median PFS was 13.1 months (95% CI, 4.3-25.7)].

Prior to pembrolizumab coming on the market, patients had a shortened and significantly toxic environment [for] survival. The treatment options were not good, and patients [experienced pain and died from] this disease in a short period once they’d had carboplatin, paclitaxel, and radiation. Doxorubicin was thrown in the mix there, which isn’t a pleasant treatment. So this is a tremendous advance in endometrial cancer management.

Have you used dostarlimab as the next-line therapy in patients with recurrent or metastatic endometrial cancer?

I have used [dostarlimab] in a clinical trial with carboplatin and paclitaxel, and I can say anecdotally—no direct comparison—I don’t think there’s any significant difference in the AEs compared with any other checkpoint inhibitor. I’ve treated a large number of patients on the clinical trial, which has been ongoing for over 2 years, and I’ve seen some amazing responses in patients who I would have expected to [die] from their disease within a short time. So based on the OS and PFS curves, some patients do get a tremendous response.^3,4

The GARNET study [NCT02715284] is the prospective study of dostarlimab, which received its first approval in endometrial cancer. It is a 2-part phase 1 trial. Part 1 is for dose finding, part 2A is for the fixed-dose and safety run-in, and part 2B is for expansion cohorts. It’s another example of an early-phase study that presented data to the FDA, leading to a quick approval because of the significant response rates and benefits. The FDA did not require a large prospective phase 3 randomized trial. Pembrolizumab was already labeled in this setting, and the data points looked like the outcomes with other checkpoint inhibitors. So it probably helped lead to its approval, with no unusual signals of toxicity.

In this study, dostarlimab was dosed at 500 mg every 3 weeks for 4 cycles, then 1000 mg every 6 weeks until PD. The primary end points were the ORR and DOR per RECIST version 1.1 criteria by blinded independent central review assessment. The key inclusion criteria were progression during or after platinum doublet therapy and 2 or fewer prior lines of treatment for advanced or recurrent disease. The patients could have had hormonal therapy and carboplatin, paclitaxel or carboplatin, paclitaxel, or doxorubicin [and join] this trial. They had to have measurable disease. They had not received prior checkpoint inhibitors and had MRD or MSI-H disease by approved laboratory testing.

They had 2 scans demonstrating PD on their last systemic therapy, so they had [experienced progression]. These were not patients with stable disease. The median time from the first dose to data lock was 27.6 months. The efficacy and safety were assessed in all patients with measurable disease.

For the study characteristics, the median age was 65 to 66 years. Slightly less than half of these patients originally had stage I or stage II disease and then [experienced] relapse, and 56% to 62% had stage III or IV disease and then [experienced] relapse. Low-grade endometrioid carcinoma accounted for 64% of the MSI-H [disease] and only 23% of non–MSI-H [disease]. Serous carcinomas flipped the other way. A small percentage were MRD or MSI-H [disease], whereas a larger percentage were MR-proficient. Grade 3 carcinomas, clear cell, and other histology types had relatively small numbers after endometrioid carcinomas and serous carcinomas. All patients had prior anticancer therapy, and the majority had 1 prior line. About 70% of the patients had prior radiation therapy.

What was the efficacy demonstrated in the GARNET trial?

The ORR was 45.5%, very similar to the [ORR from] KEYNOTE158. The CR was also very similar to [the CR from] KEYNOTE158 at 16.1%. The PR was approximately double the CR at 29.4%, and SD was about 15%. Approximately one-third of patients [experienced progression]. The duration of the CR was 60.1%. Response was ongoing in 83%. The median DOR had not been reached. These data were reported without the longterm follow-up of the KEYNOTE-158 study, but the results were so similar at this point that it got FDA approval in this setting.

The estimated probability of maintaining response at 6 months was 97%, 12 months was 93%, and 24 months was 83%. What I see in these data is that if you see a patient who’s getting a response, overwhelming odds are they’re going to continue to get a response. The question is, are they going to get a response? About one-third of patients will [experience progression]. I’m not intimately familiar with all the research going on in immunotherapy for solid tumors, but it would be a key clinical question about what’s different about these patients [with] MSI-H [disease who experience progression] on therapy. What do you do about it? Hopefully, we’ll see more answers about that in the coming years.

As of November 2021, the data cutoff, the median duration of follow-up was about 28 months. The estimated PFS rate at 12 months was 46% and 40% at 24 months. So about 40% of the patients get a long-lasting benefit from checkpoint inhibition.

How do the KEYNOTE-158 and GARNET studies compare?

The KEYNOTE-158 study with 94 patients and GARNET [study] with 143 patients were phase 2 and phase 1 studies. They were done in patients with previously [managed] MRD recurrent or advanced endometrial cancer. The primary end points were ORR in both along with DOR in the GARNET study. The follow-up was longer with KEYNOTE-158 at 54.5 months vs 27.6 months for GARNET.^2-4

The ORR was 50% in KEYNOTE-158 and 46% in GARNET. The median DOR was 63.2 months in KEYNOTE-158 and was not reached in GARNET. The 1-year DOR in GARNET was about 93% vs 87% in KEYNOTE-158 and 84% at 2 years vs 71%, respectively. So they were relatively similar, perhaps numerically slightly better in GARNET. But comparisons cannot be looked at in that manner because they are slightly different populations. The median PFS was 13.1 months in KEYNOTE-158 and 6 months in GARNET. I’m not sure why there was the big difference in PFS between them because the DOR was similar. The median OS was over 65 months in KEYNOTE-158 and not reached in GARNET. The 1-year OS look[s] rather identical.^2-4

I think there’ll be more follow-up reporting on GARNET as we get more data. My anticipation would be outcomes on these studies are going to be rather identical, and these checkpoints are probably interchangeable with the expected outcomes and AEs.

What is the safety profile of pembrolizumab and dostarlimab based on data from both studies?

For treatment-related AEs [TRAEs] in KEYNOTE-158, grade 3 and grade 4 AEs were a relatively small percentage at 12%, and treatment discontinuations were only 7%. Some AEs that we’re familiar with were pruritis, fatigue, diarrhea, arthralgia, nausea, hypothyroidism (which is not uncommon), rashes, decreased appetite, and myalgia. ASCO [American Society of Clinical Oncology] has covered it with detailed advice about managing AEs with checkpoint inhibitors.

When these drugs came out, we were all concerned about the AEs, but we’ve all seen in practice that they’re easily managed. Rarely do we get life-threatening AEs because we are monitoring these patients. So most of these things are manageable. But you do need to pay attention. The percentage of immune-related colitis was very small at 3%. For diabetes, hepatitis, [and] pneumonitis, you get down to 1%.

The GARNET safety data, compared with KEYNOTE-158 data, for AEs grade 3 or [above] had a [slightly] higher percentage. TRAEs of any grade [occurred in] 70% and grade 3 [occurred in] 17%. Treatment-related serious AEs were 11.8% in the population with MSI-H [disease] and 8.7% in the population with non–MSI-H [disease]. TRAEs leading to discontinuation were very similar at about 8%, and those leading to death were 0%. They were all managed appropriately, without toxicity or death.4 I didn’t see anything unique in the safety summary of both studies—just a small percentage of laboratory abnormalities with liver function tests, mild anemia, and low percentage of diarrhea overall.

REFERENCES

1. NCCN. Clinical Practice Guidelines in Oncology. Uterine neoplasms, version 1.2023. Accessed February 23, 2023. https://bit.ly/3Z2dsFV

2. O’Malley DM, Bariani GM, Cassier PA, et al. Pembrolizumab in patients with microsatellite instability-high advanced endometrial cancer: results from the KEYNOTE158 study. J Clin Oncol. 2022;40(7):752-761. doi:10.1200/JCO.21.01874

3. Oaknin A, Tinker AV, Gilbert L, et al. Clinical activity and safety of the antiprogrammed death 1 monoclonal antibody dostarlimab for patients with recurrent or advanced mismatch repair-deficient endometrial cancer: a nonrandomized phase 1 clinical trial. JAMA Oncol. 2020;6(11):1766-1772. doi:10.1001/ jamaoncol.2020.4515

4. 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