Novel Therapies and Combinations Lead the Way in Women’s Cancers in 2024

A NUMBER OF ADVANCES employing combination or monotherapies have been made in the gynecologic cancer arena in 2024. Potential practice-changing therapies include, in endometrial cancer, the emergence of carboplatin, paclitaxel, and PD-1 blockade, or the use of fam-trastuzumab deruxtecan-nxki (T-DXd; Enhertu); in cervical cancer, the addition of pembrolizumab (Keytruda) to standard chemotherapy/radiotherapy; and in ovarian cancer, the combination of mirvetuximab soravtansine (Elahere) plus bevacizumab (Avastin).

Claire F. Friedman, MD, a gynecologic medical oncologist and early drug development specialist at Memorial Sloan Kettering Cancer Center, provided an overview during the 42nd Annual CFS, an event sponsored by Physicians’ Education Resource, LLC.

Endometrial Cancer

“It’s been an exciting couple of years for endometrial cancer,” Friedman said. “We now have several new options for first-line treatment for patients with advanced or recurrent endometrial cancer, including treatment with platinum chemotherapy and paclitaxel plus a PD-1 inhibitor of either dostarlimab-gxly [Jemperli] or pembrolizumab, both of which have been approved by the FDA.”^2,3

The approval of dostarlimab was based on findings from the RUBY trial (NCT03981796), in which investigators observed a statistically significant overall survival (OS) improvement, with a median OS of 44.6 months (95% CI, 32.6- not reached) and 28.2 months (95% CI, 22.1-35.6) in the dostarlimab-gxly and placebo arms, respectively (HR,0.69; 95% CI, 0.54-0.89; 1-sided P =.002). Median progression-free survival (PFS) in the overall population was 11.8 months (95% CI, 9.6-17.1) and 7.9 months (95% CI, 7.6-9.5) in the dostarlimab-gxly and placebo arms, respectively (HR,0.64; 95% CI, 0.51-0.80; 1-sided P<.0001).⁴

Efficacy findings from the KEYNOTE-868/NRG- GY018 trial (NCT03914612) led to the FDA’s approval of pembrolizumab for endometrial carcinoma. The trial stratified 222 patients to the MMR- deficient (dMMR) cohort and 588 patients to the mismatch repair–proficient cohort.⁵

In April 2024, as part of the pan solid tumor approval, the FDA granted T-DXd accelerated approval for patients with unresectable or metastatic HER2-positive (immunohistochemistry 3+) solid tumors who have received prior systemic treatment and have no satisfactory alternative treatment options.⁶

Friedman added that “patients with stage III dMMR or microsatellite instability endometrial cancer can also derive benefit from chemotherapy plus PD-1 blockade, regardless of measurable disease.” Data from preplanned subgroup analyses suggest that pembrolizumab plus chemotherapy improved disease-free survival in patients with dMMR tumors in the ENGOT-en11/GOG- 3053/KEYNOTE-B21 study (NCT04634877).⁷

“We have a much better understanding of endometrial cancer than we did several years ago,” Friedman said.

Cervical Cancer

In the cervical cancer setting, 2 newly approved treatment options are now available for some subgroups of patients.

The FDA approved pembrolizumab with chemoradiotherapy in patients with International Federation of Gynecology and Obstetrics (FIGO) 2014 stage III to IVA cervical cancer.⁸ Findings from KEYNOTE-A18 (NCT04221945) led to the approval.⁹

In the phase 3 trial, 1060 treatment-naive patients with high-risk (FIGO 2014 stage IB2-IIB with node-positive disease or stage III-IVA), locally advanced, histologically confirmed cervical cancer were randomly assigned to receive either 200 mg pembrolizumab every 3 weeks plus concurrent chemoradiotherapy (CRT) followed by 400 mg pembrolizumab or placebo plus CRT followed by placebo.⁹

The median follow-up was 17.9 months in both treatment groups. PFS rates at 24 months were 68% in the pembrolizumab- CRT group vs 57% in the placebo-CRT group (HR, 0.70; 95% CI, 0.55-0.89; P = .0020). At 24 months, the OS rate was 87% in the pembrolizumab-CRT group and 81% in the placebo-CRT group (HR, 0.73; 95% CI, 0.49-1.07).⁹

Another option was demonstrated by findings in the INTERLACE trial (NCT01566240), which evaluated patients with FIGO 2008 stage IB1 disease with nod- al involvement or stage IB2, IIA, IIB, IIIB, or IVA disease.¹⁰

Patients were randomly assigned to receive either cisplatin 40 mg/m² with 45.0 to 50.4 Gy external beam radiotherapy alone or carboplatin and paclitaxel 80 mg/m² followed by standard cisplatin-based CRT.¹⁰ After a median follow-up of 67 months, 5-year PFS rates were 72% in the induction chemotherapy with CRT group and 64% in the CRT-alone group (HR, 0.65; 95% CI, 0.46-0.91; P = .013). Five-year OS rates were 80% and 72%, respectively (HR, 0.60; 95% CI, 0.40-0.91; P = .015).¹⁰

“How we’re going to incorporate these data, in addition with the KEYNOTE data, and for whom these data might be particularly relevant is a topic of discussion,” Friedman said.

Ovarian Cancer

The antibody-drug conjugate mirvetuximab soravtansine-gynx demonstrated clinical activity and a good safety profile when combined with bevacizumab in patients with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer.11 Findings led to approval for the combination,¹² based on the MIRASOL study (NCT04209855).¹³

The objective response rate (ORR) was 44%, and the median duration of response was 9.7 months. “As part of this study, investigators also treated patients with platinum-sensitive ovarian cancer. In that group, the ORR was 48%, with a median duration of response of 12.7 months,” Friedman said.

The study met its primary and key secondary end points, with statistically significant results in PFS, ORR, and OS, investigators reported. “As a result, the National Comprehensive Cancer Network listed the combination for both platinum-sensitive and platinum-resistant ovarian cancer,” Friedman concluded.

REFERENCES

1. Friedman CF. Focus on the most critical data of 2024
in women’s cancers (ovarian, endometrial, and cervical). Presented at: 42nd Annual CFS; November 13-15, 2024; New York, NY.

2. FDA expands endometrial cancer indication for dostarlimab-gxly with chemotherapy. FDA. August 1, 2024. Accessed November 15, 2024. https://tinyurl.com/yv6bhmuu

3. FDA approves pembrolizumab with chemotherapy for primary advanced or recurrent endometrial carcinoma. FDA. June 17, 2024. Accessed November 15, 2024. https:// tinyurl.com/3ss2mhv9

4. Mirza MR, Chase DM, Slomovitz BM, et al; RUBY Investigators. Dostarlimab for primary advanced or recurrent endometrial cancer. N Engl J Med. 2023;388(23):2145-2158. doi:10.1056/NEJMoa2216334

5. Eskander RN, Sill MW, Beffa L,etal. Pembrolizumab plus chemotherapy in advanced endometrial cancer. N Engl J Med. 2023;388(23):2159-2170. doi:10.1056/NEJMoa2302312

6. FDA grants accelerated approval to fam-trastuzumab deruxtecan-nxki for unresectable or metastatic HER2-positive solid tumors. FDA. April 5, 2024. Accessed November 15, 2024. https://tinyurl.com/mr4xjrm8

7. Van Gorp T, Cibula D, Lv W, et al; ENGOT-en11/GOG-3053/ KEYNOTE-B21 investigators. ENGOT-en11/GOG-3053/ KEYNOTE-B21: a randomised, double-blind, phase III study of pembrolizumab or placebo plus adjuvant chemotherapy with or without radiotherapy in patients with newly diagnosed, high-risk endometrial cancer. Ann Oncol. 2024;35(11):968-980. doi:10.1016/j.annonc.2024.08.2242

8. FDA approves pembrolizumab with chemoradiotherapy for FIGO 2014 stage III-IVA cervical cancer. FDA. January 12, 2024. Accessed November 15, 2024. https://tinyurl. com/3hhn34hy

9. Lorusso D, Xiang Y, Hasegawa K, et al; ENGOT-cx11/GOG- 3047/KEYNOTE-A18 investigators. Pembrolizumab or placebo with chemoradiotherapy followed by pembrolizumab or placebo for newly diagnosed, high-risk, locally advanced cervical cancer (ENGOT-cx11/GOG-3047/KEYNOTE-A18):a randomised, double-blind, phase 3 clinical trial. Lancet. 2024;403(10434):1341-1350. doi:10.1016/S0140-6736(24)00317-9

10. McCormack M, Eminowicz G, Gallardo D, et al; INTER- LACE investigators. Induction chemotherapy followed by standard chemoradiotherapy versus standard chemora- diotherapy alone in patients with locally advanced cervical cancer (GCIG INTERLACE): an international, multicentre, randomised phase 3 trial. Lancet. 2024;404(10462):1525- 1535. doi:10.1016/S0140-6736(24)01438-7

11. Gilbert L, Oaknin A, Matulonis UA, et al. Safety and efficacy of mirvetuximab soravtansine, a folate receptor alpha (FRα)-targeting antibody-drug conjugate (ADC), in combination with bevacizumab in patients with platinum-resistant ovarian cancer. Gynecol Oncol. 2023;170:241-247. doi:10.1016/j.ygyno.2023.01.020

12. FDA approves mirvetuximab soravtansine-gynx for FRα positive, platinum-resistant epithelial ovarian, fallopian tube, or primary peritoneal cancer. FDA. March 22, 2024. Accessed November 15, 2024. https://tinyurl.com/4ndnw5n7

13. Moore KN, Angelergues A, Konecny GE, et al. Phase III MIRASOL (GOG 3045/ENGOT-ov55) study: initial report of mirvetuximab soravtansine vs investigator’s choice of chemotherapy in platinum-resistant, advanced high-grade epithelial ovarian, primary peritoneal, or fallopian tube cancers with high folate receptor-alpha expression. J Clin Oncol. 2023;41(suppl 17):LBA5507. doi:10.1200/ JCO.2023.41.17_suppl.LBA55