Gynecologic Cancer Paradigm Sees Huge Gains With FDA-Approved Regimens

Angeles Alvarez Secord, MD, MHSc

In line with a banner year of data readouts in ovarian cancer including that with the PARP inhibitor niraparib (Zejula), the novel agent gotistobart, and fam-trastuzumab deruxtecan-nxki (T-DXd; Enhertu), which recently received a tumor-agnostic FDA approval, the tides are also changing in cervical and endometrial cancers with the addition of checkpoint inhibitors to traditional chemoradiotherapy and integration of other immunotherapy-based approaches, respectively.

During the 2024 European Society for Medical Oncology (ESMO) Congress, OncologyLive was onsite in Barcelona, Spain, and filmed a Peer Exchange with leading experts in the field of gynecologic oncology. During the discussion, the investigators highlighted multiple practice-altering clinical trial updates presented over the course of the meeting and beyond in ovarian, cervical, and endometrial cancers.

“It has been an amazing year [in gynecologic cancer research], kicking off with the Society of Gynecologic Oncology Meeting on Women’s Cancer, the American Society of Clinical Oncology meetings, and now the ESMO Congress,” Angeles Alvarez Secord, MD, MHSc, said. “We have learned so much and now we need to look at all these emerging therapies and explore the future directions of the management of these cancers and [interrogate] what we do in the clinic.”

Updated Data Provide Additional Options in Ovarian Cancer

In June 2020, the FDA approved niraparib as maintenance therapy in adult patients with advanced epithelial ovarian, fallopian tube, or primary peritoneal cancer following a complete or partial response to frontline platinum-based chemotherapy. The regulatory decision was supported by findings from the phase 3 PRIMA trial (NCT02655016).¹ “PRIMA met its primary end point, which was progression-free survival [PFS], both in the intention-to-treat group as well as in the BRCA-mutated [subgroup], so it received approval for all comers. We’ve all been awaiting the long-term overall survival [OS] data and finally we saw those [at the 2024 ESMO Congress],” Bhavana Pothuri, MD, said.

Peer Exchange Panel: Advancements

in the Management of Gynecological

Cancers: ESMO 2024

Findings from the final OS analysis of PRIMA presented during the 2024 ESMO Congress demonstrated that patients with newly diagnosed advanced ovarian cancer with a complete or partial response to frontline platinum-based chemotherapy achieved a median OS of 46.6 months vs 48.8 months with niraparib (n = 487) or matched placebo (n = 246), respectively (HR, 1.01; 95% CI, 0.84-1.23; P = .8834). However, at a median follow-up of 6.2 years, niraparib continued to display a sustained PFS benefit vs placebo (HR, 0.66; 95% CI, 0.55-0.78).²

“We didn’t necessarily see an [OS] benefit, but there are many reasons for that,” Pothuri said. “It’s important to recognize that there’s crossover and patients with ovarian cancer [often] receive so many subsequent lines [of treatment]. We should be pleased that we didn’t see any survival decrement, and I will continue using niraparib in my practice.”

For patients with platinum-resistant disease, the investigational pH-sensitive CTLA-4–preserving antibody gotistobart is emerging as a potential therapeutic option. Gotistobart is being investigated in combination with pembrolizumab (Keytruda) in the phase 2 PRESERVE-004/GOG-3081 study (NCT05446298). Preliminary findings presented during the 2024 ESMO Congress showed that the combination led to an unconfirmed objective response rate (ORR) of 25.0% (95% CI, 11.5%-43.4%) and 27.6% (95% CI, 12.7%-47.2%) among patients treated with the 1-mg/kg (n = 32) and 2-mg/kg (n = 29) dose levels of gotistobart.³

“PARP inhibitor resistance is important in this era; we’re seeing many patients [who are] not as susceptible to retreatment with platinum,” Pothuri commented. “There are many reasons for PARP [inhibitor] resistance, including reversion mutations, replication, and fork stabilization. There are some [interesting] new therapies that may overcome PARP [inhibitor] resistance.”

Another option for patients with gynecologic malignancies is the antibody-drug conjugate (ADC) T-DXd. T-DXd received approval from the FDA in April 2024 in adult patients with unresectable or metastatic HER2-positive (immunohistochemistry [IHC] 3+) solid tumors who have received prior systemic treatment and have no satisfactory alternative treatment options. The approval was supported by data from the phase 2 DESTINY-PanTumor02 trial (NCT04482309), which included patients with gynecologic cancers.⁴

“One of the biggest changes that [affected] practice [this past] year was the approval of T-DXd in the tumor-agnostic category for patients who with HER2 [IHC] 3+ staining based on gastric scoring,” Secord said. “Then the National Comprehensive Cancer Network [guidelines] came out, and, for many of our cancers, they also allowed use of that therapy in individuals who had [IHC] 2+ staining.”

Findings from DESTINY-PanTumor02 showed that patients with ovarian (n = 40), cervical (n = 40), or endometrial cancer (n = 40) achieved ORRs by independent central review of 42.5%, 40.0%, and 52.5%, respectively. The respective median durations of response (DORs) were 11.3 months (95% CI, 4.1-not estimable [NE]), 9.8 months (95% CI, 4.2-NE), and not reached (95% CI, 9.9-NE).⁵

“[T-DXd] is a total game changer; I’m excited, but don’t want to get too excited, because we have some [other] good medications that went through phase 2 and 3 [study], so I’m reserving it for later lines of therapy,” Premal H. Thaker, MD, MS, said. “When one [considers] some of the heterogeneity and the scoring, there’s a lot of work to be done. Our pathologists say that when we’re asking for ovarian, endometrial, and cervical [scoring] that they’re using more of an endometrial serous [scoring method], which [has] a 30% positivity [rate], so we may be missing some patients. We need to communicate with our pathologists to make sure that we’re getting an IHC [test] to be able to use this medication.”

Targeted Therapies Solidify Their Place in Cervical Cancer

The standard of care for patients with locally advanced cervical cancer has traditionally been external beam radiotherapy with concurrent chemotherapy and brachytherapy. However, recent clinical trial updates have shown the benefit of checkpoint inhibitors for these patients, both in addition to chemotherapy and as monotherapy.⁶

“When we [consider] advanced cervical cancer, that’s getting out of the surgical realm,” Thomas C. Krivak, MD, said. “[The standard of care] has been chemoradiation for a long period of time. I examine the patient’s PET-CT scan to see [whether] they’re diffusely metastatic [because] that’s going to help determine whether a patient is going to receive chemotherapy [plus immunotherapy] with radiation therapy or switch over to possibly a chemotherapy/bevacizumab [Avastin]/immunotherapy regimen. Many of these patients will present with advanced-stage disease and may be able to tolerate some of this treatment. The exam, the PET-CT scan, and the staging of the patients define where their disease [is] and [are] going to tailor [treatment for] that patient.”

During the first presidential symposium of the 2024 ESMO Congress, investigators presented updated findings from the phase 3 KEYNOTE-A18/ENGOT-cx11/GOG-3047 trial (NCT04221945), which examined pembrolizumab in combination with chemoradiotherapy in FIGO 2014 stage IB2 to IIB node-positive or stage III to IVA node-positive or node-negative cervical cancer. Prior data from the study supported the January 2024 FDA approval of the combination in FIGO 2014 stage III to IVA cervical cancer.^6,7

At the second interim analysis, at a median follow-up of 29.9 months (range, 12.8-43.0), patients who received pembrolizumab plus chemoradiotherapy followed by pembrolizumab maintenance (n = 529) experienced a 32% reduction in the risk of disease progression or death compared with those who received placebo plus chemoradiotherapy (n = 531; HR, 0.68; 95% CI, 0.56-0.84). In terms of the other primary end point of OS, patients experienced a 33% reduction in the risk of death in the investigational arm vs the placebo arm (HR, 0.67; 95% CI, 0.50-0.90; P = .0040). The 36-month PFS rates were 69.3% (95% CI, 62.7%-75.0%) vs 56.9% (95% CI, 50.4%-62.9%), respectively, and the 36-month OS rates were 82.6% (95% CI, 78.4%-86.1%) vs 74.8% (95% CI, 70.1%-78.8%), respectively.⁶

“This study shows the benefit of adding pembrolizumab to chemo[radio]therapy with maintenance pembrolizumab afterward [in terms of] PFS and OS,” Thaker said. “The key for us to cure patients is in the up-front setting, so [these data are] very encouraging. At least in the US, we can use it already for stage III and IV [disease]. It will be interesting to see how the presentation may change for stage I and II [disease] because the forest plots are still evolving.”

Following frontline treatment, a therapeutic option for patients with cervical cancer who experience disease progression is the ADC tisotumab vedotin-tftv (Tivdak). In April 2024, the agent received full approval from the FDA in recurrent or metastatic cervical cancer following disease progression on or after chemotherapy after receiving accelerated approval for the same indication in September 2021.⁸

“The payload of tisotumab vedotin is monomethyl auristatin E, which is like a taxane. It’s a tubulin-disrupting agent and has a unique target, tissue factor, which is highly expressed in cervical cancer, and you don’t need a biomarker. That’s a very important point to make [because] no biomarker is highly expressed in cervical cancer,” Dana M. Chase, MD, said.

The phase 3 innovaTV 301 trial (NCT04697628), which supported the approval, evaluated tisotumab vedotin vs investigator’s choice of chemotherapy as second- or third-line therapy in recurrent or metastatic cervical cancer. Updated data from the study published in July 2024 in the New England Journal of Medicine demonstrated that patients who received the ADC (n = 253) achieved a median OS of 11.5 months (95% CI, 9.8-14.9) vs 9.5 months (95% CI, 7.9-10.7) among patients in the chemotherapy arm (n = 249; HR, 0.70; 95% CI, 0.54-0.89; 2-sided P = .004). The median PFS was 4.2 months (95% CI, 4.0-4.4) vs 2.9 months (95% CI, 2.6-3.1), respectively (HR, 0.67; 95% CI, 0.54-0.82; 2-sided P < .001).⁹

“It definitely takes work [to manage the toxicity profile of tisotumab vedotin],” Chase noted. “There are 3 toxicities to be aware of: peripheral neuropathy, hemorrhage, and ocular toxicity. This drug requires active prophylaxis for ocular disease, so the patient has to see an eye care provider before they start treatment. The patient has to have eye drops, both vasoconstrictors and steroids, as well as lubricating eye drops, and it takes a certain amount of sophistication to get into the eye care provider to use the drop.”

Immunotherapy Emerges in Endometrial Cancer

The panelists concluded their discussion by shifting their focus to updates in the endometrial cancer treatment landscape. “[Recent data] have cemented that in mismatch repair–deficient [dMMR] patients we should be using chemotherapy and immunotherapy, because the PFS and OS curves are beautiful; those are the curves we all dream of as clinical trialists. Even in our mismatch repair–proficient [pMMR] patients, there is a benefit [but] not to the same extent,” Thaker commented.

The phase 3 RUBY trial (NCT03981796) examined dostarlimab-gxly (Jemperli) plus carboplatin and paclitaxel vs placebo plus carboplatin and paclitaxel in patients with primary advanced or recurrent endometrial cancer. Previous findings from part 1 the study showed that it met its co–primary end point, demonstrating a PFS benefit with the addition of dostarlimab to chemotherapy in patients with dMMR/microsatellite instability–high (MSI-H) disease (HR, 0.28; 95% CI, 0.16-0.50; P < .0001) and in the overall population (HR, 0.64; 95% CI, 0.51-0.80; P < .0001).¹⁰

“It’s a story that we’re building on and it’s very exciting,” Krivak said. “We took a disease that was once treated with surgery and radiation [where] chemotherapy wasn’t [considered] and we’re adding chemotherapy [with] biologic therapy. We have to build off this, but it’s great for patients and clinical investigators.”

In terms of the other co–primary end point of OS, updated data from part 1 of RUBY showed that patients in the dostarlimab arm (n = 245) achieved a median OS of 44.6 months compared with 28.2 months in the placebo arm (n = 249; HR, 0.69; 95% CI, 0.54-0.89; stratified log-rank P = .0020). Moreover, in a prespecified exploratory analysis patients with dMMR/MSI-H (HR, 0.32; 95% CI, 0.17-0.63; nominal P = .0002) and pMMR/microsatellite stable disease (HR, 0.79; 95% CI, 0.60-1.04; nominal P = 0.0493) experienced a trend toward an OS benefit with dostarlimab vs placebo.

Findings from the RUBY trial led to the FDA expanding the indication for dostarlimab in combination with carboplatin and paclitaxel, followed by dostarlimab monotherapy for the treatment of adult patients with primary advanced or recurrent endometrial cancer in August 2024. The regimen was previously indicated in dMMR/MSI-H advanced or recurrent endometrial cancer based on prior findings from part 1 of the study.¹¹

“In the summer [of 2024] data from the [phase 3] NRG-GY018 study [NCT03914612] led to the FDA approval of pembrolizumab [with chemotherapy], but that was for an all-comers indication,” Chase said. “Then we got an all-comers [indication] for the RUBY trial. It didn’t change [my practice] but gave me more support if I wanted to use dostarlimab in a pMMR patient population. In the pMMR population, if I can improve, reduce, or even stabilize that patient’s disease, I’ll be happy to use immunotherapy.”

Another checkpoint inhibitor/chemotherapy combination regimen was examined in patients with treatment-naive advanced endometrial cancer in the phase 3 DUO-E trial (NCT04269200). DUO-E evaluated durvalumab (Imfinzi) plus carboplatin and paclitaxel followed by durvalumab maintenance therapy with (n = 239) or without (n = 238) olaparib (Lynparza). The primary end points were PFS in the durvalumab vs control (n = 241) arms and the durvalumab plus olaparib vs control arms.¹²

Findings from DUO-E showed that patients who received durvalumab (HR, 0.71; 95% CI, 0.57-0.89; P = .003) and durvalumab plus olaparib (HR, 0.55; 95% CI, 0.43-0.69; P < .0001) with chemotherapy experienced a significant PFS benefit vs chemotherapy alone. This PFS benefit was also observed in patients with dMMR disease with durvalumab (n = 46) vs chemotherapy (n = 49; HR, 0.42; 95% CI, 0.22-0.80) and durvalumab plus olaparib (n = 48) vs chemotherapy (HR, 0.41; 95% CI, 0.21-0.75). There was also a smaller PFS benefit with durvalumab (n = 192) vs chemotherapy (n = 192; HR, 0.77; 95% CI, 0.60-0.97) and durvalumab plus olaparib (n = 191) vs chemotherapy (HR, 0.57; 95% CI, 0.44-0.73) in the pMMR subgroup.

Data from DUO-E supported the June 2024 FDA approval of durvalumab plus carboplatin and paclitaxel followed by durvalumab monotherapy for the treatment of patients with dMMR primary advanced or recurrent endometrial cancer.¹³

“These trials show that immunotherapy [is effective] in patients with recurrent, advanced endometrial cancer, definitely in the dMMR group and with some heavy signals that it may be beneficial in patients with pMMR [disease] too. [This is] a game changer,” Secord noted.

During the 2024 ESMO Congress, investigators presented findings from 2 phase 2 studies evaluating investigational TROP2-directed ADCs in endometrial and ovarian cancer: TROPION-PanTumor03 (NCT05489211) examining datopotamab deruxtecan (Dato-DXd) and KL264-I-01 (NCT04152499) of sacituzumab tirumotecan. TROP2 is highly expressed in ovarian and endometrial cancers, making it an attractive therapeutic target for the next generation of ADCs.^14,15

At a median follow-up of 13.6 months (range, 2.1-19.6), patients with advanced or metastatic endometrial cancer with disease progression on at least 1 but no more than 2 lines of chemotherapy in the TROPION-PanTumor03 trial who received Dato-DXd (n = 40) experienced a confirmed ORR of 27.5% (95% CI, 14.6%-43.9%), with a 2.5% complete response rate. The median DOR and PFS were 16.4 months (95% CI, 7.1-not calculable [NC]) and 6.3 months (95% CI, 2.8-NC), respectively.¹⁴

In KL264-I-01, patients with advanced endometrial cancer who received at least 1 prior line of platinum-based chemotherapy and prior anti–PD-L1 therapy, if dMMR/MSI-H, treated with sacituzumab tirumotecan (n = 44) achieved a confirmed ORR of 27.3%, including 41.7% among patients with a TROP2 H-score above 200. The median DOR and PFS were 5.7 months (range, 3.8-7.4+) and 5.7 months (95% CI, 3.7-9.4), respectively. Sacituzumab tirumotecan is being evaluated vs physician’s choice of chemotherapy in patients with endometrial cancer who received prior platinum-based chemotherapy and immunotherapy in the phase 3 TroFuse-005 study (NCT06132958).¹⁵

“These data [with the TROP2-directed ADCs] are very exciting,” Krivak said. “We’re [considering] the responses, DOR, and the [adverse effects]. As we learn more about these medications, we’ll [primarily consider] efficacy, interstitial lung disease, nausea/vomiting, and hematologic toxicity, then [we will] be able to select different medications for each patient based upon their prior toxicity. We’re starting to see the phase 3 trials open that are going to help differentiate some of the patient populations that are going to benefit, but there’s no doubt that TROP2 is an exciting target to tackle in endometrial cancer.”

References

1. FDA approves niraparib for first-line maintenance of advanced ovarian cancer. FDA. April 29, 2020. Accessed October 2, 2024. bit.ly/47UTXVc
2. González-Martín A, PothuriB, Barretina Ginesta MP, et al. Final overall survival (OS) in patients (pts) with newly diagnosed advanced ovarian cancer (aOC) treated with niraparib (nir) first-line (1L) maintenance: results from PRIMA/ENGOT-OV26/GOG-3012. Ann Oncol. 2024;35(suppl 2):S1222-S1223. doi:10.1016/j.annonc.2024.08.2268
3. Barlin JN, Lim PC, Pepin JT, et al. A randomized, phase II, dose optimization of gotistobart, a pH-sensitive anti-CTLA-4, in combination with standard dose pembrolizumab in platinum-resistant recurrent ovarian cancer: safety, efficacy and dose optimization (PRESERVE-004/GOG-3081). Ann Oncol. 2024;35(suppl 2):S1224-S1225. doi:10.1016/j.annonc.2024.08.2271
4. FDA grants accelerated approval to fam-trastuzumab deruxtecan-nxki for unresectable or metastatic HER2-positive solid tumors. FDA. April 5, 2024. Accessed October 2, 2024. bit.ly/4ep3pm3
5. Meric-Bernstam F, Makker V, Oaknin A, et al. Efficacy and safety of trastuzumab deruxtecan (T-DXd) in patients (pts) with HER2-expressing solid tumors: DESTINY-PanTumor02 (DP-02) interim results. J Clin Oncol. 2023;41(suppl 17):LBA3000. doi:10.1200/JCO.2023.41.17_suppl.LBA3000
6. Lorusso D, Xiang Y, Hasegawa K, et al. Pembrolizumab plus chemoradiotherapy for high-risk locally advanced cervical cancer: overall survival results from the randomized, double-blind, phase III ENGOT-cx11/GOG-3047/KEYNOTE-A18 study.Ann Oncol. 2024;35(suppl 2):S544. doi:10.1016/j.annonc.2024.08.771
7. FDA approves pembrolizumab with chemoradiotherapy for FIGO 2014 stage III-IVA cervical cancer. FDA. January 12, 2024. Accessed October 1, 2024. bit.ly/3zT5pno
8. FDA approves tisotumab vedotin-tftv for recurrent or metastatic cervical cancer. FDA. April 29, 2024. Accessed October 1, 2024. bit.ly/4erFEtp
9. Vergote I, González-Martín A, Fujiwara K, et al. Tisotumab vedotin as second- or third-line therapy for recurrent cervical cancer. N Engl J Med. 2024;391(1):44-55. doi:10.1056/NEJMoa2313811
10. Powell MA, Bjørge L, Willmott, et al. Overall survival in patients with endometrial cancer treated with dostarlimab plus carboplatin–paclitaxel in the randomized ENGOT-EN6/GOG-3031/RUBY trial. Ann Oncol. 2024;35(8):728-738. doi:10.1016/j.annonc.2024.05.546
11. FDA expands endometrial cancer indication for dostarlimab-gxly with chemotherapy. FDA. August 1, 2024. Accessed September 24, 2024. bit.ly/3Y7nIif
12. Westin SN, Moore K, Chon HS, et al. Durvalumab plus carboplatin/paclitaxel followed by maintenance durvalumab with or without olaparib as first-line treatment for advanced endometrial cancer: the phase III DUO-E trial. J Clin Oncol. 2024;42(3):283-299. doi:10.1200/JCO.23.02132
13. FDA approves durvalumab with chemotherapy for mismatch repair deficient primary advanced or recurrent endometrial cancer.FDA. June 14, 2024. Accessed September 24, 2024. bit.ly/47Rk7bb
14. OakninA, Ang JE, Rha SY, et al. Datopotamab deruxtecan (Dato-DXd) in patients with endometrial (EC) or ovarian cancer (OC): results from the phase II TROPION-PanTumor03 study. Ann Oncol. 2024;35(suppl 2):S547-S548. doi:10.1016/j.annonc.2024.08.776
15. Wang D, Wang K, An R, et al. Safety and efficacy of sacituzumab tirumotecan (sac-TMT) in patients (pts) with previously treated advanced endometrial carcinoma (EC) and ovarian cancer (OC) from a phase II study. Ann Oncol. 2024;35(suppl 2):S548. doi:10.1016/j.annonc.2024.08.777