ESMO 2023 Updates in Endometrial and Cervical Cancer Give Glimpse Into Future Care

Dana M. Chase, MD, FACOG

Although the cure rate is relatively high for patients with early-stage cervical cancer, patients with metastatic and unresectable recurrent disease have limited treatment options and a low survival rate. Similarly, patients with advanced endometrial cancer have a poor prognosis, with a 5-year overall survival (OS) rate of 40% to 65% for those with stage III disease and 15% to 17% for stage IV.1 However, updated data from several clinical trials in both settings could signal the emergence of multiple effective treatment options coming down the pike.

“Endometrial cancer is the most common gynecologic cancer in women in the United States,” Dana M. Chase, MD, FACOG, said. “In 2023, there were an estimated 66,000 new cases of endometrial cancer. The problem with endometrial cancer is it’s one of the cancers in women that is on the rise. Over the past 10 or 20 years, the rates have gone up by [approximately] 1% or 2%. Unfortunately, mortality rate has increased, especially in…older, non-Hispanic Black, and Hispanic women. We’re going to see more of it, and we have to focus on decreasing some of those disparities.” During a recent OncLive Peer Exchange, expert gynecologic oncologists from around the United States recapped key findings from pivotal clinical trials in endometrial and cervical cancer presented during the European Society for Medical Oncology (ESMO) Congress 2023, which took place from October 20 to 24, 2023, in Madrid, Spain.^2-10

Updates in Advanced Recurrent Endometrial Cancer

During ESMO 2023, investigators presented updated findings from one of the most practice-altering studies in endometrial cancer in recent years: the phase 3 RUBY trial (NCT03981796). The double-blind, multicenter trial enrolled patients with advanced or first recurrent endometrial cancer and randomly assigned them to receive either the anti–PD-1 antibody dostarlimab-gxly (Jemperli) or placebo, plus carboplatin and paclitaxel. The coprimary end points were progression-free survival (PFS) per RECIST 1.1 and OS.²

In the overall population, patients in the investigational arm (n = 245) experienced a median PFS of 11.8 months (95% CI, 9.6-17.1) compared with 7.9 months (95% CI, 7.6-9.5) in the placebo arm (n = 249; HR, 0.64; 95% CI, 0.507- 0.800; P < .0001). Additionally, patients with mismatch repair– deficient (dMMR)/microsatellite instability–high (MSI-H) disease experienced a median PFS that was not reached (NR; 95% CI, 11.8-NR) vs 7.7 months (95% CI, 5.6-9.7) in the dostarlimab (n = 53) and placebo (n = 65) arms, respectively (HR, 0.28; 95% CI, 0.162-0.495; P < .0001). Dostarlimab also conferred a pronounced benefit over placebo in terms of OS in both the overall (HR, 0.64; 95% CI, 0.464-0.870; P = .0021) and dMMR/ MSI-H (HR, 0.30; 95% CI, 0.127- 0.699) populations.²

Notably, treatment with dostarlimab also led to a significant PFS benefit over placebo among patients with TP53-mutated (HR, 0.55; 95% CI, 0.30-0.99) and dMMR/MSI-H disease (HR, 0.31; 95% CI, 0.17-0.56). Patients with no specific molecular profile experienced a 23% reduction in the risk of progression or death with the addition of dostarlimab to chemotherapy (HR, 0.77; 95% CI, 0.17-0.56). Patients with POLε-mutated disease experienced a PFS rate of 100% regardless of whether they received dostarlimab (n = 2) or placebo (n = 3).²

“Data from RUBY [showed] that [patients with] dMMR [disease are] going to have a long, durable response, with [an HR] that’s tremendously low, [which is] stuff that I never thought I’d see,” Thomas C. Krivak, MD, said. “The only reason not to have [an eligible patient] on this medication is if there’s a significant contraindication, [such as] significant multiple sclerosis or some type of autoimmune disease that was uncontrolled. If you place them on this medication, you’re probably going to have some issues, but I would try mitigation strategies to get them this medication.”

“Some of us might be surprised [to see that the patients with P53 mutations seem to have a good response, [in addition to] the [patients with] dMMR [disease]. [Additionally], although POLε-mutated [disease] is not very common in [our] clinical practice, those patients seem to do really well [regardless of treatment],” Chase said.

On July 31, 2023, the FDA approved dostarlimab in combination with carboplatin and paclitaxel, followed by single-agent dostarlimab for the treatment of patients with advanced or recurrent endometrial cancer that is dMMR/ MSI-H, as determined by an FDA-approved test. The regulatory decision was supported by findings from RUBY.¹¹

After highlighting the FDA approval of dostarlimab in endometrial cancer, panelists discussed findings from other clinical trials evaluating combination regimens in endometrial cancer that were presented during ESMO 2023. They paid particular attention to reviewing updated data from the phase 3 NRG-GY018 (NCT03914612), AtTEnd (NCT03603184), and DUO-E (NCT04269200) trials, all of which were similar to RUBY in that they combined PD-(L)1 inhibitors with standard-of-care chemotherapy in advanced or recurrent endometrial cancer.

NRG-GY018 evaluated the safety and efficacy of the addition of pembrolizumab (Keytruda) to carboplatin and paclitaxel. The trial enrolled patients with stage III/IVA, stage IVB, or recurrent endometrial cancer and randomly assigned them 1:1 to receive pembrolizumab or placebo in combination with chemotherapy.³

Patients with dMMR disease in the pembrolizumab (n = 92) and placebo (n = 92) arms experienced an objective response rate (ORR) of 82% (95% CI, 72%-89%) and 71% (95% CI, 60%-80%), respectively, including respective complete response (CR) rates of 32% and 15%.³ The median duration of response (DOR) was 28.7 months (95% CI, 20.2-NR) vs 6.2. moths (95% CI, 4.3-9.2), respectively (HR, 0.218; 95% CI, 0.13-0.37; P < .0001).3 Notably, in the subgroup of patients with mismatch repair–proficient (pMMR) endometrial cancer, the ORR was 71% (95% CI, 64%-77%) with a 15% CR rate compared with 58% (95% CI, 52%-65%) and an 8% CR rate in the pembrolizumab (n = 212) and placebo (n = 234) arms, respectively. The median DOR was 9.2 months (95% CI, 7.1-14.7) vs 6.2 months (95% CI, 4.8-6.5), respectively (HR, 0.467; 95% CI, 0.34- 0.64 P < .0001).³

“The new data from [NRG-]GY018 presented at this meeting were the response data,” Bradley Monk, MD, said. “[The data] got better [since the last update], particularly in the pMMR subset—it was already good in the dMMR subset. The second thing that they showed is, regardless of the dMMR [subtype]—whether it’s a genetic, germline, or somatic [mutation], or hypermethylation— chemotherapy and checkpoint inhibition had the same effect in both groups. That type of [dMMR] and activation didn’t seem to matter.”

The double-blind AtTEnd study randomly assigned patients with stage III or IV newly diagnosed or recurrent endometrial cancer in a 2:1 manner to receive atezolizumab (Tecentriq) or placebo, plus carboplatin and paclitaxel, followed by atezolizumab or placebo maintenance. In recurrent patients, 1 prior line of systemic platinum-based chemotherapy was allowed with a platinum-free interval of at least 6 months.⁴

Findings from AtTEnd presented at ESMO 2023 showed that at a median follow-up of 28.3 months in the overall population, the median PFS in the atezolizumab arm (n = 360) was 10.1 months (95% CI, 9.4-12.3) compared with 8.9 months (95% CI, 8.1-9.6) in the placebo arm (n = 189; HR, 0.74; 95% CI, 0.61-0.91; log-rank P = .0219). Moreover, at a median follow-up of 26.2 months, patients with dMMR disease achieved a median PFS that was not estimable (NE; 95% CI, 12.3-NE) compared with 6.9 months (95% CI, 6.2-9.0) in the atezolizumab (n = 81) and placebo (n = 44) arms, respectively (HR, 0.36; 95% CI, 0.23-0.57; P = .0005).⁴

Additionally, the interim OS analysis showed that at 43% data maturity, patients in the atezolizumab and placebo arms achieved a median OS of 38.7 months (95% CI, 30.6-NE) vs 30.2 months (95% CI, 25.0-36.1), respectively (HR, 0.82; 95% CI, 0.63-1.07; log-rank P = .0483). In the dMMR population, the median OS was NE (95% CI, NE-NE) vs 25.7 months (95% CI, 13.5-NE), respectively (HR, 0.41; 95% CI, 0.22-0.76).⁴

Notably, among patients with pMMR disease, atezolizumab did not have a significant benefit over placebo in terms of PFS (HR, 0.92; 95% CI, 0.73-1.16) or OS (HR, 1.00; 95% CI, 0.74- 1.35).5 “[The study authors] pulled pMMR out as an exploratory subgroup, and there was no benefit with atezolizumab. That’s different than [what was observed in] RUBY and [NRG-]GY018, where there was benefit with the PD-1 agents,

with [NRG-]GY018 being the study that definitively showed that in that separate group,” Leslie M. Randall, MD, said.

Finally, in DUO-E, investigators compared durvalumab (Imfinzi) plus carboplatin and paclitaxel followed by maintenance durvalumab with or without maintenance therapy with the PARP inhibitor olaparib (Lynparza) with placebo plus chemotherapy followed by placebo maintenance in patients with newly diagnosed stage III or IV or recurrent endometrial cancer. Patients were randomly assigned 1:1:1 to 1 of the 3 treatment arms.⁵

At 61% data maturity in the control (n = 241), durvalumab (n = 238), and durvalumab/olaparib (n = 239) arms, the median PFS was 9.6 months (95% CI, 9.0-9.9), 10.2 months (95% CI, 9.7-14.7), and 15.1 months (95% CI, 12.6-20.7), respectively. Patients in the durvalumab arm experienced a 29% reduction in the risk of progression or death compared with the control arm (HR, 0.71; 95% CI, 0.57- 0.89; P = .003), and those in the durvalumab/olaparib arm experienced a 45% reduction compared with the control arm (HR, 0.55; 95% CI, 0.43-0.69; P < .0001).

Moreover, durvalumab plus olaparib provided a PFS benefit over durvalumab alone (HR, 0.78; 95% CI, 0.61-0.99).⁵

Antibody-Drug Conjugates Offer Intriguing Future Directions

Outside the exciting data from late-phase trials of PD-(L)1 inhibitors in endometrial cancer, investigators also presented findings from phase 1 studies in this population, such as STRO-002-GM1 (NCT03748186). STRO-002-GM1 used a different approach than the phase 3 trials that were covered by the panelists, evaluating the anti-folate receptor alpha (FRα) antibody-drug conjugate (ADC) luveltamab tazevibulin (Luvelta) monotherapy. The single-arm study enrolled 17 patients with recurrent endometrial cancer following treatment with at least 1 platinum- or immunotherapy- based regimen, with a maximum of 3 prior regimens.6

Findings from the dose expansion portion of the study presented during ESMO 2023 showed that at a median follow-up of 10.1 months, patients with an FRα expression of at least 1% (n = 16), 25% or less (n = 9), and more than 25% (n = 7) experienced an ORR of 19%, 11%, and 29%, respectively; all responses were partial. Additionally, the disease control rates were 69%, 56%, and 86%, respectively.⁶

Treatment with the ADC also led to a manageable safety profile. Grade 3 or higher treatment-emergent adverse effects occurred at a rate of 82.2% and included neutropenia (52.9%), anemia (23.5%), and arthralgia (17.6%). Study authors concluded that luveltamab tazevibulin could represent a novel targeted treatment option in recurrent endometrial cancer and that the agent warrants further investigation.⁶

“We have a plethora of compounds and proteins that we’re going to be able to target,” David M. O’Malley, MD, said. “We’re going to get smart linkers [and] smart payloads. We’re going have options—ADC after ADC with different targets and different payloads. I’m most excited about ADCs.”

Updates in Recurrent Metastatic Cervical Cancer

Several notable updates from phase 3 clinical trials evaluating treatments for patients with cervical cancer were also presented during ESMO 2023. Although cervical cancer affects a relatively small number of women, there remains a need for additional effective treatment options.

“Cervical cancer is a rare disease; there are approximately 10,000 to 12,000 cases per year. One of the biggest risk factors for cervical cancer is persistent human papilloma virus infection. The majority of patients we see in the clinic seem to be not getting their Pap smears,” Krivak said.

The phase 3 KEYNOTE-A18 (NCT04221945) trial evaluated the addition of pembrolizumab to standard external beam radiotherapy with concurrent chemotherapy followed by brachytherapy. The study enrolled treatment-naive patients with stage IB2 to IIB node-positive disease or stage III to IVA node-positive or node-negative cervical cancer. The coprimary end points were PFS per RECIST 1.1 and OS.⁷

Findings from the study showed that at a median follow-up of 17.9 months (range, 0.9-31.0), patients who received pembrolizumab plus chemoradiotherapy (n = 529) experienced a 2-year PFS rate of 67.8% (95% CI, 61.8%-73.0%) vs 57.3% (95% CI, 51.2%-62.9%) in the placebo plus chemoradiotherapy arm (n = 531; HR, 0.70; 95% CI, 0.55-0.89; P = .0020). Although OS data were only 42.9% mature, a favorable trend toward the pembrolizumab arm was observed (HR, 0.73; 95% CI, 0.49-1.07). The median PFS and OS were NR in either arm.⁷

Findings from KEYNOTE-A18 supported the September 2023 decision by the FDA to accept for priority review a new supplemental biologics license application seeking the approval

of pembrolizumab plus external beam radiotherapy and concurrent chemotherapy, followed by brachytherapy for the treatment with definitive intent of patients with newly diagnosed high-risk locally advanced cervical cancer. The agency has set a target action date of January 20, 2024, per the Prescription Drug User Fee Act.¹²

In another phase 3 study, INTERLACE (NCT01566240), investigators again aimed to build on standard chemoradiotherapy by adding induction chemotherapy. Patients with newly diagnosed stage IB1 node-positive to stage IVA cervical cancer were randomly assigned 1:1 to receive either induction chemotherapy with carboplatin and paclitaxel followed by standard chemoradiotherapy or standard chemoradiotherapy alone. The coprimary end points were PFS and OS.⁸

In the investigational arm (n = 250), the 3- and 5-year PFS rates were 75% and 73%, respectively, vs 72% and 64% in the chemoradiation-alone arm (n = 250; HR, 0.65; 95% CI, 0.46-0.91; P = .013). Additionally, patients who received induction chemotherapy prior to chemoradiation experienced a reduced risk of death of 39% vs those who received chemoradiation alone (HR, 0.61; 95% CI, 0.40- 0.91; P = .04). The 3- and 5-year OS rates were 86% and 80%, respectively, in the investigational arm vs 80% and 72% in the control arm.⁸

“[This is] something very interesting to potentially bring back to the clinic,” Chase said. “[However], I do want to mention that cost and transportation can be very difficult for our patients with cervical cancer in the United States. This is a weekly chemotherapy regimen in a patient population [who] potentially lives 3 hours away from the cancer center. It’s interesting.”

Looking to fill an unmet treatment need for patients who are not eligible for radiation or curative surgery, the phase 3 BEATcc trial (NCT03556839) evaluated atezolizumab in combination with bevacizumab (Avastin) and a platinum-based doublet chemotherapy in patients with stage IVB, persistent, or recurrent cervical cancer. Patients were randomly assigned 1:1 to receive standard therapy with carboplatin or cisplatin, paclitaxel, and bevacizumab with or without atezolizumab. The coprimary end points were OS and PFS per RECIST 1.1.⁹

Final PFS data from the study revealed that the addition of atezolizumab significantly improved PFS; the median PFS was 13.7 months (95% CI, 12.3-16.6) in the investigational arm (n = 206) vs 10.4 months (95% CI, 9.7-11.7) in the control arm (n = 204; HR, 0.62; 95% CI, 0.49-0.78; P < .0001). Additionally, the median OS was 32.1 months (95% CI, 25.3-36.8) compared with 22.8 months (95% CI, 20.3-28.0), respectively (HR, 0.68; 95% CI, 0.52- 0.88; P = .0046).⁹

Finally, the phase 3 innovaTV 301 trial (NCT04697628) examined the ADC tisotumab vedotin-tftv (Tivdak) vs investigator’s choice of chemotherapy for the second- or third-line treatment of patients with recurrent or metastatic cervical cancer. Patients must have experienced progression on or after a chemotherapy doublet with or without bevacizumab and an anti–PD-(L)1 agent, if eligible and available. The primary end point was OS.¹⁰ D

ata from a planned interim analysis of the trial showed that the median OS in the investigational and control arm was 11.5 months (95% CI, 9.8-14.9) vs 9.5 months (95% CI, 7.9-10.7), respectively (HR, 0.70; 95% CI, 0.54-0.89; log-rank P = .0038). The ADC also provided a significant benefit in terms of PFS compared with investigator’s choice of chemotherapy (HR, 0.67; 95% CI, 0.54-0.82; log-rank P < .0001).¹⁰

“This was impressive for us to see. Those of us who treat recurrent cervical cancer know that once [patients] had 1 prior line, it’s a very high-risk [population] and definitely an unmet need,” Chase said.

References

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3. Eskander RN, Sill M, Miller A, et al. Updated response data and analysis of progression free survival by mechanism of mismatch repair loss in endometrial cancer (EC) patients (pts) treated with pembrolizumab plus carboplatin/paclitaxel (CP) as compared to CP plus placebo (PBO) in the NRG GY018 trial. Ann Oncol. 2023;34(suppl 2):S1284. doi:10.1016/j.annonc.2023.10.037
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6. Pothuri B, Naumann RW, Martin LP, et al. Luveltamab tazevibulin (STRO-002), an anti-folate receptor alpha (Fol- Rα) antibody drug conjugate (ADC), demonstrates clinical activity in recurrent/progressive epithelial endometrial cancer (EEC): STRO-002-GM1 phase I dose expansion. Ann Oncol. 2023;34(suppl 2):S508. doi:10.1016/j. annonc.2023.09.1920
7. Lorusso D, Xiang Y, Hasegawa K, et al. Pembrolizumab plus chemoradiotherapy for high-risk locally advanced cervical cancer: a randomized, double-blind, phase III ENGOT-cx11/GOG-3047/KEYNOTE-A18 study. Ann Oncol. 2023;34(suppl 2):S1279-S1280. doi:10.1016/j. annonc.2023.10.032
8. McCormack M, Gallardo Rincón D, Eminowicz G, et al. A randomised phase III trial of induction chemotherapy followed by chemoradiation compared with chemoradiation alone in locally advanced cervical cancer: the GCIG INTERLACE trial. Ann Oncol. 2023;34(suppl 2):S1276. doi:10.1016/j.annonc.2023.10.028
9. Oaknin A, Gladieff L, Martinez-Garcia J, et al. Primary results from BEATcc (ENGOT-Cx10/GEICO 68-C/ JGOG1084/GOG-3030), a randomised phase III trial of first-line atezolizumab (atezo) combined with a platinum doublet and bevacizumab (bev) for metastatic (stage IVB), persistent or recurrent cervical cancer (R/M CC). Ann Oncol. 2023;34(suppl 2):P1198-1200. doi:10.1016/j. annonc.2023.10.694
10. Vergote IB, Gonzalez Martin A, Fujiwara K, et al. innovaTV 301/ENGOT-cx12/GOG-3057: a global, randomized, open-label, phase III study of tisotumab vedotin vs investigator’s choice of chemotherapy in 2L or 3L recurrent or metastatic cervical cancer. Ann Oncol. 2023;34(suppl 2):S1276-S1277. doi:10.1016/j.annonc.2023.10.029
11. FDA approves dostarlimab-gxly with chemotherapy for endometrial cancer. FDA. July 31, 2023. Accessed November 27, 2023. https://www.fda.gov/drugs/ drug-approvals-and-databases/fda-approvesdostarlimab- gxly-chemotherapy-endometrial-cancer
12. FDA grants priority review to Merck’s application for Keytruda (pembrolizumab) plus concurrent chemoradiotherapy as treatment for patients with newly diagnosed high-risk locally advanced cervical cancer. News release. Merck. September 20, 2023. Accessed September 20, 2023. https://www. merck.com/news/fda-grants-priority-reviewto- mercks-application-for-keytruda-pembrolizumabplus- concurrent-chemoradiotherapy-as-treatmentfor- patients-with-newly-diagnosed-high-risklocally- advanced/