Emily M. Hinchcliff, MD, MPH, is an assistant professor at Feinberg School of Medicine, Northwestern Medicine.

Dr Hinchcliff on the Evolving Role of ADCs in Ovarian Cancer

"The ADCs—across the board—are an incredibly exciting opportunity for targeted therapy." 

Emily M. Hinchcliff, MD, MPH, an assistant professor of obstetrics and gynecology (gynecologic oncology) at the Feinberg School of Medicine at Northwestern Medicine, discusses the evolution of antibody-drug conjugates (ADCs) for the treatment of patients with ovarian cancer.

ADCs represent a promising advancement in targeted therapy for patients with ovarian cancer, offering a new treatment strategy with enhanced specificity, Hinchcliff begins. The success of mirvetuximab soravtansine-gynx (Elahere) in the ​phase 3 MIRASOL trial (Study 0416; NCT04209855) marked a significant milestone in ovarian cancer treatment, she says. In ​MIRASOL, patients with folate receptor α (FRα)–positive, platinum-resistant epithelial ovarian, fallopian tube, or primary peritoneal cancer who received the ADC (n = 227) achieved a median overall survival of ​16.5 months (95% CI, 14.5-24.6) vs 12.7 months (95% CI, 10.9-14.4) in those who received ​investigator’s choice of chemotherapy (n = 226; HR, 0.67; 95% CI, 0.50-0.88; 

 = .0046). Furthermore, the median progression-free survival with the ADC was 5.6 months (95% CI, 4.3-5.9) compared with 4.0 months (95% CI, 2.9-4.5) with chemotherapy (HR, 0.65; 95% CI, 0.52-0.81; 

 < .0001). These data supported the ​March 2024 regular 

FDA approval of mirvetuximab soravtansine

 for the treatment of adult patients with FRα-positive, platinum-resistant epithelial ovarian, fallopian tube, or primary peritoneal cancer who have previously received between 1 and 3 systemic treatment regimens, establishing the ADC as a valuable addition to the current therapeutic paradigm, she explains.

As more ADCs have entered clinical development, key questions have arisen regarding optimal treatment sequencing for patients with FRα expression who may also express other actionable ADC targets, Hinchcliff describes. Determining the optimal order of treatment administration, identifying potential cross-resistance mechanisms, and understanding whether prior exposure to one ADC modulates the efficacy of subsequent therapies remains an area of ongoing investigation, she notes. Additionally, beyond ovarian cancer, ADCs have also demonstrated therapeutic potential in endometrial cancer, signaling the broader efficacy of this class of agents across gynecologic oncology, she concludes.

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Emily M. Hinchcliff, MD, MPH, discusses the growing role of ADCs like mirvetuximab soravtansine for the treatment of patients with ovarian cancer. 

Dr Hinchcliff on the Benefits of Chemoimmunotherapy in Endometrial Cancer

“The key takeaways from any talk…about recent updates in endometrial cancer have to be the rapid expansion of treatment options, as well as the major effect that immunotherapy has had on our treatment regimens.”

Emily M. Hinchcliff, MD, MPH, assistant professor, Feinberg School of Medicine, Northwestern Medicine, discusses how the addition of immunotherapy to chemotherapy has affected the endometrial cancer treatment paradigm.

Recent advancements in endometrial cancer are indicative of the rapid growth of the treatment arsenal, particularly with the incorporation of immunotherapy into standard approaches, Hinchcliff begins. Since 2023, several randomized, controlled clinical trials, such as the phase 3 RUBY (NCT03981796) and KEYNOTE-868/NRG-GY018 (NCT03914612) studies, have shown the benefits of adding immunotherapy to chemotherapy and established that strategy as the standard of care for patients with endometrial cancer, she emphasizes.

the FDA approved pembrolizumab (Keytruda) in combination with carboplatin and paclitaxel

 followed by pembrolizumab monotherapy, for the treatment of adult patients with primary advanced or recurrent endometrial carcinoma. In the pivotal KEYNOTE-868/NRG-GY018 trial, among patients with mismatch repair–deficient (dMMR) disease, the median progression-free survival (PFS) was not reached (NR; 95% CI, 30.7-NR) with pembrolizumab plus chemotherapy (n = 112); conversely, the median PFS was 6.5 months (95% CI, 6.4-8.7) with placebo plus chemotherapy (n = 113; HR, 0.30 [95% CI, 0.19-0.48]; 

 < .0001). Among patients with MMR-proficient disease, the median PFS was 11.1 months (95% CI, 8.7-13.5) in the pembrolizumab arm (n = 239) and 8.5 months (95% CI, 7.2-8.8) in the placebo arm (n = 295; HR, 0.60 [95% CI, 0.46-0.78]; 

 (Jemperli) plus carboplatin and paclitaxel, followed by dostarlimab monotherapy, for the treatment of adult patients with primary advanced or recurrent endometrial cancer. This regulatory decision expanded upon the 

 for the treatment of adult patients with primary advanced or recurrent dMMR or microsatellite instability–high endometrial cancer. The expanded approval was supported by findings from part 1 of RUBY, in which patients in the overall population who received dostarlimab in combination with chemotherapy (n = 245) achieved a median overall survival of 44.6 months (95% CI, 32.6-NR) vs 28.2 months (95% CI, 22.1-35.6) with placebo plus chemotherapy (n = 249; HR, 0.69 [95% CI, 0.54-0.89]; 1-sided 

Emily M. Hinchcliff, MD, MPH, discusses how the addition of immunotherapy to chemotherapy has influenced the endometrial cancer treatment paradigm.

Dr Hinchcliff on the Addition of Dostarlimab to Chemotherapy in Advanced/Recurrent Endometrial Cancer

“The real remaining question is: Can we further delineate [the MMR] subgroups? [These subgroups are] not homogeneous and represents this large opportunity for further study. [This] brings up the question of treatment sequencing in the recurrent setting.”

Emily Hinchcliff, MD, MPH, gynecologic oncologist, assistant professor, obstetrics and gynecology, Northwestern University Feinberg School of Medicine, discusses findings from the second interim analysis of overall survival (OS) from the phase 3 RUBY trial (NCT03981796), which evaluated the addition of dostarlimab-gxly (Jemperli) to standard-of-care (SOC) chemotherapy in patients with advanced or recurrent endometrial cancer.

The interim analysis, conducted at 51% OS maturity, revealed a statistically significant HR of 0.69 (95% CI, 0.54-0.89) with the combination regimen vs placebo plus chemotherapy for the overall trial population, Hinchcliff begins. She notes that the most substantial OS benefit was observed in the mismatch repair–deficient (dMMR) subgroup, which had an OS HR of 0.32 (95% CI, 0.17-0.63), which was consistent with findings from the initial analysis, a result she describes as unprecedented in this patient population.

In contrast, the OS HR in the MMR-proficient (pMMR) subgroup showed a trend toward significance for the combination over chemotherapy alone but did not achieve the same magnitude of benefit observed in the dMMR group. Hinchcliff highlights the heterogeneity within MMR populations and emphasizes the need for further research to delineate these subgroups and explore additional combination therapies that may enhance outcomes.

A notable observation from the study was the high rate of subsequent immunotherapy use in both arms, with over 38.2% of patients in the placebo arm and 17.1% of those in the dostarlimab-containing arm receiving immunotherapy following disease progression. Despite this, the OS benefit with dostarlimab plus chemotherapy remained robust, raising important questions about treatment sequencing and optimal management strategies in the recurrent setting, according to Hinchcliff.

Hinchcliff also underscores the importance of refining treatment approaches for dMMR patients, who now benefit from the integration of immunotherapy into first-line care. She notes that these findings prompt critical considerations about the next steps in managing recurrent disease, particularly as immunotherapy becomes entrenched in the SOC.

Hinchcliff concludes that the RUBY trial results reinforce the need for continued research into subgroup-specific therapies and treatment sequencing strategies.

Emily Hinchcliff, MD, MPH, discusses the addition of dostarlimab to standard-of-care chemotherapy in patients with advanced/recurrent endometrial cancer.

Dr Hinchcliff on the Evolving Role of PARP Inhibitors in Ovarian Cancer

“Similar to the role of immunotherapy in endometrial cancer, PARP inhibitors for the HRD ovarian cancer population have changed the game.”

Emily M. Hinchcliff, MD, MPH, assistant professor, Feinberg School of Medicine, Northwestern Medicine, discusses considerations for future research directions regarding the role of PARP inhibitors in the treatment of patients with ovarian cancer.

The introduction of PARP inhibitors into the homologous recombination–deficient (HRD) ovarian cancer treatment paradigm has transformed how this disease is managed, Hinchcliff begins. This class of agents has demonstrated unprecedented efficacy in the ovarian cancer population, she says. A critical area of ongoing research is the sequencing of therapies for ovarian cancer, particularly for patients who have received PARP inhibitors in the frontline setting, she explains. This parallels the role of immunotherapy in the endometrial cancer treatment paradigm, she notes.

The field of ovarian cancer management is experiencing substantial advancements, and a growing array of therapeutic options is emerging, according to Hinchcliff. This expansion mirrors the broader treatment progress seen across gynecologic oncology, marking an exciting and transformative area of medicine, she emphasizes.

Several PARP inhibitors are currently FDA approved for the treatment of patients with ovarian cancer:

Niraparib (Zejula) is indicated as maintenance therapy in adult patients with advanced epithelial ovarian cancer who are in complete response (CR) or partial response (PR) to frontline platinum-based chemotherapy, as well as maintenance therapy for adult patients with deleterious or suspected deleterious germline 

-mutant recurrent epithelial ovarian cancer who are in CR or PR following platinum-based chemotherapy. 

Olaparib (Lynparza) is indicated as maintenance therapy for adult patients with 

-mutated advanced epithelial ovarian cancer who are in CR or PR following platinum-based chemotherapy in the frontline setting and beyond, as well as in combination with bevacizumab (Avastin) for maintenance therapy in adult patients with advanced HRD epithelial ovarian cancer who are in CR or PR following platinum-based chemotherapy in the frontline setting. 

Rucaparib (Rubraca) is indicated as maintenance therapy for adult patients with 

 mutation–associated recurrent epithelial ovarian cancer who are in CR or PR to platinum-based chemotherapy.

Emily M. Hinchcliff, MD, MPH, discusses future research directions regarding the role of PARP inhibitors for the treatment of patients with ovarian cancer.

Emily M. Hinchcliff, MD, MPH

Articles

Dr Hinchcliff on the Evolving Role of ADCs in Ovarian Cancer

Dr Hinchcliff on the Benefits of Chemoimmunotherapy in Endometrial Cancer

Dr Hinchcliff on the Addition of Dostarlimab to Chemotherapy in Advanced/Recurrent Endometrial Cancer

Dr Hinchcliff on the Evolving Role of PARP Inhibitors in Ovarian Cancer