Brian M. Slomovitz, MD, discusses the phase 3 DUO-E and AtTEnd trials of immunotherapy in endometrial cancer.

Dr Slomovitz on the DUO-E and AtTEnd Trials Investigating Immunotherapy in Endometrial Cancer

Brian M. Slomovitz, MD, director, Gynecologic Oncology, co-chair, the Cancer Research Committee, Mount Sinai Medical Center, professor, Obstetrics and Gynecology, Florida International University, discusses the phase 3 DUO-E (NCT04269200) and AtTEnd (NCT03603184) trials investigating the use immunotherapy in endometrial cancer, as presented at the 2023 ESMO Congress. 

DUO-E assessed the efficacy of durvalumab (Imfinzi) plus chemotherapy followed by durvalumab and olaparib (Lynparza) maintenance for patients with advanced newly diagnosed or recurrent endometrial cancer who were naïve to systemic therapy, Slomovitz begins. Patients received either chemotherapy alone, chemotherapy plus durvalumab, or chemotherapy plus durvalumab and olaparib.

Results showed notable benefit with the combination of chemotherapy, a checkpoint inhibitor, and a PARP inhibitor for this patient population

Patients who received either durvalumab-containing regimen experienced an improvement in progression-free survival vs chemotherapy alone. Hazard ratios (HR) for the durvalumab arm vs the control arm was 0.71, while the HR in the durvalumab plus olaparib arm was 0.55. This corresponded with 29% and 45% reductions in the risk of disease progression, respectively. Moreover, a trend toward improved overall survival (OS) with the durvalumab regimens was observed, although these data were not fully mature at the time of the interim analysis. Notably, patients whose disease was mismatch repair (MMR)–proficient experienced a more pronounced PFS benefit with the addition of olaparib to durvalumab.

The AtTEnd trial investigated the efficacy of adding atezolizumab (Tecentriq) to

 This study also yielded positive results, Slomovitz details, showing that atezolizumab plus chemotherapy elicited a statistically significant improvement in PFS vs chemotherapy alone. Notably, PFS benefit was pronounced in a subset of patients with MMR-deficient (dMMR) tumors, with median PFS increasing from 6.9 months with placebo to not evaluable in the dMMR population after a median follow-up of 26.2 months. As seen in DUO-E, this interim analysis of OS also suggested a trend favoring the atezolizumab combination.

Ultimately, these studies confirm that the addition of immunotherapy to chemotherapy regimens is an effective and viable approach for patients with advanced endometrial cancer, Slomovitz states. However, more research is needed to fully understand and optimize these regimens, he concludes.

Videos

Brian M. Slomovitz, MD, discusses the phase 3 DUO-E and AtTEnd trials investigating the use immunotherapy in endometrial cancer, as presented at the 2023 ESMO Congress.

Brian Slomovitz, MD, reviews data from a phase 3 study of tisotumab vedotin in patients with recurrent or metastatic cervical cancer.

innovaTV 301/ENGOT-cx12/GOG-3057: A Global, Randomized, Open-Label, Phase 3 Study of Tisotumab Vedotin vs Investigator’s Choice of Chemotherapy in 2L or 3L Recurrent or Metastatic Cervical Cancer

Tisotumab vedotin (TV) is an investigational antibody-drug conjugate composed of a tissue factor-directed human monoclonal antibody covalently linked to cytotoxic MMAE.

In the US, TV monotherapy received accelerated approval for the treatment of adult patients with recurrent or metastatic cervical cancer (r/mCC) with disease progression on or after chemotherapy.

Here, innovaTV 301 (NCT04697628) study results of TV vs investigator’s choice of chemotherapy in pts with r/mCC following 1L therapy are presented.

Eligible patients had r/mCC with disease progression on/after treatment with standard of care chemotherapy doublet ± bevacizumab ± anti-PD-(L)1 therapy, measurable disease per RECIST v1.1, and ECOG PS 0-1.

Patients were randomized 1:1 to TV monotherapy or investigator's choice of topotecan, vinorelbine, gemcitabine, irinotecan, or pemetrexed.

Key secondary endpoints included PFS and confirmed ORR by investigator.

502 pts were randomized (TV: 253; chemotherapy: 249)

Median survival follow-up was 10.8 mo (95% CI, 10.3-11.6).

Overall, median age was 50 yrs (range: 26-80)

Arms were balanced for demographics and disease characteristics

63.9% and 27.5% of patients had prior bevacizumab and prior anti-PD-(L)1 therapy, respectively.

The TV arm had a 30% reduction in risk of death vs chemotherapy (HR 0.70; 95% CI 0.54-0.89; P=0.0038), with significantly longer median OS (11.5 mo [95% CI 9.8-14.9] vs 9.5 mo [95% CI 7.9-10.7]).

PFS was superior in the TV vs chemotherapy arm (HR: 0.67 [95% CI, 0.54-0.82]; P<0.0001).

Confirmed ORR was 17.8% and 5.2% in the TV and chemotherapy arms, respectively (odds ratio: 4.0; 95% CI, 2.1-7.6; P<0.0001).

Most patients experienced at least 1 treatment-related adverse event (TV: 87.6% [grade ≥3: 29.2%] vs chemotherapy: 85.4% [grade ≥3: 45.2%]).

AEs were consistent with the known TV safety profile, including for ocular, peripheral neuropathy, and bleeding AEs.

In the phase 3 innovaTV 301 study, TV showed a statistically significant and clinically meaningful improvement in OS, PFS, and ORR vs chemotherapy, with a manageable and tolerable safety profile in pts with 2L/3L r/mCC.

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. Abstract presented at: ESMO Congress 2023, October 20-24, 2023.

Brian Slomovitz, MD, provides a look at an upcoming Rapid Readout program looking at the results of a phase 3 study of tisotumab vedotin in patients with recurrent or metastatic cervical cancer.

Brian M. Slomovitz, MD, director, Gynecologic Oncology, co-chair, the Cancer Research Committee, Mount Sinai Medical Center, professor, Obstetrics and Gynecology, Florida International University, discusses the optimizing the role for PARP inhibition in patients with ovarian cancer, highlighting the agents’ efficacy in patients whose disease harbors 

The use of PARP inhibitors in the treatment of patients with ovarian cancer has impacted the treatment landscape, particularly when utilized in the first-line setting, Slomovitz begins. The phase 3 SOLO-1 trial (NCT01844986) enabled this paradigm shift by demonstrating that patients with 

mutations who received the PARP inhibitor olaparib (Lynparza) experienced a significant improvement in overall survival (OS) vs placebo, Slomovitz reports. The median OS was 75.2 months in patients treated with placebo, though the median OS was not reached in patients treated with olaparib. The 60-month OS rate in the experimental group was 73.1% vs 63.4% in the control group. At 84 months, the respective rates were 67.0% for the experimental arm and 46.5% for the control arm.

Evidence from SOLO-1 indicates that PARP inhibitors provide long-term disease control and may have potential to be curative in this setting, Slomovitz says, emphasizing that this outcome is rare for patients with advanced ovarian cancer. This signifies a substantial departure from the historical trajectory of the disease, he adds.

For patients who did not receive PARP inhibitors in the first-line setting, there is still a clear indication for their use as maintenance therapy in the second line, Slomovitz continues. This includes patients displaying either somatic or hereditary 

 mutations, he notes. By extending the benefits of PARP inhibitors into the second-line setting, the medical community is further optimizing the management of ovarian cancer, particularly for individuals with specific genetic profiles, Slomovitz states. The expanding roles of PARP inhibitors in advanced ovarian cancer are a testament to the growing understanding of the disease's underlying biology and the evolution of precision medicine, he concludes.

Brian M. Slomovitz, MD, discusses the optimal role for PARP inhibition in patients with ovarian cancer, highlighting its efficacy in those harboring BRCA mutations.
 

Dr Slomovitz on the Current Role of PARP Inhibitors in Ovarian Cancer

Brian M. Slomovitz, MD, director, Gynecologic Oncology, co-chair, the Cancer Research Committee, Mount Sinai Medical Center, professor, Obstetrics and Gynecology, Florida International University, discusses the classification of molecular subtypes to guide treatment and care in endometrial cancers.

Utilizing The Cancer Genome Atlas (TCGA), investigators aimed to classify patients with endometrial cancer into 4 main risk groups by using a combination of immunohistochemistry and mutation analysis. This was done to better understand how to approach a patient’s treatment options, as certain disease characteristics are associated with a worse prognosis.

The Proactive Molecular Risk Classifier for Endometrial Cancer (ProMisE) identified 4 molecular subtypes: mismatch repair–deficient (dMMR)/microsatellite instability–high (MSI-H); 

Nonspecific or copy-number low tumors generally consist of patients with low-grade endometrioid disease, and the majority do not classify as dMMR, Slomovitz continues. 

 mutations are relatively rare; however, they are associated with the best prognosis, and this group of patients is amenable to immunotherapy, Slomovitz explains. Additionally, patients with dMMR/MSI-H tumors are the most responsive to immunotherapy, Slomovitz notes.

As further information about the molecular characteristics of endometrial cancers is gathered, the attention paid to different biomarkers, such as 

 and estrogen receptor positivity, may shift, Slomovitz adds. By shifting away from histologic classifications of the tumors, it could allow for the classification of patients into 1 of the 4 risk subtypes, Slomovitz explains. In the 2023 International Federation of Gynecology and Obstetrics (FIGO) staging, it is expected that molecular classifications will be included for endometrial cancer, Slomovitz concludes.

Brian M. Slomovitz, MD, discusses the classification of molecular subtypes to guide treatment and care in endometrial cancers.

Dr Slomovitz on the Classification of Molecular Subtypes to Guide Treatment in Endometrial Cancer

Brian M. Slomovitz, MD, director, Gynecologic Oncology, co-chair, the Cancer Research Committee, Mount Sinai Medical Center, professor, Obstetrics and Gynecology, Florida International University, discusses the evaluation of letrozole and ribociclib (Kisqali) from the phase 2 GOG 3026 trial (NCT03673124) in recurrent low-grade serous ovarian carcinoma.

Patients enrolled on the trial were treated with 600 mg of ribociclib on a 3-weeks-on/1-week-off schedule, plus 2.5 mg of oral letrozole once per day in 28-day cycles. Findings presented at the 2023 Society of Gynecologic Oncology Annual Meeting on Women’s Cancer showed that the combination elicited an overall response rate of 23% (90% CI, 13.4%-35.1%) and a clinical benefit rate of 79% (90% CI, 67.2%-88.2%). The median duration of response was 19.1 months. The median progression-free survival was 19.1 months, and the median overall survival was not yet reached.

Low-grade serous ovarian carcinoma is a rare subtype of ovarian cancer with limited treatment options , Slomovitz begins. Unlike high-grade ovarian cancer, which responds favorably to chemotherapy, the response rates to chemotherapy within this patient population are historically between 0% and 15%, Slomovitz notes, adding that response rates with hormonal therapy are also low in this patient population.

The response rate generated by letrozole and ribociclib was comparable to MEK inhibition, Slomovitz explains. Notably, the median PFS and DOR observed with the combination serve as an improvement on what would be expected with currently available therapies for patients with recurrent low-grade serous carcinoma, Slomovitz adds.

Regarding safety, letrozole and ribociclib was well tolerated, Slomovitz says, explaining that the adverse effect (AE) profile was similar to prior data and grade 3 or higher toxicities were limited. The most common any-grade AEs included decreased neutrophil count (63%), decreased white blood cell count (46%), anemia (42%), and nausea (42%). Decreased neutrophil count (44%) was the only grade 3 or higher AE reported in more than 10% of patients.

Brian M. Slomovitz, MD, discusses the evaluation of letrozole and ribociclib from the phase 2 GOG 3026 trial in recurrent low-grade serous ovarian carcinoma.

Dr Slomovitz on the Investigation of Letrozole Plus Ribociclib in Low-Grade Serous Ovarian Carcinoma

Brian M. Slomovitz, MD, gynecologic oncology, Broward Health, professor of obstetrics and gynecology, Herbert Wertheim College of Medicine, Florida International University, discusses sequencing strategies for endometrial cancer.

Traditionally, chemotherapy and radiation therapy have always been the standard treatment options for patients with advanced or recurrent endometrial cancer, says Slomovitz. However, interesting results from the GOG-258 trial demonstrated that radiation therapy, in combination with chemotherapy, does not significantly improve survival. These data indicate that holding off on radiation therapy until salvage therapy is needed may serve as an alternative option, adds Slomovitz.

Furthermore, investigators recently discovered that, depending on the patient's genetic makeup and the classification of the tumor, immunotherapies are very active in endometrial cancer, explains Slomovitz. For example, pembrolizumab (Keytruda) has been approved for patients with microsatellite instability–high (MSI-H) endometrial cancer. Conversely, for patients who do not have MSI-H disease, the combination therapy of pembrolizumab and the TKI lenvatinib (Lenvima) is an approved option available for use in certain types of endometrial cancer, says Slomovitz.

Investigators understand that these agents are effective in the second-line setting; however, they are now analyzing whether immunotherapy could be moved to an earlier setting, followed by chemotherapy, could potentially result in better outcomes for patients. Determining the right sequence could help prolong survival for patients, concludes Slomovitz.

Brian M. Slomovitz, MD, discusses sequencing strategies for endometrial cancer.
 

Dr. Slomovitz on Sequencing Strategies for Endometrial Cancer

Brian M. Slomovitz, MD, gynecologic oncology, Broward Health, professor of obstetrics and gynecology, Herbert Wertheim College of Medicine, Florida International University, discusses the importance of developing sequencing strategies in endometrial cancer treatment.

Research regarding sequencing strategies in endometrial cancer has lagged behind compared with ovarian cancer, says Slomovitz.

However, more treatment modalities are available to women with endometrial cancer compared with ovarian cancer, add Slomovitz. Patients with endometrial cancer may receive chemotherapy, radiation, hormonal therapy, immunotherapy, or other biologic agents as part of their treatment regimen.

In the absence of head-to-head data regarding sequencing, treatment considerations should be based on eliciting the best outcome for patients in the first-line setting, as well as optimizing responses from subsequent therapies, concludes Slomovitz.

Brian M. Slomovitz, MD, discusses the importance of developing sequencing strategies in endometrial cancer treatment. 



Dr. Slomovitz on the Importance of Developing Sequencing Strategies in Endometrial Cancer

Brian M. Slomovitz, MD, gynecologic oncology, Broward Health, professor of obstetrics and gynecology, Herbert Wertheim College of Medicine, Florida International University, discusses sequencing strategies in endometrial cancer.

Historically, patients with advanced and recurrent endometrial cancer have received chemotherapy and radiation, says Slomovitz. However, findings from the phase 3 GOG-258 trial showed that chemotherapy plus radiation did not prolong relapse-free survival compared with chemotherapy alone in patients with stage 3 or 4A endometrial carcinoma. As such, waiting to give radiation therapy until a patient requires salvage treatment is an alternate strategy, explains Slomovitz.

Additionally, immunotherapy has demonstrated activity in patients with microsatellite instability—high (MSI-H) endometrial cancer. In 2017, the checkpoint inhibitor pembrolizumab (Keytruda) received regulatory approval for the treatment of adult and pediatric patients with unresectable or metastatic solid tumors that are MSI-H or mismatch repair deficient (dMMR). In September 2019, the FDA granted an accelerated approval to the combination of pembrolizumab and lenvatinib (Lenvima) for the treatment of patients with advanced endometrial cancer that is not MSI-H or dMMR.

Moving immunotherapy earlier in treatment followed by chemotherapy may improve response rates and prolong progression-free survival for patients with endometrial cancer, concludes Slomovitz.

Brian M. Slomovitz, MD, discusses sequencing strategies in endometrial cancer.

Brian M. Slomovitz, MD

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