R. Wendel Naumann, MD, FACOG, FACS, professor, director, Gynecologic Oncology Research, associate medical director, Clinical Trials, Levine Cancer Institute, Atrium Health, discusses how the evolution of immunotherapy has changed the treatment landscape for patients with recurrent or metastatic cervical cancer.

The use of immunotherapy agents for cervical cancer is a moving target, and the role of these agents continues to change as they are investigated in earlier lines of therapy, Naumann begins.

In October 2021, the FDA approved pembrolizumab (Keytruda) in combination with chemotherapy, with or without bevacizumab(Avastin), for use in patients with persistent, recurrent or metastatic, PD-L1–positive cervical cancer. This approval was based on data from the phase 3 KEYNOTE-826 trial (NCT03635567).Prior to this approval, single-agent pembrolizumab also received accelerated approval for patients in this population who experienced disease progression on or after prior chemotherapy in June 2018.

The approval of the combination indicates the success of checkpoint inhibitor–based combinations in cervical cancer, Naumann says. However, now that pembrolizumab has moved to the frontlinesetting, there is a lack of effective therapies for patients who progress on this regimen, he notes. Research efforts should aim to address this unmet need in the future.

The tissue factor-directed antibody-drug conjugate tisotumab vedotin-tftv (Tivdak) received accelerated approval in September 2021 for patients with recurrent or metastatic cervical cancer with disease progression on or after chemotherapy, Naumann continues. Approval for this agent was supported by findings from the single-arm, phase 2 innovaTV 204 trial (NCT03438396). This drug is a viable option for patients in the second-line setting and may provide some benefit. However, this agent may eventually be combined with PD-L1 inhibitors for use in the frontline setting.

The continued development of novel immunotherapy combinations for patients with cervical cancer may provide less toxic alternatives to regimens that include paclitaxel, Naumann continues. This agent is associated with several adverse effects, such as joint achesand hair loss that negatively affect quality of life for women with cervical cancer, Naumann concludes.

Disclosures: Dr Naumann reports serving as a consultant or in an advisory role for Agenus, AstraZeneca, Bristol-Myers Squibb, Clovis Oncology, OncoMed, Eisai, GlaxoSmithKline/Tesaro, GOG Partner, Merck Sharp & Dohme, Seattle Genetics, Sutro Biopharma; he served on a Data Safety and Monitoring Board for Genelux (GOG 3076/OnPrime), Laekna Therapeutics,GOG for Intuitive (GOG 3043/ROCC); he served on a Speakers' Bureau for Seattle Genetics; he received institutional research funding from Bristol-Myers Squibb, OncoMed, GlaxoSmithKline/Tesaro, Gynecologic Oncology Group, Mersana, and Sutro Biopharma.

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R. Wendel Naumann, MD, FACOG, FACS, discusses how the evolution of immunotherapy has changed the treatment landscape for patients with recurrent or metastatic cervical cancer.
 



Dr Naumann on the Changing Treatment Landscape in Cervical Cancer

R. Wendel Naumann, MD, gynecologic oncologist, Levine Cancer Institute, Atrium Health, discusses the evolution of immunotherapy in endometrial cancer.

The landscape of endometrial cancer is changing dramatically with the integration of immunotherapy into the second-line setting for patients with endometrial cancer, Naumann says. For example, data from the pivotal Study 309/KEYNOTE-775 trial (NCT03517449) demonstrated improved progression-free survival and overall survival with the combination of pembrolizumab (Keytruda) and lenvatinib (Lenvima) vs investigator’s choice of chemotherapy in patients with advanced endometrial carcinoma that was not microsatellite instability high or mismatch repair deficient following prior systemic therapy. 

It appears that lenvatinib alters the tumor microenvironment, which increases the immunogenicity of the endometrial tumors so that the immune system can attack, Naumann explains.

It is possible that immunotherapy will be moved up in the course of treatment to replace frontline chemotherapy, be combined with frontline chemotherapy, or be combined with radiation therapy, which is reserved for the adjuvant treatment of patients with intermediate- or high-risk disease who are at risk of local or distant failure, Naumann concludes.

R. Wendel Naumann, MD, discusses the evolution of immunotherapy in endometrial cancer.  



Dr. Naumann on the Evolution of Immunotherapy in Endometrial Cancer 

R. Wendel Naumann, MD, a gynecologic oncologist at Levine Cancer Institute, of Atrium Health, discusses the significance of the phase 1/2 TOPACIO trial in ovarian cancer.

In the trial, investigators examined pembrolizumab (Keytruda) in combination with niraparib (Zejula) in patients with triple-negative breast cancer or ovarian cancer, according to Naumann. The regimen was utilized in a variety of clinical scenarios, including in those who had homologous recombination deficiency (HRD)–positive, 

-mutated disease. Results showed that these different subgroups experienced response rates that ranged from 10% to 28% with the doublet, according to Naumann. These data suggest that there is a potential synergistic effect between PD-L1 inhibitors and PARP inhibitors, explains Naumann.

This approach makes sense on a conceptual level because if the PARP inhibitor is creating DNA damage, the immune system should be able to recognize this. The study has featured small subgroups of patients thus far, adds Naumann. The majority of patients in the ovarian cancer group were heavily pretreated, having received 3 prior therapies or more; this is a group of patients who have limited therapeutic options available to them, Naumann concluded.

R. Wendel Naumann, MD, discusses the significance of the phase 1/2 TOPACIO trial in ovarian cancer.

Dr. Naumann on the TOPACIO Trial With Pembrolizumab/Niraparib in Ovarian Cancer

R. Wendel Naumann, MD, gynecologic oncologist, Levine Cancer Institute, Carolinas HealthCare System/Atrium Health, discusses unanswered questions with PARP inhibitors in ovarian cancer.

Patients with ovarian cancer should be tested for 

 mutations, particularly now that 2 PARP inhibitors—–olaparib (Lynparza) and niraparib (Zejula)––are approved for use as frontline maintenance therapy, says Naumann. Though not yet approved, the combination of olaparib and bevacizumab (Avastin) has also shown a benefit as frontline maintenance therapy, according to data from the phase 3 PAOLA-1 trial. Now, the field has to determine whether to give maintenance therapy, and the type of therapy to administer, says Naumann. Historically, high-risk patients received bevacizumab, and now patients with 

 mutations are being put on PARP inhibitors first.

In addition to determining whether to prescribe PARP inhibitors in all-comers, patients with homologous recombination deficiency, or only those with 

mutations, the field will have to determine how the use of PARP inhibitors as frontline maintenance therapy will impact treatment in the second- and third-line settings, reexposure to PARP inhibitors, and the optimal timing of bevacizumab.

In doing so, the risks and benefits of therapy should be considered, says Naumann. Recurrence should also factor into the decision. For example, if bevacizumab can only be used 1 time, is it more prudent to give it up front, or is it more prudent to wait and hold it for recurrence? Those questions will need to be answered in the coming years, concludes Naumann.

Dr. Naumann on Unanswered Questions With PARP Inhibitors in Ovarian Cancer

R. Wendel Naumann, MD, gynecologic oncologist, Levine Cancer Institute, Carolinas HealthCare System/Atrium Health, discusses data with STRO-002 in patients with platinum-resistant/refractory ovarian cancer.

Naumann presented data from a phase 1 dose-escalation trial (NCT03748186) with STRO-002 in patients with platinum-resistant/refractory ovarian cancer during the 2020 AACR Virtual Annual Meeting I. Patients received a median of 5 prior lines of therapy, representing a heavily pretreated population, says Naumann. Investigators evaluated 7 doses, ranging from 0.5 mg/kg to 6.0 mg/kg. The recommended phase 2 dose has not yet been determined.

To date, investigators have reported several CA-125 responses and 1 partial response, says Naumann. Moreover, the majority of patients have participated in the trial for more than 24 weeks, suggesting that the agent is well tolerated.

Dr. Naumann on Data With STRO-002 in Platinum-Resistant/Refractory Ovarian Cancer

R. Wendel Naumann, MD, gynecologic oncologist, Levine Cancer Institute, Carolinas HealthCare System/Atrium Health, discusses improving outcomes with neoadjuvant chemotherapy for the treatment of patients with ovarian cancer.

Naumann says that in the last few years, this setting has come full circle. Carboplatin and paclitaxel have had several iterations since they entered the landscape in 1996—intraperitoneal and dose-dense chemotherapy are examples. Researchers have found that none of those instances seem to improve outcomes, so they’ve optimized this regimen. The June 2018 FDA approval of upfront bevacizumab (Avastin), particularly for poor-prognosis patients, has improved outcomes and bolstered neoadjuvant chemotherapy. Patients with a poor prognosis are typically those who would need neoadjuvant chemotherapy, Naumann says.

Researchers have never been able to show that adding something upfront—whether it’s an additional chemotherapy agent or an anti—VEGF agent&mdash;has improved survival. However, Naumann says oncologists can aim to improve response rates and duration of response.

R. Wendel Naumann, MD, gynecologic oncologist, Levine Cancer Institute, Carolinas HealthCare System, discusses improving outcomes with chemotherapy for the neoadjuvant treatment of patients with ovarian cancer.

Dr. Naumann on Improving Outcomes With Chemotherapy in Ovarian Cancer

R. Wendel Naumann, MD, gynecologic oncologist, Levine Cancer Institute, Carolinas HealthCare System, discusses the use of neoadjuvant chemotherapy in patients with ovarian cancer.

Surgery still remains an important aspect of care for patients with ovarian cancer, says Naumann. The traditional paradigm has been surgery followed by chemotherapy, but emerging evidence suggests that giving neoadjuvant chemotherapy is a rational option for patients. The morbidity from surgery is lessened and there is an improvement in the complete resection rate with this approach, explains Naumann.

However, neoadjuvant chemotherapy has yet to be adopted worldwide because survival has been less than expected. That may be a result of selecting a subset of patients who are likely to do poorly in general, says Naumann. Four randomized trials have shown that neoadjuvant chemotherapy is a viable approach with an equivalent outcome to primary debulking. At Levine Cancer Institute, physicians are now looking at incorporating minimally invasive surgery to further reduce the morbidity and mortality from the primary surgery, says Naumann.

R. Wendel Naumann, MD

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