Single-Agent and Combo Immunotherapy Garners Mixed Excitement in Gynecologic Cancers

R. Wendel Naumann, MD

Immunotherapy is emerging as a preferred second-line treatment option for patients with gynecologic cancers, including endometrial and cervical cancer, said R. Wendel Naumann, MD, who added that checkpoint inhibitors may also be preferred to chemotherapy in the frontline or adjuvant settings based on improved efficacy.

“In endometrial and cervical cancers, we are seeing that immunotherapy is not only effective, but is probably more effective than chemotherapy,” said Naumann, a gynecologic oncologist at the Levine Cancer Institute of Atrium Health. “[Immunotherapy] is being taken into the frontline setting. We are steadily moving from recurrent, second-line treatment to frontline treatment or even adjuvant immunotherapy.”

However, immunotherapy has been more difficult to integrate into the treatment paradigm of ovarian cancer, although personalized combination-based approaches may hold utility.

“In ovarian cancer, we have to be a little bit smarter in terms of how we treat patients with immunotherapy. Certainly, some patients respond to immunotherapy, but we need to have a better strategy than giving a single treatment to everybody. [We need to] individualize therapy based on the profiling of these ovarian cancers,” Nauman said in an interview with OncLive® during an Institutional Perspectives in Cancer webinar on gynecologic malignancies.

The virtual meeting covered a range of topics in gynecologic cancers, including updates in endometrial and cervical cancers, as well as novel immunotherapy strategies and second-line maintenance therapy in ovarian cancer.

In the interview, Naumann, who co-chaired the event, discussed the current state of immunotherapy in gynecologic cancers, as well as key updates across the field.

OncLive®: What shifts are being seen regarding the treatment of patients with endometrial cancer?

Naumann: Endometrial cancer is a great topic because there are a lot of exciting data coming out. The landscape is going to change quite a bit. The big news is that immunotherapy is probably how we are going [to treat patients in] the second-line setting. We now have progression-free survival [PFS] and overall survival [OS] data suggesting that immunotherapy in the second-line setting is better than chemotherapy. This is even in the mismatch repair-proficient [pMMR] cancers that are typically not thought to be as immunogenic as the mismatch repair deficient [dMMR] cancers. That is with the addition of lenvatinib [(Lenvima) to pembrolizumab (Keytruda)], which probably alters the microenvironment and increases the immunogenicity of the cancers so that they can basically be attacked by the immune system. We have seen great efficacy of the combination, both in endometrial and serous cancers, which is an area of high unmet need. 

As this [research] develops, we are going to see more immunotherapy moving to the frontline setting. It may be that we will combine immunotherapy with frontline chemotherapy. We may use immunotherapy instead of frontline chemotherapy. We may combine immunotherapy with radiation therapy going forward in the intermediate- or high-risk groups that have significant risk for local or distant failure and are getting treated with adjuvant radiation therapy.

This is an exciting and pivotal time for the evolution of immunotherapy in endometrial cancer.

How could combining immunotherapy with VEGF inhibitors overcome some of the challenges seen with single-agent immunotherapy in endometrial cancer?

The problem with immunotherapy is that a patient can develop immune tolerance. Although a tumor may elicit an immune response, we have downregulation of that immune response in the form of immune tolerance. This is probably mediated in the tumor microenvironment to a large degree by VEGF. It makes sense that VEGF inhibition would potentially alter that immune tolerance.

We don’t quite understand how that works, but it certainly is interesting that, at least in the example of lenvatinib plus pembrolizumab, it appears that the combination of those 2 agents is better than either agent alone, suggesting that there is a synergy. [Such pathway inhibition] is truly something that is necessary in terms of eliciting responses.

What studies have contributed to the field’s understanding of immunotherapy in endometrial cancer?

KEYNOTE-164 [NCT02501096] set the stage for second-line immunotherapy with the phase 2 data that were presented. KEYNOTE-775 [NCT03517449] was the confirmatory trial that suggested immunotherapy was better than chemotherapy both in terms of PFS and OS. This changed the standard of care in patients with advanced endometrial cancer, even pMMR cancers.

The ROSCAN trial [NCT03651206] is probably going to give us some sense as to whether the combination of immunotherapy and PARP inhibition is potentially efficacious in endometrial cancer. We certainly hope it is. That is a 3-arm trial, so if the combination of dostarlimab with niraparib [(Zejula) is more efficacious vs niraparib or chemotherapy] and is taken to the phase 3 portion of the trial, that will be a very important step in terms of looking for other agents that are potentially added to immunotherapy.

Robert L. Coleman, MD, FACOG, FACS, of The US Oncology Network, talked about updates in locally advanced cervical cancer at the IPC meeting. Could you speak to the data we have seen with *tisotumab vedotin-tftv ((Tivdak) and why it could be an important agent in cervical cancer? What about other immunotherapies?

Just like in endometrial cancer, the landscape of cervical cancer is [expanding] very quickly. With the recent data, it is very likely that immunotherapy with checkpoint inhibitors plus chemotherapy is going to be the standard of care for frontline recurrent or metastatic cervical cancer. We know these agents like pembrolizumab are good and approved as second-line agents.

Several trials are ongoing of combination checkpoint inhibitors, including anti–PD-1 and anti–CTLA-4 antibodies. These trials are exciting, but if we move immunotherapy to the frontline setting, what are we going to use for second-line therapy? Tisotumab vedotin will probably fill that gap.

Tisotumab vedotin is an important drug [in cervical cancer]. Tisotumab vedotin is an antibody-drug conjugate [against] tissue factor. There will be some challenges with some of the toxicities and mitigation of those toxicities, particularly ocular toxicities. However, the responses are very good with that agent. We were in a situation where frontline therapy had a very marginal response rate until GOG-240 [NCT00803062] with the addition of bevacizumab [(Avastin) to chemotherapy]. Now we are talking about second- and potentially third-line chemotherapy or therapeutic agents. That is a great advance, especially in cervical cancer where many of our patients are very young.

We will see how this shakes out, but I suspect that immunotherapy will be [used in the] frontline [setting]. Then we will have to decide exactly what order to put our second- and third-line agents in.

Thomas Herzog, MD, of NewYork-Presbyterian Hospital, discussed the phase 3 PRIMA study (NCT02655016), which evaluated niraparib vs placebo as frontline maintenance treatment in ovarian cancer. Could you highlight the key efficacy and safety findings from that study?

The PRIMA trial showed that the addition of niraparib as a main strategy in frontline ovarian cancer was basically beneficial across the board, regardless of homologous recombination deficiency [HRD] status. That simplifies decisions to discuss maintenance therapy with a PARP inhibitor, which is pretty well tolerated for the most part, with patients with ovarian cancer.

As we would expect, the PRIMA trial showed that patients with HRD are going to benefit more [from niraparib] compared with patients with homologous recombination proficient tumors. There are some subtleties in terms of counseling and whether these patients are going to benefit based on the toxicity of the drug. I use [those factors] to help patients make a shared decision of whether they want to go on maintenance therapy, or even potentially look for experimental options if they have poor-prognosis tumors.

Angeles Alvarez Secord, MD, of Duke Health, spoke about second-line maintenance therapy in ovarian cancer and the utility of PARP inhibitors in platinum-sensitive disease. What updates have been seen here?

The updates have confirmed that patients with platinum-sensitive ovarian cancer respond well and benefit from PARP inhibition. We don’t need to use HRD testing in that setting. Those data are not surprising.

There has been some resistance to the use of maintenance therapy in platinum-sensitive ovarian cancer. That’s tradition more than based in science. Maintenance therapy, both in the frontline and the platinum-sensitive recurrent settings, is the standard of care, or at least the discussion of maintenance therapy with patients in those settings is.

Lastly, Ritu Salani, MD, of UCLA Health, discussed immunotherapy and novel strategies in ovarian cancer. What is the current role of checkpoint inhibitors here, and what novel strategies are you keeping an eye on?

Ovarian cancer has been difficult. We had a large flurry of up-front trials utilizing checkpoint inhibitors, PARP inhibitors, and VEGF inhibitors with a lot of promise. Unfortunately, those trials to date have not been positive. We have a few more trials to read out, but the enthusiasm for the up-front use of multiple agents in the maintenance setting is dampened by the data we’ve seen so far.

I am interested in the LEAP-001 trial [NCT03884101], which combines a checkpoint inhibitor with lenvatinib. That is potentially going to be beneficial. We certainly saw benefit in endometrial cancer, which has a similar response profile to ovarian cancer, particularly serous ovarian cancer. That is an exciting combination, but we will have to see if that plays out in that patient population.

We are going to get better [at tailoring therapy] with time. It is just a question of which strategy will work in which patients and how granular we have to divide patients out to find treatments that work.

*Editor’s Note: This interview took place prior to the September 20, 2021, FDA approval of tisotumab vedotin for the treatment of adult patients with recurrent or metastatic cervical cancer with disease progression on or after chemotherapy.