Cemiplimab Under Investigation in Cervical Cancer

Krishnansu S. Tewari, MD

The treatment options for patients with cervical cancer has been historically limited, but a new study of the anti—PD-1 agent cemiplimab (Libtayo) may prove the benefit of immunotherapy in this disease.

Cemiplimab is currently approved by the FDA for the treatment of patients with metastatic cutaneous squamous cell carcinoma (CSCC) or patients with locally advanced CSCC who are not candidates for curative surgery or curative radiation.

OncLive: Can you please provide an overview of this study, beginning with the rationale?

In an interview with OncLive, lead investigator Krishnansu S. Tewari, MD, associate professor, Division of Gynecologic Oncology, Department of Obstetrics & Gynecology, University of California, Irvine, discussed the exploration of cemiplimab and the promise of immunotherapy in cervical cancer.Tewari: Women with advanced cervical cancer have typically had no options. For 30 years, the Gynecologic Oncology Group (GOG) studied different chemotherapy combinations, doses, and schedules, and was not able to make a significant dent in overall survival until they studied bevacizumab (Avastin). These results were reported at the 2013 ASCO Annual Meeting, and led to the regulatory approval of bevacizumab for metastatic and recurrent cervical cancer, not only in the United States, but in about 60 countries around the world. This created another unmet need—patients who progress on bevacizumab.

What is the design of the study, and how many patients are you looking to enroll?

This must be exciting to see immunotherapy enter the realm of gynecologic malignancies.

How are patients are selected?

Pending the results of the study, what are you hopes for it?

Is there potential to move it up to earlier lines of therapy?

Looking at the field of cervical cancer as a whole, what evolution have you seen and where do you see it going?

We have been very interested in immunotherapy, and the GOG has now designed GOG protocol 3016. We are doing this together with our European colleges at ENGOT. We have a new study to help women who have progressed on bevacizumab or who were not good candidates for bevacizumab. These are basically patients that are in need of a second-line therapy that is effective and tolerable. GOG 3016 is hoping to fulfill that unmet need for a second-line regimen. Chemotherapy alone in the second-line setting is ineffective.It is a phased III randomized trial comparing anti—PD-1 therapy with cemiplimab to physician's choice chemotherapy. We are going to accrue approximately 450 patients, and we have thus far accrued 60 patients since activation in October 2017. We are running this in about 8 different countries, including the United States. We hope to see a significant signal that suggests that immunotherapy is effective in this disease population.It is very exciting! And scientifically, it makes sense. If you look at the mutational burden of cervical cancer, it clusters amongst other solid tumors where there have been positive phase III experiences with immunotherapy. Cervical cancer clusters with tumors like squamous cell carcinoma of the lung, adenocarcinoma of the lung, head and neck cancer, and cutaneous squamous cell carcinoma. We have seen a signal for immunotherapy in those tumors, particularly checkpoint inhibition, which is what cemiplimab does. We are very hopeful we will see it in the cervix as well.You don't have to have a positive PD-1/PD-L1 to be enrolled on the trial, but we are testing it in all the patients, so then we can stratify and make some important analyses based on the expression of those proteins.If this study is positive, we are going to need to have it reviewed by the FDA of course, and hopefully it will be approved as a second-line option for patients with recurrent or metastatic cervical cancer that have either progressed on platinum or have progressed on platinum post-bevacizumab. It will create an important area where we can offer these patients additional treatment. Definitely. I think that ideally, we would want it studied in patients who present with locally-advanced disease. In some cases, these women are curable with chemoradiation plus brachytherapy, but some of the high-risk patients, especially the ones with multiple positive lymph nodes, those with aortic nodal metastases, along with the stage IV patients with bladder or rectal involvement, are at a very high risk for failure after traditional therapy. It would be important to study [cemiplimab], as possible maintenance strategy for those women who have entered into remission after chemoradiation at the very least.One of the most important revolutions that has been understated is that we have gotten better with supportive care. In the past, especially in the United States, cervical cancer has been a disease of women who are poor, marginalized, and do not have healthcare access so they cannot get Pap smears or the HPV vaccine. In these women, the disease is often very advanced when it comes to attention, and all their medical comorbidities are in bad shape because they don't see a doctor regularly.

What we have learned with the prior study of bevacizumab was that supportive care is just as important as bevacizumab. The strides we have made in managing the medical comorbidities, correcting the malnutrition, and optimizing the pain management due to neuropathy or the tumor, has really changed the landscape. Even though they are in a very high-risk situation, they are healthier than they were before. This means that they are going to be able to tolerate some of the novel drugs that we are testing better than they had before. We are now limiting the performance status on all of these trials to 0 and 1. I think that has been a big paradigm shift. Many of these medical comorbidities that make patients sick are correctable if you pay attention and fix those things.

What other checkpoint inhibitors are being looked at in cervical cancer?

The other thing that I think will be big is immunotherapy. Not just with cemiplimab, but we are seeing a lot of excitement with tumor-infiltrating lymphocytes (TILs) in this disease, and we are looking at therapeutic vaccines. There is a therapeutic vaccine that is currently being studied as a maintenance therapy in the frontline. I think immunotherapy is going to inform the landscape whether it is PD-1, a therapeutic vaccine, or TILs, I don't know—maybe all 3. For me, it is important to have options for patients because some things may be appropriate for one patient but not another.There is atezolizumab (Tecentriq), which is an anti—PD-L1. That is being studied in the first-line for recurrent cervical cancer. It is like the population studied with bevacizumab, but in this case, it is going to be a chemotherapy doublet plus bevacizumab with or without atezolizumab. That is going to be exciting. That will possibly fulfill another option for patients in need of first-line therapy for recurrent disease.

Also for recurrent disease, maybe third- or fourth-line down the road, there is the study being done by [Iovance Biotherapeutics (formerly Lion Biotechnologies)] on TILs. There have been some durable complete responses from the NCI with this technology.

Lastly, in the primary setting for locally advanced disease, Advaxis has a therapeutic vaccine. This is a modified listeria that contains the HPV-16 E7 antigen, which is a viral oncogene. Together, they will rev up the immune system.

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GOG 3016/ENGOT-cx 9 (NCT03257267) is an ongoing, open-label, multinational, randomized phase III trial comparing cemiplimab with investigator’s choice of chemotherapy as a second-line treatment for patients with recurrent or metastatic cervical cancer.