Vaccine Therapy Shows Promise in Cervical Cancer

Sharad Ghamande, MD

Vaccine therapy is useful in both the prevention and treatment of cervical cancer, explains Sharad Ghamande, MD, and phase II findings of such treatment have demonstrated a survival benefit in a pretreated population.

In the phase II GOG/NRG-0265 study, treatment with axalimogene filolisbac (AXAL), an immunotherapy targeting human papillomavirus (HPV)-infected cells, led to an unprecedented 1-year survival rate in patients with recurrent, metastatic cervical cancer. AXAL induces antitumor T-cell immunity and breaks immune tolerance in the tumor microenvironment.

Results showed that patients had a median overall survival (OS) of 6.2 months and a 12-month survival of 38%. Disease control was achieved in 32% of patients based on investigator assessment of best response of the 50 evaluable patients treated with AXAL, 26 had received 2 or more lines prior lines of therapy.

Based on this activity, AXAL is now being investigated in the global phase III AIM2CERV trial as adjuvant monotherapy to prevent recurrence in patients with high-risk cervical cancer treated with chemoradiation (NCT02853604).

OncLive: What was the rationale of the phase II GOG/NRG-0265 study for patients with cervical cancer?

In an interview with OncLive, Ghamande, associate professor, Georgia Cancer Center, Augusta University, discussed the findings from GOG/NRG-0265, as well as the impact of vaccines for patients with cervical cancer.Ghamande: In the United States, there are 13,000 newly diagnosed cases of cervical cancer every year and about 4000 patients die. However, worldwide, there are almost 400,000 new cases of cervical cancer diagnosed every year. Unfortunately, almost 80% of patients present with advanced disease. In any given year, there are 250,000 women who die of cervical cancer.

What are the most pressing unmet needs in cervical cancer?

Overall, there are 2.3 million women with active cervical cancer in the world. These are staggering numbers. We have not made as much progress as we should have when treating cervical cancer. We are doing better with prevention, with Pap smears and the evolution of liquid-based cytology and HPV vaccines. We are at a point where we can make a tremendous impact with vaccinations that are proven to prevent against cervical cancer. However, in many parts of the world, particularly the developing world, vaccines are still not as prevalent.We need to do a better job at preventing the disease. Shockingly, it is one of the few cancers that can be prevented and, yet, we do a poor job.

What was the design of GOG/NRG-0265?

The second unmet need is that 80% of cervical cancer is advanced at presentation. If a patient has early cervical cancer, they tend to do quite well. However, with advanced cervical cancer, the survival rates are not great. Many of these patients will recur after standard radiation and chemotherapy. Once cervical cancer recurs it is almost always a lethal disease, which makes the treatment of patients with recurrent cervical cancer an unmet need.GOG/NRG-0265 was a very interesting phase II trial using a novel immunotherapy approach for patients who had recurred and had gone through 1 line of chemotherapy. If you look at the last 30 to 40 years of cervical cancer in the United States, there have only been 3 FDA-approved drugs, which is staggering compared with breast cancer where there are 60 FDA-approved drugs. The last FDA approval was with chemotherapy and bevacizumab (Avastin). However, we are still far behind. Immunotherapy is a very exciting wave of research to help this unmet need.

GOG/NRG-0265 is an immunotherapy trial using a compound called AXAL, where the HPV-16 E7 protein is combined with Listeria monocytogenes. This combination is given intravenously as a vaccine. Once the vaccine is administered, it causes a tremendous HPV-specific T-cell response that attacks the cancer cells. This is important because cervical cancer is almost all caused by HPV, making this a unique and robust way of targeting the disease.

This compound makes the tumor microenvironment better by downregulating inhibition molecules like T-regulatory cells. This is a robust combination because it has multiple ways to attack. There are no new antibodies because most of the Listeria is taken up inside the cell.

This trial investigated patients who had failed 1 line of chemotherapy in the recurrent setting. The patients received the vaccine in the first stage of the trial once a month for 3 doses. Patients could stay on the vaccine as long as they did not progress or have too many toxicities.

What other trials are you excited about?

How would you describe the role of immunotherapy in cervical cancer?

The trial showed a 12-month overall survival rate of 38%, which was about 50% more than what we previously thought. The average 12-month survival in most clinical trials is about 20%. This is a big step when you compare the results of chemotherapy over the past 30 years of research. Not only was it more effective, but it was also safe. The side effect profile was better than when patients received standard chemotherapy. AIM2CERV is a global trial with almost 150 sites in more than 20 countries. We take the patients who are destined to fail, meaning patients with either advanced cervical cancer or patients with early disease who have positive lymph nodes. These patients finish their radiation and chemotherapy and once they are in remission they are randomized 2:1 to either the vaccine for up to 1 year or a placebo. It is a registrational trial that will hopefully make a difference in these patients’ lives by preventing cervical cancer.Cervical cancer is the most promising out of the gynecologic cancers because there is the target of HPV, which is always expressed. If you look at the genesis of cervical cancer, there is always an HPV infection. The immune system in most cases, especially when we are younger, takes care of the infection. However, if it is persistent as we get older, it then causes cancerous changes. HPV is a target that is always expressed, making it a very potent target that we can exploit either by a vaccine or checkpoint inhibition. There are new advances in immunotherapy for cervical cancer which can make a difference as time goes by in the recurrent setting where there are so few options.

Cervical cancer is the most attractive target for immunotherapy. However, there are also immunotherapy trials in ovarian cancer. When a patient has platinum-resistant disease, most of those patients receive palliative chemotherapy. Now we can prolong their life and make it a chronic disease, but eventually everyone will succumb to it. There are many checkpoint inhibitor trials in ovarian cancer but, so far, the activity has been modest.

Advaxis Presents Oral Late-breaking Data on Phase 2 GOG-0265 Study of Axalimogene Filolisbac at SGO’s Annual Meeting on Women’s Cancer. http://bit.ly/2npImYZ. Published March 15, 2017. Accessed January 31, 2018.