New Immunotherapy Ups Survival in Metastatic Cervical Cancer

Alexander M. Castellino, PhD

September 23, 2015

Early results from an ongoing trial show that use of the experimental immunotherapy axalimogene filolisbac, or ADXS11-001 (Advaxis, Inc), yielded a 12-month survival of 38.5% in 26 patients with persistent/recurrent metastatic cervical cancer (PRmCC) — an improvement on the survival seen historically in such patients.

In more than 17 studies of investigational agents and regimens carried out by the same group (the Gynecologic Oncology Group [GOG)], the 12-month overall survival rate had never exceeded 30% in patients with PRmCC.

The new results were were reported by Thomas Herzog, MD, clinical director at the University of Cincinnati Cancer Institute, on September 17 in a presentation at the American Gynecological and Obstetrical Society annual meeting at Half Moon Bay, California.

Dr Herzog told Medscape Medical News: "In a heavily pretreated population with very limited options, ADXS11-001 shows survival rates higher than historical controls. But these data need to be further validated."

Dr Herzog elaborated in a press statement: "Patients with PRmCC who have failed at least one line of therapy face a life-threatening condition with an estimated survival of 4 to 7 months and no available treatment options."

"The stage 1 results for axalimogene filolisbac, which show 12-month survival, are a meaningful step forward in meeting the needs of women who require second-line treatment for PRmCC," he added.

ADXS11-011 immunotherapy contains a fusion protein of human papillomavirus (HPV). It works by targeting HPV-transformed cells, eliciting antitumor T-cell responses in the tumor microenvironment and overriding immune checkpoint inhibition and negative regulation of cellular immunity.

Approached for comment, Maurie Markman, MD, president of the Cancer Treatment Centers of America, who is also a Medscape video blogger for Markman on Oncology, shared his thoughts with Medscape Medical News. "This is an interesting study, as it employs a novel immunotherapeutic strategy in the management of persistent or recurrent carcinoma of the cervix."

However, he also said: "The 12-month survival rate of 38.5%, while satisfying prospective criteria for study continuation, is not particularly impressive, considering the fact there was likely substantial selection bias associated with patient entry." He pointed out that for 61.5% of the participants, performance status was 0.

"Similar 12-month survival data have been observed with several alternative strategies in this clinical setting. Additional efficacy data and the future results of a randomized trial are awaited with interest," Dr Markman said.

Study Details

The GOG/NRG-0265 study is a two-stage phase 2 study in which enrollment was possible only if stage 1 successfully met its statistically defined end point.

Twenty-nine patients with PRmCC were enrolled in stage 1 of the study, and 26 patients received at least one dose of ADXS11-001, using a vaccine delivery system. The study was designed to deliver a total of three doses of ADXS11-001 monotherapy during a 3-month period — on day 0, day 28, and day 56.

A single dose of ADXS11-011 consists of 1 x 109 colony-forming units of attenuated Listeria monocytogenes bioengineered to secrete a fusion protein comprising the E7 protein of HPV-16 fused with a truncated fragment of listeriolysin O.

Of the 26 patients in the analysis, 69% received all three doses, 15.5% received two doses, and 15.5% received 1 dose.

Reasons for discontinuation prior to completion of all three doses were disease progression (4 patients), patient withdrawal (2 patients), and unrelated adverse events (2 patients).

Adverse events of grades 1 or 2 were reported in 19 (73%) patients; grade 3 events were seen in 4 (15%) patients, and grade 4 events were seen in 1 (4%) patient.

Common adverse events seen in at least 10% of patients included fatigue, chills, fever, nausea, headache, hypotension, vomiting, cytokine release syndrome, myalgia, abdominal pain, flulike symptoms, and elevations in liver enzyme levels.

Dr Markman told Medscape Medical News: "The data suggest the strategy is associated with an acceptable toxicity profile, although it must be noted more than 50% of the patients experienced fatigue and chills with 40% fever and nausea."

"In addition, more serious adverse events (grade 3 hypotension, cytokine release syndrome) were noted in approximately 10% of patients," he added.

Median overall survival was 7.7 months; median progression-free survival was 3.1 months. In patients who received all three doses, median overall survival was 12.1 months. The 12-month survival was 55.6%.

Next Steps for ADX11-001

In his presentation, Dr Herzog noted that GOG/NRG-0265 was only the second trial of PRmCC in the history of the GOG to meet the protocol-specified efficacy and safety criteria to progress to stage 2.

The study is ongoing and is expected to accrue a total of 65 patients (including the 26 patients in stage 1, the results of which have just been reported).

The next step is an international Advaxis-sponsored phase 3 study (AIM2CERV) of ADXS11-001 as adjuvant treatment of high-risk, locally advanced cervical cancer. The study is currently under development in collaboration with the GOG Foundation, Dr Herzog reported.

AIM2CERV is planned to enroll approximately 350 patients with high-risk, locally advanced cervical cancer. Following chemoradiation, patients will be randomly assigned in a 2:1 ratio to receive either adjuvant ADX11-001 or placebo for up to 1 year. Progression-free survival is the primary end point of the study; overall survival is the secondary end point.

The GOG-0265 trial is being conducted in the United States by GOG, now part of NRG Oncology, under the sponsorship of the Cancer Therapy Evaluation Program of the National Cancer Institute. Advaxis provided the product.

Dr Markman receives fees from Celgene, Caris Life Sciences, Novartis, sanofi-aventis, Amgen, and Genentech, and is a Medscape video blogger.


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