HPV: THE NEED

Advaxis’ Lm Technology™ immunotherapy targets HPV-associated cancers and is in clinical trials for three potential indications: invasive cervical cancer, head and neck cancer, and anal cancer.

Cervical Cancer

THE MOST COMMON HPV-ASSOCIATED CANCER IN WOMEN

Cervical cancer, which is the most common HPV-associated cancer in women, is characterized by cancerous malignancies in the cervix. In 2017, it is expected that there will be approximately 12,820 new diagnoses of invasive cervical cancer in the United States,1 and according to company market research, an estimated 16,000 new cases are expected in Europe. An estimated 4,210 women in the United States are expected to die from cervical cancer each year.1

New data published in the journal Cancer in 2017 underscores the need for new therapeutic options as the research shows that the U.S. cervical cancer mortality rate is higher than initially thought. When accounting for hysterectomies, the mortality rate for cervical cancer is 10.1 per 100,000 black women and 4.7 per 100,000 white women, increased from previously recorded rates of 5.7 and 3.2, respectively.2

Worldwide, cervical cancer is the third most common cancer among women and the second most frequent cause of cancer-related death, accounting for nearly 300,000 deaths annually. In developing nations, it is often the most common cause of cancer-related death among women and a leading cause of death overall.3

Anal Cancer

THOUSANDS OF NEW CASES EACH YEAR IN THE U.S. AND EUROPE

Anal cancer is a fairly rare form of cancer in the United States, but the number of new cases has been rising over the past decade.4  On average, this cancer effects people in their early 60s. In 2017, an estimated 8,200 people in the United States, including 5,250 women and 2,950 men, will develop anal cancer.5  In Europe, there will be an estimated 1 new anal cancer case for every 100,000 males, and 3 in 100,000 females.6  An estimated 650 women and 450 men will die from the disease this year in the U.S.5

1 American Cancer Society. What is Cervical Cancer. Retrieved June 1, 2017 from http://www.cancer.org/cancer/cervicalcancer/detailedguide/cervical-cancer-key-statistics
2 Anna L. Beavis, Patti E. Gravitt and Anne F. Rositch (2017, January 23) American Cancer Society. Cancer Society. Hysterectomy-corrected cervical cancer mortality rates reveal a larger racial disparity in the United States [Electronic Version]. Cancer, 123(6), 1044-1050. Retrieved June 1, 2017 from http://onlinelibrary.wiley.com/doi/10.1002/cncr.30507/full
3 National Institutes of Health.  Fact Sheets: Cervical Cancer.  October 2010.
4 National Cancer Institute. Anal Cancer: for patients. Retrieved June 1, 2017 from http://www.cancer.gov/types/anal
5 American Cancer Society. What are the Key Statistics about Anal Cancer? Retrieved June 1, 2017 from http://seer.cancer.gov/statfacts/html/anus.html
6 Anal cancer incidence statistics. Retrieved June 1, 2017 from http://www.cancerresearchuk.org/health-professional/cancer-statistics/statistics-by-cancer-type/anal-cancer/incidence#heading-Zero

LEADING DRUG CANDIDATES

 

AXALIMOGENE FILOLISBAC

There has only been one new treatment for cervical cancer in the past 30 years, with an average benefit of only 3 additional months of survival.  When treatment inevitably fails and the cancer progresses, there are no FDA approved options for these patients.  These are the forgotten women, and over 4000 of them die each year in the US.  This underserved population is the target for our leading drug candidate, axalimogene filolisbac  for metastatic cervical cancer and anal cancer.

While vaccines have proven effective at HPV prevention, they cannot treat or have any affect once the infection is contracted. Likewise, HPV-associated cancers cannot be treated with present-day HPV vaccines.

Because HPV vaccines have no therapeutic effect on HPV-associated cancers, there is an immediate need for new treatments that do. Until everyone is vaccinated, treatments will be needed, meaning therapeutic options need to be developed for at least the next 50 years.

Axalimogene filolisbac is the only known cancer immunotherapy agent shown in preclinical studies to alert the body’s immune system to the presence of cancer, diminish that cancer’s natural defense mechanisms and then rally the body’s killer T cells to attack the cancer. 

Advaxis’ lead Lm Technology™ immunotherapy, axalimogene filolisbac, targets HPV-associated cancers and is in clinical trials for three potential indications: invasive cervical cancer, head and neck cancer, and anal cancer. The U.S. Food and Drug Administration (FDA) has granted axalimogene filolisbac orphan drug designation in each of these three clinical settings, as well as a Special Protocol Assessment for the Phase 3 AIM2CERV trial in cervical cancer, and Fast Track Designation. Axalimogene filolisbac is currently being evaluated in eight clinical trials for HPV-associated cancers. Please visit www.ClinicalTrials.gov for more information on Advaxis clinical trials.

ADXS-DUAL

Advaxis and Bristol-Myers Squibb have begun a clinical development collaboration for a global, randomized and controlled registrational study to evaluate Advaxis’s ADXS-DUAL and Bristol-Myers Squibb’s PD-1 immune checkpoint inhibitor, Opdivo® (nivolumab), as a potential combination treatment for women with persistent, recurrent or metastatic (squamous or non-squamous cell) carcinoma of the cervix. ADXS-DUAL is the next generation of Advaxis’s immunotherapy targeting HPV-associated cancers. ADXS-DUAL was developed from the learnings from axalimogene filolisbac (AXAL), and includes additional HPV antigens intended to provide even stronger coverage against certain HPV types which are more frequent in metastatic cervical cancer, while maintaining the activity of AXAL in cervical cancer and other HPV-associated cancers. ADXS-DUAL has the potential to promote more potent T-cell responses for patients with metastatic cervical cancer, where patients may have a greater disease burden.

Cervical cancer can be caused by strains of oncogenic HPV that are derived essentially from 2 HPV virus families, the alpha9 and alpha7 families. Axalimogene filolisbac has demonstrated the potential to prolong survival in patients with cervical cancer caused by all oncogenic strains detected. However, in evaluating the data from GOG-265, Advaxis observed that there was a significantly higher representation of patients with the alpha7 family viruses than are typically seen at the initial diagnosis of cervical cancer. Since patients with recurrent or metastatic cervical cancer (later stage disease) need a potent therapy to try to impede cervical cancer, especially after progressing from chemotherapy with or without Avastin, ADXS-DUAL was developed to have the potential to be even more potent against the alpha7 family strains found in metastatic cervical cancer. Combined with nivolumab, ADXS-DUAL may give patients the best chance of benefit in this setting.

Axalimogene filosibac and ADXS-DUAL clinical trials in HPV-related cancers

While most HPV infections do not have harmful effects, some high-risk strains of the virus hide in the body for some time and may cause changes on the cellular level that can lead to certain types of cancer including cervical cancer, anal cancer and some head and neck cancers. According to the CDC, there are roughly 38,793 new HPV-associated cancer cases in the United States each year, affecting approximately 23,000 females and 15,793 males.

"Just as we need options to prevent HPV-related cancers, there is a significant need for more therapeutic options to treat those with cancer. No woman should die from cervical cancer."

Deborah Arrindell

Vice President, Health Policy

CERVICAL CANCER: PHASE 3 AIM2CERV STUDY

AXAL has shown promising anti-tumor activity and acceptable tolerability across several clinical trials. Advaxis has reached an agreement on a Special Protocol Assessment (SPA) with the U.S. Food and Drug Administration (FDA) in June 2016 for the Phase 3 AIM2CERV study, evaluating the safety and efficacy of AXAL administered in the adjuvant setting after completion of cisplatin-based chemotherapy and radiotherapy in patients with locally advanced cervical cancer at higher risk for recurrence, progression, or death. The study plans to enroll approximately 450 patients, and is on track with enrollment. The Phase 3 trial will be conducted in collaboration with the GOG Foundation, Inc, now part of NRG Oncology. AXAL also received Fast Track Designation from the FDA as an adjuvant therapy for HRLACC patients and was classified as an advanced-therapy medicinal product by the European Medicines Agency’s Committee for Advanced Therapies for the treatment of cervical cancer.

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"The 12-month survival rate of axalimogene filolisbac reached unprecedented levels in this study, which is both impressive and important given the lack of innovation in metastatic cervical cancer."

Warner K. Huh, MD

Director, Division of Gynecologic Oncology

CERVICAL CANCER: PHASE 2 GOG-0265 STUDY

A phase 2 study was recently completed in collaboration with the GOG.  GOG-0265, a single arm trial evaluating axalimogene filolisbac for the treatment of persistent or recurrent metastatic (squamous or non-squamous cell) carcinoma of the cervix (PRmCC) had primary endpoints to assess the safety and efficacy of axalimogene filolisbac in women with PRmCC.  The primary efficacy endpoint was overall survival at 12 months from initial treatment with axalimogene filolisbac. The primary safety endpoints were to evaluate the number of patients with dose-limiting toxicities and the frequency and severity of adverse effects.

The final efficacy results of GOG-0265 demonstrated that 38% of patients (n = 19/50) with heavily pretreated PRmCC were alive 12 months following treatment with axalimogene filolisbac.  The GOG-0265 study protocol used a logistic model-based calculation to establish the expected 12-month survival rate.  The model identified the key prognostic factors of age, race and performance status significantly related to survival from a database of approximately 500 patients with PRmCC who participated in 17 previous phase 2 studies conducted by the Gynecologic Oncology Group (GOG), now part of NRG Oncology.  Using this model, the expected 12-month survival rate of patients enrolled in the study was calculated to be 24.5%.  As a result, the 38% 12-month survival rate of patients treated with axalimogene filolisbac represents a 52% improvement over the expected survival rate and is the highest 12-month survival rate achieved to date in this setting.  The probability of this survival improvement being detected by chance versus a true treatment effect was calculated to be 0.02.  A compelling and ongoing complete response of 18.5 months was observed and the longest ongoing survival is 40.6 months.

The safety profile was consistent with previous clinical experience.  The most common Grade 1 or Grade 2 treatment-related adverse events (TRAEs) were hypotension and symptoms related to cytokine release (e.g., nausea, chills, fever).  Eighteen out of 50 patients experienced a Grade 3 TRAE and two out of 50 patients experienced a Grade 4 TRAE, which were hypotension and symptoms related to cytokine release.

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“We are proud to honor Advaxis for their continued research on underserved cancers and breakthrough discoveries in the treatment of anal cancer and other HPV-associated cancers.”

Alana Stewart, MD

President and CEO

ANAL CANCER: PHASE 2

Advaxis has collaborated with Brown University Oncology Group on a Phase 1/2 clinical study assessing the safety and efficacy of AXAL administered with concurrent standard chemotherapy and radiation treatment in HPV-associated locally advanced anal cancer. Preliminary data show clinical complete response and no recurrence in all 10 patients who completed the AXAL-containing treatment regimen.

In June 2016, Advaxis began dose administration for a Phase 2 clinical study of AXAL in metastatic anal cancer. The study is called FAWCETT (Fighting Anal Cancer with CTL-Enhancing Tumor Therapy), in honor of Farrah Fawcett, and is the company’s second Phase 2 study of AXAL in anal cancer. The two-part, multi-center, open-label study is designed to evaluate the efficacy and safety of AXAL as a monotherapy in patients with HPV-associated metastatic anal cancer who have received at least one prior treatment regimen for advanced disease.

Advaxis has also entered into a clinical trial collaboration agreement with the Radiation Therapy Oncology Group (RTOG) Foundation to evaluate the safety and efficacy of ADXS-HPV in a pivotal Phase 2/3 anal cancer trial, which will be run by NRG Oncology.

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"The fact that we are seeing increased T-cell response, evidence of epitope spreading, and signs of increased immune activation consistent with expansion and infiltration of activated T cells in the tumor at this preliminary point in the study suggests that AXAL has the potential to generate beneficial immunologic responses in patients with HPV+ head and neck cancer."

Andrew Sikora, MD, PhD

Associate Professor of Otolaryngology

PHASE 2 AXAL COMBO WITH DURVALUMAB STUDY

AXAL is under evaluation in two clinical trials for HPV-associated head and neck cancer. The first is a “window of opportunity” Phase 2 study, conducted by the Icahn School of Medicine at Mount Sinai, investigating the effects of AXAL in patients newly diagnosed with HPV-positive head and neck cancer during the window of time between initial diagnosis and receiving any treatment, including surgery, chemotherapy or radiation. As of April 2016, the trial enrolled eight AXAL-treated patients and six no-treatment observational patients with stage II-IV HPVOPC. Clinical data showed increased T-cell response in several patients, evidence of epitope spreading, and signs of increased immune activation consistent with expansion and infiltration of activated T cells into the tumor.

The second is a Phase 1/2 study evaluating the safety and efficacy of AXAL alone or in combination with MedImmune’s investigational anti-PD-L1 immune checkpoint inhibitor, durvalumab (MEDI4736), for the treatment of patients with advanced, recurrent or refractory cervical cancer and HPV-associated head and neck cancer. The first and second dose-escalation cohort in the trial has been completed, and the Companies have commenced enrollment for the Part A expansion and Part B of the study.

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