Phase II Data of ADXS-HPV for Cervical Cancer are Encouraging, Ready to Move to Pivotal Study
On November 9, Advaxis (NASDAQ:ADXS) announced final updated 18-month survival data from Phase II ADXS-HPV (Lm-LLO-E7-15) study evaluating the safety and efficacy of ADXS-HPV (1x109 cfu) with and without cisplatin (40 mg/m2, weekly x5) in 110 patients with recurrent cervical cancer in two treatment arms of 55 patients each. The primary endpoint of the study is overall survival. These data were presented at the 2013 Society for Immunotherapy of Cancer (SITC) Annual Meeting in National Harbor, MD, on November 9, 2013 (Poster #258).
ADXS initiated the Phase II study in November 2010 in India in 110 Patients with recurrent or refractory cervical cancer. This study is being conducted at 22 sites in India. All patients randomized to the trial have been previously treated with chemotherapy, radiotherapy or both, and their cancer has progressed subsequent to treatment and has been confirmed by CT or radiologic scan.
Patients are randomized into 2 groups of 55 patients receiving: ADXS-HPV or ADXS-HPV + cisplatin (40 mg/m2, weekly x5). Patients got either 3 doses of ADXS-HPV at 1 x 109 CFU or 4 doses of ADXS-HPV at 1 x 109 CFU with cisplatin chemotherapy. Naprosyn and oral promethazine are given as premedications and a course of ampicillin is given 72h after infusion thereby clearing any residual vector. Patients receive CT scans at baseline and Days 84, 184, 273, 365 and 545. The primary endpoint is 12 month survival.
Enrollment was completed in May 2012 and results were presented at multiple scientific meetings.
The last patient last visit (Day 545) occurred on October 18, 2013. The final 18-month survival data are 28% (31/110) which is updated from the preliminary18-month survival of 22% (16/73) reported at the 2013 ASCO Annual Meeting on June 2, 2013. The final 12-month survival was 36% (39/110). These data are comparable to the results for the landmark 2004 Moore Phase III study conducted by the Gynecologic Oncology Group of cisplatin alone and cisplatin plus paclitaxel in recurrent cervical cancer patients with the same initial performance (health) status (0-2). In that study, 12 month survival was presented as 35% for cisplatin alone and 32% for the combination and 18 month survival was presented as 20% for combination therapy and 12% for cisplatin, alone.
Median overall survival in the Advaxis study was approximately 8.5 months which is indicative of the late stage of disease and baseline performance status of the patients. Those patients that completed the study will continue to be followed for survival. Survival results were not significantly different between treatment groups with or without cisplatin chemotherapy or who had previous therapy comprised of a combination of chemotherapy and radiation, radiation alone, or chemotherapy alone.
The tumor response rate was 11% with 6 complete responses and 6 partial responses/110 patients and was similar in both treatment groups per RECIST 1.1 criteria. Stable disease >3 months was observed in 35 additional patients, for a disease control rate of 43% (47/110). Average duration of response after 12 month minimum follow-up was 10.5 months for both treatment groups. In those patients treated with ADXS-HPV alone who had stable disease, the average duration of response was 6 months compared to 4.1 months in patients treated with ADXS-HPV plus cisplatin. Activity was observed against all high risk HPV strains detected, including 16, 18, 31, 33, and 45.
Subset analyses showed that the combination arm (addition of cisplatin to ADXS-HPV) did not significantly improve survival or tumor response; and survival and tumor response were equally strong in patients with aggressive disease (defined as recurrence ≤2 years from initial diagnosis) versus non-aggressive disease (defined as recurrence >2 years from initial diagnosis).
The tolerability of ADXS-HPV continues to compare favorably with single agent and combination chemotherapies active in this disease setting. 110 patients received 264 doses of ADXS-HPV at 1x109 cfu per dose. 42% (46/110) of patients experienced 104 mild-moderate Grade 1-2 adverse events and 2% (2/110) of patients experienced a serious adverse event (1 Grade 3 and 1 Grade 4) related/possibly related to ADXS-HPV. This compares to published serious adverse event rates of 100%-400% related to treatment in studies on a range of chemotherapy regimens for cervical cancer.
Advaxis also presented data on initial biomarker analysis of a subset of serum samples collected from patients in Lm-LLO-E7-15, pre- and post-dosing with ADXS-HPV. Administration of ADXS-HPV immunotherapy resulted in increased expression of cytokines (IL6, IL-8, IL10, INF-γ and TNF-α) and chemokines (MIP-1α, MIP-1β and MCP-1) indicating activation of innate immunity. An association was also found between changes in the expression of cytokine and/or other serum factors and the severity of adverse events. These data may provide future screening tools to assist in predicting clinical efficacy and to monitor and manage side effects.
Next Step: Advaxis plans to conduct end of Phase II meeting with FDA soon. The company is preparing the Phase III protocols and will submit a SPA to the FDA. Two Phase III trials will be conducted.
We believe the data presented at the SITC are very encouraging. After 110 patients and 264 doses, the safety data is encouraging. ADXS-HPV continues to demonstrate a well-tolerated and manageable safety profile with 42% of patients reporting Grade 1 or 2 transient, flu-like symptoms that self-resolve or respond to symptomatic treatment. Less than 2% of patients reported serious adverse events associated with ADXS-HPV. Published studies on chemotherapy treated patients like these show 100% of patients experiencing severe adverse events, usually multiple times.
Great efficacy has been observed which are very promising. Compared to GOG historical one year survival of 5%, ADXS-HPV has achieved 36% one year survival rate. This is a huge improvement. Other literature data showed that generally, recurrent cervical cancer has a poor 1-year survival rate of 15% and a 5-year survival rate of 3-13%. ADXS-HPV's 36% one year survival rate is also a 100% improvement. 18 month survival also reached 28%. Further investigation is warranted.
ADXS-HPV appears to be emerging as an active agent in recurrent/refractory cervical cancer with significantly less toxicity than chemotherapy.
The positive ADXS-HPV data may trigger partnership talks for Advaxis in our view.
ADXS-HPV for cervical cancer is the company's current focus. Advaxis plans to conduct new short term clinical trials to support its partnership talks as well as the planned Phase III trial of ADXS-HPV.
Two Phase I/II Trial of ADXS-HPV Initiated for Head and Neck Cancer
On October 23, 2013, Advaxis announced that the first patient has been dosed in REALISTIC, a Phase I/II study being funded by Cancer Research UK (CRUK) to investigate the use of ADXS-HPV for the treatment of HPV-positive head and neck cancer.
As a reminder, on May 8, 2012, Advaxis' partner Cancer Research U.K. (CRUK) began to enroll patients into REALISTIC, a Phase I/II study to investigate the use of ADXS-HPV for the treatment of 27 patients with HPV positive head and neck cancer. HPV is associated with 40-70% of head and neck cancers.
This trial is being conducted at the Aintree Hospital at the University of Liverpool, the Royal Marsden Hospital at the University of London, and the Cardiff Hospital at the University of Wales. The study will investigate the safety and efficacy of ADXS-HPV in preventing recurrence of head and neck cancer among patients who have been treated with surgery, radiotherapy, and/or chemotherapy; alone or in combination. A maximum of 45 patients are to be enrolled in this study, and all costs will be assumed by CRUK.
Due to regulations in the U.K., the first patient was dosed on October 23, 2013.
Also on November 20, 2013, Advaxis announced that the Icahn School of Medicine at Mount Sinai (ISMMS) will initiate another Phase I/II study of ADXS-HPV in 25 patients with HPV-positive head and neck cancer.
This clinical trial will be the first study to evaluate the effects of ADXS-HPV in patients when they are newly diagnosed with HPV-associated head and neck cancer, prior to receiving any chemotherapy or radiation. This study will be an important first step toward understanding ADXS-HPV's potential to treat this type of cancer before chemotherapy and/or radiation and its potential to reduce the need for these treatments.
This non-randomized investigator-initiated study has been designed to evaluate the safety and immunogenicity of ADXS-HPV in patients with HPV-positive stage II-IV squamous cell carcinoma of the oropharynx (OPCSC). In this study, 15 patients will receive ADXS-HPV treatment followed by ablative transoral robotic surgery (TORS), and 10 patients will serve as the control group and receive only TORS. TORS is FDA-approved for head and neck cancer and is considered to be the standard of care therapy for OPCSC in appropriate patients.
These two trials further expands the ADXS-HPV clinical development program to another HPV-associated tumor type.
According to the National Cancer Institute and the American Cancer Society, head and neck cancers represent approximately 3 percent of all cancers in the United States and are twice as common in men as in women. Historically, head and neck cancer has been associated with people over the age of 50 and with the use of alcohol and tobacco (including smokeless tobacco), however, there has been a recent rise in HPV-related oropharyngeal cancers in Caucasian men under the age of 50. Recurrence rates in patients are high, in some studies over 80% within 2 years. ADXS-HPV may provide a treatment option for doctors and patients with HPV-related head and neck cancers.
ADXS-HPV is granted orphan drug designation for treatment of HPV-associated head and neck cancer in the US.
ADXS-HPV Combination Study Significantly Improves Therapeutic Efficacy in Preclinical Study
On September 5, Advaxis announced the publication of preclinical research with ADXS-HPV in combination with PD-1 antibody for the treatment of HPV-associated cancers.
The studies demonstrated that treatment with ADXS-HPV immunotherapy, in combination with an anti-PD-1 antibody, significantly improved immune and therapeutic efficacy in preclinical mouse models. In addition, the study showed that a significant reduction of regulatory T cells (Treg) and myeloid-derived suppressor cells (MDSC) in both the spleen and the tumor microenvironment were mediated solely by the ADXS-HPV immunotherapy. The addition of anti-PD-1 antibody to the immunotherapy treatment resulted in a significant increase in antigen-specific immune responses in the periphery and in CD8 T cell infiltration into the tumor. As a result, this treatment combination led to significant inhibition of tumor growth and prolonged survival/complete regression of tumors in treated animals.
Given the findings in the mouse model, additional studies were conducted to evaluate activity in human cells. In separate studies, ADXS-HPV immunotherapy treatment was found to significantly up-regulate surface PD-L1 expression on human monocyte-derived dendritic cells isolated from healthy volunteers. This finding suggests that the combination of ADXS-HPV immunotherapy with an anti-PD-1 antibody could have clinical application.
ADXS-cHER2 Has the Potential to Provide Partnership with Big Pharma
In addition to human clinical trial programs, ADXS is also developing ADXS-cHER2 for canine osteosarcoma.
ADXS-cHER2 is an Lm-LLO immunotherapy for HER2 overexpressing cancers (such as breast, gastric and other cancers in humans and for osteosarcoma in canines). ADXS-cHER2 secrets the cHER2 antigen, fused to LLO, directly inside APC that are capable of driving a cellular immune response to cHER2 overexpressing cells.
On August 2, 2012, Advaxis announced the initiation of a Phase I study of ADXS-cHER2 for canine osteosarcoma at the University of Pennsylvania, School of Veterinary Medicine. In this trial, dogs that have undergone standard of care treatment for osteosarcoma, including limb amputation and follow up chemotherapy, and that over-express the tumor marker HER-2/neu in their tumors, are treated with Advaxis agent ADXS-cHER2. This immunotherapy is designed to stimulate the dog's immune system to attack cancer cells that express the HER-2/neu marker. The goal is to elicit anti-tumor immunity and prolong survival.
On July 17, Advaxis announced positive preliminary data from the dose escalation Phase I study evaluating the safety and efficacy of ADXS-cHER2 in the treatment of dogs with osteosarcoma that overexpress human epidermal growth factor receptor-2 (HER2).
Updated preliminary data from the first two of three dose groups (6 dogs/3 dogs per dose group) show a significant survival advantage for dogs that received standard of care (SOC) plus ADXS-cHER2 compared to 11 dogs whose owners elected not to participate in the trial but who were followed for survival (p=0.04). At this point in the study, 8 of 9 dogs treated with ADXS-cHER2 are alive (mean survival undefined), compared with 5 of 11 dogs in the control group (mean survival 265 days).
ADXS-cHER2 continues to be well-tolerated with the dogs experiencing only mild, easily managed side effects (fever, increased heart rate, and vomiting) consistent with immune activation (cytokine release syndrome) observed at the time of treatment. There is no evidence of any cumulative or long-term side effects on the dogs, including their cardiovascular systems.
Once the dose has been selected, the study is intended to expand into Phase II and additional collaborative academic centers will be added.
Canine osteosarcoma is a leading killer of large breed dogs that causes tumors to form on long leg bones. Dogs undergoing standard of care (SOC) treatment (affected limb amputation and follow-up chemotherapy) have a median survival rate of only 1 year. We believe there is a significant commercial opportunity for ADXS-cHER2 in the veterinary medical market. Advaxis is discussing these data with animal health divisions of several major pharmaceutical companies.
1. This study is being conducted by the Gynecologic Oncology Group
Balance Sheet Boosted Dramatically by Recent Financing
On October 22, Advaxis announced the closing of its public offering of 6,612,500 shares of common stock, and warrants to purchase up to an aggregate of 3,306,250 shares of its common stock, including 862,500 shares and warrants to purchase 431,250 shares that were offered and sold by Advaxis, Inc. pursuant to the full exercise of the underwriters' over-allotment option, at a price to the public of $4.00 per share and $0.001 per warrant. The warrants have a per share exercise price of $5.00, 125% of the public offering price of the common stock, are exercisable immediately, and expire five years from the date of issuance. Total gross proceeds from the offering were approximately $26,500,000, before deducting underwriting discounts and commissions and other offering expenses payable by Advaxis, Inc.
This financing after the 1-for-125 reverse stock split is a great achievement for Advaxis. It not only boosts the company's balance sheet dramatically, but also validates the company's cancer vaccine technology and clinical programs.
Current cash could last through 2Q15 according to our financial model. With boosted balance sheet, Advaxis should be able to focus on advancing its promising lead drug candidate ADXS-HPV.
ADXS Is Undervalued
We maintain our Outperform rating for ADXS and reiterate our 12-month price target of $7.50 per share.
We think Advaxis' live, attenuated Listeria technology is a unique immunotherapeutic platform which can target various cancer indications and infectious diseases. This technology has advantages over other immunotherapies in three unique ways:
- Advaxis' Listeria-based cancer vaccine can deliver bioengineered cancer antigen fused with a unique, proprietary strong adjuvant LLO which elicits both innate and adaptive immune systems in the body to fight cancer. The immune response elicited by Advaxis' cancer vaccines has been the most comprehensive and robust so far in the industry.
- Advaxis' cancer vaccines can reduce the amount of regulatory T cells and myeloid suppressor cells which help protect tumors from attacking by cytotoxic T cells.
- Another distinctive feature of Advaxis' cancer vaccines is its ability to change the ratio between killer T-cells and regulatory T cells (the Kill Ratio) inside the tumor from a 1:1.3 to a 22.7:1.
Based on this unique platform technology, Advaxis has established a pipeline targeting a variety of cancer indications including cervical cancer/cervical dysplasia, head and neck cancer, prostate cancer, anal cancer and breast/brain cancers. The company's ADXS-HPV is the first cervical cancer vaccine which will move into pivotal trial soon.
In terms of valuation, we think Advaxis is undervalued in our view. Currently, the company shares are trading at about $3.40 per share which values the company at about $38 million in market cap based on 11.5 million outstanding shares. This is certainly a deep discount.
We also remind investors that the company recently completed a $26.5 million financing, which boosted the balance sheet greatly. Further, according to management, partnership talks continue with big pharma companies about its cervical cancer program. With the preliminary positive Phase II data of ADXS-HPV for cervical cancer, partnership may be able to materialize in 2014.
ADXS-HPV has a huge market potential. Cervical cancer is a worldwide problem and ranks as the 2nd leading cause of cancer death of women in the world. According to WHO, about 630 million people are infected with one of the over 100 strains of HPV. Global prevalence of clinically pre-malignant HPV infections is between 28 to 40 million women. Approximately 500,000 women are diagnosed of cervical cancer each year and about 11.4% of women in the general population are estimated to harbor cervical HPV infection. In the U.S., about 12000 new cases of cervical cancer are diagnosed each year. Prevalence of cervical cancer is higher in developing countries and India, China and South America are the three regions with highest cervical cancer prevalence (50% of cervical cancer burden).
In addition to cervical cancer, ADXS-HPV has potential to target other HPV-mediated cancers, which further expand ADXS-HPV's market. The Company already initiated clinical studies of ADXS-HPV for head and neck cancer as well as anal cancer.
Our price target of $7.50 per share values the company at $86 million in market cap, which is still conservative. Apparently, risk is also high for Advaxis at this stage.