In 1971, the year that President Richard Nixon signed the National Cancer Act and initiated a federally mandated “war on cancer,” the five-year survival rate for women diagnosed with stage 0 cervical cancer was less than 50%—compared with a 93% survival rate today.
A late-stage diagnosis was almost a guaranteed death sentence. Today, 32% of women diagnosed with stage IIIB cervical cancer are alive five years later, as are 15% of women diagnosed with stage IV cancer—the absolute worst-case scenario.
According to the Pharmaceutical Researchers and Manufacturers of America (PhRMA), since 1980, the incidence of cervical cancer has declined by 45% while the mortality rate associated with cervical cancer has declined by 49%.
These statistics are a direct result of innovative changes in the prevention and treatment landscape for cervical cancer, with major breakthroughs dating back to the 1950’s, when the Pap smear was introduced, allowing clinicians to detect potentially precancerous and cancerous cells in the cervix, which are easy to treat.
The introduction of Merck’s Gardasil vaccine in 2006 and GlaxoSmithKline’s (GSK) Cervarix vaccine in 2009—both designed to prevent persistent, cancer-causing HPV infections—have played a significant role in recent declines in the incidence of cervical cancer. A third option, Merck’s Gardasil 9, which was approved by the FDA in December 2014, broadens the level of protection against not only cervical cancer, but also anal cancer and throat cancer.
Although 72 million individuals worldwide have received HPV vaccination, large percentages of those who are eligible for vaccination have not received the vaccines. The Advisory Committee on Immunization Practices (ACIP) recommends vaccination for all girls and boys between the ages of 11 and 12, followed by catch-up vaccines.
But uptake has been very slow. And HPV vaccination in general has been mired in controversy and concerns about side effects and safety issues. According to the Centers for Disease Control and Prevention (CDC), only 57% of adolescent girls and 35% of adolescent boys received HPV vaccination in 2013.
Because of ongoing concerns about reports of two conditions—complex regional pain syndrome (CRPS) and postural orthostatic tachycardia syndrome (POTS)—linked to HPV vaccination, the European Medicines Agency (EMA) is undertaking a full safety review of HPV vaccines in order clarify the frequency of CRPS and POTS, as well as the causality factor. Depending on the outcomes, the EMA may decide to recommend changing the product information.
The impact of HPV vaccine uptake dynamics
According to a report from the Henry J. Kaiser Family Foundation HPV prevalence has decreased significantly since introduction of the HPV vaccine. Between 2003-2006 and 2007-2010, the prevalence of HPV fell from 11.5% to 5.1% among girls between the ages of 14 and 19—although only one-third of the girls in this age cohort were vaccinated.
The implications for slow uptake of HPV vaccines are multifaceted. First, there is the issue of underutilization of preventive measures that could improve long-term outcomes and lower the incidence of HPV-related cancers.
Also, from a revenue perspective, analysts are only forecasting $1.9 billion in revenues for Gardasil 9 in 2018, which is much less than earlier forecasts pegging Gardasil vaccines as a $10 billion sales category by 2018.
Regardless, it comes down to one simple fact: On a large scale, the benefits of HPV vaccination far outweigh the risks, especially when all relevant variables are taken into consideration. The need to investigate safety concerns around HPV vaccination does not render the research and development of these products, or the messaging around them, any less innovative. Rather, the need to have ongoing post-marketing surveillance should be considered a built-in feature of innovative drug development.
Roche’s innovative approach to cervical cancer
Unfortunately, many of the 12,360 women who were diagnosed with cervical cancer last year, as well as the 4,020 women who died, did not have the option of receiving an HPV vaccine since it has only been available for about 10 years.
Nonetheless, there are treatment options for cervical cancer, including bleomycin, which was approved in 1962 and topotecan, which is manufactured by GSK and was approved by the FDA as Hycamtin in 2007. There are also companies working hard to develop new therapies for cervical cancer, including Inovio, which is conducting early-stage trials on an immunotherapy product for women with metastatic cervical cancer.
But the biggest news in cervical cancer treatment in the last few years has been Roche’s Avastin (bevacizumab). The treatment received FDA approval for treatment of metastatic cervical cancer in November 2014 and EMA approval in April 2015.
Avastin's (which was first approved in 2004 for colorectal cancer) cervical cancer indication was a big deal because of the therapy's widespread use and history of testing in other cancers such as metastatic breast cancer, kidney cancer, ovarian cancer, and post-surgical glioblastoma.
Oncologists have experience using it to treat various types of tumors and feel comfortable using it in combination with other therapies. This bodes well for uptake for use in cervical cancer. In fact, Avastin, which is already a $6.5 billion per year drug, is on pace to become a $10 billion drug because of its well-vetted utility, according to analysts.
"The approval of Avastin in advanced cervical cancer was important news for the cervical cancer community, as it was the first treatment in nearly a decade to improve survival," a Roche spokesperson told BioPharma Dive. "Before Avastin’s approval, treatment options in Europe for women who had advanced cervical cancer were limited to chemotherapy alone, with the approval of topotecan chemotherapy in 2006 being the last treatment innovation to improve survival before Avastin.
"With Avastin’s approval, women with advanced cervical cancer now have the chance to live an average of nearly four months longer when treated with Avastin plus chemotherapy compared to chemotherapy alone."
How Roche used its knowledge base to innovate new diagnostic strategies
Phase 3 clinical trial data showed a significant survival advantage for women with cervical cancer treated with Avastin. In a study of 452 women, those treated with Avastin plus chemotherapy, compared with chemotherapy alone, had a 26% reduction in the risk of death, resulting in overall median survival of 16.8 months versus 12.9 months. They also had a significant rate of tumor shrinkage, with an objective response rate of 4.5% compared with 3.4% for chemotherapy-only treated patients.
Roche has developed an entire portfolio of genomic-based testing and diagnostic tools to enhance it cancer franchise. "Roche is committed to further developing technologies that improve the standard of care," said the Roche spokesperson. "Raising awareness of the importance of regular cervical screening and the importance of HPV testing in particular is a key focus for our communications on prevention.
"In fact, one third of cervical cancers occur in women with a normal Pap smear. HPV testing on the other hand is able to pinpoint the high risk genotypes most commonly associated with cervical cancer, therefore identifying women most at risk from this life threatening but preventable disease.
"For those women diagnosed with cervical cancer, there is a dramatic difference in survival rates between early and advanced disease. At least nine out of 10 women will live for five years following diagnosis of early stage disease but the survival rate drops to below one in six women when the disease has spread to other parts of the body."
Every battle counts
When President Nixon declared war on cancer, he set up a cluster of federally funded research institutes, with the understanding that this war would be one of attrition.
While he could not have foreseen the precise advances in genomics and oncologic strategies that have developed over the last 45 years, leading up to the just-announced Cancer MoonShot 2020 initiative and National Immunotherapy Coalition, he must have anticipated that innovative research would be the key to unlocking the mystery of hundreds of complex and highly varied molecular diseases collectively known as cancer.