Sustained High Efficacy of Gardasil Against Precancerous Cervical Lesions Confirmed in Longest Follow-up of Large Phase III Studies
Results further substantiate strong evidence for long-lasting protection
Studies ended to vaccinate women in the placebo group for ethical reasons
LYON, France, 7th February 2008 – A combined analysis of four phase II/III studies which enrolled more than 20,000 women confirmed that the quadrivalent (6,11,16,18) cervical cancer vaccine Gardasil® has sustained 98% to 100% efficacy in the prevention of vaccine virus type-related precancerous cervical lesions in young women. These new data were presented this week at the 19th International Congress on Anti-Cancer Treatment (ICACT) in Paris, France.[1]
"The results complete Gardasil®'s impressive track record of sustained high efficacy. They include by far the longest follow-up for any cervical cancer vaccine in large phase III studies and strongly substantiate the evidence that the protection provided by Gardasil® will be long-lasting", comments lead study investigator Prof. Elmar Joura, from the University of Vienna, Austria.
In light of the high and sustained efficacy of Gardasil®, the independent Data and Safety Monitoring Board of the large phase III studies in young women (FUTURE I & II) had recommended that these studies be terminated as soon as feasible in order to provide the benefits of Gardasil® to the women in the placebo group. Thus, the studies were ended earlier than originally planned and the women in the placebo group have been vaccinated.
In the primary study population of young women (16-26 years)[*], Gardasil® prevented 98%[†] of HPV 16/18-related precancerous cervical lesions (CIN2/3[‡] or AIS[§]) according to the combined analysis. Supplementary analyses in a sub-population of young women (16-26 years)[**] revealed 100%[††] efficacy against HPV 16/18-related CIN2/3 or AIS.
The sub-population approximates even better than the primary study population the target group of vaccination programmes (adolescent girls), where maximal benefit of vaccination is expected before exposure to the virus.
The new results are consistent with previous results from the five years follow up of the pivotal phase II study in a smaller population. "This extends the robustness of the data from a few hundred to many thousand women", adds Patrick Poirot, vice president medical and scientific affairs at Sanofi Pasteur MSD. "Phase III results are of greatest importance for regulatory and health authorities when they evaluate a vaccine."
The follow up of the pivotal phase II study has ended, too after five years; the women in the placebo group have been vaccinated not to let them any longer unprotected.
In addition to the robust follow ups in phase II and phase III studies, Gardasil® has been demonstrated to induce immune memory. Demonstrating immune memory means demonstrating that the immune system has memorised the vaccine virus types and can be expected to provide protection when exposed again to these types, even many years later.[2] Experts consider the demonstration of immune memory a hallmark of long-term protection.
"With five years of follow up in phase II studies followed by the demonstration of immune memory plus the longest ethically acceptable follow up in our large phase III studies we have provided the three key elements to make mothers, young women, physicians and health authorities confident about long-term protection with Gardasil®", concludes Patrick Poirot.
***
About the studies
The FUTURE I and II studies are phase III, prospective, double-blind, placebo-controlled randomised studies conducted in 16 countries. Over 17,000 women participated in the trials. They were aged 16 to 26 and received three doses of either Gardasil® or placebo at day 1, month 2, and month 6.
FUTURE I evaluated the incidence of pre-cancerous and early cervical lesions (CIN 1-3), pre-cancerous and early vulvar and vaginal lesions (VIN1-3 and VaIN1-3) and external genital warts caused by the HPV 6, 11, 16 and 18. FUTURE II evaluated the prevention of pre-cancerous cervical lesions (CIN 2/3) and non-invasive cancers (AIS) caused by HPV types 16 and 18.
For the phase II/III combined analysis, 16,957 women (16–26 years) were enrolled and randomised to receive either Gardasil® (n = 8,493) or placebo (n = 8464) at day 1, and month 2 and 6 and were followed for up to 4 years after the start of vaccination. Pap tests were taken at regular 6 or 12-month intervals and evaluated using the Bethesda System-2001. Comprehensive anogenital examinations were scheduled at day 1, and every 6 to 12 months thereafter. Colposcopy referral was algorithm-based. Biopsies were HPV typed. Histology slides were read by a blinded pathology panel. Analyses were per protocol (received 3 doses, had no major protocol violations, were seronegative at day 1 and DNA negative day 1 to month 7 to the HPV vaccine types). There were two cases of CIN3 observed in the vaccine group (n = 8,493) and 112 cases observed in the placebo group (n = 8,464). Supplementary analyses were done in subjects who were negative to the four HPV vaccine types and ten additional types at day 1 (generally HPV naïve). There was no case observed in the vaccine group compared to 52 cases observed in the placebo group
Notes to editors
Since its first approval in 2006, Gardasil® has been approved in 93 countries worldwide and launched in 76 of them and has met with rapid adoption (more than 20 million doses distributed worldwide).
The burden of cervical cancer and other human papillomavirus diseases
Despite screening for early detection, cervical cancer remains the second most common cause of death from cancer (after breast cancer) among young women (15-44 years) in Europe[‡‡].[3] Around 33,500 women are diagnosed with, and 15,000 women die from cervical cancer each year.[4]
In addition, hundreds of thousands of women are diagnosed with other genital human papillomavirus diseases that start before the occurrence of cervical cancer and can touch other genital organs than the cervix. These diseases include pre-cancerous and early cervical lesions[5],[6],[7], vulvar and vaginal cancer[8],[9],[10], pre-cancerous vulvar and vaginal lesions[11],[12],[13],[14] and genital warts.[15]
It is estimated that types 6/11/16/18 cause 75% of cervical cancer in Europe[16] (types 16/18), 70% of vulvar and vaginal cancers, 70% of pre-cancerous(CIN2/3) and 35-50% of early cervical lesions(CIN1), 70% of pre-cancerous vulvar and vaginal lesions, and 90% of genital warts.[17],[18]
Virus types 6/11 cause 10% of early cervical lesions in Europe in addition to the 25% of early cervical lesions caused by types 16 and 18.17,[19],[20] Virus types 6 /11 also cause 90% of genital warts 15,17, [21],[22],[23]
Current EU indication of Gardasil®
Gardasil®, human papillomavirus vaccine [types 6,11,16,18] (recombinant, adsorbed), can be given to children and adolescents 9 to15 years and adult females 16 to 26 years of age and is indicated for the prevention of cervical carcinoma (cervical cancer), high grade cervical dysplasia CIN2/3 (precancerous cervical lesions), high grade vulvar dysplastic lesions VIN 2/3 (precancerous vulvar lesions) and external genital warts (condyloma acuminata) caused by human papillomavirus types 6, 11, 16 and 18.
About Sanofi Pasteur MSD
Sanofi Pasteur MSD is a joint venture between sanofi pasteur, the vaccine division of sanofi-aventis, and Merck & Co., Inc. Combining innovation and expertise, Sanofi Pasteur MSD is the only company in Europe dedicated exclusively to vaccines. Sanofi Pasteur MSD is able to draw on the research expertise of sanofi pasteur and Merck & Co., Inc., together with their teams throughout the world, to focus on the development of new vaccines for Europe, which aim to extend protection to other diseases and perfect existing vaccines in order to improve the acceptability, efficacy and tolerability of vaccination.
Contact
Dr. Arne Näveke
Executive Director, Communication Europe
Sanofi Pasteur MSD
Tel +33 4 37 28 40 40
Fax +33 4 37 28 44 04
References
[*] Not exposed to the four human papillomavirus (HPV) types (6,11,16,18) targeted by Gardasil® before vaccination
[†] 95% CI [94,100], through a mean follow up of up to four years after the start of vaccination
There is good evidence suggesting that the two cases of CIN3 in the vaccine group were caused by virus types not targeted by the vaccine. Nevertheless, the cases were counted as HPV-16 related CIN3 according to the strict and conservative case definitions and study standards.
[‡] Cervical Intraepithelial Neoplasia grades 2 and 3
[§] Adenocarcinoma in Situ
[**] Not exposed to the four vaccine types and to ten additional HPV types before vaccination
[††] 95% CI [93,100], through a mean of follow up of four years after the start of vaccination
[‡‡] European Union member states (except Romania and Bulgaria) plus Iceland, Norway & Switzerland
[1] Joura EA et al. Sustained protection by quadrivalent HPV (type 6, 11, 16, 18) vaccine through 4 years against HPV 6/11/16/18-related cervical intraepithelial neoplasia grade 2/3 (CIN2/3) and adenocarcinoma in situ (AIS) of the cervix; Abstract presented at the 19th International Congress on Anti-Cancer Treatment (ICACT), 5-8 February 2008, Paris, France.
[2] Olsson SE et al. Induction of immune memory following administration of a prophylactic quadrivalent human papillomavirus (HPV) types 6/11/16/18 L1 virus-like particle (VLP) vaccine. Vaccine 2007;25:4931-4939.
[3] Ferlay J, Bray F, Pisani P et al, editors. Globocan 2000: Cancer incidence, mortality and prevalence worldwide. IARC Cancer Base No.5. version 1.0. IARC Press, Lyon 2001.
[4] Ferlay J, Bray F, Pisani P et al, editors. Globocan 2002: Cancer incidence, mortality and prevalence worldwide. IARC Cancer Base No.5. version 2.0. IARC Press, Lyon 2004.
[5] Clifford GM, Smith JS, Aguado T et al. Comparison of HPV type distribution in high-grade cervical lesions and cervical cancer: A meta-analysis. Br J Cancer 2003;89101–105.
[6] Clifford GM, Rana RK, Franceschi S et al. Human Papillomavirus genotype distribution in low-grade cervical lesions: Comparison by geographic region and with cervical cancer. Cancer Epidemiol Biomarkers Prev 2005;14:1157–1164.
[7] Insinga RP, Glass AG and Rush BB. Diagnoses and outcomes in cervical cancer screening: A population-based study. Am J Obstet Gynecol 2004;191:105–113.
[8] Daling JR, Madeleine MM, Schwartz SM et al. A population-based study of squamous cell vaginal cancer: HPV and cofactors. Gynecol Oncol 2002;84:263–270.
[9] Madeleine MM, Daling JR, Carter JJ et al. Cofactors with Human Papillomavirus in a population-based study of vulvar cancer. J Natl Cancer Inst 1997;89:1516–1523.
[10] Parkin DM, Whelan SL, Ferlay J et al. Cancer incidence in five continents (GIS). Volume VIII. p606–611.
[11] van Beurden M, ten Kate FJW, Smits HL et al. Multifocal intraepithelial neoplasia grade III and multicentric lower genital tract neoplasia is associated with transcriptionally active Human Papillomavirus. Cancer 1995;75:2879–2884.
[12] Hording U, Junge J, Poulson H et al. Vulvar intraepithelial neoplasia III: A viral disease of undetermined progressive potential. Gynecol Oncol 1995;56:276–279.
[13] Dodge JA, Eltabbakh GH, Mount SL et al. Clinical features and risk of recurrence among patients with vaginal intraepithelial neoplasia. Gynecol Oncol 2001;83:363–369.
[14] Jones RW. Vulval intraepithelial neoplasia: Current perspectives. Eur J Gynaecol Oncol 2001;22:393–402.
[15] UK Health Protection Agency. CDR Weekly 2003;3(44)
[16] Smith JS et al. Human papillomavirus type distribution in invasive cervical cancer and high-grade cervical lesions: A meta-analysis update. Int J Cancer 2007; 121:621-632.
[17] Gardasil®, Summary of Product Characteristics 2007
[18] EPAR Gardasil®, Scientific Discussion (http://www.emea.europa.eu/humandocs/PDFs/EPAR/gardasil/070306en6.pdf) last accessed 29.01.2008
[19] Clifford GM et al. Human papillomavirus genotype distribution in low-grade cervical lesions: Comparison by geographic region and with cervical cancer. Cancer Epidemiol Biomarkers Prev 2005;14:1157-1164.
[20] Insinga RPet al. Diagnoses and outcomes in cervical cancer screening : A population-based study. Am J Obstet Gynecol 2004;191:105-113.
[21] Jones RW. Vulval intraepithelial neoplasia: Current perspectives. Eur J Gynaecol Oncol 2001;22:393–402.
[22] Wieland U and Pfister H. papillomaviruses in human pathology: Epidemiology, pathogenesis and oncologic role. In: Gross, Barasso Eds.Human Papilloma Virus Infection: A clinical atlas. Ullstein Mosby 1997; p1-18.
[23] von Krogh G. Management of anogenital warts (condylomata acuminata). Eur J Dermatol 2001;11:598–603.
Posted: February 2008
