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Study to assess immunotherapy combination for HPV-associated head, neck cancers
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Researchers at Atlantic HPV Center at Leonard B. Kahn Head and Neck Cancer Institute will study immunotherapy combinations in a cohort of patients with HPV-associated head and neck cancers.
Missak Haigentz, MD, chief of hematology and oncology at Morristown Medical Center and medical director of Atlantic Hematology and Oncology of Atlantic Medical Group at Carol G. Simon Cancer Center, and colleagues will conduct a phase 1b/phase 2a study that will assess an experimental HPV vaccine and treatment with the PD-L1 inhibitor durvalumab (Imfinzi; AstraZeneca).
The rationale behind the study is that HPV may cause significantly more squamous malignancies of this kind than previously thought.
HemOnc Today spoke with Haigentz about the challenges of this patient population, the specifics of the combination therapy, and when results can be expected.
Question: Why is this patient population so challenging, and how does this factor into the need for more effective therapies ?
Answer: Approximately 70% of oropharyngeal cancers diagnosed in the United States are HPV associated. The prevalence of these cancers is expected to increase over the next several decades, resulting in a major public health concern. HPV vaccines in clinical use are potentially preventive but have no therapeutic effect for patients with this disease.
Although HPV-associated head and neck cancers are generally associated with excellent outcomes, as reflected in the new AJCC 8th Edition staging system for this disease, approximately 20% of patients have recurrent disease and have limited treatment options. But the treatment of HPV-associated head and neck cancer has been developed with the same approaches used for tobacco- and carcinogen-associated cancers. Beyond its prognostic implications, therapeutic targeting of oncogenic HPV infection is of high clinical and scientific interest, as it provides a targeted approach for treating this distinct disease.
Q: What is the rationale behind the regimen that will be assessed in this study?
A: This phase 1b/phase 2a study (NCT03162224) evaluates the safety and efficacy of MEDI0457 (MedImmune/AstraZeneca) in combination with durvalumab for patients with recurrent/metastatic HPV-associated head and neck cancer. MEDI0457 is a plasmid DNA vaccine comprised of three plasmids expressing HPV-16 and HPV-18 E6 and E7 oncoproteins along with interleukin-12. Among patients with HPV positive head and neck cancer, MEDI0457 — delivered intramuscularly, followed by electroporation pulses that increase expression of E6 and E7 antigens — is tolerable and induces HPV 16/18-specific humoral and cellular immune responses that may promote cytotoxic T-lymphocyte activation and enhanced efficacy of PD-1/PD-L1 checkpoint inhibition.
Q: Why did you think this combination of oncoproteins and IL-12 would be effective in this setting?
A: The E6 and E7 viral oncoproteins — primarily responsible for HPV-driven carcinogenesis — are excellent immunogens for therapeutic vaccination, and IL-12 is a potent adjuvant.
Q: What results are you hoping to achieve?
A: The primary study endpoints are the safety and objective response rate of MEDI0457 in combination with durvalumab. Secondary endpoints include other measures of clinical benefit — such as disease control rate at 16 weeks, as well as PFS and OS — and evaluations of the cellular and humoral immune response associated with this regimen.
Q: Can you describe the study design and patient population?
A: This study is enrolling patients with HPV-associated, recurrent/metastatic head and neck cancer. Eligible patients include those with prior platinum exposure, though those who are platinum ineligible may also be enrolled if they received an approved treatment that failed. Importantly, prior exposure to immune-mediated cancer therapy — specifically T cell-directed or NK cell-directed therapy — is not permitted.
Q: Do you think more similar combinations will be used for this population going forward?
A: Although immunotherapy targeting the PD-1/PD-L1 immune checkpoint has dramatically improved outcomes of some patients with recurrent and metastatic head and neck cancer, fewer than 20% of patients respond to this therapy. Efforts to improve on this treatment approach are highly desirable, and a combination with a therapeutic HPV vaccine capable of promoting CD8-positive T-cell activation such as MEDI0457 has high scientific rationale for this patient population.
Q: Why do so few patients respond to this therapy?
A: Resistance to cancer immunotherapy may be from primary, adaptive or acquired mechanisms. In the era of active cancer immunotherapy, rational, nonredundant immunotherapy combinations are a promising investigational approach for patients to have deeper and more durable tumor responses with greater frequency.
Q: When do you expect results?
A: This study was presented as a Trials in Progress abstract at ASCO Annual Meeting earlier this month. The study is actively recruiting subjects at multiple sites in the United States and has a planned enrollment of 50 patients. – by Rob Volansky
Reference:
Aggarwal C, et al. Abstract TPS6093. Presented at: ASCO Annual Meeting; June 1-5, 2018; Chicago.
For more information:
Missak Haigentz, MD, can be reached at Morristown Medical Center, 100 Madison Ave., 2nd Floor, Morristown, NJ 07962; email: missak.haigentz@atlantichealth.org.
Disclosure: Haigentz reports consultant fees from AstraZeneca.