Dr Posner on the Mechanism of Action of Danivatirsen in HNSCC

Marshall Posner, MD, professor of medicine, director, Head and Neck Medical Oncology, associate director, Center for Personalized Cancer Therapeutics, co-leader, Cancer Clinical Investigation Program, Tisch Cancer Institute, discusses the mechanism of action of danvatirsen (AZD9150) in recurrent and/or metastatic head and neck squamous cell carcinoma (HNSCC).

Danvatirsen is a 16-nucleotide, generation 2.5 antisense oligonucleotide designed to down-regulate the expression of human STAT3 mRNA, Posner states. Following intravenous administration, the stabilized antisense oligonucleotide travels through the bloodstream and enters cells, he details. There, it binds to mRNA, which is particularly expressed in tumors, thereby blocking the production of the STAT3 protein in both normal and tumor cells, he explains.

STAT3 is ubiquitously expressed in various tissues throughout the body, Posner continues. When expressed in tumor cells, it plays a critical role in promoting an immuno-suppressive microenvironment and the survival of tumor cells, he says, adding that this protein also promotes the growth of the tumor through angiogenesis and reduction of pro-inflammatory cytokines.

Accordingly, the administration of danvatirsen is designed to reduce the supportive infrastructure of the tumor that is not malignant, and to directly attack the tumor cells by inhibiting the production of cytokines and other factors that promote tumor growth, Posner explains. It function is similar to that of a bispecific antibody, as it promotes tumor suppression through cytokine inhibition and enhances tumor immunity by improving the immune milieu around the tumor, he notes.

The ongoing phase 2 PEMDA-HN study (NCT05814666) is evaluating the addition of danvatirsen to pembrolizumab (Keytruda) in patients with recurrent and/or metastatic HNSCC with PD-L1–positive disease. The study will include approximately 81 patients who will receive danvatirsen at either 3 mg/kg on days 1, 3, and 5 of week 1, then 3 mg/kg once per week thereafter, plus pembrolizumab 200 mg once every 3 weeks; or pembrolizumab monotherapy at 200 mg once every 3 weeks. The study's primary end point is investigator-assessed overall response rate per RECIST 1.1 criteria.

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Marshall Posner, MD, discusses the mechanism of action of danvatirsen in recurrent and/or metastatic head and neck squamous cell carcinoma.

Marshall Posner, MD, professor of medicine, director of head and neck medical oncology, associate director of the Center for Personalized Cancer Therapeutics, and co-leader of the Cancer Clinical Investigation Program for the Tisch Cancer Institute at Mount Sinai, shares his clinical experience with the use of tipifarnib in patients with head and neck cancer whose tumors harbor 

Studies have shown that tipifarnib elicits favorable responses in patients with 

 mutations, Posner says. However the drug may have limited use for this population, as only 3% to 5% of patients with head and neck cancer have tumors that harbor these mutations, according to Posner. He adds that he is currently treating 3 patients with 

 mutations, 1 of whom has a salivary gland tumor. This patient was granted compassionate use of tipifarnib and experienced a response of about 9 months, Posner adds.

Tipifarnib has showcased a high level of efficacy and control of disease, Posner explains. Although the duration of disease control may not be as long as desired, but there may be other ways to achieve this after establishing whether patients harbor 

Marshall Posner, MD, shares his clinical experience with the use of tipifarnib in patients with head and neck cancer whose tumors harbor HRAS mutations.

Dr. Posner on Leveraging Tipifarnib in HRAS-Mutant Head and Neck Cancer 

Marshall Posner, MD, Medical Director, Head and Neck Oncology Center, Mount Sinai Medical Center, discusses factors that contribute to an improved prognosis for patients with HPV-positive head and neck cancer when compared to patients who are HPV-negative. 

Posner explains that several retrospective studies have confirmed that HPV-positive oropharynx cancer is highly response to surgery, radiotherapy, and chemotherapy. This translates into a better prognosis for patients with HPV-positive disease. This variation is associated with biologic and demographic differences between the two patient populations.

Patients with environmentally caused, HPV-negative, head and neck cancer generally have a higher risk of developing a second tumor, Posner explains. Additionally, they deal with higher rates of smoking-related comorbidities. Inversely, those with HPV-positive tumors are usually younger and healthier. Biologically, HPV-positive tumors respond significantly better to treatment than negative.

Marshall Posner, MD, from Mount Sinai Medical Center, discusses the factors that improve the prognosis for patients with HPV-positive head and neck cancer when compared to patients who are HPV-negative.

Dr. Posner on HPV-Positive Oropharynx Cancer

Marshall Posner, MD, Medical Director, Head and Neck Oncology Center, Mount Sinai Medical Center, discusses the growing need for preventive measures to prevent the spread of human papillomavirus (HPV) related cancers.

Cancers associated with HPV is unique because the virus is transmitted sexually. Twenty-five percent of teenage girls are infected; this number increases by the time they reach their mid-20s. In addition the virus also affects the men that come into contact with the infected women.

HPV is the cause of cervical cancer in women and is becoming predominately associated with oropharyngeal cancer in men. As the amount of cancers associated with the virus increases it becomes increasingly clear that prevention is needed.

Posner notes that prevention will not impact the rate of cancer until it has been in place for nearly 30 years; the cancer rates will only begin to decline if the vaccine is capable of preventing virus inoculation.

Dr. Marshall Posner, from Mount Sinai Medical Center, Discusses the Link Between HPV and Cancer

Marshall Posner, MD

Articles

Dr Posner on the Mechanism of Action of Danivatirsen in HNSCC

Dr. Posner on Leveraging Tipifarnib in HRAS-Mutant Head and Neck Cancer

Dr. Posner on HPV-Positive Oropharynx Cancer

Dr. Posner Discusses the Link Between HPV and Cancer