Phase II Trial of MEDI0457 and Durvalumab for Patients With Recurrent/Metastatic Human Papillomavirus-Associated Cancers.

BACKGROUND: Human papillomavirus (HPV) types 16/18 drive oncogenesis for most patients with cervical, anal, and penile cancers. MEDI0457, a therapeutic DNA vaccine containing plasmids for E6 and E7 HPV-16/18 viral oncogenes and IL-12 adjuvant, is safe and provokes an immune response against E6/E7. We tested MEDI0457 with the anti-PD-L1 antibody durvalumab for patients with HPV-associated cancers. METHODS: Patients with recurrent/metastatic, treatment-refractory HPV-16/18 cervical cancer, or rare HPV-associated (anal and penile) cancers were eligible. Prior immune checkpoint inhibition was not permitted. Patients received MEDI0457 7 mg intramuscularly (weeks 1, 3, 7, 12, and every 8 weeks thereafter) and durvalumab 1500 mg intravenously every 4 weeks. The primary endpoint was overall response (RECIST 1.1). In this Simon two-stage phase 2 trial (Ho: p < 0.15; Ha: p ≥ 0.35), ≥2 responses were needed in both cervical and non-cervical cohorts during the first stage for the trial to proceed to stage 2 with an additional 25 patients (34 total) enrolled. RESULTS: Twenty-one patients (12 cervical, 7 anal, and 2 penile) were evaluable for toxicity and 19 for response Overall response rate was 21% (95% CI, 6%-46%) among evaluable patients. Disease control rate was 37% (95% CI, 16%-62%). Median duration of response among responders was 21.8 months (95% CI, 9.7%-not estimable). Median progression-free survival was 4.6 months (95% CI, 2.8%-7.2%). Median overall survival was 17.7 months (95% CI, 7.6%-not estimable). Grades 3-4 treatment-related adverse events occurred in 6 (23%) participants. CONCLUSIONS: The combination of MEDI0457 and durvalumab demonstrated acceptable safety and tolerability in patients with advanced HPV-16/18 cancers. The low ORR among patients with cervical cancer led to study discontinuation despite a clinically meaningful disease control rate.

Targeting the PI3K Pathway in Gynecologic Malignancies.

PURPOSE OF REVIEW: This review explores the PI3K pathway aberrations common in gynecologic malignancies, the relevant therapeutic targets that have been explored to date particularly given their success in endometrial cancers, and predictive biomarkers of response to therapy. RECENT FINDINGS: Landmark trials have been noted involving this pathway, particularly in endometrial cancers. One phase II trial of the potent orally bioavailable mTOR inhibitor, everolimus, in combination with letrozole demonstrated an unprecedented clinical benefit rate (CBR) of 40% and high objective response rate (RR) of 32% in hormone agnostic endometrial cancers. This was followed by GOG 3007 that compared everolimus and letrozole to hormonal therapy yielding similar response rates but double progression-free survival rates. The phosphoinositide 3-kinase (PI3K) signaling pathway is implicated in tumorigenesis given its regulation over cell growth, cellular trafficking, and angiogenesis. In gynecologic malignancies, alterations in PI3K signaling are common. Therefore, developing modulators of the PI3K pathway and identifying molecular markers to predict response are of great interest for these cancer types.

Physical Activity Decreases Inflammation and Delays Development of Obesity-Associated Pancreatic Ductal Adenocarcinoma.

Obesity is a risk factor for pancreatic ductal adenocarcinoma (PDAC), a deadly disease with limited preventive strategies. Lifestyle interventions to decrease obesity represent a potential approach to prevent obesity-associated PDAC. Here, we examined whether decreasing obesity through physical activity (PA) and/or dietary changes could decrease inflammation in humans and prevent obesity-associated PDAC in mice. Comparison of circulating inflammatory-associated cytokines in subjects (overweight and obese) before and after a PA intervention revealed PA lowered systemic inflammatory cytokines. Mice with pancreatic-specific inducible KrasG12D expression were exposed to PA and/or dietary interventions during and after obesity-associated cancer initiation. In mice with concurrent diet-induced obesity (DIO) and KrasG12D expression, the PA intervention led to lower weight gain, suppressed systemic inflammation, delayed tumor progression, and decreased pro-inflammatory signals in the adipose tissue. However, these benefits were not as evident when obesity preceded pancreatic KrasG12D expression. Combining PA with diet-induced weight loss (DI-WL) delayed obesity-associated PDAC progression in the genetically engineered mouse model, but neither PA alone nor combined with DI-WL or chemotherapy prevented PDAC tumor growth in orthotopic PDAC models regardless of obesity status. PA led to upregulation of IL-15ra in adipose tissue. Adipose-specific overexpression of IL-15 slowed PDAC growth but only in non-obese mice. Overall, our study suggests that PA alone or combined with DI-WL can reduce inflammation and delay obesity-associated PDAC development or progression. Lifestyle interventions that prevent or manage obesity or therapies that target weight loss-related molecular pathways could prevent progression of PDAC.

Exceptional Response to Pembrolizumab for Treatment of Metastatic Chemorefractory Endometrial Carcinoma in a Patient with Lynch Syndrome: A Case Report.

Advanced endometrial cancer is associated with poor outcomes and few treatment options exist. Recently, the US Federal Drug Administration approved pembrolizumab for the treatment of endometrial cancers that are deficient in mismatch repair and have high microsatellite instability (MSI). Lynch syndrome is an autosomal dominant disease that causes MSI-high endometrial cancer. We report a case of a 46-year-old woman with Lynch syndrome and advanced endometrial cancer who experienced progressive disease after treatment with chemotherapy with carboplatin and paclitaxel. She was then treated with single-agent pembrolizumab and had an exceptional response. She was noted to have a significant decrease in the size of a large uterine mass extending into the vagina and vulva, as well as decrease in the size of lymphadenopathy. Data are limited at this time for patients with Lynch syndrome treated with single-agent pembrolizumab. Our case report seeks to add to the body of literature that suggests that this patient population may particularly benefit from this novel therapy.

Physical Activity Delays Obesity-Associated Pancreatic Ductal Adenocarcinoma in Mice and Decreases Inflammation.

BACKGROUND & AIMS: Obesity is a risk factor for pancreatic ductal adenocarcinoma (PDAC), a deadly disease with limited preventive strategies. Lifestyle interventions to decrease obesity might prevent obesity-associated PDAC. Here, we examined whether decreasing obesity by increased physical activity (PA) and/or dietary changes would decrease inflammation in humans and prevent PDAC in mice. METHODS: Circulating inflammatory-associated cytokines of overweight and obese subjects before and after a PA intervention were compared. PDAC pre-clinical models were exposed to PA and/or dietary interventions after obesity-associated cancer initiation. Body composition, tumor progression, growth, fibrosis, inflammation, and transcriptomic changes in the adipose tissue were evaluated. RESULTS: PA decreased the levels of systemic inflammatory cytokines in overweight and obese subjects. PDAC mice on a diet-induced obesity (DIO) and PA intervention, had delayed weight gain, decreased systemic inflammation, lower grade pancreatic intraepithelial neoplasia lesions, reduced PDAC incidence, and increased anti-inflammatory signals in the adipose tissue compared to controls. PA had additional cancer prevention benefits when combined with a non-obesogenic diet after DIO. However, weight loss through PA alone or combined with a dietary intervention did not prevent tumor growth in an orthotopic PDAC model. Adipose-specific targeting of interleukin (IL)-15, an anti-inflammatory cytokine induced by PA in the adipose tissue, slowed PDAC growth. CONCLUSIONS: PA alone or combined with diet-induced weight loss delayed the progression of PDAC and reduced systemic and adipose inflammatory signals. Therefore, obesity management via dietary interventions and/or PA, or modulating weight loss related pathways could prevent obesity-associated PDAC in high-risk obese individuals.