Limited clinical activity of palbociclib and ribociclib monotherapy in advanced cancers with cyclin D-CDK4/6 pathway alterations in the Dutch DRUP and Australian MoST trials

The Dutch Drug Rediscovery Protocol (DRUP) and the Australian Cancer Molecular Screening and Therapeutic (MoST) Program are similar nonrandomized, multidrug, pan-cancer trial platforms that aim to identify signals of clinical activity of molecularly matched targeted therapies or immunotherapies outside their approved indications. Here, we report results for advanced or metastatic cancer patients with tumors harboring cyclin D-CDK4/6 pathway alterations treated with CDK4/6 inhibitors palbociclib or ribociclib. We included adult patients that had therapy-refractory solid malignancies with the following alterations: amplifications of CDK4, CDK6, CCND1, CCND2 or CCND3, or complete loss of CDKN2A or SMARCA4. Within MoST, all patients were treated with palbociclib, whereas in DRUP, palbociclib and ribociclib were assigned to different cohorts (defined by tumor type and alteration). The primary endpoint for this combined analysis was clinical benefit, defined as confirmed objective response or stable disease ≥16 weeks. We treated 139 patients with a broad variety of tumor types; 116 with palbociclib and 23 with ribociclib. In 112 evaluable patients, the objective response rate was 0% and clinical benefit rate at 16 weeks was 15%. Median progression-free survival was 4 months (95% CI: 3-5 months), and median overall survival 5 months (95% CI: 4-6 months). In conclusion, only limited clinical activity of palbociclib and ribociclib monotherapy in patients with pretreated cancers harboring cyclin D-CDK4/6 pathway alterations was observed. Our findings indicate that monotherapy use of palbociclib or ribociclib is not recommended and that merging data of two similar precision oncology trials is feasible.     

Real-world effectiveness of HPV vaccination against cervical neoplasia among birth cohorts ineligible for routine vaccination

Human papillomavirus (HPV) vaccine effectiveness may differ between settings. Here we present the first real-world effectiveness study of HPV vaccination on high-grade cervical lesions from Norway, among women who received HPV vaccine outside the routine program. We performed an observational study of all Norwegian women born 1975 to 1996 and retrieved individual data from nationwide registries on HPV vaccination status and incidence of histologically verified high-grade cervical neoplasia during 2006 to 2016. We estimated the incidence rate ratio (IRR) and 95% confidence intervals (CI) for vaccination vs no vaccination by Poisson regression stratified by age at vaccination <20 years and ≥20 years. The cohort consisted of 832 732 women, of which 46 381 (5.6%) received at least one dose of HPV vaccine by the end of 2016. The incidence rate of cervical intraepithelial neoplasia grade 2 or worse (CIN2+) increased with age regardless of vaccination status and was highest at age 25 to 29, at 637/100 000 among unvaccinated women, 487/100 000 among women vaccinated before age 20 and 831/100 000 among women vaccinated at age 20 or older. The adjusted IRR of CIN2+ between vaccinated and unvaccinated women was 0.62 (95% CI: 0.46-0.84) for women vaccinated below age 20, and 1.22 (95% CI: 1.03-1.43) for women vaccinated at age 20 or older. These findings indicate that HPV vaccination among women too old to be eligible for routine HPV vaccination is effective among women who are vaccinated below age 20 but may not have the desired impact among women who are vaccinated at age 20 or older.     

Parental age and birth defects: a sibling study

European Journal of Epidemiology - Higher parental age at childbearing has generated much attention as a potential risk factor for birth disorders; however, previous research findings are mixed....     

Neoadjuvant Therapy for Locally Advanced Rectal Cancer: Recent Advances and Ongoing Challenges

Locally advanced rectal cancer has a rising global incidence. Over the last 4 decades, advances first in surgery and later in radiotherapy and chemoradiotherapy have improved outcomes, particularly with regard to local recurrence. Unfortunately, distant metastases remain a significant problem. In clinical trials of patients with stage II and III disease, distant relapse occurs in 25% to 30% of patients regardless of the treatment approach. Recent phase 3 trials have therefore focused on intensification of systemic therapy for localized disease, with an aim of reducing the distant relapse rate. Early results of trials of total neoadjuvant therapy with combination systemic therapy provided in the neoadjuvant setting are promising; for the first time, a significant improvement in the rate of distant relapse has been noted. Longer-term follow-up is eagerly awaited. On the other hand, trimodal therapy with chemotherapy, radiotherapy, and surgery is toxic. Several trials are currently assessing the feasibility of a watch-and-wait approach, omitting surgery in those with complete response to neoadjuvant treatment, in an attempt to reduce the burden of treatment on patients. The future for rectal cancer patients is likely to be highly personalized, with more intense approaches for high-risk patients and omission of unnecessary therapy for those whose disease responds well to initial treatment. Biomarkers such as circulating tumor DNA will help to more accurately stratify patients into risk groups. Improvements in survival and quality of life are expected as the results of ongoing research become available throughout the next decade.     

COVID-19 and mental health: a longitudinal population study from Norway

European Journal of Epidemiology - Existing research has found adverse short-term effects of the COVID-19 pandemic on mental health, but longer-term effects have been less documented. Using newly...