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Check point inhibitors, such as anti- programmed death 1 (PD-1) (Nivolumab, Pembrolizumab)/ anti-programmed death-ligand 1 (PD-L1) therapies (Atezolizumab, Avelumab and Durvalumab) have dramatically changed the therapeutic and prognostic landscape for several types of malignancy. These agents provide significant survival benefits in many cancers, but the efficacy of these treatments varies considerably across different cancer types. Therefore, identifying the underlying variables associated with this cancer type–specific response was an important challenge.

To address this, Lee JS et al [1] demonstrated that among the 36 variables, estimated CD8+ T-cell abundance was the most predictive of the response to anti–PD-1/PD-L1 therapy across cancer types (R = 0.72), followed by the tumor mutational burden (R = 0.68), and the fraction of samples with high PD1 gene expression (R = 0.68). Importantly, combination of these 3 variables highly correlated with response (R = 0.90), explaining more than 80% of the ORR variance observed across different tumor types.

This is an important finding which can be used to predict likelihood of response to anti-PD-1 or anti-PD-L1 therapy; and to identify the subset of patients most likely to derive clinical benefit to get cost-effective solution.

Reference: 1. Lee JS, Ruppin E. Multiomics Prediction of Response Rates to Therapies to Inhibit Programmed Cell Death 1 and Programmed Cell Death 1 Ligand 1. JAMA Oncol.2019 Aug 22.

Accelerated approval to Polivy (Polatuzumab vedotin), in combination with the chemotherapy bendamustine and rituximab (P-BR) by the U.S. FDA for the treatment of patients with relapsed or refractory diffuse large B cell lymphoma (DLBCL), indicates the unmet need and necessity of newer therapies for the treatment of this aggressive disease despite the availability of CAR-T cell therapies.

Approval of Polivy was based on complete response (CR) rate and duration of response (DOR) in a open-label clinical trial (Study GO29365). The study randomized 80 patients with relapsed or refractory DLBCL after at least one prior therapy to either P+ BR (N = 40) or BR alone (N = 40) for six cycles. At the end of treatment, the CR rate was 40% with P-BR compared to 18% with BR alone. Of the 25 patients who achieved a partial or complete response to P-BR, 16 (64%) had a DOR of at least six months and 12 (48%) had a DOR of at least 12 months.

Reviewer acknowledged that the magnitude of the treatment effect with the addition of Polatuzumab is uncertain because of the small sample size. However, the observed differences between arms in depth of response at end of therapy, ORR, and DoR were clinically meaningful. These response data provided substantial evidence of effectiveness and were the basis for the recommended accelerated approval, though the PFS and OS data were not sufficiently robust to support a regular approval. At the same time, the recommended indication has been restricted to patients with relapsed or refractory DLBCL after at least two prior therapies due to the paucity of data in patients with one prior therapy. Thus, Polivy became the first chemoimmunotherapy regimen approved by the US FDA for patients with relapsed or refractory DLBCL.

– Dr Mohini Barde, MD

Medical Director at Med Indite Communications

https://www.linkedin.com/pulse/accelerated-approval-polivy-dr-mohini-barde-md/?trackingId=NRv6f8QZKnuSHeb1kWQ5Yg%3D%3D

Recommendations of an Oncology Drugs Advisory Committee (ODAC) against approval of Quizartinib further opened debate on effective end point for registration studies of acute myeloid leukemia (AML). Though, the Study AC220-007 showed encouraging results a statistically significant improvement in overall survival (OS) with Quizartinib as compared to Standard-of-Care (SOC) Chemotherapy (hazard ratio (HR)-0.77), the analysis of event-free survival (EFS), did not show improvement (HR- 0.9). This raised doubts regarding the credibility of the OS results, in the backdrop of some of other issues identified by the US FDA reviewer.

In general, OS is the most commonly used end point for approval of new therapies. However, it may not be a perfect indicator of a new drug’s efficacy as advances in rescue therapies have made it possible to keep patients alive after AML has relapsed or failed to show complete response. Interestingly, FDA too has similar opinion. The Oncologic Drugs Advisory Committee in their meeting on July, 2017, stated that emergence of multiple new effective drugs for AML that may be used as post-study treatments may confound the OS results and hence, OS may no longer be an accurate reflection of the treatment effect in clinical trials. The committee advocated the use of EFS, which relies on events that would occur prior to use of post-study treatments and thus may better reflect a single treatment efficacy.

The Study AC220-007 (QuANTUM-R) was designed as a randomized, open-label, active-control study to compare Quizartinib with SOC chemotherapy in 367 patients with relapsed/refractory AML with FLT3-ITD+ mutation. The chemotherapy to be used for an individual patient was declared prior to randomization, so that patients could be stratified by intensity (intensive chemotherapy or low-intensity chemotherapy), thus effectively it resulted into four subgroups (a. Intensive chemotherapy declared patients who received Quizartinib; b. Intensive chemotherapy declared patients who received intensive chemotherapy; c. Low-intensity chemotherapy declared patients who received Quizartinib; d. Low-intensity chemotherapy declared patients who received low-intensity chemotherapy). The primary endpoint of the study was OS. Post discontinuation of study treatment, the patients could proceed for one or other post-study therapies (e.g. Allogeneic transplantation, intensive chemotherapy, or other FLT3 inhibitors).

A single agent FLT3 therapies are reported to support successful bridging to transplantation in patients with relapsed FLT3+AML. During Quizartinib application review, the FDA observed confounding of OS response by the post-study therapies which patients received after discontinuation from the study. A total of 41 % patients received a post-study therapies; 38% patients on the Quizartinib arm and 48% patients on the chemotherapy arm. Allogeneic transplantation was mainly used for 35% patients on Quizartinib arm and 17% patients on the chemotherapy arm (but only to intensive chemotherapy subgroup). No patients that received low-intensity chemotherapy proceeded to transplantation. Thus, it is clear that, allogeneic transplantation which is done for curative intent might have influence the OS response in this case.

Although FDA reviewer admitted that the use of post-study therapies is consistent with the Intention to Treat analysis (ITT) principle, an imbalance in use of post-study therapies (e.g. transplantation in 35% in Quizartinib arm and 17% in chemotherapy arm) raises questions about its contribution to the observed OS treatment effect.

FDA also observed that the significance level of the OS results for the ITT population appear to be driven by the large effect in low-intensity chemotherapy subgroup (HR: 0.59) and therefore there is uncertainty on the generalization of the study results. In addition, the results for the secondary and additional efficacy endpoints do not provide substantial supportive evidence of effectiveness as there was only 4% CR rate, 11% CR/CRh rate, and 27% achievement of transfusion independence.

Imbalances in the rates of patients who were early-censored for OS and in the number of patients randomized but not treated (RNT) suggest that the statistical OS advantage of Quizartinib over chemotherapy observed in the primary OS analysis, is not robust in the presence of differential early-censoring and randomized-not-treated.

To defend the findings, the applicant presented a sensitivity analysis whereby patients who underwent subsequent allogeneic transplantation were censored at the time of transplantation, the results of which were similar to those from the primary analyses. However, FDA reviewer noted that this approach does not address the uncertainty of attributing the treatment effect to Quizartinib compared to the subsequent transplantation due to the differential censoring between the arms, as well as differential application of other therapies between the arms.

To summarize, the FDA flagged significant concerns regarding the credibility of the OS results and with the negative recommendations from the FDA advisory committee, it is unlikely that the FDA will approve the Quizartinib despite having encouraging survival benefit with Quizartinib.

https://www.linkedin.com/pulse/end-point-dilemma-quizartinib-aml-trial-dr-mohini-barde-md/?trackingId=lOUsNJnPBm4JidCAxEG6tQ%3D%3D

Eboigbodin K.E. et al., Diagnostic Microbiology and Infectious Disease, 2016

Recent worldwide large outbursts of the ZIKV necessitate the availability of a rapid, cost-effective and quick diagnostic method for ZIKV detection. Conventional diagnostic methods rely upon serological methods or nucleic acid amplification tests (NAATs), both of which are time consuming. The authors present an improved alternative to NAATs; the reverse transcriptase strand invasion based amplification (RT-SIBA), which has been used previously for rapid detection of DNA and RNA. RT-SIBA is essentially parallel to the PCR reaction. The investigators compared the method with conventional ones to assess the applicability, functionality (on the basis of reaction completion time and sample purity), specificity (with respect to sample source), performance (with respect to viral load) and reproducibility (in-field; on different types of in-house instruments). They established that this method was specific for the ZIKV, showed a lesser reaction completion time, independent of the degree of purity of the sample and showed comparable results when performed using in-house instruments. This method may be a powerful molecular diagnostic tool for ZIKV detection and finds an application during outbreaks, thus allowing treatment management and preventing the spread of the virus, especially in low-resource areas. Nevertheless, the assay still needs to be fully validated for direct detection of clinical specimens infected with the ZIKV.

http://www.dmidjournal.com/article/S0732-8893(16)30267-X/pdf

Salje H. et al., PNAS, 2016

Contraction of the disease during an infectious disease epidemic is dependent on interrelated factors, that may be directly related to the individual (age, sex), his family or the wider community of which he is a part. Advances in statistical modelling have aided studies to monitor compact communities like households or schools that help in the elucidation of the determinants of transmission in such small social structures, but have failed to include the wider context of the episode. Salje et al attempted to obtain a more comprehensive view of the risk factors associated with the contraction and spread of disease, using the case of chikungunya outbreak in a rural community in Bangladesh. Through statistical modelling, they found out that females were 1.5 times more likely to become infected by the virus, when compared to their male counterparts and attributed this to the mosquitoes being ‘lazy’ and the resultant subsequent transmission to females as they rarely moved from their households. The mosquitoes’ lazy nature allows them to get infected from an individual from a particular household, undergo the incubation period by staying in the same household and then infecting a person from the same house. The scientists also observed that the use of mosquito repellents had no impact on transmission. The result of the study showed that the complex interplay between the characteristics of an individual and his close and wider environment contributes to the shaping of infectious disease epidemics and it also offer key insights into how health officials can combat other diseases that spread the same way.

 

https://www.ncbi.nlm.nih.gov/pubmed/27821727

Lebel C. et al., Biological Psychiatry, 2016

 

It is well- known that perinatal maternal depression is a serious health concern, with its negative effects lasting on children. Prenatal depression is associated with altered brain gray matter in children, though the relation between postpartum depression, children’s brains and role of white matter are unclear. The study by Lebel et al, is first to report associations between maternal depression and altered brain structure in children. They observed 52 women during each trimester of pregnancy and at 3 months postpartum. Their depression was monitored both pre-and postpartum using the Edinburgh Postnatal Depression Scale (EPDS); and their children underwent MRI at the age of 2.6 years to 5.1 years. Associations between maternal depressive symptoms and MRI measures of cortical thickness and white matter structure in the children were investigated. They observed that higher maternal depressive symptoms prenatally and postpartum are associated with altered gray matter structure, with the white matter being correlated to the postpartum period. The reduced cortical thickness and diffusivity were suggestive of premature brain development in children who were exposed to higher maternal perinatal depressive symptoms. Results highlight the importance of ensuring optimal women’s mental health throughout the perinatal period, as maternal depressive symptoms appear to increase children’s vulnerability to nonoptimal brain development which predisposes them to depression and anxiety in their later age.

 

https://www.ncbi.nlm.nih.gov/pubmed/26822800

Marso S.P. et al., NEJM 2016

 

In order to fulfil regulatory requirement of establishing cardiovascular safety of new diabetes therapies in patients with type 2 diabetes a non inferiority trial as compared to placebo was planned for semaglutide (a glucagon-like peptide 1 analogue with an extended half-life of approximately 1 week) to evaluate its cardiovascular and other long term effects. 3297 patients with type 2 diabetes who were on a standard-care regimen were randomized to receive once-weekly semaglutide (0.5 mg or 1.0 mg) or placebo for 104 weeks. All participants had either established cardiovascular disease or additional cardiovascular risk factors.

The primary composite outcome was the first occurrence of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke. The primary outcome occurred in 108 of 1648 patients (6.6%) in the semaglutide group and in 146 of 1649 patients (8.9%) in the placebo group (hazard ratio, 0.74; 95% confidence interval [CI], 0.58 to 0.95; P<0.001). Nonfatal myocardial infarction occurred in 2.9% of the patients receiving semaglutide and in 3.9% of those receiving placebo (hazard ratio, 0.74; 95% CI, 0.51 to 1.08; P=0.12); nonfatal stroke occurred in 1.6% and 2.7%, respectively (hazard ratio, 0.61; 95% CI, 0.38 to 0.99; P=0.04). The mean glycated hemoglobin reduced to -1.1% and -1.4% for patients receiving 0.5 mg and1.0mg of semaglutide respectively, compared with 0.4% in the placebo group. Mean weight loss in the semaglutide group was 3.6 kg and 4.9 kg, respectively, compared with about 0.5 kg in the placebo group. Mortality rates from cardiovascular causes were similar in the two groups. New or worsening nephropathy was less common and diabetic retinopathy complications and gastrointestinal disorders were more common in the semaglutide group than in the placebo group. The trial achieved its primary end- point of showing noninferiority in safety of semaglutide compared with placebo in patients with type 2 diabetes at high cardiovascular risk. (Funded by Novo Nordisk; SUSTAIN-6 ClinicalTrials.gov number, NCT01720446.)

 

 

Zhang P. et al., 2017, The Lancet

 

Utidelone, a genetically engineered epothilone analogue, has emerged as a potential treatment for breast cancer in phase 1 and 2 trials. This phase III multicentre, open- label, randomized controlled trial was planned to compare the efficacy and safety of utidelone-capecitabine combination versus capecitabine alone in 270 patients with metastatic breast cancer. Patients were randomly assigned (2:1) to a 21-day cycle of either utidelone (30 mg/m2 IV once per day on days 1–5) plus capecitabine (1000 mg/m2 orally twice per day on days 1–14), or capecitabine alone (1250 mg/m2 orally twice per day on days 1–14), until disease progression or unacceptable toxicity occurred. PFS (progression free survival) was assessed as the primary end- point. Median PFS in the combination group was 8·44 months (95% CI 7·95–9·92) compared with 4·27 months (3·22–5·68) in the capecitabine alone group. Peripheral neuropathy and Palmar-plantar erythrodysaesthesia were the most prominent grade 3 adverse event in the combination and monotherapy group respectively. 155 patients died (99 in combination therapy, 56 in monotherapy). All deaths, except one in each group were due to disease progression. This study has demonstrated that the combination was more efficacious compared to capecitabine alone, with mild toxicity and a longer PFS; thus making it an effective option for patients with metastatic breast cancer.

 

http://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(17)30088-8/abstract

Pradeep A. R. et al, November 2016, Journal of Periodontology

 

Gingivitis, the early stage of periodontal disease, is an infection of the tissues that surround your teeth, and is caused by a buildup of plaque.Anantiplaqueagent with minimal side effects that can be used as an effective adjunct to mechanical plaque control is needed. Recently a randomized control trial was planned to evaluate the efficacy of triphala (TRP) mouthwash in reduction of plaque and gingivitis.  Ninety individuals with chronic generalized gingivitis were randomly assigned to three groups: placebo mouthwash; TRP mouthwash; chlorhexidine (CHX) mouthwash and were instructed to rinse with their respective mouthwash twice daily. 1) Plaque index (PI); 2) gingival index (GI); 3) oral hygiene index-simplified (OHI-S); and 4) microbiologic colony counts were recorded at different time intervals. A significant difference was noticed in all four parameters in group I compared with groups II and III. However, there were no significant differences found between groups II and III for any parameters at any time intervals. From these results it was concluded that TRP mouthwash was comparable with that of CHX mouthwash for improvement in gingivitis and therefore it can be considered a potential therapeutic agent in the treatment of gingivitis.

 

http://www.joponline.org/doi/10.1902/jop.2016.130406

Pradeep A. R. et al, November 2016, Journal of Periodontology

 

Since the discovery of antibiotics in the 1940s, research in this domain has been continuous, giving the world of an array of antibiotics. However, development of resistance to these antibiotics is a challenge that the researchers face on a daily basis. In a major breakthrough, scientists have discovered a fresh antibiotic, Teixobactin, produced by a screen of unculturable bacteria. Using a multichannel device, iChip, scientists cultured the unculturable bacteria in soil, screened the extracts obtained and identified Teixobactin. Further investigations into the activity spectrum and mechanism of action revealed that the antibiotic exhibited excellent activity against Gram- positive pathogens, including the drug- resistant strains; that expanded to difficult-to-treat enterococci, M. tuberculosis, C. difficle, B. anthracis and the very infamous, S. aureus MRSA. It inhibited cell wall synthesis, without affecting the DNA/ RNA and protein functions. To examine the development of resistance, Teixobactin was tested in a low dose against S. aureus and M. tuberculosis. Mutant strains did not develop, thus proposing a possible solution to antibiotic- resistance among pathogens. In vitro studies on cell lines showed no signs of apparent toxicity and in vivo efficacy studies in mouse models displayed superior efficacy. After decades of research channelled towards discovering antibiotics that do not allow for resistance development, discovery of Teixobactin has definitely given the research community hope to ‘unearth’ similar compounds.

 

http://www.nature.com/nature/journal/v517/n7535/full/nature14098.html

https://veedacr.com/2016-year-in-review/