Oncology News / Literature Review / 2018

Press release in Oncology: A.Tzovaras ,Medical Oncologist, phD.     1) Nivolumab plus Ipilimumab versus Sunitinib in Advanced Renal-Cell Carcinoma Nivolumab plus ipilimumab produced objective responses in patients with advanced renal-cell carcinoma in a pilot study. This phase 3 trial compared nivolumab plus ipilimumab with sunitinib for previously untreated clear-cell advanced renal-cell carcinoma We randomly assigned adults in a 1:1 ratio to receive either nivolumab (3 mg per kilogram of body weight) plus ipilimumab (1 mg per kilogram) intravenously every 3 weeks for four doses, followed by nivolumab (3 mg per kilogram) every 2 weeks, or sunitinib (50 mg) orally once daily for 4 weeks (6-week cycle). The coprimary end points were overall survival (alpha level, 0.04), objective response rate (alpha level, 0.001), and progression-free survival (alpha level, 0.009) among patients with intermediate or poor prognostic risk A total of 1096 patients were assigned to receive nivolumab plus ipilimumab (550 patients) or sunitinib (546 patients); 425 and 422, respectively, had intermediate or poor risk. At a median follow-up of 25.2 months in intermediate- and poor-risk patients, the 18-month overall survival rate was 75% (95% confidence interval [CI], 70 to 78) with nivolumab plus ipilimumab and 60% (95% CI, 55 to 65) with sunitinib; the median overall survival was not reached with nivolumab plus ipilimumab versus 26.0 months with sunitinib (hazard ratio for death, 0.63; P<0.001). The objective response rate was 42% versus 27% (P<0.001), and the complete response rate was 9% versus 1%. The median progression-free survival was 11.6 months and 8.4 months, respectively (hazard ratio for disease progression or death, 0.82; P=0.03, not significant per the prespecified 0.009 threshold). Treatment-related adverse events occurred in 509 of 547 patients (93%) in the nivolumab-plus-ipilimumab group and 521 of 535 patients (97%) in the sunitinib group; grade 3 or 4 events occurred in 250 patients (46%) and 335 patients (63%), respectively. Treatment-related adverse events leading to discontinuation occurred in 22% and 12% of the patients in the respective groups. The recommended schedule and dose for this combination is nivolumab, 3 mg/kg, followed by ipilimumab, 1 mg/kg, on the same day every 3 weeks for 4 doses, then nivolumab, 240 mg, every 2 weeks or 480 mg every 4 weeks. Overall survival and objective response rates were significantly higher with nivolumab plus ipilimumab than with sunitinib among intermediate- and poor-risk patients with previously untreated advanced renal-cell carcinoma. On 16 April 2018, the US Food and Drug Administration (FDA) granted approvals to nivolumab and ipilimumab (Opdivo and Yervoy, Bristol-Myers Squibb Co.) in combination for the treatment of intermediate or poor risk, previously untreated advanced renal cell carcinoma (RCC). 2)Cabozantinib versus sunitinib as initial therapy for metastatic renal cell carcinoma of intermediate or poor risk (Alliance A031203 CABOSUN randomised trial): Progression-free survival by independent review and overall survival update. The randomised phase 2 CABOSUN trial comparing cabozantinib with sunitinib as initial therapy for advanced renal cell carcinoma (RCC) of intermediate or poor risk met the primary end-point of improving progression-free survival (PFS) as assessed by investigator. Previously untreated patients with advanced RCC of intermediate or poor risk by IMDC criteria were randomised 1:1 to cabozantinib 60 mg daily or sunitinib 50 mg daily (4 weeks on/2 weeks off). A total of 157 patients were randomised 1:1 to cabozantinib (n = 79) or sunitinib (n = 78). Median PFS per IRC was 8.6 months (95% confidence interval [CI] 6.8-14.0) versus 5.3 months (95% CI 3.0-8.2) for cabozantinib versus sunitinib (hazard ratio [HR] 0.48 [95% CI 0.31-0.74]; two-sided p = 0.0008), and ORR per IRC was 20% (95% CI 12.0-30.8) versus 9% (95% CI 3.7-17.6), respectively. Subgroup analyses of PFS by stratification factors and MET tumour expression were consistent with results for the overall population. With a median follow-up of 34.5 months, median OS was 26.6 months (95% CI 14.6-not estimable) with cabozantinib and 21.2 months (95% CI 16.3-27.4) with sunitinib (HR 0.80 [95% CI 0.53-1.21]. The incidence of grade 3 or 4 adverse events was 68% for cabozantinib and 65% for sunitinib. In this phase 2 trial, cabozantinib treatment significantly prolonged PFS per IRC compared with sunitinib as initial systemic therapy for advanced RCC of poor or intermediate risk. 3) Survival with Durvalumab after Chemoradiotherapy in Stage III NSCLC. An earlier analysis in this phase 3 trial showed that durvalumab significantly prolonged progression-free survival, as compared with placebo, among patients with stage III, unresectable non-small-cell lung cancer (NSCLC) who did not have disease progression after concurrent chemoradiotherapy. Here we report the results for the second primary end point of overall survival. We randomly assigned patients, in a 2:1 ratio, to receive durvalumab intravenously, at a dose of 10 mg per kilogram of body weight, or matching placebo every 2 weeks for up to 12 months. Randomization occurred 1 to 42 days after the patients had received chemoradiotherapy and was stratified according to age, sex, and smoking history. The primary end points were progression-free survival (as assessed by blinded independent central review) and overall survival. Secondary end points included the time to death or distant metastasis, the time to second progression, and safety. Of the 713 patients who underwent randomization, 709 received the assigned intervention (473 patients received durvalumab and 236 received placebo). As of March 22, 2018, the median follow-up was 25.2 months. The 24-month overall survival rate was 66.3% (95% confidence interval [CI], 61.7 to 70.4) in the durvalumab group, as compared with 55.6% (95% CI, 48.9 to 61.8) in the placebo group (two-sided P=0.005). Durvalumab significantly prolonged overall survival, as compared with placebo (stratified hazard ratio for death, 0.68; 99.73% CI, 0.47 to 0.997; P=0.0025). Updated analyses regarding progression-free survival were similar to those previously reported, with a median duration of 17.2 months in the durvalumab group and 5.6 months in the placebo group (stratified hazard ratio for disease progression or death, 0.51; 95% CI, 0.41 to 0.63). The median time to death or distant metastasis was 28.3 months in the durvalumab group and 16.2 months in the placebo group (stratified hazard ratio, 0.53; 95% CI, 0.41 to 0.68). A total of 30.5% of the patients in the durvalumab group and 26.1% of those in the placebo group had grade 3 or 4 adverse events of any cause; 15.4% and 9.8% of the patients, respectively, discontinued the trial regimen because of adverse events. Durvalumab therapy resulted in significantly longer overall survival than placebo. No new safety signals were identified.   4)Cancer Risks for PMS2-Associated Lynch Syndrome. Lynch syndrome due to pathogenic variants in the DNA mismatch repair genes MLH1, MSH2, and MSH6 is predominantly associated with colorectal and endometrial cancer, although extracolonic cancers have been described within the Lynch tumor spectrum. However, the age-specific cumulative risk (penetrance) of these cancers is still poorly defined for PMS2-associated Lynch syndrome. Using a large data set from a worldwide collaboration, our aim was to determine accurate penetrance measures of cancers for carriers of heterozygous pathogenic PMS2 variants. In total, 284 families consisting of 4,878 first- and second-degree family members were included in the analysis. PMS2 mutation carriers were at increased risk for colorectal cancer (cumulative risk to age 80 years of 13% [95% CI, 7.9% to 22%] for males and 12% [95% CI, 6.7% to 21%] for females) and endometrial cancer (13% [95% CI, 7.0%-24%]), compared with the general population (6.6%, 4.7%, and 2.4%, respectively). There was no clear evidence of an increased risk of ovarian, gastric, hepatobiliary, bladder, renal, brain, breast, prostate, or small bowel cancer. Heterozygous PMS2 mutation carriers were at small increased risk for colorectal and endometrial cancer but not for any other Lynch syndrome-associated cancer. This finding justifies that PMS2-specific screening protocols could be restricted to colonoscopies. The role of risk-reducing hysterectomy and bilateral salpingo-oophorectomy for PMS2 mutation carriers needs further discussion. 5)First-Line Atezolizumab plus Chemotherapy in Extensive-Stage Small-Cell Lung Cancer. Enhancing tumor-specific T-cell immunity by inhibiting programmed death ligand 1 (PD-L1)-programmed death 1 (PD-1) signaling has shown promise in the treatment of extensive-stage small-cell lung cancer. Combining checkpoint inhibition with cytotoxic chemotherapy may have a synergistic effect and improve efficacy. We conducted this double-blind, placebo-controlled, phase 3 trial to evaluate atezolizumab plus carboplatin and etoposide in patients with extensive-stage small-cell lung cancer who had not previously received treatment. Patients were randomly assigned in a 1:1 ratio to receive carboplatin and etoposide with either atezolizumab or placebo for four 21-day cycles (induction phase), followed by a maintenance phase during which they received either atezolizumab or placebo.The two primary end points were investigator-assessed progression-free survival and overall survival in the intention-to-treat population. A total of 201 patients randomly assigned to the atezolizumab group, and 202 patients to the placebo group. were At ea mdian follow-up of 13.9 months, the median overall survival was 12.3 months in the atezolizumab group and 10.3 months in the placebo group (hazard ratio for death, 0.70; 95% confidence interval [CI], 0.54 to 0.91; P=0.007). The median progression-free survival was 5.2 months and 4.3 months, respectively (hazard ratio for disease progression or death, 0.77; 95% CI, 0.62 to 0.96; P=0.02). The safety profile of atezolizumab plus carboplatin and etoposide was consistent with the previously reported safety profile of the individual agents, with no new findings observed. The addition of atezolizumab to chemotherapy in the first-line treatment of extensive-stage small-cell lung cancer resulted in significantly longer overall survival and progression-free survival than chemotherapy alone. 6) Osimertinib versus standard-of-care EGFR-TKI as first-line treatment in patients with EGFRm advanced NSCLC: FLAURA Asian subset. FLAURA a multicentre, international, randomised, double-blind, active-controlled trial conducted in 556 patients with EGFR exon 19 deletion or exon 21 L858R mutation-positive, unresectable or metastatic NSCLC who had not received previous systemic treatment for advanced disease. Patients were randomised (1:1) to receive osimertinib 80 mg orally once daily or standard-of-care (SoC) treatment of gefitinib 250 mg or erlotinib 150 mg orally once daily. Of those randomised to SoC, 20% received osimertinib as the next line of antineoplastic therapy. The estimated median progression-free survival (PFS) was 18.9 months (95% CI: 15.2, 21.4) in the osimertinib arm and 10.2 months (95% CI: 9.6, 11.1) in the SoC arm (hazard ratio 0.46 (95% CI: 0.37, 0.57), p < 0.0001). The confirmed overall response rate was 77% for the osimertinib arm and 69% for the SoC arm. The estimated median response durations for the osimertinib and SoC arms were 17.6 and 9.6 months, respectively. At the time of the primary PFS analysis, there were too few deaths to estimate or compare overall survival. The most common adverse reactions (occurring in at least 20% of patients treated with osimertinib) were diarrhoea, rash, dry skin, nail toxicity, stomatitis, and decreased appetite. Serious adverse reactions were reported in 4% of patients treated with osimertinib. The most common serious adverse reactions (≥1%) were pneumonia (2.9%), interstitial lung disease/pneumonitis (2.1%), and pulmonary embolism (1.8%).The recommended dose of osimertinib is 80 mg orally once daily, with or without food. On 18 April 2018, the US Food and Drug Administration (FDA) approved osimertinib (Tagrisso, AstraZeneca Pharmaceuticals LP) for the first-line treatment of patients with metastatic non-small cell lung cancer (NSCLC) whose tumours have epidermal growth factor receptor (EGFR) exon 19 deletions or exon 21 L858R mutations, as detected by an FDA-approved test.   7) Dacomitinib versus gefitinib as first-line treatment for patients with EGFR-mutation-positive non-small-cell lung cancer (ARCHER 1050): a randomised, open-label, phase 3 trial. The FDA approved the kinase inhibitor dacomitinib (Vizimpro, Pfizer) for the first-line treatment of patients with metastatic non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) exon 19 deletion or exon 21 L858R substitution mutations as detected by an FDA-approved test. The approval was based on a randomized, multicenter, open-label, active-controlled trial (ARCHER 1050) comparing the safety and efficacy of dacomitinib with gefitinib (Iressa, AstraZeneca) in 452 patients with unresectable, metastatic NSCLC. Patients were required to have no prior therapy for metastatic disease or recurrent disease, with a 12-month minimum of disease-free status after completion of systemic non-EGFR tyrosine kinase inhibitor–containing therapy; an ECOG status of 0 or 1 and EGFR exon 19 deletion or exon 21 L858R substitution mutations.  Patients were randomly assigned (1:1) to receive either 45 mg of dacomitinib orally once daily or 250 mg of gefitinib orally once daily until disease progression or unacceptable toxicity.The researchers were looking for a significant improvement in progression-free survival (PFS), no improvement in overall response rate or overall survival. The median PFS, as determined by an independent review committee, was 14.7 and 9.2 months in the dacomitinib and gefitinib arms, respectively (hazard ratio, 0.59; 95% CI, 0.47-0.74; P<0.0001). Of 394 patients who received dacomitinib, serious adverse reactions occurred in 27%. The most common adverse reactions resulting in discontinuation of dacomitinib were diarrhea and ILD. The most common adverse reactions of dacomitinib were diarrhea, rash, paronychia, stomatitis, decreased appetite, dry skin, decreased weight, alopecia, cough and pruritus. “The findings from ARCHER 1050 suggest that Vizimpro should be considered as a new first-line treatment option for patients with EGFR-mutated non-small cell lung cancer exon 19 deletion or exon 21 L858R substitution mutations.”     &nbsp

Genomic basis of ecological niche divergence among cryptic sister species of non-biting midges

Background: There is a lack of understanding the evolutionary forces driving niche segregation of closely related organisms. In addition, pinpointing the genes driving ecological divergence is a key goal in molecular ecology. Here, larval transcriptome sequences obtained by next-generation-sequencing are used to address these issues in a morphologically cryptic sister species pair of non-biting midges (Chironomus riparius and C. piger). Results: More than eight thousand orthologous open reading frames were screened for interspecific divergence and intraspecific polymorphisms. Despite a small mean sequence divergence of 1.53% between the sister species, 25.1% of 18,115 observed amino acid substitutions were inferred by α statistics to be driven by positive selection. Applying McDonald-Kreitman tests to 715 alignments of gene orthologues identified eleven (1.5%) genes driven by positive selection. Conclusions: Three candidate genes were identified as potentially responsible for the observed niche segregation concerning nitrite concentration, habitat temperature and water conductivity. Additionally, signs of positive selection in the hydrogen sulfide detoxification pathway were detected, providing a new plausible hypothesis for the species’ ecological differentiation. Finally, a divergently selected, nuclear encoded mitochondrial ribosomal protein may contribute to reproductive isolation due to cytonuclear coevolution

Oncology News / Literature Review / July-December 2019

1.                 Overall survival (OS) results of a phase III randomized trial of standard-of-care therapy with or without enzalutamide for metastatic hormone-sensitive prostate cancer (mHSPC): ENZAMET (ANZUP 1304), an ANZUP-led international cooperative group trial. Testosterone suppression (TS) is the backbone of treatment for metastatic hormone-sensitive prostate cancer (mHSPC). Overall survival is improved by the addition of early docetaxel (DOC) or abiraterone to TS. The randomised phase 3 ENZAMET trial assessed the effects of enzalutamide (ENZA), a potent androgen receptor (AR) inhibitor, versus a nonsteroidal anti-androgen (NSAA: bicalutamide, nilutamide, or flutamide) in addition to SOC in mHSPC. Men (1125) with mHSPC were randomly assigned 1:1 to receive TS plus either ENZA (160 mg daily, by mouth, until clinical disease progression or prohibitive toxicity) or NSAA (conventional NSAA, by mouth until clinical disease progression or prohibitive toxicity). All participants were to receive standard background therapy with a LHRHA or surgical castration, as per standard of care. The choice of the LHRHA or surgical castration was at the discretion of the treating clinician. Randomization was stratified by: volume of disease (high vs low, according to CHAARTED); planned early DOC; planned anti-resorptive therapy, comorbidity score (ACE-27), and study site. The primary endpoint was overall survival. Subgroup analyses to assess possible modulation of the treatment effect were specified a priori and included planned early docetaxel (yes vs no) and volume of disease (high vs low). After a median follow-up of 33 months. Overall survival was prolonged by ENZA. At 3 years, 36% NSAA vs 64% ENZA were still on their assigned study treatment. Serious adverse events (regardless of attribution) within 30 days of study treatment occurred in 42% ENZA vs 34% NSAA, commensurate with the different durations of study treatment. ENZA significantly improved OS when added to SOC in mHSPC while the benefits appeared lower in those planned to receive early DOC

NEMESYS: Enhanced Network Security for Seamless Service Provisioning in the Smart Mobile Ecosystem

As a consequence of the growing popularity of smart mobile devices, mobile malware is clearly on the rise, with attackers targeting valuable user information and exploiting vulnerabilities of the mobile ecosystems. With the emergence of large-scale mobile botnets, smartphones can also be used to launch attacks on mobile networks. The NEMESYS project will develop novel security technologies for seamless service provisioning in the smart mobile ecosystem, and improve mobile network security through better understanding of the threat landscape. NEMESYS will gather and analyze information about the nature of cyber-attacks targeting mobile users and the mobile network so that appropriate counter-measures can be taken. We will develop a data collection infrastructure that incorporates virtualized mobile honeypots and a honeyclient, to gather, detect and provide early warning of mobile attacks and better understand the modus operandi of cyber-criminals that target mobile devices. By correlating the extracted information with the known patterns of attacks from wireline networks, we will reveal and identify trends in the way that cyber-criminals launch attacks against mobile devices.Comment: Accepted for publication in Proceedings of the 28th International Symposium on Computer and Information Sciences (ISCIS'13); 9 pages; 1 figur

Two-Dimensional Convolutional Recurrent Neural Networks for Speech Activity Detection

Speech Activity Detection (SAD) plays an important role in mobile communications and automatic speech recognition (ASR). Developing efficient SAD systems for real-world applications is a challenging task due to the presence of noise. We propose a new approach to SAD where we treat it as a two-dimensional multilabel image classification problem. To classify the audio segments, we compute their Short-time Fourier Transform spectrograms and classify them with a Convolutional Recurrent Neural Network (CRNN), traditionally used in image recognition. Our CRNN uses a sigmoid activation function, max-pooling in the frequency domain, and a convolutional operation as a moving average filter to remove misclassified spikes. On the development set of Task 1 of the 2019 Fearless Steps Challenge, our system achieved a decision cost function (DCF) of 2.89%, a 66.4% improvement over the baseline. Moreover, it achieved a DCF score of 3.318% on the evaluation dataset of the challenge, ranking first among all submissions

FMM-X3D: FPGA-based modeling and mapping of X3D for Human Action Recognition

3D Convolutional Neural Networks are gaining increasing attention from researchers and practitioners and have found applications in many domains, such as surveillance systems, autonomous vehicles, human monitoring systems, and video retrieval. However, their widespread adoption is hindered by their high computational and memory requirements, especially when resource-constrained systems are targeted. This paper addresses the problem of mapping X3D, a state-of-the-art model in Human Action Recognition that achieves accuracy of 95.5\% in the UCF101 benchmark, onto any FPGA device. The proposed toolflow generates an optimised stream-based hardware system, taking into account the available resources and off-chip memory characteristics of the FPGA device. The generated designs push further the current performance-accuracy pareto front, and enable for the first time the targeting of such complex model architectures for the Human Action Recognition task.Comment: 8 pages, 6 figures, 2 table