Health-related quality of life in patients with a germline BRCA mutation and metastatic pancreatic cancer receiving maintenance olaparib

Background: Patients with metastatic pancreatic cancer often have a detriment in health-related quality of life (HRQoL). In the randomized, double-blind, phase III POLO trial progression-free survival was significantly longer with maintenance olaparib, a poly(ADP-ribose) polymerase inhibitor, than placebo in patients with a germline BRCA1 and/or BRCA2 mutation (gBRCAm) and metastatic pancreatic cancer whose disease had not progressed during first-line platinum-based chemotherapy. The prespecified HRQoL evaluation is reported here. Patients and methods: Patients were randomized to receive maintenance olaparib (300 mg b.i.d.; tablets) or placebo. HRQoL was assessed using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30-item module at baseline, every 4 weeks until disease progression, at discontinuation, and 30 days after last dose. Scores ranged from 0 to 100; a ≥10-point change or difference between arms was considered clinically meaningful. Adjusted mean change from baseline was analysed using a mixed model for repeated measures. Time to sustained clinically meaningful deterioration (TSCMD) was analysed using a log-rank test. Results: Of 154 randomized patients, 89 of 92 olaparib-arm and 58 of 62 placebo-arm patients were included in HRQoL analyses. The adjusted mean change in Global Health Status (GHS) score from baseline was <10 points in both arms and there was no significant between-group difference [-2.47; 95% confidence interval (CI) -7.27, 2.33; P = 0.31]. Analysis of physical functioning scores showed a significant between-group difference (-4.45 points; 95% CI -8.75, -0.16; P = 0.04). There was no difference in TSCMD for olaparib versus placebo for GHS [P = 0.25; hazard ratio (HR) 0.72; 95% CI 0.41, 1.27] or physical functioning (P = 0.32; HR 1.38; 95% CI 0.73, 2.63). Conclusions: HRQoL was preserved with maintenance olaparib treatment with no clinically meaningful difference compared with placebo. These results support the observed efficacy benefit of maintenance olaparib in patients with a gBRCAm and metastatic pancreatic cancer. ClincalTrials.gov number: NCT02184195

NUTMEG: A randomized phase II study of nivolumab and temozolomide versus temozolomide alone in newly diagnosed older patients with glioblastoma.

BACKGROUND: There is an immunologic rationale to evaluate immunotherapy in the older glioblastoma population, who have been underrepresented in prior trials. The NUTMEG study evaluated the combination of nivolumab and temozolomide in patients with glioblastoma aged 65 years and older. METHODS: NUTMEG was a multicenter 2:1 randomized phase II trial for patients with newly diagnosed glioblastoma aged 65 years and older. The experimental arm consisted of hypofractionated chemoradiation with temozolomide, then adjuvant nivolumab and temozolomide. The standard arm consisted of hypofractionated chemoradiation with temozolomide, then adjuvant temozolomide. The primary objective was to improve overall survival (OS) in the experimental arm. RESULTS: A total of 103 participants were randomized, with 69 in the experimental arm and 34 in the standard arm. The median (range) age was 73 (65-88) years. After 37 months of follow-up, the median OS was 11.6 months (95% CI, 9.7-13.4) in the experimental arm and 11.8 months (95% CI, 8.3-14.8) in the standard arm. For the experimental arm relative to the standard arm, the OS hazard ratio was 0.85 (95% CI, 0.54-1.33). In the experimental arm, there were three grade 3 immune-related adverse events which resolved, with no unexpected serious adverse events. CONCLUSIONS: Due to insufficient evidence of benefit with nivolumab, the decision was made not to transition to a phase III trial. No new safety signals were identified with nivolumab. This complements the existing series of immunotherapy trials. Research is needed to identify biomarkers and new strategies including combinations

Small HER2-positive breast cancer : should size affect adjuvant treatment?

Limited data exist regarding the effect of adjuvant trastuzumab in women with small, node-negative, HER2- positive breast cancers. We examined outcomes for women with £ 2-cm, node negative, HER2-positive breast cancer treated in 4 cancer centers in Australia and found that adjuvant trastuzumab administered with chemotherapy reduced recurrence and improved survival. Introduction: The adjuvant trastuzumab trials largely excluded women with small, node-negative, HER2-positive breast cancers. Accordingly, limited data exist regarding the effect of trastuzumab in the management of these patients. Our aim was to assess the outcomes of, and treatments administered to, women with small (≤amp; 2 cm), node-negative, HER2-positive breast cancer in 4 Australian cancer centers. Patients and Methods: A retrospective analysis of data on all women with node-negative, HER2-positive breast cancers ≤ 2 cm diagnosed between 1 January 2001 and 31 December 2011 and treated at 4 cancer centers in Sydney, Australia was undertaken. The primary outcomes were recurrence-free survival (RFS) and overall survival (OS). Results: In total, 128 patients with node-negative, HER2-positive breast cancers ≤amp; 2 cm were identified. Of these, 83 women (65%) received adjuvant trastuzumab which, in 96% of cases, was in addition to adjuvant chemotherapy. At 3-year follow-up, the RFS was 100% and 79.2% and the OS was 100% and 92.6% for women treated with, and without, trastuzumab, respectively. There were 14 recurrence events and 6 deaths in the study population. There were no significant differences in RFS and OS for the 46 women treated with, or without, trastuzumab for those with tumors ≤ 1 cm. Conclusion: There is a growing body of evidence to support the use of adjuvant trastuzumab therapy in the management of small, node-negative, HER2-positive breast cancers. However, future studies with longer follow-up and prospective biomarker analysis might assist in clinical decision-making for this patient group

A phase III randomized trial of adding topical nitroglycerin to first-line chemotherapy for advanced nonsmall-cell lung cancer: The Australasian lung cancer trials group NITRO trial

Background: We sought to determine whether the substantial benefits of topical nitroglycerin with first-line, platinum-based, doublet chemotherapy in advanced nonsmall-cell lung cancer (NSCLC) seen in a phase II trial could be corroborated in a rigorous, multicenter, phase III trial. Patients and methods: Patients starting one of five, prespecified, platinum-based doublets as first-line chemotherapy for advanced NSCLC were randomly allocated treatment with or without nitroglycerin 25 mg patches for 2 days before, the day of, and 2 days after, each chemotherapy infusion. Progression-free survival (PFS) was the primary end point. Results: Accrual was stopped after the first interim analysis of 270 events. Chemotherapy was predominantly with carboplatin and gemcitabine (79%) or carboplatin and paclitaxel (18%). The final analysis included 345 events in 372 participants with a median follow-up of 33 months. Topical nitroglycerin had no demonstrable effect on PFS [median 5.0 versus 4.8 months, hazard ratio (HR) = 1.07, 95% confidence interval (CI) 0.86-1.32, P = 0.55], overall survival (median 11.0 versus 10.3 months, HR = 0.99, 95% CI 0.79-1.24, P = 0.94), or objective tumor response (31% versus 30%, relative risk = 1.03, 95% CI 0.82-1.29, P = 0.81). Headache, hypotension, syncope, diarrhea, dizziness, and anorexia were more frequent in those allocated nitroglycerin. Conclusion: The addition of topical nitroglycerin to carboplatin-based, doublet chemotherapy in NSCLC had no demonstrable benefit and should not be used or pursued further

Oral THC:CBD cannabis extract for refractory chemotherapy-induced nausea and vomiting : a randomised, placebo-controlled, phase II crossover trial

Background: This multicentre, randomised, double-blinded, placebo-controlled, phase II/III trial aimed to evaluate an oral THC:CBD (tetrahydrocannabinol:cannabidiol) cannabis extract for prevention of refractory chemotherapy-induced nausea and vomiting (CINV). Here we report the phase II component results. Patients and methods: Eligible patients experienced CINV during moderate-to-high emetogenic intravenous chemotherapy despite guideline-consistent antiemetic prophylaxis. Study treatment consisted of one cycle of 1–4 self-titrated capsules of oral THC 2.5 mg/CBD 2.5 mg (TN-TC11M) three times daily, from days −1 to 5, and 1 cycle of matching placebo in a crossover design, then blinded patient preference for a third cycle. The primary end point was the proportion of participants with complete response during 0–120 h from chemotherapy. A total of 80 participants provided 80% power to detect a 20% absolute improvement with a two-sided P value of 0.1. Results: A total of 81 participants were randomised; 72 completing two cycles were included in the efficacy analyses and 78 not withdrawing consent were included in safety analyses. Median age was 55 years (range 29–80 years); 78% were female. Complete response was improved with THC:CBD from 14% to 25% (relative risk 1.77, 90% confidence interval 1.12–2.79, P = 0.041), with similar effects on absence of emesis, use of rescue medications, absence of significant nausea, and summary scores for the Functional Living Index-Emesis (FLIE). Thirty-one percent experienced moderate or severe cannabinoid-related adverse events such as sedation, dizziness, or disorientation, but 83% of participants preferred cannabis to placebo. No serious adverse events were attributed to THC:CBD. Conclusion: The addition of oral THC:CBD to standard antiemetics was associated with less nausea and vomiting but additional side-effects. Most participants preferred THC:CBD to placebo. Based on these promising results, we plan to recruit an additional 170 participants to complete accrual for the definitive, phase III, parallel group analysis

[In Press] Utility of multigene panel next-generation sequencing in routine clinical practice for identifying genomic alterations in newly diagnosed metastatic nonsmall cell lung cancer

Background: The standard of care in newly diagnosed metastatic non-small cell lung cancer (NSCLC) is to test for aberrations in three genes for driver mutations – ALK, ROS1 and epidermal growth factor receptor (EGFR) – and also for immunohistochemistry to be performed for programmed death-ligand 1 expression level. Next-generation sequencing (NGS), with or without RNA fusion testing, is increasingly used in standard clinical practice to identify patients with potentially actionable mutations. Stratification of NGS mutation tiers is currently based on the European Society of Medical Oncology Scale for Clinical Actionability of Molecular Targets (ESCAT) Tiers I–V and X. Aim: Our aim was to analyse NSCLC tumour samples for the prevalence of Tiers I–V mutations to establish guidance for current and novel treatments in patients with metastatic disease. Methods: NGS was performed employing the Oncomine Precision Assay (without RNA fusion testing) that interrogates DNA hotspot variants across 45 genes to screen 210 NSCLC tissue samples obtained across six Sydney hospitals between June 2021 and March 2022. Results: In our cohort, 161 of 210 (77%) had at least one gene mutation identified, with 41 of 210 (20%) having two or more concurrent mutations. Tier I mutations included 42 of 210 (20%) EGFR mutations (EIA) and five of 210 (3%) MET exon 14 skipping mutations (EIB). Non-Tier I variants included 22 of 210 (11%) KRAS G12C hotspot mutations (EIIB), with a further 47 of 210 (22%) having non-G12C KRAS (EX) mutations. NGS testing revealed an additional 15% of cases with Tier II ESCAT mutations in NSCLC. Forty-six percent of patients also demonstrated potential Tier III and IV mutations that are currently under investigation in early-phase clinical trials. Conclusions: In addition to identifying patients with genomic alterations suitable for clinically proven standard-of-care therapeutic options, the 45-gene NGS panel has significant potential in identifying potentially actionable non-Tier 1 mutations that may become future standard clinical practice in NSCLC

NUTMEG: A randomized phase II study of nivolumab and temozolomide versus temozolomide alone in newly diagnosed older patients with glioblastoma

BackgroundThere is an immunologic rationale to evaluate immunotherapy in the older glioblastoma population, who have been underrepresented in prior trials. The NUTMEG study evaluated the combination of nivolumab and temozolomide in patients with glioblastoma aged 65 years and older.MethodsNUTMEG was a multicenter 2:1 randomized phase II trial for patients with newly diagnosed glioblastoma aged 65 years and older. The experimental arm consisted of hypofractionated chemoradiation with temozolomide, then adjuvant nivolumab and temozolomide. The standard arm consisted of hypofractionated chemoradiation with temozolomide, then adjuvant temozolomide. The primary objective was to improve overall survival (OS) in the experimental arm.ResultsA total of 103 participants were randomized, with 69 in the experimental arm and 34 in the standard arm. The median (range) age was 73 (65-88) years. After 37 months of follow-up, the median OS was 11.6 months (95% CI, 9.7-13.4) in the experimental arm and 11.8 months (95% CI, 8.3-14.8) in the standard arm. For the experimental arm relative to the standard arm, the OS hazard ratio was 0.85 (95% CI, 0.54-1.33). In the experimental arm, there were three grade 3 immune-related adverse events which resolved, with no unexpected serious adverse events.ConclusionsDue to insufficient evidence of benefit with nivolumab, the decision was made not to transition to a phase III trial. No new safety signals were identified with nivolumab. This complements the existing series of immunotherapy trials. Research is needed to identify biomarkers and new strategies including combinations

Ototoxicidade da cisplatina e otoproteção pelo extrato de ginkgo biloba às células ciliadas externas: estudo anatômico e eletrofisiológico Cisplatin ototoxycity and otoprotector to cilliated cells by ginkgo biloba extract: anatomic and eletrophisiologic study

A Cisplatina é uma potente droga antineoplásica, largamente utilizada para o tratamento do câncer, tanto em adultos quanto em crianças. Dentre seus efeitos colaterais, a ototoxicidade se apresenta como um dos mais importantes e leva à perda auditiva irreversível, bilateral, para as altas freqüências (4KHz#8KHz). Estudos têm tentado identificar drogas que, associadas à cisplatina possam atuar como otoprotetores. Sabe-se que o mecanismo da ototoxicidade pela cisplatina está relacionado a alterações nos mecanismos antioxidantes das células ciliadas, principalmente as células ciliadas externas da cóclea. OBJETIVO: Nossa proposta foi de avaliar através de emissões otoacústicas, por produtos de distorção (EOAPD) e por microscopia eletrônica de superfície (ME), a ação do extrato de ginkgo biloba (EGB 761), que tem conhecida ação antioxidante, como possível otoprotetor, utilizando como modelo experimental cobaias albinas. FORMA DE ESTUDO: Experimental. MATERIAL E MÉTODO: Observamos EOAPD presentes pré e pós tratamento no grupo EGB (100 mg/Kg/dia via oral) e 90 minutos após cisplatina (80 mg/Kg/dia via intraperitoneal) por 8 dias. RESULTADO: Houve também manutenção da arquitetura ciliar nas células ciliadas externas em todas as espiras da cóclea, enquanto que no grupo tratado somente com cisplatina (80 mg/Kg/dia via intraperitoneal) por 8 dias, houve desaparecimento das EOAPD pós tratamento, com desaparecimento dos cilios das células ciliadas externas e distorção na arquitetura dos cílios remanescentes à ME. CONCLUSÃO: Concluímos que a EGB, por sua ação antioxidante, atua como fator otoprotetor à ototoxicidade pela cisplatina, devendo ser testada tal ação na prática clínica em pacientes que utilizam a cisplatina, pois o uso do EGB está extremamente difundido no tratamento de diferentes doenças.<br>Cisplatin is an antineoplastic drug for cancer treatment in children and adults. The side effects of cisplatin ototoxycity are important with irreversible auditory and bilateral damage to high frequencies (4kHz - 8 kHz). Reports recognize some drugs that are associated with cisplatin to obtain an otoprotector effect. The ototoxycity mechanisms of cisplatin are related to injury of conduct the hair cell oxidation mechanism, with particular injury to outer hair cells. AIM: We intend to studies using otoacoustic emissions - distortion products (DPOEA) and scanning microscopy to verify the action of ginkgo biloba (GBE-761) that has well known antoxidizing characteristics, that can function like otoprotector effects. STUDY DESIGN: Experimental. MATERIAL AND METHOD: We use an experimental guinea pig model. We found DPOEA positive before and after treatment in the GBE group (100 mg/ Kg/ day - oral) and after 90 minutes cisplatin (8,0 mg/ Kg/ day - intraperitoneal - 8 consecutive days). RESULTS: The normal cilium architecture of outer hair cells was supported in all cochlear spirals and in the group treated only with cisplatin (8,0 mg/ Kg/ day - intraperitoneal - 8 consecutive days), the DPOEA was not present and strong injury to cilium of outer hair cells showed cilium disorders upon scanning microscopy. CONCLUSION: We conclude that GBE has a potential otoprotector effect against cisplatin ototoxycity and could be used in clinical trials