EY1920 Year Book

29 28 Clinical Oncology, Queen Mary Hospital > Supporting Aberdeen Football Club Pub-crawling during freshers week Mid-autumn festival with HK students Travelling to Santorini vv vv Systematic review and meta-analysis on the trAEs in combination EGFR tyrosine- kinase inhibitor and immune checkpoint inhibitor in EGFR-mutant, advanced NSCLC Daisy Wai Ka Chan (MBBS) 1 , Horace Cheuk Wai Choi (PhD) 2 , Victor Ho Fun Lee (MD) 2,3 1 LKS Faculty of Medicine, The University of Hong Kong, Hong Kong, China. 2 Department of Clinical Oncology, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong, China. 3 Clinical Oncology Center, The University of Hong Kong-Shenzhen Hospital, Shenzhen, China. Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) have been the standard first-line treatment for EGFR-mutated advanced non-small cell lung cancer (NSCLC). Despite the evolving generations of TKI such as osimertinib, patients will usually develop acquired drug resistance. Post-TKI resistance renders the use of novel treatment strategies in combining TKI with immune checkpoint inhibitors (ICI). However, recent studies 1-7 on either combinational or sequential use of TKI and ICI reported increased risks of toxicities especially interstitial lung diseases (ILD). This finding prompted us to perform systematic review and meta-analysis to assess the incidence and nature of treatment-related adverse events (trAEs) in combination TKI and ICI in patients with EGFR-mutant NSCLC after failure to TKI. Background 1 Oxnard,G.,etal.,TATTON:Amulti-arm,phase Ibtrialofosimertinibcombinedwith selumetinib, savolitinibordurvalumabinEGFR-mutant lungcancer.AnnalsofOncology, 2020. 2 Yang, J.C.-H.,etal.,Pembrolizumab incombinationwithErlotiniborGefitinibas first-line therapy foradvancedNSCLCwith sensitizingEGFRmutation. JournalofThoracic Oncology,2019. 14(3):p.553-559. 3 Oshima,Y.,etal.,EGFR–TKI-associated interstitialpneumonitis innivolumab-treated patientswithnon–smallcell lungcancer. JAMAoncology,2018.4(8):p. 1112-1115. 4 Chih-HsinYang, J.,etal.,OsimertinibPlusDurvalumabversusOsimertinibMonotherapy inEGFRT790M–PositiveNSCLC followingPreviousEGFRTKITherapy:CAURALBrief Report. Journalof thoraciconcology,2019. 5 Schoenfeld,A.,etal.,Severe immune-relatedadverseeventsarecommonwith sequentialPD-(L) 1blockadeandosimertinib.AnnalsofOncology,2019. 30(5):p.839-844. 6 Kotake,M.,etal.,High incidenceof interstitial lungdisease followingpracticaluseof osimertinibinpatientswhohadundergone immediatepriornivolumab therapy.Annals ofOncology,2017.28(3):p.669-670. 7 Uchida,T.,etal.,Different incidenceof interstitial lungdiseaseaccording todifferent kindsofEGFR - tyrosinekinase inhibitorsadministered immediatelybeforeand/orafter anti - PD - 1antibodies in lungcancer.Thoraciccancer,2019. 10(4):p.975-979. References Conclusion A higher proportion of ILD was found in combination TKI and ICI than TKI alone. Owing to the small study number, the results warrant further confirmation. While our findings cannot serve as a recommendation on how to administer TKI and ICI judiciously, as these agents could be safely used in some patients in the clinical trials selected, caution should be given to increased risks of ILD when combining TKI and ICI. The primary objective was to determine the pooled incidence of overall and organ-specific including gastrointestinal, pulmonary and dermatological trAEs of combination EGFR-TKI ad ICI. The secondary objective was to compare the pooled incidence of trAEs between combination therapy and TKI monotherapy. Outcome Articles in English from the MEDLINE, EMBASE, and Cochrane databases were searched through March 2020 for Phase I-III randomised clinical trials, non-randomised controlled trials and retrospective studies. Data from TKI monotherapy trials was used as the reference for this meta-analysis. The pooled incidences of overall and organ-specific trAEs were calculated using R package. Methodology Randomised and non-randomised controlled trials, single arm studies and retrospective studies that fulfilled the following criteria were included: (i) recruited patients aged 18 and above with advanced NSCLC (stage IIIB or IV) who are previously treated with EGFR-TKI; (ii) evaluated the safety and tolerability of combination EGFR-TKI plus ICI; (iii) administered EGFR-TKI and ICI regardless of sequence, either concurrently or sequentially, and; (iv) reported incidence of treatment-related adverse events that include any-grade and grade 3 or above events. Selection criteria Eleven full-text articles were assessed for eligibility. Seven studies fulfilled our selection criteria. The overall incidence of trAEs in combination TKI and ICI was 100% (95% CI 96- 100%) for any-grade and 30% (95% CI 12-52%) for high-grade events. Organ-specific trAEs were most frequently observed in the skin (62%, 95% CI 49-74%), gastrointestinal tract (45%, 95% CI 21-88%), followed by ILD (24%, 95% 18-31%). ILD was higher in combination therapy than TKI monotherapy [24% (95% CI 18-31%) vs 3% (1-4%), p value <0.001]. High- grade skin and gastrointestinal trAEs were more frequent in combination therapy [(2%, 95% CI 0-8% vs 0%, 0-1%, p value = 0.082), (4%, 95% CI 0-12% vs 1% 0%-2%, p value = 0.076)], reaching borderline significance. Results PRISMAFlowDiagram Records identified through database searching (n= 4014 ) Screening Included Eligibility Identification Additional records identified throughother sources (n= 2 ) Recordsafterduplicates removed (n= 3634 ) Records screened (n=3634) Recordsexcluded (n=3622 ) Full-textarticlesassessed foreligibility: Clinical trials (n= 4 ) Retrospective studies (n=7) Full-textarticlesexcluded, with reasons Clinical trials (n=1):did notpreviously failTKI Retrospective studies (n=3): case reports Studies included in qualitative synthesis (n= 7 ) Studies included in quantitative synthesis (meta-analysis) (n=7) Study Fixedeffectmodel Heterogeneity: I 2 =49%, τ 2 = 0.0086, p = 0.07 CheckMate0122018 (E+N3mg/kg) CAURAL2019 (O+D10mg/kg) TATTON2019 (O+D3mg/kg) TATTON2019 (O+D10mg/kg) Oshima 2018 (A/E/G/O+N) Kotake2017 (O+N) Uchida2019 (O/A+N) Events 1 1 2 4 18 4 26 Total 219 21 12 10 13 70 19 74 0.1 0.2 0.3 0.4 0.5 0.6 Proportionof anygrade ILD Proportion 0.24 0.05 0.08 0.20 0.31 0.26 0.21 0.35 95%-CI [0.18; 0.31] [0.00;0.24] [0.00;0.38] [0.03;0.56] [0.09;0.61] [0.16;0.38] [0.06;0.46] [0.24;0.47] Weight 100.0% 9.7% 5.6% 4.7% 6.1% 31.7% 8.8% 33.5% Study Fixed effectmodel Heterogeneity: I 2 =0%, τ 2 =0, p = 0.89 FLAURA 2018 CAURAL 2019 (O) AURA32017 Nie 2017 Events 11 0 9 2 Total 649 279 17 279 74 0 0.05 0.1 0.15 Proportionof anygrade ILD Proportion 0.03 0.04 0.00 0.03 0.03 95%-CI [0.01; 0.04] [0.02; 0.07] [0.00; 0.20] [0.01; 0.06] [0.00; 0.09] Weight 100.0% 42.9% 2.7% 42.9% 11.4% Limitations Our findings mainly focused on trials of combination osimertinib plus durvalumab. Additional data will be needed to clarify the relative risks of other TKIs following PD-(L)1 blockade. The exclusion of case reports may result in selection bias, even though the ability to draw statistical conclusions from case reports is limited. Further, the number of studies included in this meta-analysis is small. The limited patient size hinders us from performing clinically meaningful statistical analysis to further compare the risk of AEs between concurrent and sequential treatment of the two agents. While ILD were reported to be higher in the Japanese population 1 , subgroup analysis was not possible due to the lack of reporting on patient demographics. Larger studies are warranted to more comprehensively determine the relative risks of trAEs between concurrent and sequential treatment of ICI and TKI, and to investigate whether there is an ethnic correlation of ILD. Figure 1:Study flowchart for identificationand selectionof included studies Table 1:Pooled incidenceof trAE,% (95%confidence interval) incombinationTKIand ICI vsTKI monotherapy trAEs Combination ofTKI and ICI Osimertinib monotherapy p-value (Wald-test) Overall Anygrade 100* (96-100) 88* (68-99) 0.076 High grade (≥3) 30* (12-52) 14* (0-4) 0.27 Skin Anygrade 61 (47-74) 43 (25-61) 0.12 High grade (≥3) 2 (0-8) 0 (0-1) 0.082 Gastrointestinal Anygrade 44 (21-68) 40 (23-60) 0.79 High grade (≥3) 4 (0-12) 1 (0-2) 0.076 Interstitial lung disease (ILD) Anygrade 24 (18-31) 3 (1-4) <0.001 High grade (≥3) 4 (1-10) 1 (0-2) 0.0026 Figure2:Any-grade ILD incombinationTKIand ICI (a)andosimertinibmonotherapy (b) (a) (b) MBBS Enrichment Year 2019/20 Chan Wai Ka Daisy Sem 1 < IC - HKUWW Exchange Programme at University of Aberdeen, UK >; Sem 2 < R A - Systematic review and meta - analysis on the trAEs in combination EG FR tyrosine - kinase inhibitor and immune check p oint inhibitor in EG FR- mutant, advanced NSCLC at D e p artment of Clinical Oncology, HKU, Hong Kong> Chan Wai Ka Daisy SEMESTER 1: HKUWW Exchange at the University of Sydney, Australia SEMESTER 2: Research Attachment with Dr. Patrick Chung 1. My gain in academic knowledge Course 1: ‘Structures, Functions and Diseases’ The review in medial knowledge of different body systems, focusing on: Pathologies Treatment Radiology Course 2: ‘Biological Aspects of ageing’ The decline in functional capacity of different body systems with age. Examples: Menopause Osteoporosis Immunosenescence Course 3: Learning in Outdoor Education - The ecology, history and geography of two famous national parks in Sydney (Royal National Park and Blue Mountains) - experiential learning (through hiking and and staying in a cabin with new friends for two nights) - Learnt how to appreciate the natural environment with my five senses and to slow down my pace of living 2. Polished my English - Speaking: The fluency and accents of my English have been improved. I also find it easier to select the correct word to express my feelings because I practiced a lot with native English speakers during exchange - Listening: Australians tend to speak English pretty quickly so this trains me to sort out the main points instantly in daily conversations 3. The expansion of my social circle - Built a strong bond with my flat-mates - Made friends with other HKU students 4. Cultural Exchange - Weekly cultural sharing night with my flat-mates (E.g. I served them Chinese cuisines and played them Cantonese songs) - Learnt how to say Hello in other languages (e.g. Dutch and Spanish) 5. Personal growth - Stepped out of my comfort zone to try something new (e.g. setting a fire, surfing) - Became more independent - Learnt how to embrace new changes in life Research Topic: Evaluating the validity of EHIDA scan in the diagnosis of Biliary Atresia in infants of Queen Mary Hospital Background Biliary Atresia (BA) is considered a fatal pediatric disease that requires prompt and accurate diagnosis and surgical intervention by Kasai portoenterostomy. Over the years, EHIDA scan has been used routinely as a pre-operative assessment to find out the causes of neonatal cholestasis. However, previous researches showed that there could be potential inaccuracy in its use to diagnose BA, posing a public concern so it is important to re-evaluate its role in BA diagnosis. Objectives - To evaluate the accuracy of EHIDA scan in distinguishing between BA and other causes of cholestatic jaundice - To analyze the factors that potentially affect the validity of EHIDA scan in confirming the diagnosis of BA Methodology Results and discussion - EHIDA scan has a high sensitivity and negative predictive value (100%) = it can rule out BA accurately - Low specificity (67.6%) and positive predictive value (40%) = not diagnostic of BA - Factors that increase the accuracy of EHIDA scan: (1) The prescription of 5mg/kg/day Phenobarbital for 3-5 days before the procedure (2) The use of Mebrofenin as a radiotracer - Factors that decrease the accuracy of EHIDA scan: (1) Concurrent liver disease (2) Severe BA (3) High level of bilirubin (> 20mg/dL) (4) Poor patient performance during the study Conclusion - EHIDA scan is less useful nowadays because of its potential inaccuracy - QMH utilizes EHIDA scan to a smaller extent to diagnose BA - Surgical exploration (e.g. intraoperative cholangiogram ) is more preferred under a high clinical suspicion of BA due to the following advantages: (1) High accuracy (2) Of therapeutic use (3) Laparoscopy poses minimal surgical risk as it is well-developed The review of published articles From medical websites: Pubmed, Web of Science, Medscape and through the search engine: Google scholars Retrospective studies A. All patients (forty five) who received EHIDA scan in QMH from 2009-2019 B. All BA patients ( thirty six ) from 1997-2017 MBBS Enrichment Year 2019/20 Chan Wing Ki Sem 1 < IC - HKUWW Exchange Programme at T he University of Sydney, Australia >; Sem 2 < R A - Evaluating the validity of EHI D A scan in the diagnosis of biliary atresia in infants of Q ueen M ary Hos p ital at D e p artment of Surgery, HKU, Hong Kong > Chan Wing Ki