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Making progress in metastatic breast cancer Dr Caroline Michie Consultant Medical Oncologist, Honorary Clinical Senior Lecturer & NRS Research Clinician MedAll lecture October 2024Disclosures • Consulting/Educational: AstraZeneca, Eli Lilly, Gilead, Novartis, Pfizer, Roche, Exact Sciences, MSD, Seagen • Travel grants: Roche, Novartis, MSD • Advisory Board: Astra Zeneca, Gilead, Eisei • Institutional research support: Astra Zeneca 2Agenda Background to MBC Where we were Where we are now; - Emerging therapies; evidence & toxicities - Brain metastases & MDT approach - Global challenges The future 3What is cancer? • Definition: (The Free Dictionary) – Cancer is not just one disease, but a large group of diseases. It’s two main characteristics are uncontrolled growth of the cells in the human body and the ability of these cells to migrate from the original site and spread to distant sites. – If the spread is not controlled, cancer can (but often does not!) result in death . 45How does cancer cause death? · Invasion and metastasis •· Direct infiltration and organ dysfunction (eg liver failure, brain involvement) • · Major obstruction; airway, bowel, ureter (causing kidney failure) · Generally weakening the patient - risk of infection eg pneumonia · Other complication – eg blood clot, treatment complication (hopefully rare)In 2000: ▪ We weren’t really sure who to treat when ▪ Tamoxifen personified ▪ We weren’t really sure why some ‘personalised therapy’ cancers recurred while others didn’t... ▪ We had a small number of only modestly effective agents ▪ Or why some responded and some didn’t... Time Magazine, May 2001 8Tuesday, February 2, 20XX Sample Footer Text 9From Cancer and it’s Management, 2003: • Re metastatic breast cancer with bone metastases: “…the ultimate outcome for such patients is poor, with a median survival of only about 12-15 months, although some may survive for several years if sufficiently hormone-responsive” • Re chemotherapy in MBC: “Despite some impressive response rates, any benefits are often short-lived, and the expected lifespan for patients with MBC has changed little, if at all, as a result of more widespread use of these treatments”. 10 R Souhami & J Tobias, 2003What changed?Breast cancer - biology matters E DIEASE HER-2 + NOTASIN L With agreement from facingourrisk.orgClinical trials; How progress has been made 13Slide from https://mstrials.org.au The argument for clinical trials For centres: For patients: QC/QA for supporting departments Earlier access to novel agents or improved (pathology, surgical or RT techniques etc) technology/techniques Can offload high cost drug budget Increases centre profile More personal, closer support Altruistic element - “giving back” Improves clinician recruitment/retention/ More comprehensive follow-up research funding Earlier clinical experience with novel agents Better toxicity management or techniques, in a controlled manner For rarer cancers, can be only Confidential –avenue to treatment (if no data) 15(i) HER2 positive breast cancer 16HER2 is overexpressed in ~20% breast cancers Poor prognostic factor with increased risk of relapse and worse survival Median OS in chemo alone Arm: 20mo Including patients from Edinburgh 17 5 DESTINY-breast 03 : 2L Trastuzumab Deruxtecan The changing HER2+ landscape vs T-DM1: 1L trastuzumab and Median OS not even chemotherapy improves measurable; m12m OS CLEOPATRA : 2 was 94.1% PFS from 4. 6 to 7.4mo 1 th Median OS 20 months 1L Docetaxel/Pertuzumab/ In DESTINY-01 (a 7 line in observation arm Trastuzumab trial), mOS was 29mo6 Median PFS 18.7mo HR for PFS 0.28 Became available in UK in ~ 2003 Median OS 56.5mo RR 80% vs 34% 2001 2005 2012 2012 2022 HERA :4 EMILIA : Adjuvant Trastuzumab after 2L Trastuzumab Emtansine chemotherapy reduces recurrence (HR median OS from start of 2L: 0.54) 30.9 months UK availability since 2006 1: Slamon, NEJM 2001; 2: Baselga et al, NEJM 2012; 3: Verma et al, NEJM 2012; 4: Piccart-Gebhart et al, NEJM 2005; 5: Cortes et al, NEJM 2022; 6 Modi, Proc SABCS 2021 18 CLEOPATRA - Dual HER2 blockade: First-line pertuzumab, trastuzumab & docetaxel At the time, was the longest improvement in OS ever seen in any solid tumour Swain, Lancet Oncol 2020; Apr;21(4):519-530 Fighting cancer with bullets; the antibody- drug conjugate (ADC) revolution Tuesday, February 2, 20XX Sample Footer Text 20The new ADCs ■ Trastuzumab Emtansine (T-DM1/ Kadcyla) ■ Trastuzumab Deruxtecan (Enhertu) ■ Sacituzumab Govitecan (Trodelvy - TNBC) ■ Dato-Deruxtecan (in clinical trials) Chau, Lancet 2019; Vol 394, Issue 10200, p793-804Data from Modi et al, NEJM 2022, slide courtesy ofDestiny Breast-01: Phase 2, open label study in heavily pre-treated HER2+ mBC 6% Complete response 54.9% Partial response inc Edinburgh patients Modi S et al, NEJM 2022; 387:9-20• HR 0.28 • Interstitial lung disease is an important toxicity J Cortés et al. N Engl J Med 2022;386:1143-1154Data from Cortes et al, N Engl J Med 2022;386:1143-1154 diagram courtesy of Astra ZenecaFirst interim analysis of OS in DB-03 Median OS in 2001 Cortes J et al ,NEJM 2022 26 The DESTINY breast cancer trial programme Zenecacourtesy of Astra Q: Can we use this to CURE more cancers? Important toxicity - ILD 1-2% mortality across differing 1 trials www.medicalimages.com 1 Powell et al, ESMO Open 2022: 7; 4: 1-11 28 Pooled analysis of ILD in trials A pooled analysis of 1150 patients receiving T-Dxd monotherapy across 9 phase I & II trials (44% BC): Overall incidence of adjudicated ILD 15.4%; 77% G1/2; grade 5 2.2% 87% occurred in first year of treatment; median was 5.4 months Adjudicated ILD on average diagnosed earlier than investigators in 53% (median of 43 days earlier) Advice is for regular CT scanning to try to identify G1 (asymptomatic) toxicity in dose >6.4 mg/kg, oxygen saturation <95%, mod-severe renal impairment, presence of lung comorbidities, and time since initial diagnosis22: 7; 4: 1-11 Risk Factors Known to be Linked to Drug-Induced ILD/Pneumonitis History of ILD/ pneumonitis or lung 1-4 Prior disease extensive Poor overa5l treatment 1, 2 health 1,4 1 Male sex Smoking Japanese andAfrican Advanced American age 1, 2, 4 ethnicity2,6 1. Skeoch S, et al. J Clin Med. 2018;7(10):356. 2. Schwaiblmair M, et al. Open Res Med J. 2012;6:63-74. 3. Sakurada T, et al. Ann Pharmacother. 2015;49(4):398-404. 4. Osawa M, et al. Int J Clin Oncol. 2015;20(6):1063-1071. 5. Yonemori K, et al. Cancer Sci. 2016;107:1830-1836. 6. Vansteenkiste J. ESMO Open. 2017;2(suppl 1):e000119, © Daiichi Sankyo, Inc. and AstraZeneca 2021• ast ■ 3 line setting with Tucatinib (a TKI) ■ 47.5% patients had brain mets at baseline Murthy et al, N Engl J Med 2020; 382:597-609OS in HER2CLIMB: 22months in 3 line rd Murthy et al, N Engl J Med 2020; 382:597-609 CNS response to T-Dxd 504 patients Over 50% had CNS disease involvement 60% with prior brain RT CNS ORR 51.7% overall BM cohort 12month PFS 61.6% in BM cohort Tuesday, February 2Sample Footer Text 33(ii) ER+ HER2 negative BC 35ER+ HER2 negative BC • Luminal A vs Luminal B • Bone is first site of metastatic disease in ~40% of patients (all subtypes) • Most common site of metastatic disease in ER+ BC; between 55-70% of patients with metastatic disease have disease in bone • Lobular BC is a distinct entity Cancer Res. 2008;68(9):3108-3114. doi:10.1158/0008-5472.CAN-07-5644 54yo lady, working FT in postal service Diagnosed in 2015 with metastatic ER+ HER2 negative breast cancer with multiple bone metastases in ribs and spine Treatment: letrozole, goserelin & zoledronic acid Case 1 Still on 1L treatment for MBC with stable CT in June 2020 Admitted in July 2020 unwell with fever and SOB. Sats 75% on air; High suspicion of COVID (subsequently confirmed)Documentation Reviewing Registrar: Admitting Junior Dr for “Not for ICU/escalation in Medicine: “Not for ICU. view of metastatic Discuss DNACPR” cancer” Post-take Consultant ward round notes: “1. Escalation/DNACPR 2. Discuss with oncology discussed/documented?” (A) Less than 6 months (B) 6-12 months (C ) 12-24 months What would you estimate her (D) 2-3 years prognosis to be? (E ) 4-5 years (F) 5-10 years (G) More than 10 years 39Estimating prognosis is complex in MBC Specific cancer Prior treatment Baseline fitness subtype (is it response(s) and (Performance Status) treatment disease-free interval and co-morbidities responsive?) (DFI) (tumour (are they fit for biology?) treatment?) Burden of disease/ sites of metastases/ Lines of future therapy organ function availableCDK4/6 inhibitors - standard of care in first line ER+ HER2 negative MBC since ~2018 • Oral agents: Palbociclib, Ribociclib and Abemaciclib • Very well tolerated for majority • Similar studies performed for all three drugs with very similar HR for PFS • Delay use of chemo by ~ 1 year ● ~50% visceral metastases CDK4/6 inhibitors disease spreadr more separate sites of Finn RS., NEJM 2016: 375: 1925-1936OS with Ribociclib • HR for death, 0.76; 95% CI, 0.63 to 0.93; two-sided P=0.008 • Nearly 60% had visceral metastases & 34% had 3 or more sites of disease • Also 2 ndline studies for all 3 agents in combination with fulvestrant • Now median OS exceeds 5 years Hortobagyi GN et al. NEJM 2022 The clinical spectrum of ER+/HER2- disease Highly sensitive Likely sensitive Sensitivity De novo Long DFI (>2 Moderately metastatic or sensitive Moderately very long TFI years after resistant Likely resistant (eg 10 years) completion of Short DFI after after completion adjuvant ET) completion of Progression while Early (<1 year on of adjuvant ET adjuvant ET Predominant on adjuvant ET adj ET), fast Bone only bone and soft (after ~3-5 years) progression or tissue disease Bone +/- visceral life-threatening disease More extensive disease Asymptomatic visceral disease Minimal A few symptoms Extensive symptoms Symptomatic visceral disease, Adapted from Barrios, C: Proc SABCS 2023 with very symptomaticThe newer “HER2 low” concept • = HER2 1+ or 2+ (or now ‘ultralow’) • Can be ER+ or negative • DESTINY-breast 04 – phase III randomised trial of T-Dxd versus TPC in 2nd rd or 3 line HER2 low MBC • n=557 patients • 89% were ER+ Modi et al, NEJM 2022Destiny Breast 04 – ER+ cohort results Turned down by NICE but approved in Scotland in 2024 Modi et al, NEJM 2022(iii) Triple negative BC 47 Triple negative breast cancer (TNBC) ~15% of breast Disproportionately Defined as ER, PR & cancers; BRCA1 affects younger women and black HER2 negative mutations more women (3x fold common increase) Propensity for visceral and brain metastases, less Median survival in bone metastases mTNBC = 12-18 and typically early months relapse (< 3 years) 48Treatment options have changed 49In 2023: P Schmid,, personal communication 50“WHAT ABOUT IMMUNOTHERAPY , DOCTOR?”10/6/2024 52Pharmacy Times, 2019 53Pembrolizumab – KEYNOTE 355 – 1 line study of immune checkpoint inhibitor Results N= 847 pts (2:1 randomisation) Pembrolizumab and chemotherapy was superior to placebo and chemotherapy in pts with PD-L1 CPS≥ 10 HR for OS 0.73 (0.55-0.95 ) in the CPS ≥10 subgroup Cortes et al; Lancet 2020: 396(10265):1817-1828 and table from Cortes, Proc SABCS 2022 Immune-related toxicity • Significant, immune-related Timing is less predictable: toxicity can occur even many months after discontinuationTuesday, February 2, 20XX Sample Footer Text 57Graphics courtesy of Gilead Patients without brain metastases; rd Median OS 12.1 months in 3 line (remember we had said median OS was 12-18mo from Dx?) Bardia et al, N Engl J Med 2021: 384:1529-1541 BRAIN METASTASES – AN MDT APPROACH IS KEY 10/7/2024 60Case 2 A fit and well 47F is brought by ambulance to the ED following a first tonic-clonic seizure PMH of a T2 N1 ER+ HER2+ breast cancer in 2021 with a complete response to neoadjuvant therapy, surgery & tamoxifen Her left arm has been increasingly weak for 2-3 months CT scan with contrast shows large lesion in the R frontal lobe with extensive oedema and 6mm midline shift, and meningeal enhancement suspicious for LMD CT body scan – no extra-cranial disease 61What do you think is her likely prognosis? (A) Less than 6 months (B) 6-12 months (C) 12-18 months (D) 1-2 years (E) 2-3years Don’t forget an MRI… (F) More than 4 years 62Times have changed (with BCBM)Breast cancer brain metastases (BCBM) • Devastating, feared, and increasingly common consequence of BC • Seen in~ 15% of patients with MBC 1 • Incidence in advanced BC : • 35% TNBC; 50% HER2+;14% ER+ • Risk shown to be higher with: • younger age (<35 years) • positive nodal status • presence of visceral metastases (lung in particular) • TNBC or HER2  positive disease BC • grade III tumour 1 https://doi.org/10.1002/cam4.5021Outcomes by tumour subtype (2019) s s 1.0 CNS Metastasis-Free Survival 1.0 OS From Diagnosis of CNS Metastases s t HER2+/HR+ e 0.8 0.8 HER2+/HR- n S HER2-/HR+ r f Triple negative B 0.6 y 0.6 t l e b T 0.4 b 0.4 o P t 0.2 0.2 i a r 0 Log-rank P < .0001 0 Log-rank P < .0001 P 20 30 40 50 60 70 80 90 100 18 24 30 36 42 48 0 10 0 6 12 Mos Since Diagnosis of Metastatic Cancer Mos Since Diagnosis of Brain Metastases HER2+/ HER2+/ HER2-/ HER2+/ HER2+/ HER2-/ TNBC TNBC HR+ HR- HR+ HR+ HR- HR+ CNSM-FS, Mos 12.8 8.5 15.1 5.8 Median OS, 18.9 13.1 7.1 4.4 (95% CI) (11.5-14.4) (6.8-9.6) (14.3-16.1) (4.8-6.7) Mos (95% CI) (15.0-23.0) (11.7-15.2) (6.3-7.9) (4.0-4.8) Darlix. Br J Cancer. 2019;121:991 . Options for treatment of brain metastases – carefully individualised • SURGICAL RESECTION – Post op SRS +/- WBRT – good KPS, single lesion; survival benefit seen • STEREOTACTIC RADIOSURGERY (SRS) – single or multi metastatic disease – Fractionated vs single SRS • Hippocampal sparing WBRT • Whole brain RT • Systemic Anti cancer therapy • Best Supportive Care • Referral outwith centre – cyberknife unitConsider re-biopsy – especially if pattern of progression surprises you 15-20% alterations in ER/PR/HER2 – with treatment implicationsOur newer treatments…. Are more effective Are more personalised/targeted Can more often be given ‘until progression’ Generally are easier to tolerate, but most do have some important toxicities More lines of therapy across all subtypes 6869 • Most novel anti-cancer agents cost Cost of new anti- > US$100 000 per year per patient • One 21 day cycle of T-DxD: UK cancer drugs price of £1,455 per 1 vial containing 100 mg powder (BNF list price, June 2024) = one dose at 5.4mg/kg for an average 80kg patient £7275 or £130 950 per year • One month of ribociclib: £2,950.00 for a 63‑tablet pack of 200 mg tablets (NICE appraisal 2021; NB starting dose is 600mg) 70Access to novel drugs in LMICs ●Comprehensive cancer services only reported in < 15% of LMICs vs 90% of high-income countries in 2019 1 ● <50% of cancer medicines on the WHO essential medicines list are still not available to patients living in LMICs ● > 80% of the world’s population has little or no access to key Tuesday, February 2, 20XX 71 pain medicinesd other opioids.Global radiotherapy access as important a challenge; >50% of cancer cases recommended to include RT as part of care 72Possible barriers Nature Reviews Clinical Tuesday, February 2, 20XX Sample Footer Text Oncology volume 20, pages7–15 73The other major challenge: this progress = major resource pressures: Oncology NHS Fife Some outstanding research priorities in MBC TNBC remains the most unmet need – More research in Overcoming finding other targets “HER2 low” group & endocrine “No man’s land” – has proved lobular BC needed resistance ER3/4/5 cancers challenging Treatment of Better biomarkers – Targeting brain Management of oligometastatic TILs, use of liquid metastases/LMD treatment toxicity disease – SABR, biopsies other local interventions • A hugely exciting time to be working in breast Summary oncology • For most women diagnosed with BC in UK today, the 5-year risk of BC death is now <3% 76 BMJ 2023;381:e074684Keen to Extremely rewarding; the patients are all lovely. You genuinely get to know your patients and their families well learn more Unparalleled opportunities for clinical or academic outcomes; witness meaningful improvements in patient about a minimal research input through to lab team leader career in Also many opportunities for teaching, management or oncology? even political strategy commitmentor LTFT and only infrequent consultant on call A rapidly growing specialty 77Thank you