ABC4 Conference. ESO/ESMO 4 th Advanced Breast Cancer International Consensus Conference ABC4. Metronomic Chemotherapy: A good old friend!

Transcription

1 ESO/ESMO 4 th Advanced Breast Cancer International Consensus Conference ABC4 Metronomic Chemotherapy: A good old friend! Nagi S. El Saghir, MD, FACP Professor & Director, Breast Center of Excellence Naef K. Basile Cancer Institute American University of Beirut Beirut, Lebanon Lisbon, Portugal November 2-4,

2 Metronomic ChemoTherapy (M-CT): A Good Old Friend! Presentation Outline: Definitions Various Effects of M-CT Single Agents M-CT: Oral and/or IV Combination M-CT Clinical Trials and Metaanalysis Ongoing Clinical Trials Conclusions and Perspectives 2

3 Definitions: Conventional ChemoTherapy C-CT CT is delivered at Maximum Tolerated Dose (MTD) and repeated periodically, usually every 2-4 weeks. This is based on Dose Intensity. C-CT Targets cancer dividing cells (Desired): log killing of cancer cells q interval: multiple doses are required C-CT also affects normal dividing cells ( AE, SAE, ) Intervals: Necessary and designed to allow recovery of normal cells. During Intervals: Normal cells, Cancer cells and endothelial cells may grow back and may even acquire resistance! 3

4 Definitions: Metronomic ChemoTherapy (M-CT) Can we administer chemo in a way that maintains response and reduces side effects? Yes we can! By using lower doses of chemo drugs but at shorter free intervals Near continuous exposure of cancer cells to potentially effective drugs = Dense administration of drugs Metronomic ChemoTherapy (M-CT): 4

5 Metronomic chemotherapy: Therapeutic Effects 1. Cancer cells: Cytotoxic and/or Cytostatic effects 2. Endothelial cells (tumor & normal endothelial cells): Antiangiogenic 3. T-cells: may selectively reduce Regulator T-Cells May Restore immune response and induce tumor dormancy Munzone E, Colleoni M. Nat Rev Clin Oncol. 2015; 12(11): Andre M et Nat Rev Clin Oncol 2014) 5

6 Frequent, Dense administration of drugs The Norton-Simon Model: Kills rapidly growing cells first Reduces time that allows cells to regrow: Dense administration of Drugs Chemo Q 2 weeks or Q 1 week Example in adjuvant setting: CALGB 9741 study: dd adjuvant AC-T, q 2weeks) Norton L and Simon R (1986) The Norton-Simon hypothesis revisited. Cancer Treat Rep 70:

7 Metronomic chemotherapy: Potential Therapeutic Advantages Anti-neoplastic therapeutic effects against cancer Low toxicity on normal tissues Added better quality of life for patients Low costs for patients and society 7

8 M-CT: Anti-angiogenic Effects Metronomic Chemotherapy targets: Tumor endothelial cells (tumor microenvironment) Normal endothelial cells M-CT undermines the repair process of endothelial cells - This anti-angiogenic effect is better seen with lesser interruptions of drugs Kathy D. Miller, Christopher J. Sweeney, George W. Sledge Jr. JCO Munzone E, Colleoni M. Clinical overview of metronomic chemotherapy in breast cancer. Nat Rev Clin Oncol. 2015; 12(11): doi: /nrclinonc [PubMed] 8

9 M-CT: Effects on Immune System: immunoregulatory Effects on T-Cells T-Reg Cells: Suppress Immune Response (T-Reg Cells vs T-Effector Cells Ratio Balance) Petrausch U, Poehlein CH, Jensen SM, et al. Cancer Immunotherapy: The Role Regulatory T cells Play and What can be Done to Overcome their Inhibitory Effects. Current molecular medicine. 2009;9(6):

10 Fig.1 Fig.2 Low dose cyclophosphamide: lowers selectively the CD4+CD25+ regulatory T cells, and restores T and NK effector functions, (rather than lowering all T-Cells) Ghiringhelli F1, Menard C, Puig PE, Ladoire S, Roux S, Martin F, Solary E, Le Cesne A, Zitvogel L, Chauffert B. Cancer Immunol Immunother May;56(5): Fig.3 10

11 M-CT, A Good Old Friend : Did it all start with first chemotherapies for breast cancer!!! CMF, CMFVP, WEEKLY CAF (Combined M-CT & C-CT) REMINDER OF CMF Prolonged cyclic CMF Adjuvant treatment to radical mastectomy in primary breast cancer with positive ALN. Advantage: in all subgroups of patients Patients with +ALN: >= 4 worse than <4 Drug Dose Route Schedule Freq Cyclo 100mg/m2 Oral Day 1-14 Q28d Methotrexate 40mg/m2 IV D1, D8 q28d 5-FU 500mg/m2 IV D1, D8 q28d CMF Regimen No. patients f-up after 27 months Chemo group % Control group % DFS at 27 months (p < 10^ -6) Bonnadona, et al. Combination chemotherapy as an adjuvant treatment in operable breast cancer. N Engl J Med Feb 19;294(8): Cooper, et al. Cancer 1979; 44: Ellis GK, et al. CAF with weekly A : 2000 (Proceedings AACR) Livingston RB, Gralow JR, et al. Dose-dense anthracycline-based chemotherapy for node-positive breast cancer. J Clin Oncol. 2002;20: [PubMed]

12 Metronomic Chemotherapy: Single Agents and Combinations Oral Drugs with good bioavailability IV Drugs given frequently Oral: Cyclo Methotrexate Capecitabine Vinorelbine Oral + Oral C M Vino + CAPE: VICTOR-2 study Cyclo + Cape + Vino (call it CCV) (VEX Study) IV + PO: CMF with weekly IV 5-FU CAF with weekly IV Adria Oral Cyclo + weekly Adria (Combined conventional doses, metronomic scheduling) IV, Frequent Paclitaxel Nab-paclitaxel (Reported at conventional doses, metronomic scheduling)

13 Metronomic Chemotherapy: Select Single Agent and Combination studies Drug Dose No. Pts ORR CBR PFS (m) TTP (m) OS (m) Authors Cyclophosphamide 50 mg/day Emmenger 2004 Cyclophosphamide and methotrexate Cyclo, MTX and Thalido C: 50mg qd MTX: 2.5mg BIW C:50 mg QD M:2.5 mg BID+/- Th: (200 mg QD 63 pts 20% 40% at 6m Colleoni M (Ann Oncol % 3.8 m Colleoni M Ann Oncol 2006 Capecitabine 852mg/m2 d1-21 q28 33 pts 6.9 m Taguchi (Chemoth 2010) Capecitabine 1500 mg qd 62% 7 m 17 m Fedele (EJC: 2012) Cyclo + Cape + Beva Cape :500 mg TID. C:50 mg QD. B:10 mg/kg Q2 weeks 46 pts TTF: 42w (10+m) Dellapasqua JCO 2008 Vinorelbine 50 mg/ TIW 73 pts Briasoulis et.al. Vinorelbine dose Vino: 40 mg/tiw 34 pts 58.1% Victor-1 (Cazzaniga) Vino + Cape Cyclo, Cape, Vino (Naïve pts) Cyclo, Cape, Vino (pre-treated) Vino 40mg/d TIW Cape 500mg TID Cyclo: 50mg/d, Vino 30mg/d (or 40mg) Cape 500mg TID Cyclo: 50mg/d, Vino 30mg/d (or 40mg) Cape 500mg TID 80 pts m Victor-2 (Cazzaniga, et al: BCRT 2016) 43 pts 25.1m 11.2m VEX (Montagna: Ca letters 2017) 65 pts VEX (Montagna: Ca Letters 2017) 13

14 VICTOR-2 study: Vino + Cape in 1 st Line & 2 nd Line; (28 patients had TNBC) Metronomic, Open label, phase 2, multicenter trial ( ), 80 pts Vino: 40mg qod & Cape: 500mg TID 1 st line 2 nd line and more Patients 35 patients 45 patients CBR 45.7% 51.1% ORR 35.5% 25.6% MDR 11.3 months 6.4 months TTP 7.9 m months 7.2 months PFS at 1yr 24.3% 22.2% In 28 pts TNBC CBR: 35,7% Study Conclusions: mvnb + mcape: Has clinical activity, easy schedule Low toxicity (Main Grade 3 / 4 AEs: HFS: N/V: Fatigue: 0.7%; Febrile N: 0.4%) Cazzaniga ME, et al. Breast Cancer Res Treat (2016) 160:

15 VEX Trial: Metronomic Cyclo + Cape + Vino (CCV) Single arm; phase 2 study; 108 Hormone Receptor-positive MBC pts (43 de novo, 65 pre-treated); 71% had visceral disease VEX Trial Naive Pre-treated PATIENTS TTP 25.1m 11.2m CCV Activity does not seem to be inferior to : Adverse events per patient Total population (n=108) G1/2 G3 G4 Untreated Pretreate d Untreate Pretreated Untreate Pretreate d (n=43) (n=65) d (n=43) (n=65) d (n=43) (n=65) Nausea / Vomiting 49%/19% 31%/8% - 0/2% - - Diarrhoea 45% 37% 2% 2% - Increased ASAT/ALAT 37% 53% 5% HFS 36% 24% 5% 7% - - Neutropenia 32% 29% 5% 2% - - Anemia 21% 29% 2% TILs: correlated with high Ki67, and conferred a worse prognosis Fig 1. Time to disease progression Montagna, et al. Cancer Letters (2017) 1-6; Montagna E, et al. Breast Aug;34:83-88 Miller K, et al. N Engl J Med 2007; 357: ; O Shaughnessy J, Miles D, Vukelja S. et al. JCO 2002, 20,

16 M-CT data in older patients Drug Dose No. Pts PFS (m) TTP (m) Authors Vinorelbine 40mg TIWx3 Q4w 34 pts 7.7 m Addeo R et al. Vinorelbine 30mg, qod 32 pts 9.2 m De Iuliis F et al. Vinorelbine + Cape Vino: 40 mg/tiw 18 pts 10.5 m Cazzaniga ME, et al. VICTOR-1 Addeo R et al. Clin Breast Cancer 2010;10:301-6 De Iuliis F et al. Tumori 2015;101(1):30-5. Cazzaniga ME, et al. Breast Cancer Res Treat (2016) 160:

17 Metronomic + Celecoxib COX2 pathway: apoptosis, angiogenesis, invasion, production of carcinogens; high level of COX-2 expression is found in cancer cells A single-arm, mono-institutional, non-randomized, phase II, Metronomic Cyclo (50 mg po qd) + COX-2 inh. Celecoxib (200 mg p.o.bid) 20 ABC Patients, progressed to anthracyclines, taxanes and capecitabine, 4 chemotherapy schemes; good performance status CBR: effective, showing low toxicity profile and excellent tolerability. CB was 55 %, and time to progression (TTP) was 21.1 wks (5+ mnths). Median TTP in patients who achieved CBL: 35.6 weeks, mean overall survival: wks Circulating endothelial cells (CECs) increased at time progression Serum VEGF decreased, svegfr-2 increased, VEGF/sVEGFR-2 ratio decreased during treatment Perroud HA et al. Cancer Chemotherapy and Pharmacology February 2016, Volume 77, Issue 2, pp

18 Meta-analysis of M-CT Studies 22 Clinical Trials (Mostly single arm, non-randomized studies) 1360 patients (heterogeneous patient populations) ORR CBR PFS OS Pooled Grade ¾ AEs Results 34% 55% 29.5% At 6 months 56% At 12 months 70% At 24 months 40% Trend showing lower toxicity rates with the use of MCT alone compared to use of MCT with other anti-cancer therapies (P = 0.070). Conclusions: M-CT may be effective for use in patients with MBC. M-CT used alone is possibly equally effective and less toxic than combination therapies Liu, et al. PLoS One Mar 15;12(3):e

19 Ongoing Studies:metronomic _ Anti-HER2 EORTC : Open Label Trial (mct +P+T vs P+T) Pertuzumab 80 pts HER2+ MBC 70 Years ( 65/ 60y with co-morbidity) Primary endpoint: PFS at 6 months of PH or PHM Secondary endpoints: OS, BCSS, toxicity, RR according RECIST v1.1, HRQoL, evolution of geriatric assessment during treatment + Trastuzumab 1:1 PD TDM1 Pertuzumab + Trastuzumab + metronomic CT Stratification: ER and/or PR pos vs both negative, previous HER2 treatment (none vs adj only vs metastatic), G8< or equal 14 vs G8>14 Pertuzumab: 840 mg loading dose, further 420 mg q3w iv Trastuzumab: 8 mg/kg loading dose, further 6 mg/kg q3w iv Chemotherapy: Metronomic chemotherapy: cyclophosphamide 50 mg/d po continuously On progression: Option to have T-DM1 (3.6 mg/kg iv q3w) till progression Hans Wilder: SABCS: 12/7/2017; 7-9 AM (poster discussion) 19

20 Ongoing Metronomic Vinorelbine Studies ( Study Phase Stage Drugs Status Ref TEMPO-1 II, randomized MBC, HR+, HER2-, 1 st L. VICTORIANE III, randomized MBC, HR+, HER2-, 1 st L CHEOPS II, randomized MBC, 2 nd, 3 rd L. chemo VinoMetro II, Open Label, 1 st line, after endocrine resistance Vino regular 60/ then 80/m2, qw vs mvino 50 TIW NSAI + Vino NSAI + Placebo Vino + NSAI Vino + Placebo Vino 30mg/d continuous Recruiting (Already ~120 pts) Recruiting Recruitment stopped (3 cases of severe neutropenia & sepsis) Trial stopped after one death occurred (out of 9 recruited). Amdmnt: Daily temp, immediate reporting to MD, weekly CBC first 8w Villanueva et al: SABCS 2016 Heudel et al (France) Ch. Thomssen et al. ABC4, Nov 2-4, 2017; Poster #82

21 Treatment recommendations for post-menopausal patients, having received adjuvant taxane and anthracycline therapy German expert panel AGO Breast Committee : metronomic therapy is recommended for women with HR+, HER2-negative MBC treated previously with taxanes and anthracyclines ( Especially those who are not suitable to receive conventional cytotoxic therapy. In case of comorbidities or severe side effects of prior treatment, metronomic chemotherapy may offer the possibility of prolonged treatment with fewer side effects. Furthermore, as a maintenance treatment it can prolong the efficacy of conventional cytotoxic treatments (LoE 2b/B/AGO +) Thill M, Liedtke C, AGO Recommendations for the Diagnosis and Treatment of Patients with Advanced and Metastatic Breast Cancer: Update Breast Care 2016;11:

22 YES: 38/43 (88.3%; NO: 3/43 (6.9%); ABSTAIN: 2/43 (4.6%)? New statement Metronomic chemotherapy is an reasonable treatment option, for patients not requiring rapid tumor response. (LoE: 1 B) The better studied regimen is CM (low dose oral cyclophosphamide and methotrexate); other regimens are being evaluated (including capecitabine and vinorelbine). Randomized trials are needed to accurately compare metronomic CT with standard dosing regimens. Cardoso, et al. ABC3 ESO/ESMO Guidelines. Annals Oncol 2017 & The Breast 2016

23 Metronomic Chemotherapy Conclusions and Perspectives-1 M-CT has shown effectiveness and reduced toxicity in many small trials Results do not seem to be inferior to full dose Conventional-CT M-CT is well tolerated, low toxicity and low costs Reasonable chemo option for 1 st or later lines MBC, patients with prior anthracyclines and taxanes exposure, older patients, patients with co-morbidities, and per patient s choice Most commonly useful drugs are: Cyclophosphamide, Methotrexate, Capecitabine and Vinorelbine Combinations are being tested and data is encouraging 23

24 Metronomic Chemotherapy Conclusions and Perspectives-2 Useful combinations: C+M or Cape+Vino or Cyclo+Cape +Vino Should we use Cape / Vino combos or keep them sequential?! Are metronomic combinations useful if drugs were already used in conventional MTD? M-CT Option is listed in ESO/ESMO (ABC3) and AGO Guidelines We need Phase III trials to more accurately know the role of M-CT, but, What kind of trials? We need Innovative Trials that focus on select patient groups and biomarkers! Who will do them? Pharma? Academia? 24

25 Acknowledgements Medical Literature & Authors/Investigators Limited personal experience Discussions with colleagues: Ahmad Awada, Fatima Cardoso, Larry Norton, Bella Kaufmann, Matti Aapro, Christoph Thomssen Ongoing trials slides from Gustavo Villanova of Pierre Fabre Medicament Ongoing EORTC trial slide from Hans Wilder Help of my Research Fellows: Paul El-Tomb and Johny Fares Thank you for your Kind Attention! 25

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27 Maintenance Therapy: Chemotherapy, Endocrine Therapy, Biologics Prudence Francis Peter MacCallum Cancer Centre Melbourne, Australia

28 Conflict of Interest AstraZeneca: Honorarium Pfizer: Overseas lecture

29 Maintenance Therapy Therapy given following 4-6 months of a chemotherapy-containing regimen for MBC in patients without disease progression

30 Maintenance Therapy Chemotherapy-based regimen for 4-6 months Disease control Maintenance Therapy Progressive Disease San Antonio Breast Cancer Symposium, December 9-13, 2014 No Maintenance Therapy Chemotherapy-based regimen for 4-6 months Disease control Cease Rx regimen Careful monitoring Progressive Disease Further Therapy Further Therapy This presentation is the intellectual property of John F. R. Robertson. Contact at for permission to reprint and/or distribute

31 Maintenance Therapy: Standard and Investigational Endocrine therapy HER2-targeted therapy Chemotherapy Some or all of same agents Different agents to induction Immunotherapy Biologic agent ie. inhibitors of CDK4/6 or PARP or PI3K/AKT or angiogenesis etc Combinations

32 Maintenance Therapy Goals (1) Prolong duration of disease control (2) Maintain QoL and function by delaying symptoms of disease progression through use of acceptable therapy (3) Delay subsequent therapy that may be more toxic (4) Improve Overall Survival (5) Psychological benefit for patients with preference for continuing therapy vs. a break from therapy until disease progression

33 Maintenance Therapy Considerations Patient preferences Toxicities, including cumulative/irreversible Quality of Life Ease of administration Frequency of attendance required Monitoring required Financial Costs Opportunity Costs (ie. curtailed holidays)

34 Maintenance Endocrine Therapy Adequate randomized trials to provide clear data have not been conducted

35 Maintenance Endocrine Therapy ER+ve HER2-negative MBC If Chemotherapy (CT) is indicated as 1 st Rx for MBC, a switch to maintenance Endocrine Therapy (ET) may be utilized between chemotherapy regimens, if chemotherapy is ceased for cumulative toxicity. CT1 ET1 ET2 CT2 CT3 CT1 ET1 CT2 ET2 CT3

36 Retrospective Analysis of Maintenance Endocrine Therapy after 1 st Line Chemotherapy 560 patients with HR+ve MBC from No progression during first 3 months of 1 st line chemo Median duration 1 st line chemo 4.4 ( ) months 308 pts received maintenance Endocrine Therapy (ET) Dufresne et al. Int J Med Sciences 2008

37 Retrospective Analysis of Maintenance Endocrine Therapy after 1 st Line Chemotherapy Maintenance ET associated with significantly longer PFS: 16.3 months vs 7.7 months Maintenance ET associated with significantly longer overall survival: 48.1 months vs 30.0 months, and in multivariate analysis? Selection bias as non-randomized Dufresne et al. Int J Med Sciences 2008

38 ER POSITIVE / HER-2 NEGATIVE MBC Endocrine treatment after CT (maintenance ET) to maintain benefit is a reasonable option, though it has not been assessed in randomized trials (LoE: 1 C) Total number of votes: YES: 88% (28) 2. NO: 3% (1) 3. ABSTAIN: 9% (3)

39 Total # of votes: 1. YES: 2. NO: 3. ABSTAIN: ER + / HER2+ MBC For patients with ER+/HER-2+ MBC, for whom CT + anti-her2 therapy was chosen as 1 st line therapy and provided a benefit, it is reasonable to use ET + anti-her2 therapy as maintenance therapy, after stopping CT, although this strategy has not been studied in randomized trials. (LoE: 1 C) (NB. CLEOPATRA Trial did not permit maintenance ET in ER+ disease) 79.4% 10.2% 10.2% (39) (31) (04) (04)?

40 Maintenance HER2-targeted Therapy Is considered standard for HER2+ MBC based on value of HER2-targeted Rx beyond progression

41 Cleopatra Trial tested dual HER2-targeted therapy during induction and maintenance Median PFS absolute improvement of 6.3 months Median Overall Survival improvement of 15.7 months Swain et al, N Engl J Med 2015

42 Total # of votes: 1. YES: 2. NO: 3. ABSTAIN: HER-2 POSITIVE MBC In patients achieving a complete remission, the optimal duration of maintenance anti-her2 therapy is unknown and needs to be balanced against treatment toxicity, logistical burden and cost. Stopping anti-her2 therapy, after several years of sustained complete remission, may be considered in some patients, particularly if treatment re-challenge is available in case of progression. (LoE: Expert Opinion) 92.8% 7.1% 0.0% (42) (39) (03) (00)?

43 Maintenance Chemotherapy

44 Duration of First-line Chemotherapy MBC Trial Meta-analysis: Effect on PFS Gennari et al. J Clin Oncol 2011

45 Duration of First-line Chemotherapy Meta-analysis: Effect on Overall Survival Gennari et al. J Clin Oncol 2011

46 KCSG-BR07-02 Trial: Phase 3 Maintenance Chemotherapy after 6 cycles 1 st line Paclitaxel + Gemcitabine for MBC 321 pts enrolled, med age 48 y, ~ 20% prior ET for MBC Paclitaxel 175 mg/m 2 d1+gem 1250 mg/m 2 d1+8 q 21 d 231 pts with disease control (CR+PR+SD) after 6 cycles Randomized to Maintenance Chemo or Obs till PD Median 6 additional cycles PG in Maintenance arm Med PFS Maintenance 7.5 vs 3.8 months (P=0.026) Median OS Maintenance 32.3 vs 23.5 mths (P=0.047) Park et al, J Clin Oncol 2013

47 KCSG-BR07-02 Trial: Maintenance Chemotherapy vs Obs 1 st line P+ Gem for MBC: PFS analysis Park et al, J Clin Oncol 2013

48 CHEMOTHERAPY GENERAL Usually each regimen (except anthracyclines) should be given until progression of disease or unacceptable toxicity. What is considered unacceptable should be defined together with the patient. (LoE: 1B) Total number of votes: YES: 72% (21) 2. NO: 21% (6) 3. ABSTAIN: 7% (2)

49 Maintenance Therapy Investigational Approaches

50 PATINA Trial: HR+ve HER2+ve MBC Randomized 1st-line Maintenance Therapy Induction with up to 8 cycles of taxane (or vinorelbine) plus HER2-targeted Rx Primary Objective: Prolongation of PFS

51 Maintenance Therapy in mtnbc 1 st line chemotherapy - challenge of dose-limiting toxicities with maintenance Chemotherapy with anthracyclines (cardiac) and taxanes (neuropathy) Phase 3 mtnbc trials testing PD-1/PD-L1 inhibitors combined with chemotherapy during induction, and then continued maintenance Immunotherapy Rx

52 IMpassion 130 Trial: 1 st line mtnbc anti-pd-l1 or placebo can continue as maintenance Rx after cessation taxane enrolment completed 2017

53 Keynote 355 Trial 1 st line mtnbc Chemotherapy + Pembrolizumab/Placebo

54 DORA Trial : mtnbc 1 st or 2 nd line Platinum Chemo

55 Maintenance Therapy Judicious use of maintenance therapy to enhance MBC patient outcomes is an important option Consider clinical trials

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57 ORAL DRUGS: Challenges for the Oncology Nurse Interdisciplinary Team Christine B. Boers-Doets, MSc Drug Success Master author of The TARGET System & 7 Pillars of Drug Success 2

58 CHRISTINE BOERS-DOETS IS CONSULTANT, RESEARCHER, SPEAKER, TRAINER, COACH, AND MENTOR FOR: Reference 3

59 7 PILLARS OF ULTIMATE DRUG SUCCESS Reference 1. Boers-Doets CB. The Target System. 1 ed. Wormer: IMPAQTT;

60 MEDICATION ADMINISTRATION As many treatments has shifted from intravenous delivery in the infusion center to oral delivery at home, so has the burden of medication administration. In the home setting, patients and their families and other members of their social support network bear the responsibility for proper medication administration. Reference 1. Boers-Doets CB. The Target System. 1 ed. Wormer: IMPAQTT;

61 ASK Reference 1. CB. Boers-Doets in an unexpected setting 6

62 ADVERSE EVENTS / SIDE EFFECTS an effect of the drug that is not it's intended effect i.e. not why you take it are just extra effects a drug causes. In some cases they are positive Reaction = response countermovement chemical process Toxic reaction = permanent and damaging effects (cell death) poisonousness Non-toxic reaction ~itis = inflammation irritation swelling 8

63 48 RULE 9

64 INVOLVE ADVERSE EVENT MASTERS 12

65 BASIC MEASURES 13

66 ORAL MUCOSITIS STOMATITIS Oral mucositis, chemotherapy Stomatitis, TKI mias, mtori Reference 1. Photo: Rajesh V. Lalla, USA, Lalla RV, Sonis ST, Peterson DE. Dent Clin North Am. 52(1), (2008); National Cancer Institute Photo: Joel B. Epstein, USA 3. Photo: M.E. Lacouture

67 MIAS RECURRENT APHTHOUS STOMATITIS (RAS) mias Reference 1. Photo: C.B. Boers-Doets 2. Photo: Postepy Dermatol Alergol Apr; 30(2): RAS

68 ORAL PAIN BURNING SENSATION 17

69 HAND-FOOT SYNDROME HAND-FOOT SKIN REACTION 1 HFS capecitabine References 1. Photo: N. Schrama 2. Photo: C.B. Boers-Doets 3. Photo: N.. Schrama 2 HFSR 3 HFSR

70 DIARRHEA LOOSE/MUSHY STOOL Type 7: Diarrhea Type 6: Loose/Mushy Stool Reference

71 7 STOOL TYPES Reference Type 1 Separate hard lumps, like nuts (hard to pass) Type 2 Sausage-shaped but lumpy Type 3 Like a sausage but with cracks on its surface Type 4 Like a sausage or snake, smooth and soft. Type 5 Soft blobs with clear-cut edges (passed easily) Type 6 Fluffy pieces with ragged edges, a mushy stool. Soft. Type 7 Watery, no solid pieces. Entirely Liquid. 1. Bristol Stool Chart; Lewis SJ, Heaton KW (1997). Stool form scale as a useful guide to intestinal transit time. Scand. J. Gastroenterol. 32 (9):

72 TREATMENT-RELATED CARDIAC DYSFUNCTION (MYOCARDIAL DEPRESSION) TYPE I AGENTS (CELLULAR DEATH) TYPE II AGENTS (PREDOMINANTLY REVERSIBLE CELLULAR DYSFUNCTION) Reference 1. Slide of: Michael S. Ewer, M.D., J.D. Type I (e.g, doxorubicin) Cellular death Damage starts with the first administration Biopsy changes Cumulative dose-related Permanent damage (myocyte death) Risk factors: Combination CT Prior/concomitant RT Age Previous cardiac disease Hypertension Type II (e.g, trastuzumab) Cellular dysfunction No typical anthracycline-like biopsy changes Not cumulative dose-related Predominantly reversible (myocyte dysfunction) Risk factors: Prior/concomitant anthracyclines or paclitaxel Age Previous cardiac disease Obesity (BMI > 25 kg/m 2 ) 21

73 THIS RAISES QUESTIONS "Managing side effects requires no unique talent... it is a SYSTEM, a FORMULA! 22

74 SYSTEMATIC 6 STEP APPROACH Reference TERM ASSESS REPORT TACKLE 1. Boers-Doets CB. The Target System. 1 ed. Wormer: IMPAQTT; GRADE EVALUATE 24

75 COMMON IMMUNO-ONCOLOGY-ASSOCIATED ADVERSE EVENTS Adverse Event anti-ctla4 anti-pd1 Symptoms & Signs Gastro-intestinal 39.7% 11% Diarrhea: sometimes bloody and abdominal pain Colitis/enterocolitis: abdominal cramps Hepatitis: almost never symptomatic Pancreatitis Endocrine 33.7% % Almost never symptomatic Hypophysitis: sometimes fatigue, sometimes headache Thyroiditis: sometimes hunted feeling or heartbeat Dermatologic 25.6% % Rash, pruritus, vitiligo, dermatitis, urticaria, dry skin, local swelling, etc., etc., etc. Ophthalmologic 10.3% 10% Uveitis, conjunctivitis, orbital inflammation, etc. Neurologic 9.8% 10% Encephalitis, Guillian-Barre syndrome, etc. Hematologic 3.8% - Thrombocytopenia, pancytopenia, neutropenia, etc Genitourinary 2.5% % Renal failure, nephritis, etc.: almost never symptomatic Respiratory 2.5% % Pneumonitis: coughing, dyspnea, respiratory infection, etc. Reference 1. Noha Abdel-Wahab, PLoS One; 2016; 11(7): 2. Dr. J.W.B. de Groot, medical oncologist, Isala, Zwolle, The Netherlands 26

76 MANAGEMENT OF IMMUNO-ONCOLOGY-ASSOCIATED ADVERSE EVENTS Immune-associated Treatment grade 2 Treatment grade 3/4 adverse event Pulmonary/Pulmonal 1 mg/kg/day* 2 till 4 mg/kg/day* Gastrointestinal local guideline 1 till 2 mg/kg/day* Hepatic local guideline 1 till 2 mg/kg/day* Renal 0,5 till 1 mg/kg/day* 1 till 2 mg/kg/day* Endocrine 1 till 2 mg/kg/day* *+ mineralocorticoid** Neurological 0,5 till 1 mg/kg/day* 1 till 2 mg/kg/day* Dermal local guideline 1 till 2 mg/kg/day* *Glucocorticoids; iv methylprednisolone or oral equivalents **Fludrocortisone Reference 1. Bristol-Myers Squibb B.V Management van immuungerelateerde bijwerkingen; Richtlijnen voor behandeling. Opdivo (nivolumab) 27

77 EFFECT GLUCOCORTICOIDS Drug Equivalent dose (mg) Main features: anti-inflammatory & immunosuppressive (antiallergic) Relative antiinflammatory action cortisone hydrocortisone prednisolone Methylprednisolone (Medrol ) triamcinolone dexamethasone betamethasone Reference 1. Relative mineralocortic oid activity 28

78 TAKE HOME MESSAGE There is only one King of The Road - that s NOT the healthcare professional ASK, ASK, ASK the human being - NOT the patient = EXPLORE Empower the patient: let her/him lead Approach adverse events systematically in 6 steps Institute adverse event masters Work interdisciplinary - not multidisciplinary Institute adverse event subtypes Manage adverse events according to its subtype Let the patient decide how intensive your adverse event management will be Work with high dose & short term adverse event management 30

79 KEEP IN TOUCH: Read more at: Connect with me on: Join Planet Chris and get support at: 31

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81 Clinical challenges ABC elderly patient management Laura Biganzoli Breast Centre Istituto Toscano Tumori Prato - Italy

82 Why it is a challenge? Functional Status Comorbidities Organ Function The two ladies have the same chronological age Ernestine Shepherd Old frail woman Cognition Social Support Culture Spirituality Psychological status Polypharmacy Finances

83 Why it is a challenge?

84 Falandry et al. Eur J Cancer 2013 Very few UNFIT patients included in elderly BC patient-focused clinical trials! I wish I had a crystal ball

85 Survival according to age in M+ BC: a SEER population based analysis Breast cancer specific survival (BCSS) Breast cancer specific survival (BCSS) Chen et al. Scientific Reports 2017

86 Focus on targeted agents Targeted agents used in combination with endocrine therapy - Everolimus - CDK4/6 inhibitors HER-2 targeted agents - Pertuzumab - T-DM1

87 Chemotherapy Elderly patients with metastatic breast cancer are expected to derive similar benefits from chemotherapy as younger patients Preference should be given to chemotherapy agents with better safety profiles (such as weekly taxanes, pegylated liposomal doxorubicin, capecitabine, vinorelbine.) that have been studied in older patients Older patients are generally at higher risk of toxicity from chemotherapy agents Biganzoli et al. Lancet Oncol 2012

88 CARG Score Predicting chemotoxicity Score Age 72 years 2 Cancer type GI or GU 2 Standard CT dose 2 Polychemotherapy (>1 CT drug) 2 Hemoglobin <11 g/dl (males); <10 g/dl (females) Creatinine clearance <34 ml/min 3 Hearing impairment 2 Functional impairment Any falls in last 6 months IADL: some help/unable to take medications Walking 1 block (somewhat) limited Decreased social activity Total Grade 3-5 Toxicities 100% 80% 60% 40% 20% 0% SCORE RISK 1-5 low 6-9 medium 10 Low (30%) 25% 32% Medium (52%) 50% 54% high 77% Total Risk Score High (83%) 89%

89 BOLERO-2 Post-menopausal HR+, HER2 M+BC Refractory to non-steroidal AI Cardoso et al. Ann Oncol 2016 R Everolimus Exemestane + placebo Exemestane + everolimus Primary endpoint PFS PFS (median PFS 8.9 vs 2.8 mos) AEs: fatigue, stomatitis, rash, anorexia, diarrhea, hyperglycemia, non-infectious pneumonitis Baselga et al. N Engl J Med 2012

90 BOLERO vs <70 Everolimus in old BC patients Similar efficacy & incidence of AEs More AE-related study discontinuations (17.4% vs 6.3%) More on-treatment deaths with AE as primary cause (7.7% vs 1.3%) Pritchard et al. Clin Breast Cancer 2013 BALLET (Expanded-access trial) 2133 patients, 26% 70+ (n=563 ) 70+ vs <70 More AE-related study discontinuations (23.8% vs 13.0%) More dose reductions (37.7% vs 26.7%) and interruptions (60.5% vs 54.2%) AEs (%) 70+ <70 Stomatitis, any grade (G3/4) 56(12) 52(8) Asthenia, any grade (G3/4) 29(6) 21(3) Decreased appetite Jerusalem et al. Ann Oncol 2016

91 First-line HT pretreated CDK4/6 inhibitors: established treatment option for advanced HR+HER2-BC PALBOCICLIB RIBOCICLIB ABEMACICLIB Finn et al. N Engl J Med 2016 Hortobagyi et al. N Engl J Med 2016 Di Leo et al. ESMO 2017 Cristofanilli et al. Lancet Oncol 2016 side-effects ie. neutropenia (> P&R) diarrhea (A) treatment discontinuation Sledge et al. J Clin Oncol 2017

92 PALOMA trials: Subgroup analysis in elderly patients PALOMA-1 (phase II) 1 ST line AI+P vs AI PALOMA-2 1 ST line AI+ P or placebo PALOMA-3 Fulvestrant + P or placebo Age groups in the pooled population and by palbociclib combination Improvement in PFS ageindependent More neutropenia and decreased appetite in 75+ More AE-related study discontinuations (Overall 9% vs 5%; yrs 13% vs 6%; 75y 19% vs 13%) PK: no need of dose adjustment based on age Rugo et al. SABCS Proc 2016 (Abst P )

93 Other data of CDK4/6 inhibitors in the elderly Improvement in PFS is age-independent also for ribociclib and abemaciclib a) A subgroup analysis of the MONALEESA-2 study showed that the elderly cohort [295 pts aged 65 years; median age of 71 years (range, 65-91), 150 pts on ribociclib+letrozole] demonstrated similar tolerability to the overall population b) No safety data are available for older breast cancer patients treated with abemaciclib a) Hortobagyi et al. N Engl J Med 2016; Di Leo et al. ESMO 2017; Sledge et al. J Clin Oncol 2017 b) Sonke et al. ECCO 2017

94 CLEOPATRA PFS per age group 65 y n=127; 75 y n=19 More diarrhoea, fatigue, asthenia, decreased appetite, vomiting and dysgeusia in patients aged 65+ in both treatment arms Pertuzumab AEs Grade 3 reported more frequently in the pertuzumab arm AEs % < Febrile neutropenia TH THP TH THP Diarrhea Peripheral neuropathy Miles et al. Breast Cancer Res Treat 2013

95 EMILIA T-DM1 vs lapatinib+capecitabine N=991 (65-74 n=113; 75+ n=25) T-DM1 TH3RESA T-DM1 vs Physician s choice N=602 (65-74 n=74; 75+ n=19) PFS: less definitive benefit PFS: benefit consistent across among pts 75 + subgroups (including age) KAMILLA Krop et al. Lancet Oncol 2014 Global safety study; N=2001 pts (373 pts 65 yrs; 75+ n=101) The overall incidences of T-DM1 related G3 AEs (fatal AEs 0.8% vs 0.4%), SAEs (8% vs 5.2%), and AE-related discontinuations (12.3% vs 7.7%) were higher in 65 years No age difference in the proportion of T-DM1 associated AEs (thrombocytopenia, hepatoxicity, hemorrhage) Barrios et al. JCO 2015 (Abst 603)

96 Conclusions Chronological age does not have an impact on treatment efficacy An increase in AEs is reported globally across multiple agents Close monitoring and proactive management of toxicities should clearly be undertaken in older patients Patient s age should not limit the access to treatments (including new treatment options) Difficult to translate the results of trials conducted in selected patients to the overall population of older adults, especially to those with comorbidities and increased susceptibility to adverse events The SIOG 10 Priorities Initiative 9. Increase the relevance of clinical trials for elderly patients (dedicated research programs for elderly!)