Chemotherapy: when less is more? Marina E Cazzaniga Director, Clinical research Phase 1 Centre ASST Monza & Milano Bicocca School of Medicine and Surgery Chieti, 15 Giugno 2017

Il Network HERMIONE Monza, 27 febbraio 2017

Perché la necessità di un Network? Vista la numerosità di studi di ricerca clinica indipendente promossi da singoli, si è creata la volontà e la necessità di ideare una piattaforma di collegamento fra i vari centri, che possa essere messa a disposizione di tutto il gruppo, ma anche di singoli Centri HERMIONE si propone come strumento di collaborazione per la ricerca clinica INDIPENDENTE nel tumore della mammella metastatico HR+ HERMIONE non vuole replicare, o porsi come alternativa, a gruppi cooperatori già esistenti sul territorio nazionale

Cos’è la piattaforma HERMIONE? HERMIONE è una piattaforma interattiva, che funge da strumento di collegamento a diversi livelli: Fra Centri diversi sul territorio nazionale All’interno di un singolo Centro All’interno di un gruppo di persone di un singolo centro, o di centri diversi HERMIONE funge da repository di materiale bibliografico, slides, ecc HERMIONE funge da Forum per lo scambio di opinioni fra clinici, discussione di casi clinici, ecc – diversi livelli di scambio

DE-ESCALATION IN CHEMOTHERAPY TREATMENT Less number of drugs  poly-chemotherapy vs monotherapy Less patients treated  better selection of patients Less toxicity from the same drugs  changing in schedule and way of administration

CHEMOTHERAPY vs ENDOCRINE THERAPY (Cardoso F, Ann Oncol 2017) (Cazzaniga ME, ASCO 2017, #1057)

POLYCHEMOTHERAPY vs MONOTHERAPY Adherence to International ESO-ESMO (ABC) guide-lines in HER2-ve metastatic breast cancer (MBC) patients (pts) – Preliminary results of the GIM 13 - AMBRA Study n/N (% of adherence) 1 - Anthracycline- or taxane-based regimens, preferably as a single agent, would usually be considered as first-line CHT, in those pts who have not received these regimens as adjuvant treatment Ant/Tax Mono 59/270 (21.8%) 160/270 (59.2%) Ant/Tax Poly 101/270 (37.4%) 2 - In pts with taxane-naive and anthracycline-resistant MBC, taxane-based therapy, preferably as a single agent, would usually be considered as the treatment of choice. Tax Mono 89/431 (20.6%) 208/431 (48.2%) Tax Poly 119/431 (27.6%) 3 - Other options are Capecitabine and Vinorelbine Cape/Vino 135/586 (23.0%) 4 - If given in the adjuvant setting, a taxane can be re-used in the metastatic setting, particularly if there has been at least 1 year of disease-free survival. DFI > 12 months 74/79 (93.7%) 79/151 52.3%) DFI  12 months 5/79 (6.3%) (Cardoso F, Ann Oncol 2017) (Cazzaniga ME, submitted ESMO 2017)

IMPROVEMENT IN PATIENTS SELECTION

IMPROVEMENT IN PATIENTS SELECTION Does subclonality make the primary tumour a poor proxy for the metastatis seeding clone?

IMPROVEMENT IN PATIENTS SELECTION Does subclonality make the primary tumor a poor proxy for the metastasis seeding clone?

Metronomic chemotherapy(mCT) : definition CHANGEMENT IN SCHEDULE AND ADMINISTRATION Metronomic chemotherapy(mCT) : definition “Indeed, metronomic chemotherapy may be better defined as a frequent, regular administration of drug doses designed to maintain low, but active, range of concentrations of chemotherapeutic drugs during prolonged periods of time without inducing excessive toxicities.” Bocci & Kerbel. Nat Rev Clin Oncol in press “Metronomic chemotherapy is defined as the minimum biologically effective dose of a chemotherapic agent given as a continuous dosing regimen with no prolonged drug-free breaks that leads to antitumour activity ” Klement G.L & Kamen BA J Paediatr. Haematol. Oncol. 33,1-3, 2011 “The cumulative doses administered over the course of long-term metronomic treatments can be similar or even higher than those administered in conventional MTD regimens, making the terminology ‘low dose chemotherapy’ somewhat misleading.” Andre, Carry, Pasquier. Nat Rev Clin Oncol, vol 11, 2014

Antivascular effects of MTD & Metronomic CHT MTD regimens Vascular repair activity during the drug-free periods because of up-regulation of pro-angiogenic factors Metronomic regimens Increase of the antivascular effects by blocking the recovery of new vascularization without increasing adverse events Emmenegger U, Chou A, Bocci G. 2010, Springer

mVRL significantly decreases pro-angiogenic genes expression and promotes anti-angiogenic genes

MDA RESULTS (MTT assay) MET STD (Cazzaniga ME, submitted)

mCT: Depletion of Tregs and modulation of myeloid-derived suppressor cells (MDSC) Pere H et al. Oncoimmunology 2012 Andre N et al. Nat Rev 2014

Single-agent or combination regimens of mCHT (Cazzaniga ME, Dionisio MR and Riva F, Cancer Letters 2016)

FINAL RESULTS OF THE VICTOR-2 STUDY ORIGINAL ARTICLE METRONOMIC CHEMOTHERAPY WITH ORAL VINORELBINE (mVNR) AND CAPECITABINE (mCAPE) IN ADVANCED HER2-NEGATIVE BREAST CANCER PATIENTS: IS IT A WAY TO OPTIMIZE DISEASE CONTROL? FINAL RESULTS OF THE VICTOR-2 STUDY   M.E. Cazzaniga1, L. Cortesi2, A. Ferzi3, L. Scaltriti4, F. Cicchiello1, M. Ciccarese M5, S. Della Torre6, F. Villa7, M. Giordano8, C. Verusio9, M. Nicolini10, A.R. Gambaro11, L. Zanlorenzi12, E. Biraghi13, L. Legramandi14, E. Rulli14 on behalf of the VICTOR Study Group 1 Primary end point CBR=OR+SD≥24 weeks 2 Secondary end points ORR=CR+PR DCR=OR+SD PFS, TTP Cazzaniga ME, Cortesi L, Ferzi A et Al. Breast Cancer Res Treat, 2016

Median time to response: 2.0 months VICTOR-2 Study Primary end point CBR = OR+SD ≥ 6 months   Clinical Benefit n/N Clinica Benefit % (95% CI) Chemotherapy line First line 16/35 45.7 [28.8 – 63.4] Second line 23/45 51.1 [35.8 – 66.3] Overall 39/80 48.8 [37.4 – 60.2] Receptor status HR+ve 11/22 50.0 [28.2 – 71.8] TNBC 5/13 38.5 [13.9 – 68.4] Tumor site Visceral 10/23 43.5 [23.2 – 65.6] Non visceral 6/12 50.0 [21.1 – 80.0] 18/30 60.0 [40.6 – 77.3] 5/15 33.3[11.8 – 61.6] 45.7 [28.8 – 63.3] 7/10 70.0 [34.8 – 93.3] 29/52 55.8 [41.3 – 69.5] 10/28 35.7 [18.6 – 55.9] 26/58 44.8 [31.7 – 58.5] 13/22 59.1 [36.4 – 79.3] CBR=48.8% CBR=55.8% Median time to response: 2.0 months Cazzaniga ME, Cortesi L, Ferzi A et Al. Breast Cancer Res Treat, 2016

PFS rate at 1 year: 1st-line=24.3% - 2nd-line=22.2% VICTOR 2 Study – Efficacy results PFS according to treatment line and hormone receptor status PFS rate at 1 year: 1st-line=24.3% - 2nd-line=22.2% Cazzaniga ME, Cortesi L, Ferzi A et Al. Breast Cancer Res Treat, 2016

The median TTP was 25.1 months in the pre-treated group in the naïve group and 11.2 months (95% CI: 9.2e17.0) in the pre-treated group Montagna E et Al, 2017

The better studied regimen is CM (low-dose oral cyclophosfamide and methotrexate); other regimens are being evaluated (including capecitabine and vinorelbine)

Patients’ selection for metronomic chemotherapy «The majority of these trials enrolled HR+ve patients, with indolent disease or bone metastases, so far all these disease characteristics could serve as pratical guide lines for patients’ selection» (Cazzaniga ME et Al, J Cancer Clin Trials, 2016)

Take-home message & conclusion The way to reach a clear de-escalation of CHT in ABC patients is far from be defined Lack of predictive biomarkers Lack of clinical tools to select patients Metronomic CHT could be considered a good example of CHT de-escalation: Well tolerated Administered orally Relatively low cost The ability to target angiogenesis, cancer stem cells and modulate the immune system provides an opportunity to overcome resistance and delay tumour progression CBR, clinical benefit rate; ORR, overall response rate