Malattia HER2 positiva

(1)

Francesca Notari

Ospedale Oncologico “A. Businco”

I SESSIONE - IL TEMPO GUADAGNATO, A COSA DARE VALORE?

Carcinoma Mammario Malattia HER2 positiva

(2)

Tempo,

Tempo comunque vadano le cose lui passa E se ne frega se qualcuno è in ritardo

Puoi chiamarlo bastardo Ma tanto è già andato

E fino adesso niente lo ha mai fermato E tutt'al più forse lo hai misurato Con i tuoi orologi di ogni marca e modello Ma tanto il tempo resta sempre lui quello

L'unica cosa che ci è data di fare È avere il tempo da poter organizzare…

(L.Cherubini)

(3)

(4)

La malattia HER2 positiva

(5)

La malattia HER2 positiva

(6)

Kronos e Kairòs

(7)

Kronos e Kairòs

…..è il tempo astratto che scorre, la durata quantitativa.

…..invece è qualitativo: giusto, opportuno, il momento preciso, propizio, adatto,

conveniente, stabilito, la situazione, la buona occasione, la circostanza, ma anche uno specifico periodo di tempo e il movimento del

tempo che coincide con l’eterno.

v

PFS e OS

QOL

pCR

(8)

(9)

Reach the stars Fly a fantasy Dream a dream

And what you see will be Rhymes that keep their secrets

Will unfold behind the clouds And there upon a rainbow

Is the answer to a never ending story…

(Limahl)

(10)

Anti-Her2 drugs

(11)

Anti-Her2 timeline(s)

(12)

Anti-Her2 timeline(s)

(13)

(14)

Aver fatto di tutto per non stare alla porta E trovarsi da soli col poco che resta Rifugiarsi in un luogo lontano dal mondo Dove sembra infinito anche un solo secondo…

M.Mengoni

(15)

pCR is defined as the absence of cancer cells in the breast and/or axilla after BC surgery¹

Commonly called pCR

(German Breast Group)¹ Total pCR

(MDACC)^1,2 Breast pCR

(NSABP)^1,2

TNM classification ypT0 ypN0 ypT0/is ypN0 ypT0/is

EFS(%)

Time since randomisation (years)

10 0 8 0 6 0 4 0 2 0 0

0 5 10 15 20

EFS²

ypT0 ypN0 (n = 1554); HR 0.44 (95% CI = 0.39, 0.51) ypT0/is ypN0 (n = 2131); HR 0.48 (95% CI = 0.43, 0.54) ypT0/is (n = 2598); HR 0.60 (95% CI = 0.55, 0.66) 1.0

DFS (months)

Proportion disease-free

0.8 0.6 0.4 0.2

0 25 50 75 100 125 ypT0 ypN0 (n = 955)

ypT/is ypN0 (n = 309) ypT0/is ypN+ (n = 186) ypT1mic ypN+/- (n = 478) ypT > 1mic ypN+/- (n = 4449)

DFS¹

Adapted from 1. von Minckwitz, et al. J Clin Oncol 2012; 2. Cortazar P, et al. Lancet 2014. MDACC, MD Anderson Cancer Center; NSABP, National Surgical Adjuvant Breast and Bowel Project

pCR

pCR is a widely used end point to evaluate response to

neoadjuvant therapy

(16)

Anti HER2 in fase Neoadiuvante

Pertuzumab Trastuzumab

Lapatinib

(17)

NeoSphere

(18)

• Primary

– To assess the pCR rate at the time of surgery

• Arm A (HT) vs. Arm B (PHT)

• Arm A (HT) vs. Arm C (PH)

• Arm B (PHT) vs. Arm D (PT).

• Secondary

– To evaluate the safety profiles of each regimen, including neoadjuvant and adjuvant treatment – To determine the time to clinical response, time to response, disease-free survival and

progression-free survival – To evaluate biomarkers

– To compare the rate of breast-conserving surgery for all patients with T2–3 tumours for whom mastectomy was planned at diagnosis

– To make a preliminary assessment of the efficacy of neoadjuvant treatment with pertuzumab and docetaxel.

NeoSphere: endpoints

Gianni L, et al. Lancet Oncol 2012; 13(1): 25-32. (study protocol available with the publication online).

(19)

NeoSphere: pCR results

Consistent with findings in previous studies, fewer pathological complete responses were noted in tumours that

were hormone receptor-positive

The proportion of patients who were lymph node-negative at surgery and

achieved pathological complete response in the breast was highest

in group PHT

(20)

NeoSphere: conclusions

• Pertuzumab and trastuzumab plus docetaxel significantly increased the pCR rate without substantial differences in tolerability

– pCR rate of 45.8% vs. 29.0% with PHT vs. HT, respectively.

• Substantial anti-tumour activity and a very favourable therapeutic ratio was observed for the pertuzumab plus trastuzumab doublet without chemotherapy.

Gianni L, et al. Lancet Oncol 2012; 13(1): 2532; Gianni L, et al. St. Gallen Breast Cancer Conference 2013 (Abstract 250; poster presentation), available at http://www.poster- submission.com/search/sresult - Last acces Feb 2015.

Gianni L. et al Lancet Oncol. 2016 Jun;17(6):791-800. doi: 10.1016/S1470-2045(16)00163-7. Epub 2016 May 11.

1. FDA: Guidance for Industry Pathologic Complete Response in Neoadjuvant Treatment of High-Risk Early-Stage Breast Cancer: Use as an Endpoint to Support Accelerated Approval. October 2014.

5y follow-up analysis

• The combination of neoadjuvant pertuzumab and trastuzumab plus docetaxel improved long-term outcomes

– The results are descriptive, but the point estimates are consistent with the primary analysis of pCR

– The improvement was greater for patients with hormone receptor-negative disease.

• Overall, patients who achieved tpCR had a reduced risk of a PFS or DFS event.

(21)

NeoSphere: conclusions

(22)

NOAH

(23)

• Primary

– compare event-free survival, which was defined as time from randomisation to disease recurrence or progression (local, regional, distant, or contralateral) or death from any cause

• Secondary

– pathological complete response in breast tissue

– total pathological complete response (in breast and axilla) – overall clinical response rates

– cardiac safety

– survival in all three groups of patients

– and event-free survival (measured from study registration)

NOAH: endpoints

Gianni L, et al. Lancet 2010.

(24)

NOAH: pCR results

43%

22%

38%

19%

p =

0.0007 p = 0.001

0 20 40

10 30 50

With H (n = 117)

Without H (n = 118)

bpCR tpCR

With H (n = 117)

Without H (n = 118)

pCR (%)

HER2-positive disease p value*

HER2- negative

disease p value†

With trastuzumab

(n=117)

Without trastuzumab

(n=118)

Without trastuzumab

(n=99)

bpCR 50 (43%) 26 (22%) 0·0007 17 (17%) 0·37 tpCR 45 (38%) 23 (19%) 0·001 16 (16%) 0·52 OR‡ 102 (87%) 87 (74%) 0·009 70 (71%) 0·62

Data are n (%). bpCR=pathological complete response in breast tissue. tpCR=total pathological complete response (in breast and axillary nodes). OR=overall

response. *For comparison of HER2-positive disease groups. †For comparison of without trastuzumab groups. ‡Complete and partial clinical responses.

Graphical elaboration from table data Gianni L, et al. Lancet 2010; 375: 377–84.

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NOAH: pCR results

Increased pCR rates with trastuzumab added to chemotherapy resulted in improved EFS, but 42% of patients experienced disease recurrence at 5 years

0 20 40

10 30 50

With H Without H

pCR (%)

tpCR

38%

19%

p = 0.001

n = 117 n = 118

(26)

NOAH: results

Time (years)

42%

HR 0.64 (95% CI 0.44, 0.93);

p = 0.016 Without H With H

0 1 2 3 4 5

60 40 20 0 100 80 70 50 30 10 90

EFS (%)

Increased pCR rates with trastuzumab added to chemotherapy resulted in improved EFS, but 42% of patients experienced disease recurrence at 5 years

Graphical elaboration from table data Gianni L, et al. Lancet Oncol 2014; 15: 640–47.

bpCR, pathological complete response in the breast; H, Herceptin; tpCR, total pathological complete response.

HER2 Positive HER2

Negative Trastuzumab

plus chemotherap

y (n=117)

Chemotherap y alone

(n=118) HR (95% CI) P value

Chemotherap y alone

(n=99) 5 year event-

free survival 58% (48-66) 43% (34-52) 0·64 (0·44-

0·93) 0·016 61% (50-70) 5 year overall

survival 74% (64-81) 63% (53-71) 0·66 (0·43-1·01) 0·055 76% (66-84) 5 year

relapse-free

survival* 65% (54-73) 47% (36-57) 0·58 (0·38-0·90) 0·012 67% (56-77) 5 year breast

cancer-specific

survival 77% (69-85) 64% (55-73) 0-59 (0·37-0·92) 0·021 79% (70-86) Data are % (95% CI). HR=hazard ratio. *in patients who had surgery after neoadjuvant systemic therapy (HER2-positive: trastuzumab plus chemotherapy n=98, chemotherapy alone n=90; HER2- negative: n=83).

(27)

NOAH: conclusions

- In patients with HER2-positive locally advanced or inflammatory breast cancer, addition of 1 year of trastuzumab to neoadjuvant chemotherapy improved

overall response rates, almost doubled rates of pathological complete

response, and reduced risk of relapse, progression, or death compared with patients who did not receive trastuzumab.

- The encouraging improvements in pathological complete response rate seen when neoadjuvant trastuzumab was given in combination with neoadjuvant chemotherapy suggest that this approach has other advantages. For example, in patients with operable breast cancer, this treatment could improve rates of breast-conserving therapy

(28)

NeoALTTO

(29)

• Primary

– pathological complete response, defined as the absence of invasive tumour cells in the breast at the time of surgery (ypT0).

• Secondary

- Disease-free survival - Overall survival

- Safety

- Tolerability

NeoALTTO: endpoints

E.de Azambuja et al., The Lancet August 15, 2014

(30)

NeoALTTO: pCR results

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NeoALTTO: conclusions

- Women with pathological complete response after neoadjuvant anti-HER2 therapies had significantly better event-free and overall survival

- Women treated with lapatinib plus trastuzumab who achieved pathological complete response had improved 3-year event-free survival, and significantly lower risk of an event, which was not noted for patients receiving lapatinib or trastuzumab alone

(32)

tpCR resulted in longer EFS and OS than no tpCR for all patients with eBC

CTNeoBC meta-analysis

(33)

HR-positive, HER2-negative HER2-positive Triple negative

Time since randomisation (years) 0 1 2 3 4 5 6 7 8 9 0

100 80

20 60 40

Event-free survival (%)

HR 0.49 (95% CI 0.33–0.71)

No pCR pCR

100 80

20 60 40

HR 0.39 (95% CI 0.31–0.50)

No pCR pCR

100 80

20 60 40

HR 0.24 (95% CI 0.18–0.33)

No pCR

pCR

Adapted from Cortazar P, et al. Lancet 2014.

* Meta-analysis included patients treated with chemotherapy only and with HER2-targeted therapy plus chemotherapy.

CTNeoBC meta-analysis

pCR is more closely associated with long-term outcomes in

subtypes at high risk of recurrence

(34)

CTNeoBC meta-analysis

OBJECTIVE To assess the utility of pathologic complete response (pCR) for neoadjuvant drug development in human epidermal growth factor receptor 2 (HER2 [also referred to as ERBB2])- positive breast cancer.

Kristine R. Broglio er al. Jamaoncology June 2016 Volume 2, Number 6

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CONCLUSIONS AND RELEVANCE Pathologic complete response in HER2-positive breast cancer is associated with substantially longer times to recurrence and death. This relationship is

maintained in RCTs. For any particular new therapy the relationship between pCR and survival may differ. Quantifying the importance of pCR is necessary for designing efficient clinical trials, which should adapt to the relationship between pCR and survival for the therapy under

investigation.

RESULTS A total of 36 studies with EFS by pCR status representing 5768 patients with HER2- positive breast cancer were included in the patient-level analysis. Overall, the improvement in EFS for pCR vs non-pCR was substantial: HR, 0.37 (95% probability interval [PI], 0.32-0.43). This association was greater for patients with hormone receptor–negative disease (HR, 0.29 [95% PI, 0.24-0.36]) than hormone receptor–positive disease (HR, 0.52 [95% PI, 0.40-0.66]). In RCTs, the R2 correlations between odds ratios for pCR and HRs were 0.63 for EFS and 0.29 for OS. Based on absolute treatment improvements in pCR rate, predicted HRs for EFS for RCTs were

concordant with observed HRs.

CTNeoBC meta-analysis

Kristine R. Broglio er al. Jamaoncology June 2016 Volume 2, Number 6

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Adjuvant

Chemotherapy

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Io sto parlando di un tempo che è scrivo in questo momento

e canto per te

le rose, le spine, l'onore e il sapore siamo quello che siamo io altro non so…

G.Todrani

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APHINITY

(39)

APHINITY

ANTHRACYCLINE- BASED

CHEMOTHERAPY

3–4 FEC or FAC q3w → 3–4 T +H/+HP

– 5-FU 500-600 mg/m² – epirubicin 90–120 mg/m²

(doxorubicin

50 mg/m² is acceptable)

– cyclophosphamid 500–600 mg/m² – docetaxel 75–100 mg/m² q3w [oder

paclitaxel 80 mg/m² weekly]

4 AC or EC → 3–4 T +H/+HP

– AC (or EC) q3w or dosedense q2w with G-CSF support

• doxorubicin 60 mg/m² (epirubicin 90–120 mg/m²)

• cyclophosphamid 500–600 mg/m²

– docetaxel 75–100 mg/m² q3w [or paclitaxel 80 mg/m² weekly]

ANTHRACYCLINE-NON- BASED

CHEMOTHERAPY

6 TC q3w +H/+HP

– docetaxel 75 mg/m²

– carboplatin AUC 6 (max. dose 900 mg)

ER and/or PgR +: hormonal agents should be started at the end of chemotherapy consisting of tamoxifen or an aromatase inhibitor for post-menopausal patients; or tamoxifen with or without ovarian suppression or an aromatase inhibitor with ovarian suppression for pre-menopausal patients.

Hormonal therapy should be given for at least 5 years in accordance with the protocol recommendations.

Radiotherapy is to be given as clinically indicated at the end of chemotherapy in accordance with protocol recommendations

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APHINITY: endpoints

• Primary endpoint:

– Invasive disease-free survival between treatment arms.

• Secondary endpoints:

– Invasive disease-free survival including second non-breast cancer – Disease-free survival

– Overall survival

– Recurrence-free interval

– Distant recurrence-free interval – Cardiac and overall safety

– Health-related quality of life.

www.clinicaltrials.gov/ct2/show/NCT01358877; von Minckwitz G, et al. Cancer Res 2011; 71(15 December suppl.): Abstract OT1-02-04 (and associated poster presentation).

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APHINITY: iDFS results

Von Minckwitz G, et al. N Engl J Med 2017 Jun 5.

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APHINITY: iDFS results

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APHINITY: secondary efficacy endpoints

Pertuzumab + trastuzumab + chemotherapy

N= 2400

Pertuzumab + trastuzumab + chemotherapy

N= 2404 IDFS (STEEP definition)

Patients with an event 189 (7.9) 230 (9.6) 3-year event-free

rate— % 93.5 92.5

95% CI 92.5-94.5 91.4-93.6

Stratified hazard ratio 0.82

95% CI 0.68-0.99

p-value (log-rank) 0.043

Disease-Free Survival

Patients with an event 192 (8.0%) 236 (9.8%) 3-year event-free

rate— % 93.4 92.3

95% CI (0.67, 0.98)

Recurrence-Free Interval

rate— % 95.2 94.3

95% CI (0.63, 0.99)

Distant recurrence-free interval

rate— % 95.7 95.1

95% CI (0.64, 1.04)

(44)

APHINITY: conclusions

Von Minckwitz G, et al. Oral Presentation LBA500 presented at ASCO 2017 - Available at http://meetinglibrary.asco.org/record/145538/abstract - Last access June 2017.

• The APHINITY study met its primary objective

– Pertuzumab reduced the risk of an IDFS event by 19% compared with placebo (HR 0.81; 95% CI 0.66, 1.00; p=0.045) at a median follow up of 45.4 months (3 years IDFS of 94.1% with pertuzumab and 93.2% with placebo)

• Treatment effect was homogenous throughout all subgroups, however the N+ and HR- negative cohorts appeared to derive most benefit at the current point of time

– with a relative risk reduction of 23% and 24%, respectively and – a 3-year IDFS absolute increase of 1.8% and 1.6% respectively

• Continued follow up for up to 10 years is important for overall survival, longer-term IDFS and safety analyses. Next analysis will be time-driven in 2.5 years.

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KATHERINE

(46)

KATHRINE: endpoints

• Primary endpoint:

– Invasive disease-free survival (iDFS)

• Secondary endpoints:

- invasive-disease events plus second primary nonbreast cancer was used as a secondary end point

- disease-free survival (including noninvasive breast cancers) - overall survival

- distant recurrence–free survival - safety

(47)

KATHERINE: iDFS results

(48)

KATHERINE: results

(49)

KATHRINE: conclusions

 Adjuvant T-DM1 demonstrated both a statistically significant and clinically meaningful improvement in IDFS compared with trastuzumab

– Unstratified HR=0.50; 95% CI 0.39–0.64; P<0.0001

– 3-year IDFS rate improved from 77.0% to 88.3% (difference=11.3%)

 Benefit of T-DM1 was consistent across all key subgroups including HR status, extent of residual invasive disease, and single or dual HER2-targeted

neoadjuvant therapy

 Additional follow-up will be necessary to evaluate the effect of T-DM1 on OS

 The KATHERINE data will likely form the foundation of a new standard of care in this population and increase the use of neoadjuvant therapy in HER2-

positive EBC

(50)

Metastatic

Disease

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Time waits for nobody Time waits for no one

We've got to build this world together Or we'll have no more future at all

Because time It waits for nobody

Nobody

F.Mercury

(52)

TH3RESA

Malattia metastatica

CLEOPATRA EMILIA

(53)

Malattia metastatica

(54)

Malattia metastatica

(55)

Malattia metastatica

(56)

Malattia metastatica

(57)

Malattia metastatica

(58)

Malattia metastatica: pensieri in libertà

Ad oggi disponiamo di una prima linea che può “regalare” in media 18.5 mesi di PFS e 56.5 mesi di OS…..

…..ulteriori due linee di trattamento che possono continuare a concedere circa 10 mesi di PFS e 35 di OS

Le tre linee con farmaci anti-HER2 hanno un profilo di tossicità, tutto sommato, discreto, con effetti collaterali solitamente ben gestibili…

(59)

E non m'annoio e no che non m'annoio Non m'annoio

Io no che non m'annoio

Non m'annoio no che non m'annoio No che non m'annoio…

L.Cherubini

(60)

Conclusioni

Con l’arrivo, in un prossimo futuro, nel setting neoadiuvante di un farmaco come il Pertuzumab, con i tassi di pCR evidenziati

dagli studi presentati oggi…..

…..le novità che potrebbero arrivare in adiuvante, come il TDM1 in caso di non completa risposta alla terapia

neoadiuvante…..

…..sommando a tutto questo i dati in fase metastatica che ormai siamo abituati a vedere…..

…..alla luce dei profili di tossicità di questi farmaci, che ci sono familiari e che abbiamo imparato a gestire, direi

discretamente…..

Penso che si riuscirà, ed in parte lo stiamo già facendo, a far si che sia Kronos che Kairòs siano dalla parte delle pazienti.

(61)

Dubbi

Ma se ci giochiamo tutto subito, è vero che ho una maggior probabilità di risposte patologiche complete e, di conseguenza,

un aumento di DFS e OS, ma…se la malattia si

ripresenta….come dovremo cambiare il nostro algoritmo terapeutico?

(62)

Dieci secondi sono un lasso di tempo lungo nella vita di un eroe. Diego Armando Maradona danzò e partì come un proiettile impazzito. Con il

pallone, il corpo e la velocità, si prese gioco di cinque sudditi dell’Impero britannico e alla fine segnò un gol meraviglioso nella memoria di tutti. Accadde in Messico nel 1986, sul campo Inghilterra e

Argentina.

(Jorge Valdano)

(63)

Grazie per l’attenzione

…sei la cosa più bella che indosso, sei risorsa, sei il cielo e sei il mondo, sei la strada che porta alla vita…