News in HER2+ metastatic breast cancer? Current treatment options for HER2-positive MBC First Line trastuzumab sensitive First Line trastuzumab resistant Second Line ... Irreversible

News in HER2+ metastatic breast cancer?

Filippo Montemurro

Direzione Day Hospital Oncologico MultidisciplinareIstituto di Candiolo, FPO-IRCCS

Current treatment options for HER2-positive MBC

First Linetrastuzumab sensitive

First Linetrastuzumab resistant

Second Linetrastuzumab (and pertuzumab)

and lapatinib resistant

Further lineTrastuzumab, (pertuzumab)

and T-DM1 resistant

Trastuzumab-Pertuzumab-

Taxane

CLEOPATRA

EMILIAT-DM1

TH3RESAT-DM1

Lapatinib CapecitabineTrastuzumab + chemotherapy

Trastuzumab + LapatinibTrastuzumab + Endocrine ther.

Chemotherapy

EGF100151, EGF194900CEREBEL, EGF108919, GBG 03-05, non-randomizedtrials*

Based on Giordano et al, J Clin Oncol 32; 2078, 2014

Ramakrishna et al, J Clin Oncol 36;2804, 2018

Some low-disease burden, HR positive

disease can benefit from alternative approaches

Patients enrolled in EMILIA and TH3ERESA not previously exposed

to pertuzumab

Choices in this setting based on indirect

evidence

TanDEM, eLEcTRA,

*Pertuzumab can not be used in Italy beyond first line

CNS??

8-year follow-up of the CLEOPATRA trial (OS)

Swain et al, Abstr. 1020, ASCO 2019Pertuzumab AUC 0.6771x^2 - 1.4118x + 1.0431

Swain et al, Abstr. 1020, ASCO 2019

Sorry for picture quality!! OS in non visceral disease still not different

Some patients may be treated with targeted therapy only

Rimawi et al, J Clin Ocol 36;2826, 2018

PERTAIN

Relevant PFS with pertuzumab, trastuzumab and endocrine therapy

Rimawi et al, J Clin Ocol 36;2826, 2018

Margetuximab: FC-engineered to activateimmune responses

SOPHIA design

Rugo et al, ASCO 2019, Abstr. 1000

SOPHIA patient characteristics

Rugo et al, ASCO 2019, Abstr. 1000

SOPHIA primary end-point: PFS (ITT Population)

Rugo et al, ASCO 2019, Abstr. 1000

SOPHIA planned exploratory analyses basedon FCGRA3 158 variants

Rugo et al, ASCO 2019, Abstr. 1000

SOPHIA ORR and CBR

Rugo et al, ASCO 2019, Abstr. 1000

NALA study

Saura et al, ASCO 2019, abstr.1002

NALA patient characteristics

Swain et al, Abstr. 1020, ASCO 2019

NALA summary of results

Swain et al, Abstr. 1020, ASCO 2019

NALA safety considerations

Swain et al, Abstr. 1020, ASCO 2019

PHENIX: context

PHENIX study design

PHENIX primary endpoint: PFS

PHENIX ORR and CBR

Two (among others) randomized trials are still to come

Strategia Farmaco Studio Setting Bracci

Irreversible PAN-HER TKI Neratinib PUMA-NALA ≥2 HER-2 directed metastatic lines Lapatinib Capecitabine

Neratinb Capecitabine

Selective HER2 TKI Tucatinib HER2-CLIMB After T, P and TDM-1, with or without CNS metastases

Trastuzumab Capecitabine

Trastuzumab Capecitabine Tucatinib

Fc optimized MoAb Margetuximab SOPHIA 1-3 prior HER2-directed lines fo MBC Trastuzumab Chemo

Margetuximab Chemo

Newer-ADO DS 8201a DESTINY-BREAST 3 Eligible for T-DM1 T-DM1

DS 82001a

Trastuzumab-deruxtecan; a potent newcomer

Pan et al, ASCO 2018

PFS in heaviliy pre-treated patients

Tamura et al, Lancet Oncol 20;816, 2019

PFS2/PFS1; 1.5

Conclusions

• No practice changing results from ASCO 2019 in women with HER2-positive advanced breast cancer

• Encouraging signals which might consolidate TKIs as third line treatments…or as fist line after Pertuzumab and T-DM1 in the future

• Indirect comparisons do not suggest that Neratinib-Capecitabine may challenge T-DM1 in trastuzumab-resistant patients, but NALA had60% of patients pre-treated with pertuzumab, T-DM1 or both. Food for thinking…

• Margetuximab is a Trastuzumab "on steroids" and it is worthy of further investigation in earlier lines of therapy. The signal in low-affinity CD16A-158F carriers is weak but encouraging.

8-year follow-up of the CLEOPATRA trial: PFS

Swain et al, Abstr. 1020, ASCO 2019

Is there a role for chemotherapy duration?

< 6 cycles of docetaxel

just 6 cycles of docetaxel

> 6 cycles of docetaxel

Miles et al, Ann Oncol 28;2761, 2017