news in her2+ metastatic breast cancer? current treatment options for her2-positive mbc first line...
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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