La malattia HR-positiva/HER2-negativa: quale terapia 1a linea? Come scegliere?

LA MALATTIA METASTATICA

La malattia HR positiva/HER2 negativa: quale terapia di I

linea? Come scegliere?

Jennifer Foglietta

P.O. Narni-Amelia (TR)

Outline

• Re-testing metastatic disease

• Chemo- vs endocrine-therapy

• CDK4/6 inhibitors

• PI3KCA inhibitors

In case of chemotherapy:

• Prefer sequential monochemotherapy; combination in selected cases

• No data on best CT sequence (but antra and taxane most active)

HR+/HER- MBC: first line chemo- vs endocrine

therapy

Resistance is a continuum and these definitions help mainly clinical trials

and not necessarily clinical practice

Inibitori di CDK 4/6: sviluppo clinico nel carcinoma mammario metastatico

X

X

First line ER+/HER2- metastatic breast cancer

First-line HR+/HER2- MBC

Monaleesa-7

Triphaty D et al. Sabcs 2017

Goetz M. et al SABCS 2017

Monarch-3

Goetz M. et al SABCS 2017

Monarch-3

Wedam SB, et al. J Clin Oncol 2018

PFS and OS for the pooled trials demonstrated improved outcomes for the bone-only (BO) subgroup compared with:

- bone with other metastases (BWO)

- No bone metastases (NBM) subgroups

- BO v BWO PFS hazard ratio [HR], 0.64;

95% CI, 0.591 to 0.696;

- BO v NBM PFS HR, 0.70; 95% CI, 0.65 to 0.76; BO v BWO OS HR, 0.56; 95% CI, 0.50 to 0.61;

- BO v NBM OS HR, 0.68; 95% CI, 0.61 to

0.76).

ER +/HER2- endocrine resistant MBC

Cristofanilli M, et al. Lancet Oncol 2016; Turner et al. NEJM 2018; Sledge GW, et al. J Clin Oncol 2017; Slamon DJ, et al. J Clin Oncol 2018

Purpose of most recent treatment

Palbo+ful, n (%)

placebo+fulv, n(%)

adjuvant 74 (21%) 40 (23%)

Advanced/metastatic 273 (79%) 133 (76%)

Most recent endocrine therapy

abema+ful, n (%)

placebo+fulv, n(%)

adjuvant 263 (59%) 133 (59.6%)

metastatic 171 (38.3%) 85 (38.1%)

Prior endocrine therapy setting

Ribo+ful, n (%)

placebo+fulv, n(%)

adjuvant 289 (59.7%) 142 (58.7%) Advanced/metastatic 110 (22.7%) 40 (16.5%)

Cristofanilli M, et al. Lancet Oncol 2016; Sledge GW, et al. J Clin Oncol 2017;

Slamon DJ, et al. J Clin Oncol 2018 MONALEESA-3

RCTs in endocrine-resistant MBC

0 2 4 6 8 10 12 14 16 18 20 22 Time (Month)

0 10 20 30 40 50 60 70 80 90 100

Progression-Free Surviv al Probability (%)

Palbociclib+Fulvestrant (N=347) Median PFS=11.2 months 95% CI (9.5, 12.9)

Placebo+Fulvestrant (N=174) Median PFS=4.6 months 95% CI (3.5, 5.6)

HR=0.497

95% CI (0.398, 0.620) 1-sided p<0.000001

347 276 245 215 189 168 137 69 38 12 2 1

PAL+FUL

174 112 83 62 51 43 29 15 11 4 1

PBO+FUL

Number of patients at risk

PALOMA 3:FINAL PROGRESSION-FREE SURVIVAL (ITT)

• Absolute improvement in median PFS in the palbociclib arm vs the placebo arm was 6.6 months.

Turner et al. NEJM 2018

60% visceral metastases

PALOMA3: OVERALL SURVIVAL (ITT)

Turner et al. NEJM 2018 22

Prespecified stratification:

- Sensitivity to endocrine therapy - Visceral metastatic disease - Menopausal status

0 6 12 18 24 30 36 42 48 54

Time (Month)

10 20 30 40 50 60 70 80 90 100

Overall Survival Probability (%) Palbociclib+Fulvestrant (N=347)

Median OS=34.9 months 95% CI (28.8, 40.0)

Placebo+Fulvestrant (N=174) Median OS=28.0 months 95% CI (23.6, 34.6)

Stratified HR=0.814 95% CI (0.644, 1.029) 1-sided p=0.0429 Unstratified HR=0.791 95% CI (0.626, 0.999) 1-sided p=0.0246

347 321 286 247 209 165 148 126 17

PAL+FUL

174 155 135 115 86 68 57 43 7

PBO+FUL

Number of patients at risk



In patients with sensitivity to prior ET, absolute improvement in median OS in the palbociclib arm vs the placebo arm was 10.0 months.



relatively few patients with intrinsic endocrine resistance

OVERALL SURVIVAL BY SENSITIVITY* TO PRIOR ET

Patients With Sensitivity to Prior ET

23

Patients Without Sensitivity to Prior ET

0 6 12 18 24 30 36 42 48 54

Time (Month) 0

10 20 30 40 50 60 70 80 90 100

Overall Survival Probability (%) Palbociclib+Fulvestrant (N=73)

Median OS=20.2 months 95% CI (17.2, 26.4)

Placebo+Fulvestrant (N=38) Median OS=26.2 months 95% CI (17.5, 31.8)

HR=1.137

95% CI (0.705, 1.836) 1-sided p=0.2969

73 64 53 39 27 19 17 16 3

PAL+FUL

38 33 28 22 16 11 9 8 2

PBO+FUL

Number of patients at risk

0 6 12 18 24 30 36 42 48 54

Time (Month) 0

10 20 30 40 50 60 70 80 90 100

Overall Survival Probability (%) Palbociclib+Fulvestrant (N=274)

Median OS=39.7 months 95% CI (34.8, 45.7)

Placebo+Fulvestrant (N=136) Median OS=29.7 months 95% CI (23.8, 37.9)

HR=0.721

95% CI (0.551, 0.942) 1-sided p=0.0081

274 257 233 208 182 146 131 110 14

PAL+FUL

136 122 107 93 70 57 48 35 5

PBO+FUL

Number of patients at risk

Turner et al. NEJM 2018

* Clinical benefit for ≥24 weeks in MBC or treated for more than 2 years of adjuvant endocrine therapy

MAGNITUDE OF TREATMENT EFFECT WAS MAINTAINED ACROSS ENDPOINTS

25

6.6 months 6.9 months

PAL+FUL

PAL+FUL PBO+FUL

PBO+FUL

OS PFS

Turner et al. NEJM 2018

PFS surrogate of OS?

0 5 10 15 20 25 30 35

Time (Month)

mPFS=11.2 mo mPFS=4.6 mo

mOS=34.9 mo mOS=28 mo

mTEST=18.8 mo mTEST=14.1 mo

mTCT=17.6 mo mTCT=8.8 mo

mTET=11.0 mo

PAL+FUL

PAL+FUL PBO+FUL

PBO+FUL

PAL+FUL PBO+FUL

mTCT=median time from randomization to the start of postprogression chemotherapy; mTEST=median time from randomization to the end of the immediate subsequent line of postprogression therapy; mTET=median time from randomization to end of study treatment.

Cardoso F. ESMO 2018

SOLAR-1: study disegn

50% lung/liver metastases

5-6% prior CDK4/6I treatments

SOLAR-1: locally assessed PFS in the PI3KCA-

mutant cohort

SOLAR-1: adverse events and dose adjustments

Alpelisib+fulvestrant Placebo+fulvestrant

Conclusion first-line therapy ER+/HER2-

• Re-testing if possible

• Hormonotherapy before (mono)chemotherapy if not true visceral crisis

• Menopausal status does not change the treatment

• CDK4/6I treatment as a standard options:

– Consistent improvements in PFS across all 3 available agents BUT:

- few data on OS (not statistically significant in Paloma3) - Selection of patients

- Toxicity profile requiring active management

- Timing? Sequence of treatment and comparison with other new drugs (eg. PI3KCA-I) or

continuing beyond progression?