LA MALATTIA METASTATICA. La malattia HR positiva/her2 negativa: quale terapia di I linea? Come scegliere? Jennifer Foglietta P.O.

Transcription

1 LA MALATTIA METASTATICA La malattia HR positiva/her2 negativa: quale terapia di I linea? Come scegliere? Jennifer Foglietta P.O. Narni-Amelia (TR)

2 Outline Re-testing metastatic disease Chemo- vs endocrine-therapy CDK4/6 inhibitors PI3KCA inhibitors

3

4 HR+/HER- MBC: first line chemo- vs endocrine therapy In case of chemotherapy: Prefer sequential monochemotherapy; combination in selected cases No data on best CT sequence (but antra and taxane most active)

5 Resistance is a continuum and these definitions help mainly clinical trials and not necessarily clinical practice

6

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

8 First line ER+/HER2- metastatic breast cancer

9 First-line HR+/HER2- MBC

10

11 Monaleesa-7 Triphaty D et al. Sabcs 2017

12

13 Monarch-3 Goetz M. et al SABCS 2017

14 Monarch-3 Goetz M. et al SABCS 2017

15 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, 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). Wedam SB, et al. J Clin Oncol 2018

16 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

17 RCTs in endocrine-resistant MBC Purpose of most recent treatment Palbo+ful, n (%) adjuvant 74 (21%) 40 (23%) placebo+fulv, n(%) 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%) MONALEESA-3 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

18 PALOMA 3:FINAL PROGRESSION-FREE SURVIVAL (ITT) Progression-Free Survival Probability (%) HR= % CI (0.398, 0.620) 1-sided p< 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) Number of patients at risk Time (Month) PAL+FUL PBO+FUL 60% visceral metastases Absolute improvement in median PFS in the palbociclib arm vs the placebo arm was 6.6 months. Turner et al. NEJM 2018

19 PALOMA3: OVERALL SURVIVAL (ITT) Overall Survival Probability (%) Stratified HR= % CI (0.644, 1.029) 1-sided p= Unstratified HR= % CI (0.626, 0.999) 1-sided p= 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) Time (Month) Number of patients at risk PAL+FUL PBO+FUL Prespecified stratification: - Sensitivity to endocrine therapy - Visceral metastatic disease - Menopausal status Turner et al. NEJM

20 OVERALL SURVIVAL BY SENSITIVITY* TO PRIOR ET Patients With Sensitivity to Prior ET Patients Without Sensitivity to Prior ET Overall Survival Probability (%) 100 HR= % CI (0.551, 0.942) 1-sided p= 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) Time (Month) Number of patients at risk PAL+FUL PBO+FUL Overall Survival Probability (%) 100 HR= % CI (0.705, 1.836) 1-sided p= 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) Time (Month) Number of patients at risk PAL+FUL PBO+FUL 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 * Clinical benefit for 24 weeks in MBC or treated for more than 2 years of adjuvant endocrine therapy Turner et al. NEJM

21 MAGNITUDE OF TREATMENT EFFECT WAS MAINTAINED ACROSS ENDPOINTS 6.6 months 6.9 months PAL+FUL PBO+FUL mpfs=4.6 mo mpfs=11.2 mo PFS PFS surrogate of OS? PAL+FUL PBO+FUL mos=28 mo mos=34.9 mo OS PAL+FUL PBO+FUL PAL+FUL PBO+FUL PAL+FUL PBO+FUL mtet=11.0 mo mtet=4.6 mo mtct=17.6 mo mtct=8.8 mo mtest=18.8 mo mtest=14.1 mo Time (Month) 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. Turner et al. NEJM

22 Cardoso F. ESMO

23 SOLAR-1: study disegn 50% lung/liver metastases 5-6% prior CDK4/6I treatments

24 SOLAR-1: locally assessed PFS in the PI3KCAmutant cohort

25 SOLAR-1: adverse events and dose adjustments Alpelisib+fulvestrant Placebo+fulvestrant

26 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?