Terapia adiuvante con inibitori delle Kinasi Cliclina Dipendenti 4/6: quale futuro? Filippo Montemurro

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1 Terapia adiuvante con inibitori delle Kinasi Cliclina Dipendenti 4/6: quale futuro? Filippo Montemurro Unit of Investigative Clinical Oncology Istituto di Candiolo (IRCCS)

2 Disclosures Speaker s Honoraria Astra Zeneca Novartis Roche Travel grants Astra Zeneca Roche

3 Presentation outline Discussing the rationale Overview of the most important ongoing Phase III trial evaluating the addition of CDK 4/6 inhibitors to endocrine therapy Some speculation on what to expect Conclusions

4 Long-term prognosis of HR+/PgRbreast cancer Cortazar et al, Lancet 384; 164, 2014

5 Activity seen in the metastatic setting fully supports studies in operable breast cancer Study Treatment ORR CBR Median DFS (m) Median OS (m) PALOMA 2 Letrozole+Placebo 34.7% 70.3% 14.5 N.A Letrozole+ Palbociclib 42.1% 84.9% 24.8 N.A. MONNALEESA 2 Letrozole+Plac 27.5% 72.8% Letrozole+Ribociclib 40.7% 79.2% 25.3 N.R.* MONARCH 3 Let. or Ana. + Placebo 34.5% 71.5% 14.7 N.A 0.54 Let or Ana + Abemaciclib 48.2% 78.0% N.R. N.A. Finn et al, NEJM 375;1925, 2016 Hortobagyi et al, NEJM 375;1738, 2017 Di Leo et al, ESMO 2017

6 Randomized, Open-label Phase III Study of Palbociclib + Adjuvant Endocrine Therapy vs. Adjuvant Endocrine Therapy Alone in HR+/HER2 Early Breast Cancer: PALLAS Histologically confirmed HR+/HER2 early invasive breast cancer Stage IIA or III Pre- or postmenopausal women Men are eligible 12 months since initial pathologic diagnosis Prior chemotherapy allowed N=4600 RANDOMIZATION 1:1 Arm A Palbociclib (2 years) + Endocrine therapy (5 10 years) Arm B Endocrine therapy (5 10 years) Primary endpoint: idfs Secondary endpoints: idfs excluding second primary cancers of nonbreast origin; DRFS; LLRFS; OS; PROs; safety Stratification factors: Pathologic stage (IIA vs. IIB/III) or clinical stage (if preoperative therapy was given with the higher stage determining eligibility); neo/adjuvant chemotherapy (yes vs. no); age (<50 vs. 50 years); geographic region (North America vs. Europe vs. Asia) 1. ClinicalTrials.gov. NCT (Accessed April ) 2. Meyer E, et al. Presented at SABCS 2015; San Antonio, Texas, USA (Oral presentation OT )

7 Phase III Study of Palbociclib in High-risk Early Breast Cancer: PENELOPE PENELOPE a,1,2 Early ER+ breast cancer high risk (CPS-EG 3*) Premenopausal/postmenopausal Completed taxane-based neoadjuvant therapy, surgery, radiotherapy N=800 RANDOMIZATION 1:1 Palbociclib X 13 cycles (125 mg QD, 3/1 schedule) + SOC Placebo X 13 cycles (3/1 schedule) + SOC Primary endpoint: idfs Secondary endpoints: OS, idfs excluding second non-breast cancer, DDFS, LRFS, idfs by commercially available multigene assay subtyping, safety, PROs, biomarkers CPS-EG; clinical patologic stage estrogen/score AKA Neo-Bioscore Non-study adjuvant endocrine therapies being taken for 5 10 years after surgery were permitted during the study: tamoxifen (pre- and postmenopausal women) Stratification factors: lymph node status, age, biomarkers (Ki67, prb, Cyclin D), and region goserelin agonists (premenopausal) AIs: anastrozole, letrozole (postmenopausal) 1. ClinicalTrials.gov NCT Data on file, Pfizer

8 EarLEE-1: adjuvant therapy for high-risk early breast cancer HR+, HER2 EBC Men and pre- and postmenopausal women High risk of recurrence - AJCC 8th ed, Prognostic Stage Group III - Residual disease in LN(s) and breast tissue after neoadjuvant chemotherapy N=2000 RANDOMIZATION Endocrine therapy a + Ribociclib (600 mg/d, 3 weeks on/1 week off 26 cycles [24 mo]) Endocrine therapy + Placebo (3 weeks on/1 week off 26 cycles [24 mo]) Primary endpoint: idfs Secondary End points: RFS DDFS QS Qol a Endocrine therapy can be started up to 12 weeks before randomization and continue for at least 60 months. AJCC, American Joint Committee on Cancer; EBC, early breast cancer; DDFS, distant disease-free survival; HER2, human epidermal growth factor receptor-2 negative; HR+, hormone receptor-positive; idfs, invasive disease-free survival; LN, lymph node; NACT, neoadjuvant chemotherapy; OS, overall survival; QoL, quality of life; RFS, recurrence-free survival. EarLEE-1 Clinical Trial Protocol

9 EarLEE-2: adjuvant therapy for moderate risk early breast cancer HR+, HER2 EBC Men and pre- and postmenopausal women Intermediate risk of recurrence - AJCC 8th ed, Prognostic Stage Group II - No neoadjuvant chemotherapy and/or endocrine therapy N=2000 RANDOMIZATION Endocrine therapy a + Ribociclib (600 mg/d, 3 weeks on/1 week off 26 cycles [24 mo]) Endocrine therapy + Placebo (3 weeks on/1 week off 26 cycles [24 mo]) Primary endpoint: idfs Secondary Endpoints RFS DDFS QS Qol a Endocrine therapy can be started up to 12 weeks before randomization and continue for at least 60 months. AJCC, American Joint Committee on Cancer; EBC, early breast cancer; DDFS, distant disease-free survival; HER2, human epidermal growth factor receptor-2 negative; HR+, hormone receptor-positive; idfs, invasive disease-free survival; LN, lymph node; NACT, neoadjuvant chemotherapy; OS, overall survival; QoL, quality of life; RFS, recurrence-free survival. EarLEE-1 Clinical Trial Protocol

10 monarche: adjuvant treatment for HR+/HER2-, high risk operable breast cancer N = 3850 HR+, HER2 EBC Men and pre- and postmenopausal women N+ and at least one of the following 4 metastatic lymph nodes T3 G3 Ki67 20% (cohort B) RANDOMIZATION Endocrine therapy a + Abemaciclib [24 mo] Endocrine therapy Primary endpoint: idfs Secondary Endpoints: IDFS according to Ki67 (cutoff 20%) OS Pharmacokinetics Qol

11 Summary of key points Trial Population Risk Neo/Adj chemo PALLAS PENELOPE-B EarLEE1 EarLEE2 monarche Pre-Post menop Women, Men Pre-Post menop women Pre-Post menop Women, Men Pre-Post menop Women, Men Pre-Post menop Women, Men CDKi duration Accrual target Early results expected* Completion IIA-III Allowed 2 y 4600 Sep 2020 Sep 2025 CPS-EG 3 Group** III or residual disease after NACT Group** III Neoadj Mandatory ~1y 800 Dec 2020 Nov 2023 Allowed ~2y 2000 Sep 2023 Sep 2023 None allowed ~2 y 2000 Sep 2023 Sep 2023 High-risk N+ Allowed? 3850 June 2022 Jun 2027 *Final data collection date for primary outcome measure *AJCC 8 th Edition

12 What to expect Could we expect increased cure rate due to a sort of "pcr in micrometastatic sites" effect? Cortazar et al, Lancet 384; 164, 2014

13 Neoadjuvant palbociclib and letrozole vs chemotherapy Cottu et al., Esmo 2017

14 pcr rates remain globally low, but PEPI scores is better with palbo and letrozole Cottu et al., Esmo 2017 Ellis, JNCI 2008

15 PEPI score is largely driven by residual Ki67 in surgical specimen Dowsett et al. JNCI 100; 1380, 2008 Cottu et al., Esmo 2017

16 For short treatment exposures, Ki67 raises sharply upon CDK 4/6 treatment interruption ER+ (Allred 6-8) HER2- Neoadjuvant palbociclib and anastrozole (NEOPALANA study). 4 weeks B (PIK3CA mutational B B analysis) 2 weeks If ki67 >10% patients go off study Surgery C0D1 Anastrozole +/-Goserelin C1D1 Ana. + Pal. +/-Goserelin PIK3CAwt 32 PIK3CAmut 16 C1D15 Ana. + Pal. +/-Goserelin C2D1 Ana. + Pal. +/-Goserelin 4 cycles (5 in 8 patients) Ma et al, Clin Cancer Res, epub 2017

17 CDK 4/6 inhibition and prolonged G1 arrest may induce cancer cell senescence Kovatcheva et al, Oncotarget 6;8226, 2015 Evidence that this occurs in: Vemurafenib-resistant melanoma (PMID ), Sarcoma (PMID ), Neuroblastoma (PIMD ), Breast (PIMD ), Glioblastoma multiforme (PMID ), Hepatocellular carcinoma (PIMD ), Leukemia (PMID ) and others

18 Senescence is capable of stimulating clearance by the immune system Experimentally impaired immune surveillance Wong-Kang et al, Nature 479; 547, 2011

19 Changes occurring in the tumor bed in the neoadjuvant setting with abemaciclib H&E Total T cells (CD3) Suppressor/ Cytotoxic T cells (CD8) T Regulatory cells (FOXP3) Baseline C1D15 C5D28 Moderately Differentiated Ki67: 20% (Abemaciclib monotherapy) Well Differentiated Ki67: 3.4% (Abemaciclib & Anastrozole) Well Differentiated Ki67: 0.2% Hurvitz SABCS 2016

20 CDK 4/6 inhibition triggers anti-tumour immunity Collectively, these results establish that CDK4/6 inhibitors induce breast cancer cell cytostasis without directly causing their apoptosis, and enhance their capacity to present antigen and stimulate cytotoxic T cells Goel et al, Nature; epub 2017

21 Conclusions Adding CDK 4/6 inhibitors to adjuvant endocrine in highrisk, ER+/HER2- breast cancer patients has a strong rationale Biology suggests a potential eradicating effect based on induction of senescence and clearance by the immune system Safety in patients who have been recently exposed to cytotoxic chemotherapy needs to be addressed Potential effects of senescence on normal cells need to be clarified Which type of tumors will be faced with upon progression?

22 Development in the Neoadjuvant setting Criscitiello et al, Curr Opin Oncol, epub 2017

23 Toxicity, dose adjustments and discontinuation without progression Paloma 2 Monnaleesa 2* Monarch 3 Item (% any grade/% G3-4) Palbociclib Placebo Ribociclib Placebo Abemaciclib Placebo Any 99/76 96/24 98/81 97/33 98/55 90/22 Neutropenia 80/66 6/1 74/59 5/1 41/21 2/1 Febrile Neutropenia Anemia 24/24 11/1 19/1 4/1 28/6 5/1 Diarrhea 26/1 19/1 35/1 22/1 81/37 30/1 Nausea 35/0 26/2 52/3 28/1 38/12 20/2 Vomiting 16/1 17/1 29/4 16/1 28/9 12/4 Alopecia 33/0 16/0 33/0 16/0 27/0 11/0 Need for dose interruption 67% 41% 77% 41% 43% 6% Need for dose adjustment Discontinuation for adv. ev

24 Rationale for using CDK 4/6 in the adjuvant treatment of HR positive breast cancer Cossetti et al. J Clin Oncol 33; 65, 2017

25 SWOG 8814: Disease-free survival according to Recurrence Score and treatment arm Albain et al, Lancet Oncol 11;55, 2016