Recent advances in the management of metastatic breast cancer in older adults

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1 Recent advances in the management of metastatic breast cancer in older adults Laura Biganzoli Medical Oncology Dept New Hospital of Prato Istituto Toscano Tumori Italy

2 Important recent advances in the management of advanced breast cancer Luminal disease - mtor inhibitor - CDK 4/6 inhibitor HER2+ disease - Pertuzumab - T-DM1

3 Everolimus= mtor inhibitor Post-menopausal HR+, HER2 metastatic BC Refractory to non-steroidal AIs: Recurrence on or 12 months after end of adjuvant treatment with non-steroidal AI Progression on or 1 month after end of treatment with non-steroidal AI for advanced disease N=485 2:1 RANDOMIZATION N=239 Primary end point: PFS (on the basis of radiographic studies assessed by the local investigators) Exemestane (25mg) + everolimus (10 mg) Exemestane + placebo mtor, mammalian target of rapamycin

4 Progression-free Survival Overall Survival P ro b a b ility o f O v e ra ll S u rv iv a l Censoring times HR = 0.89 (95% CI, ) Log-rank P =.14 Kaplan-Meier medians EVE+EXE: months PBO+EXE: months EVE+EXE (n/n = 267/485) 0 PBO+EXE (n/n = No. at risk Time, months EVE+EXE PBO+EXE Piccart M et al, proc. EBCC

5 SAEs attributed to study treatment reported in 11% (EE) vs 1% pts (EP) * Sepsis (n=2), pneumonia, tumor hemorrhage, cerebrovascual incident, renal failure, suicide *

6 Median follow-up=18 months

7 AEs of special interest (all grades) that occurred more frequently with everolimus than with placebo: stomatitis, infections, rash, pneumonitis, and hyperglycemia Elderly everolimus-treated patients had similar incidence of these AEs as did younger patients Patients, % Age <70 years Age 70 years Variable E+E (n=364) E+P (n=196) E+E (n=121) E+P (n=43) Discontinued Reasons - Progressive disease - Pt withdrew consent - Adverse events - Death - - Other On treatment deaths with AE as primary cause, n (exposure adjusted %) 3 (1.3) 1 (1.3) 4 (7.7) 0

8 PALOMA-1/TRIO-18 :Phase 2 Study Palbociclib= CDK 4/6 Inhibitor Part 1 Part 2 Postmenopausal ER+, HER2 BC status No prior treatment for advanced disease R A N D O M I Z A T I O N 1:1 Palbociclib 125 mg QD a + Letrozole 2.5 mg QD Letrozole 2.5 mg QD Postmenopausal ER+, HER2 BC with CCND1 amplification and/or loss of p16 No prior treatment for advanced disease R A N D O M I Z A T I O N Palbociclib 125 mg QD a + Letrozole 2.5 mg QD 1:1 Letrozole 2.5 mg QD N=66 Key Eligibility Criteria Measurable disease (RECIST 1.0) or bone-only disease ECOG PS of 0 or 1 Adequate blood counts and organ function No prior/current brain metastases N=99 a Schedule 3/1 Stratification Factors Disease Site (Visceral vs Bone only vs Other) Disease-Free Interval (>12 vs 12 mo from end of adjuvant to recurrence or de novo advanced disease) CDK, Cyclin-Dependent Kinase

9 Finn et al. AACR 2014

10 Finn et al. AACR 2014

11 CLEOPATRA: trastuzumab and pertuzumab in the 1st-line MBC Pertuzumab= humanized monoclonal antibody that binds HER2 n=406 Placebo + trastuzumab P D Patients with HER2-positive MBC No prior chemotherapy for MBC (N = 808) 1:1 n=402 Docetaxel* 6 cycles recommended Pertuzumab + trastuzumab Docetaxel* 6 cycles recommended P D Graphical elaboration from text data * <6 cycles allowed for unacceptable toxicity or PD; >6 cycles allowed at investigator discretion MBC, metastatic breast cancer; PD, progressive disease Baselga et al. N Engl J Med. 2012

12 Baselga et al. N Engl J Med 2012 Median survival Ptz+T+D=56,5 months 15,7 months gain vs Pla+T+D ESMO 2014

13 CLEOPATRA: AEs before and after discontinuation of docetaxel The safety profile was generally similar in the two groups, with no increase in LVEF dysfunction; the rates of febrile neutropenia and diarrhea of grade 3 were higher in the pertuzumab group than in the control group Swain SM et al. Lancet Oncol. 2013

14 Breast Cancer Res Treat 2013

15 Safety data Diarrhoea, fatigue, asthenia, decreased appetite, vomiting and dysgeusia were reported more frequently in patients aged 65 years in both treatment arms Neutropenia and febrile neutropenia were reported less frequently in the older age group (dose of docetaxel reduced more frequently and median number of cycles lower in 65) AEs grade 3 reported more frequently in the pertuzumab arm Febrile neutropenia (especially in the younger subgroup) and diarrhea (especially in the older subgroup) Peripheral neuropathy only in patients aged 65 (8%)

16 EMILIA Study Design Trastuzumab emtansine (T-DM1) = antibody drug conjugate in which trastuzumab is chemically linked to the emtansine HER2-positive LABC or MBC (N=980) Prior taxane and trastuzumab Progression on metastatic treatment or within 6 months of adjuvant treatment 1:1 T-DM1 3.6 mg/kg q3w IV Capecitabine 1000 mg/m 2 PO bid, days 1 14, q3w + Lapatinib 1250 mg/day PO qd PD PD Stratification factors: World region, number of prior chemo regimens for MBC or unresectable LABC, presence of visceral disease Primary endpoints: PFS by independent review, OS, and safety Verma S. et al N Engl J Med. 2012

17 PFS benefit was consistently observed across clinically relevant subgroups, with a less definitive benefit among patients aged 75 years (n=25) and those with non visceral or non measurable disease

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19 EMILIA - Adverse Events Grade 3 AEs With Incidence 2% Cap + Lap (n=488) T-DM1 (n=490) Adverse Event All Grades, % Grade 3, % All Grades, % Grade 3, % Diarrhea Hand-foot syndrome Vomiting Neutropenia Hypokalemia Fatigue Nausea Mucosal inflammation Thrombocytopenia Increased AST Increased ALT Anemia Rates of grade 3 or 4 adverse events were higher with lapatinib plus capecitabine than with T-DM1 (57% vs. 41%). The incidences of thrombocytopenia and increased serum aminotransferase levels were higher with T-DM1, whereas the incidences of diarrhea, nausea, vomiting, and palmar plantar erythrodysesthesia were higher with lapatinib plus capecitabine Verma S. et al N Engl J Med. 2012

20 Recent advances in the management of metastatic breast cancer in older adults Patient age should not limit the access to new treatment options; Close monitoring and proactive management of toxicities should clearly be undertaken Difficult to translate the results of these trials, conducted in selected patients, to the overall population of older adults, especially to those with comorbidities and increased susceptibility to adverse events

21 Back up

22 Patients, % Age <70 years Age 70 years Variable E+E (n=364) E+P (n=196) E+E (n=121) E+P (n=43) Discontinued Reasons - Progressive disease - Pt withdrew consent - Adverse events - Death - - Other On treatment deaths with AE as primary cause, n (exposure adjusted %) 3 (1.3) 1 (1.3) 4 (7.7) 0

23 Safety data Diarrhoea, fatigue, asthenia, decreased appetite, vomiting and dysgeusia were reported more frequently in patients aged 65 years in both treatment arms. Neutropenia and febrile neutropenia were reported less frequently in the older age group. Ten most common grade 3 adverse events (AE) Most common grade 3 AEs in the pertuzumab arm Febrile neutropenia and diarrhea in both age groups Peripheral neuropathy only in 65

24 Ann Oncol 2014; The Breast 2014 The decision to treat must take into account the relevant toxicities associated with this combination and should be made on a case-by-case basis

25 Finn et al. AACR 2014

26 PFS benefit was consistently observed across clinically relevant subgroups, with a less definitive benefit among patients aged 75 years (n=25) and those with non visceral or non measurable disease