Advances in Breast Cancer Therapeutics in the Adjuvant and Metastatic Settings Eve Rodler, MD University of California at Davis October 2016
17th Annual Advances in Oncology September 30-October 1, 2016 Sacramento, CA Anna Orlowski, J.D. End of Life Option Act: Medical Legal Considerations. No relevant financial relationships in the past twelve months by presenter or spouse/partner. The speaker will directly disclosure the use of products for which are not labeled (e.g., off label use) or if the product is still investigational.
Early Stage Breast Cancer Extended adjuvant endocrine therapy Anthracyclines in HER2- breast cancer Platinum in TNBC Capecitabine for residual disease Dual HER2 blockade Metastatic Breast Cancer Endocrine monotherapy versus combination therapy Endocrine resistance and PI3K inhibition Role of T-DM1 in HER2+ disease Checkpoint inhibitors in TNBC
Early Stage Breast Cancer
Long term recurrence risks after use of endocrine therapy for only 5 years EBCTCG: Data from 91 trials on each individual with ER+ disease allocated only 5 years of endocrine therapy N= 46,000 women who were alive and disease free at 5 years Main finding: Even after 5 years of endocrine therapy, recurrences continue steadily, at least to year 20; significant even for T1N0 disease Pan H et al, 2016 ASCO Annual Meeting, abstract 505
EBCTCG: Long term recurrence risks after 5 years of endocrine therapy Slide 12 Pan H et al, 2016 ASCO Annual Meeting, abstract 505
Benefits of extended adjuvant endocrine therapy MA.17: After 5 years of tamoxifen, the addition of 5 years of adjuvant letrozole reduces breast cancer recurrence by 43% compared to placebo (HR 0.57; p < 0.001), and improves survival by 39% at 64 months f/u (HR 0.61; p < 0.001) 1,2 ATLAS/aTTOM: Compared to 5 years of tamoxifen, 10 years of tamoxifen reduces breast cancer mortality by 15% in all years and by 25% starting at year 10. 3,4 1. Goss P et al. NEJM 2003;349(19):1793-802 2. Jin H et al. J Clin Oncol 2012;30(7):718-21. 3. Davies C et al. Lancet 2013;381:805-16 4. Gray RG et al. J Clin Oncol 2013;31 (suppl;abstr 5).
MA.17R Trial Study Design n=1918 randomized phase III Letrozole 2.5 mg po daily +/- Tamoxifen any duration AI 4.5 to 6 Years R Hormone receptor positive Postmenopausal and disease-free 1:1 Placebo 5 years Goss P, et al. ASCO 2016, LBA1
MA.17R Disease-free survival Median f/u 6.3 years Goss P, et al. ASCO 2016, LBA1
MA.17R DFS by pre-specified subgroups Goss P, et al. ASCO 2016, LBA1
MA.17R MA.17R is the first study to show benefit of extending AI use beyond 5 years 34% reduction in disease recurrence. There were no significant differences between the placebo group and the letrozole group related to most measures of quality of life. Bone health remains an issue. Biomarkers/multi-gene signatures are needed to determine which patients are most at risk for late recurrences
1 Can anthracyclines be omitted in patients with high risk lymph node negative or node positive, HER2- negative breast cancer? TC x 4 vs AC x 4 demonstrated OS superior for TC (HR =0.69; p=0.032) 2 However, no comparison to combination or sequential anthracycline and taxane regimen. TC x 6, often used in clinical practice, became the standard to compare with TaxAC regimens 1 Blum JL et al, ASCO 2016, abstract 1000 2 Jones S et al, J Clin Oncol 2009;27:1173-83
ABC Trials Study Design HER2 - Lymph node + High Risk LNn = 4,130 phase III R Arm 1 (TaxAC) TAC q 3 wk x 6 cycles or AC q 3 wk x 4 cycles paclitaxel q 1 wk x 12 or AC q 2 wk x 4 cycles paclitaxel q 1 wk x 12 or AC q 2 wk x 4 cycles paclitaxel q 2 wk x 4 Arm 2 Docetaxel/cyclophosphamide (TC) TC x 6 cycles * High risk lymph node negative defined as pt2-t3 pn0; or pt1c if pn0 then must be either ER and PR negative; ER+ or PR+ and either Grade 3 or Oncotype Dx Recurrence Score > 31 for USOR 06-090 and > 25 for B-46I/07132 and B-49
ABC Trials: Invasive Disease Free Survival The primary aim: Determine if invasive disease free survival with TC is non-inferior compared to TaxAC, defined by HR of less than 1.18 Blum JL et al, ASCO 2016, abstract 1000
Slide 17 Blum JL et al, ASCO 2016, abstract 1000
Triple Negative Breast Cancer has Worse Outcome if Residual Disease Present after Neoadjuvant Chemotherapy TNBC pts (n=255) compared with non-tnbc pts (n=863) had higher pcr rates (22% vs 11%) However, TNBC pts had lower 3-yr PFS and OS rates If pcr was achieved, TNBC pts and non-tnbc pts had similar outcome If residual disease present, TNBC pts had worse outcome compared with non-tnbc pts Liedtke C et al. J Clin Oncol 2008;26:1275-81
GeparSixto Neoadjuvant Study Design TNBC regimen n = 315 phase II TNBC R Paclitaxel 80 mg/m2 q 1 wk x 18 Non-pegylated liposomal doxorubicin 20 mg/m2 q 1wk x 18 Bevacizumab 15 mg/kg q 3 wk Paclitaxel 80 mg/m2 q 1 wk x 18 Non-pegylated liposomal doxorubicin 20 mg/m2 q 1wk x 18 Bevacizumab 15 mg/kg q 3 wk Carboplatin AUC 1.5 q wk x 18 S U R G E R Y pcr, % PMCb PM P Value TNBC (n = 315) gbrca wild type (n = 241) gbrca mutant (n = 50) 53.2 50.8 61.5 36.9 33.1 50.0.005.005.413 von Minckwitz G et al. SABCS 2015. Abstract S2-04.
GeparSixto: DFS advantage demonstrated with carboplatin in TNBC von Minckwitz G et al. SABCS 2015. Abstract S2-04.
CALGB 40603: phase II trial neoadjuvant chemo/bev +/- carbo +/- bev pcr rate in TNBC Sikov, JCO 2015
CALGB 40603: No DFS advantage with carboplatin in TNBC Sikov WM, et al. J Clin Oncol. 2015;33:13-21.
Platinum therapy in early stage TNBC Prospective randomized data are conflicting regarding use of pathologic CR as surrogate for DFS on a trial level, though underpowered to show this. Studies consistently show that achieving a pathologic CR is prognostic on an individual patient level. The routine addition of a platinum agent to ACT-based neoadjuvant therapy for patients with early stage TNBC should not be considered a standard of care. However, higher pcr rates associated with the addition of carboplatin may be beneficial for some patients. Incorporation of robust correlative studies in future trials is needed to identify TNBC patients who will benefit from platinum.
NRG-BR003 - Randomized Phase III Trial of Adjuvant Therapy Comparing Doxorubicin Plus Cyclophosphamide Followed by Weekly Paclitaxel with or without Carboplatin for Node-Positive or High-Risk Node-Negative Triple-Negative Invasive Breast Cancer N = 990 Resected LN+ or High Risk LN- ER/PR/HER2- Early stage BC Primary endpoint: IDFS R AC q 2 wks x 4 followed by paclitaxel q 1 wk x 12 AC q 2 wks x 4 followed by paclitaxel q 1 wk x 12 plus carboplatin AUC 5 q 3 wk x 4
Residual disease after neoadjuvant chemotherapy and surgery: CREATE-X n = 910 phase III HER2-, Stage I-IIIB NAC Surgery Pathology Non-pCR or node + R Control Standard Therapy Standard Therapy + Capecitabine 2500 mg/m 2 /d d 1-14 q 3 wk x 8 Stratified by ER status, age, neoadjuvant chemotherapy, use of 5- FU, institution, node status Standard therapy: HR+: Hormone therapy HR-: No further systemic treatment 1. Toi M, et al. SABCS 2015. Abstract S1-07. 2. Ohtani S, et al. SABCS 2013. Abstract P3-12-03.
CREATE-X: 5-Yr Efficacy Capecitabine achieved significantly higher 5-yr DFS and OS in HER2- BC pts with residual disease Characteristic, % Capecitabine (n = 440) No Capecitabine (n = 445) 5-yr DFS 74.1 67.7 5-yr OS 89.2 83.9 HR (95% CI) 0.70 (0.53-0.93) 0.60 (0.40-0.92) P Value.00524 <.01 Toi M, et al. SABCS 2015. Abstract S1-07.
Capecitabine may have benefit in high risk populations CREATE-X subgroup analysis suggests the benefit was predominantly in the TNBC subgroup (HR 0.58). Other studies have shown benefits of (neo)adjuvant capecitabine added to standard chemotherapy in TNBC subgroups (ABCSG-24; FinnXX), but did not achieve their primary endpoints, so were negative overall. Results of CREATE-X should be confirmed in an adjuvant study that would evaluate high risk population of TNBC patients.
EA1131: A randomized phase III post-operative trial of platinum agent chemotherapy vs. capecitabine in patients with residual triple-negative breast cancer (TNBC) following neoadjuvant chemotherapy Accrual goal 750 TNBC Stage II/III NAC Surgery Pathology > 1 cm residual disease Tissue submission PAM 50 analysis R Cisplatin 75 mg/m 2 d1 q 3 wk x 4 cycles or Carboplatin AUC 6 d1 q 3 wk x 4 cycles Capecitabine 1000 mg/m 2 /d d1-14 q 3 wk x 6 cycles * Choice of platinum agent will be per treating physician discretion Primary endpoint: IDFS in patients with basal-like TNBC Secondary endpoints: IDFS in patients with non basal-like TNBC, OS, RFS
Metastatic Breast Cancer
Endocrine monotherapy in first line metastatic setting Postmenopausal patients with HR+ metastatic breast cancer without prior exposure to AIs, or those with late relapses, recommendation is for non-steroidal AI monotherapy (ASCO guidelines). Phase II FIRST trial results suggest fulvestrant may be superior to non-steroidal AI as front-line therapy. fulvestrant (500mg) (F) vs anastrazole (A) n = 205 postmenopausal, HR+ pts TTP: F 23.4 mo A 13.1 mo HR 0.66 p= 0.01 OS: F 55.1 mo A 48.4 mo HR 0.70 p=0.04 Confirmatory phase III FALCON trial ongoing Ellis M, et al, J Clin Oncol 2015; Robertson J et al, SABC 2010, abstract S1-3 Robertson J, et al, J Clin Oncol 2009;27:4530-35
Endocrine combination therapy in first line metastatic setting Preclinical studies identified luminal ER positive subtype as being palbociclib-sensitive with synergy demonstrated between palbociclib and anti-estrogens. 1 PALOMA-I, randomized phase II study of palbociclib plus letrozole vs letrozole alone as first-line therapy for HR+ advanced breast cancer 2 Addition of palbociclib to letrozole demonstrated 10- month improvement in PFS over letrozole alone (HR 0.49; p = 0.0004) and acceptable safety profile Accelerated FDA approval granted 1. Finn et al, Breast Cancer Research 2009; 2. Finn et al, Lancet Oncol 2015.
PALOMA 2 Study Design Prospective, randomized, double-blind, placebo-controlled phase III trial n = 666 phase Postmenopausal HR+ HER2- advanced breast cancer No prior treatment for advanced disease AI resistant patients excluded R Palbociclib 125 mg daily (3/1 schedule) + Letrozole 2.5 mg daily Placebo (3/1 schedule) + Letrozole 2.5 mg daily Finn R et al, ASCO 2016, Abstract 507
PALOMA 2 PFS Investigator-Assessed (ITT Population) Finn R et al, ASCO 2016, Abstract 507
PALOMA 2 Finn R et al, ASCO 2016, Abstract 507
PALOMA-2 Safety Most common AE was neutropenia: 80% in palbociclib plus letrozole arm vs 6% in placebo plus letrozole. SAEs occurred in < 1% of pts, except febrile neutropenia in 1.6% in the palbociclib plus letrozole arm vs 0 in placebo arm. Grade 3/4 non-hematologic AEs uncommon in both arms. Deliverabilty was > 90% in palbociclib arm and 94% in placebo arm Finn R et al, ASCO 2016, Abstract 507
PALOMA 3: Palbociclib and fulvestrant in endocrine resistant metastatic breast cancer PALOMA 3 phase III trial (n=512) evaluated palbociclib plus fulvestrant versus fulvestrant alone in patients with HR+ advanced breast cancer that had progressed on prior endocrine therapy Palbociclib plus fulvestrant demonstrated significant increase in PFS, 9.2 mo vs 3.8 mo (HR 0.42; p < 0.001), similar toxicity profile as observed in PALOMA-1 Basis for FDA approval of palbociclib with fulvestrant Turner NC, et al. NEJM 2015;373:1672-1683
Sequencing endocrine therapies in the metastatic setting for postmenopausal patients 1 st line options: nonsteroidal AI monotherapy fulvestrant monotherapy (await FALCON) non-steroidal AI plus CDK 4/6 inhibitor (PALOMA-2) non-steroidal AI plus fulvestrant (SWOG 0226) If use non-steroidal AI plus CDK 4/6 inhibitor upfront, then challenging to determine subsequent lines of therapy after progression If use non-steroidal AI monotherapy upfront, then can use fulvestrant plus CDK 4/6 inhibitor 2 nd line and exemestane +/- everolimus 3 rd line
PI3K inhibition in endocrine resistant metastatic breast cancer: BELLE-2 Study n = 1147 phase III Postmenopausal HR+ HER2- advanced breast cancer with progression on/after AI therapy R Buparlisib 100 mg/day + Fulvestrant 500 mg Placebo + Fulvestrant 500 mg Baselga J, et al. SABCS 2015. Abstract S6-01.
BELLE-2: PFS results and efficacy by PI3KCA mutation in ctdna Median PFS, Mos n Buparlisib + Fulvestrant (n = 576) Placebo + Fulvestrant (n = 571) Overall population 1,147 6.9 5.0 PI3K-activated pts 372 6.8 4.0 ctdna PIK3CA mutant ctdna PIK3CA nonmutant 200 7.0 3.2 387 6.8 6.8 HR (95% CI) 0.78 (0.67-0.89) 0.76 (0.60-0.97) 0.56 (0.39-0.80) 1.05 (0.82-1.34) PFS significantly longer with use of buparlisib + fulvestrant in the overall population but not significantly extended in pt population with a known PI3K activation status (threshold p =.01 in trial design) Buparlisib + fulvestrant extended PFS in pts with PIK3CA mutations in circulating tumor DNA versus fulvestrant alone, but not in pts with non-mutant PIK3CA. P Value <.001.014 <.001.642
TH3RESA: Study Design N = 602 Phase 3 Pts with HER2+ advanced breast cancer, 2 prior anti- HER2 therapies R T-DM1 3.6 mg/kg q3w IV Therapy of Physician s Choice PD PD T-DM1 Optional crossover. Wildiers H, et al. SABCS 2015. Abstract S5-05.
TH3RESA: Final OS analysis Median OS significantly improved with use of T-DM1 vs physician-selected therapy in pretreated pts with HER2+ MBC: 22.7 months vs 15.8 months HR 0.68 (95% CI: 0.54-0.85; P =.0007) 44.9% of TPC arm pts received T-DM1 crossover therapy T-DM1 is preferred treatment for patients whose metastatic disease has progressed after treatment with a combination of a taxane based chemotherapy and trastuzumab, with or without pertuzumab. Wildiers H, et al. SABCS 2015. Abstract S5-05.
Immunotherapy in TNBC Cancer cells can use PD1/PDL1 pathway to evade the immune system by expressing PDL1 and down regulating immune responses. Blocking the interaction of PD1 and PDL1 releases the stop on T cells and allows T cell mediated immune responses against tumor cells. There is higher expression of PDL1 mrna in TNBC compared to non-tnbc. TNBCs have high mutational burden and may produce neoantigens leading to an immune response. 20 to 30% of TNBCs are associated with tumor infiltrating lymphocytes (TILs) which can facilitate an immune response.
Immune checkpoint blockade in metastatic TNBC Pembrolizumab ant-pd-1 antibody blocks interaction PD- 1 receptor and its ligands PD-L1 and PD-L2 Phase 1B trial in metastatic TNBC KEYNOTE-012 n = 32; 46.9% had > 3 prior line of therapy all tumors positive for PD-L1 expression pembrolizumab 10 mg/kg IV every 2 weeks response rate 18.5% (CR 1 pt; PR 4 pts) median duration of response not reached (range 15 to 40 months) trend toward more clinical benefit with increasing PD-L1 expression Buisseret L et al, Annals of Onc 2015 ;26 : 6-9.
Immune checkpoint blockade with chemotherapy in metastatic TNBC Atezolizumab anti-pdl1 antibody blocks PD-L1/PD-1 and PD-L1/B7.1 interaction. Phase 1-b evaluated atezolizumab in combination with weekly nabpaclitaxel in metastatic TNBC pts Up to 3 prior lines of chemotherapy Responses seen in pts with (77%) and without (57%) PD-L1 expression Adams S et al. ASCO 2016, abstract 1007.
Conclusions Early Stage Breast Cancer Extended adjuvant AI therapy for 10 years improves DFS in HR+ postmenopausal BC patients. Adjuvant anthracyclines improve DFS in LN positive and high risk LN negative HER2- early stage BC patients. The role of platinum in early stage TNBC is not yet defined. Trials are ongoing to determine who will benefit. Capecitabine for TNBC patients with residual disease after surgery improved OS in one study and needs confirmation. Advanced breast cancer CDK 4/5 inhibition plus endocrine therapy improves DFS in advanced HR+ BC, but which line of therapy, which patients? T-DM1 improves OS in HER2+ advanced breast cancer in 2 nd line therapy and beyond. Checkpoint inhibition in TNBC can provide durable responses and is being tested further. Some PDL-1 expression appears better than none.