ASCO 2002 Advances in the Adjuvant Chemotherapy of Breast Cancer Alessandro Riva, MD Breast Cancer International Research Group

Adjuvant Chemotherapy NIH Consensus Conference: Nov, 2000 Polychemotherapy for women with T > 1 cm, regardless of nodal, menopausal, or hormone receptor status Anthracycline-containing (ie, epirubicin or doxorubicin) regimens (4-6 cycles) Taxanes not yet recommended: based on 3 phase III trials with paclitaxel NIH Consensus Development Panel. J Natl Cancer Inst. 2001;93:979-989.

Adjuvant Chemotherapy EBCTCG Meta-Analysis: 1995, 2000 Reduction in Annual Odds, % Therapy Recurrence Death Polychemotherapy vs. 23.5 15 no chemotherapy (1995) (P < .00001) (P < .00001) Anthracyclines vs. 12 11 CMF (1995) (P = .006) (P = .02) Anthracyclines vs. 10.8 15.7 CMF (2000) (P = .0005) (P < .00001) Taxanes vs. Not done Not done Anthracyclines

Adjuvant Paclitaxel in Breast Cancer Summary of Reported Trials Sequential Regimens Study Regimen No. of Median DFS OS Pts F/U CALGB 9344 AC x 4 3,170 52 - mo 70% 81% (Henderson, 2000) AC x 4 ® P x 4 73 % 84 % P =.032 P =.074 NSABP B - 28 AC x 4 3,060 34 - mo 81% 90% (Mamounas, 2000) AC x 4 ® P x 4 81% 92 % M.D. Anderson FAC 4 ® FAC x 4 524 60 - mo 83% NR (Buzdar, 2002) P x 4 ® FAC x 4 86 %

Adjuvant Chemotherapy St Adjuvant Chemotherapy St. Gallen Consensus: Feb, 2001 Taxanes not yet recommended Goldhirsch et al. J Clin Oncol. 2001;19:3817-3827.

Adjuvant chemotherapy Major Areas of controversy (I) Which patients should not be treated ? Small primary tumor (Node neg., T< 1cm) ? Elderly patients (> 70 years old) ? ASCO 2002, Abs. 145: Epi-Dox+Tam vs. Tam Which is the optimal duration of anthracycline-based therapy ? 3 months (4cy) vs. 5 to 6 months (6 cy)? North American trial is planned

4 cycles better than 6 cycles? Anthracycline vs. CMF NSABP B-23 AC (4cy) = CMF (6cy) Intergroup 0102 CAF (6cy) > CMF (6cy) MA 5 CEF (6cy) > CMF (6cy) Danish-Swedish CEF (9cy) > CMF (9CY)

Adjuvant chemotherapy Major Areas of controversy (II) Which is the best schedule of adjuvant chemo-hormonal therapy? Sequential vs. concurrent? ASCO 2002, Abs. 143 and 144 Which is the benefit of adding Taxanes? Taxanes vs. no Taxanes ? BCIRG 001, ASCO 2002, Abs. 141, TAC vs. FAC

BCIRG 001: Efficacy Summary At 33 months median follow-up, TAC provides over FAC: Primary endpoint: Disease-Free Survival Overall 32% reduction (p=0.0011) By nodal status 1-3: 50% reduction (p=0.0002) 4+: 14% reduction (p=0.33) By hormonal status HR- : 38% reduction (p=0.005) HR+: 32% reduction (p=0.02) Relapse rate Secondary endpoint: Overall Survival Overall 24% reduction (p=0.11) By nodal status 1-3: 54% reduction (p=0.006) 4+: No difference Mortality rate

BCIRG 001 Disease Free Survival by HER2 status Negative (FISH) Positive (FISH) 100 100 90 90 TAC 80 80 % Alive and Disease Free TAC 70 FAC 70 60 60 50 242 with missing FISH RR = 0.74 p = 0.06 50 RR = 0.59 p = 0.02 FAC 40 40 12 24 36 48 12 24 36 48 Months Months N at Risk N at Risk TAC 485 467 433 102 1 TAC 138 131 118 32 FAC 478 455 402 108 FAC 148 135 107 26

BCIRG 001 Hematological Toxicity Treated (n=1,480) TAC n=744 FAC n=736 % ANC <1000 65.1* 49.0 Febrile Neutropenia§ 23.9* 2.4 Infection (Gr 3/4) 3.1 1.5 Septic Death Anemia (Gr 3/4) 4.8* 2.2 Thrombocytopenia (Gr 3/4) 1.8  Protocol required blood counts every 3 weeks § Gr 4 neutropenia at time of grade > 2 fever and i.v. antibiotics * p0.05

TAC n=744 FAC n=736 % Nausea 5.1 9.5* Vomiting 4.3 7.3* Diarrhea 3.4* BCIRG 001 Non-Hematological Toxicity Grade 3 or 4 with Incidence >1% TAC n=744 FAC n=736 % Nausea 5.1 9.5* Vomiting 4.3 7.3* Diarrhea 3.4* 1.0 Stomatitis 7.1* 2.0 Asthenia 11.2* 5.3 CHF 1.6 0.7 Premenopausal pts n=383 n=375 Amenorrhea 51.4* 32.8 *p0.05

Year 2002 What do Taxanes add to anthracycline regimens? Paclitaxel: CALGB 9344 (n=3170), NSABP B-28 (n=3060) AC (60,600;4cy) vs. AC (60,600;4cy) ® P (4cy) Docetaxel: BCIRG 001 (n=1491) FAC (500,50,500;6cy) vs. TAC (75,50,500;6cy)

CALGB 9344/NSABP B-28 vs. BCIRG 001 Comparators - Number of cycles: 4 (AC) vs. 6 (FAC) - Total dose doxo: 240 vs. 300 mg/m2 Taxane containing arms - Paclitaxel vs. docetaxel - Sequential vs. combination - 8 cycles (24 wks) vs. 6 cycles (18 wks) Patient and tumor characteristics

Patient and Tumor Characteristics CALGB 9344 NIH 11/00 (n=3170) NSABP B-28 NIH 11/00 (n=3060) BCIRG 001 ASCO 5/02 (n=1491) Age<50 60% 51% 54% 1-3 Positive Nodes 46% 70% 62% 4+ Nodes 54% 30% 38% T>2cm 63% 41% 60% HR+ 65% 66% 69% %Tamoxifen 60% 84% 69%

CALGB 9344/NSABP B-28 vs. BCIRG 001 Use of Tamoxifen CALGB 9344 and BCIRG 001: - all patients HR+ - after chemotherapy NSABP B-28: - all patients > 50 yrs old - all patients < 50 yrs and HR+ - concomitant with chemotherapy

Primary Endpoint: Disease-Free Survival CALGB 9344 n=3170 CALGB 9344 n=3170 NSABP B-28 n=3060 BCIRG 001 n=1491 Med Follow-up 30mo 52mo 34mo 33mo No. Events 624 (20%) 901 (28%) 551 (18%) 289 (19%) Risk Reduction Hazard Ratio p-value Log-rank Cox model 22% 0.78 (0.67-0.91) NA 0.0022 13% 0.87 (0.77-1.00) NA 0.0324 7% 0.93 (0.78-1.10) 0.38 NA 32% 0.68 (0.54-0.86) 0.001 0.0002

Secondary Endpoint: Overall Survival CALGB 9344 n=3170 CALGB 9344 n=3170 NSABP B-28 n=3060 BCIRG 001 n=1491 Med Follow-up 30mo 52mo 34mo 33mo No. Events Risk Reduction Hazard Ratio p-value Log rank Cox model 342 (11%) 26% 0.74 (0.60-0.92) NA 0.0065 589 (18%) 14% 0.86 NA 0.0746 269 (9%) 0% 1.00 (0.78-1.27) 0.98 NA 133 (9%) 24% 0.76 (0.54-1.07) 0.11 0.049

Absolute Differences Disease-Free and Overall Survival % Patients Disease-Free % Patients Alive CALGB 9344 3-yr AC ® P AC % Difference 79 74 5 88 85 3 NSABP B-28 3-yr 82 82 0 91 91 0 BCIRG 001 3-yr TAC FAC 82 8 92 87

Subgroup analyses: Hormone Receptor Status CALGB 9344† FDA 4/99 (n=3170) BCIRG 001 ASCO 5/02 (n=1491) Median Follow-up DFS Receptor Positive Risk Reduction Hazard Ratio Receptor Negative 30mo 8% 0.92 (0.73-1.16) 32% 0.68 (0.55-0.85) 33mo 32% 0.68* (0.49-0.95) 38% 0.62** (0.44-0.86) *p=0.02; **p=0.005 †Unplanned retrospective analysis

CALGB 9344 and NSABP B-28 Subgroup analysis Relative Risk of Recurrence (95% CI) Without Tam With Tam Adapted from the 2000 NIH Consensus Development Conference on Adjuvant Therapy for Breast Cancer.

Adjuvant Taxanes: Take home message Adjuvant Taxanes improve DFS (Level 1 evidence?): 2 positive trials (CALGB 9344, BCIRG 001) 1 negative trial (NSABP B-28) but: Tamoxifen concomitant to chemotherapy Tamoxifen to all patients > 50 years old Adjuvant Taxanes are becoming a reality for breast cancer patients: Clinical practice Comparators in the adjuvant trials The full integration of adjuvant Taxanes need: Longer follow up of the available studies: survival Results from the completed trials (n=10,000 pts)

Adjuvant Taxanes-Combination Regimens Only docetaxel studies: PK rationale ECOG (N+1-3, High risk N-, n=2,200, closed) AT (4cy) vs. AC (4cy) BIG 02-98 (N+, n=2,900, closed) AT (4cy) ® CMF (3cy) vs. AT (4cy) ® CMF (3cy)

OTHER ADJUVANT TRIALS WITH DOCETAXEL SEQUENTIAL REGIMENS ACCRUAL COMPLETED BIG 02-98 (N+) AC x 4  CMF x 3 AT x 4  CMF x 3 A x 4  CMF x 3 A x 3  T x 3  CMF x3 Italian Study (N>3) Epi x4  CMF x 4 Epi x4  T x 4  CMFx4 French Study (N+) FEC x 6 FEC x 3  T x 3 NSABP B-27 AC x 4  Surgery AC x 4  SurgeryT x 4 AC x 4  T x 4  Surgery A = Adriamycin; C = Cyclophosphamide; M = Mitomycin C; F = 5 FU; T = Taxotere; E = Epirubicin

Adjuvant Taxanes Other open questions (I) Which is the role of Taxanes in high risk node negative patients? ECOG (AT vs. AC): High risk N- and N 1-3; - n=2,200 (closed) - is a subgroup analysis reliable enough? GEICAM (TAC vs. FAC): High risk N- - n=1,100 (ongoing) - is the sample size large enough?

Adjuvant Taxanes Other open questions (II) 2. Which is the best Taxane? Intergroup, AC ® T(weekly; q-3 weekly) vs. AC ® P(weekly; q-3 weekly) 3. Which is the best schedule of a regimen containing Taxane and anthracycline ? Sequential vs. combination (only docetaxel studies) BCIRG 005, TAC (6) vs. AC (4) ® T (4) NSABP B-30, TAC (4) vs. AT (4) vs. AC ® T

BCIRG ADJUVANT STUDIES INTEGRATION OF NEW AGENTS Cytotoxic agents Capecitabine (Planned) Biologic agents Trastuzumab (Ongoing) TKIs (Planned) Anti-VEGFs (Planned)

AC vs. A ® C Intergroup 0137, ASCO 2002, Abs 142 Patient population/Study design N-, N1-3; n= 3176 AC (18 wks) vs. A (12 wks) ® C (6 wks) Prophylactic G-CSF in both groups Cumulative doses (mg/m2) A=324 and C=7200 in both groups Dose Intensity (mg/m2/wk) AC: A=18; C=400 A ® C: A=27; C=1200

Adjuvant Taxanes Other open questions (II) 2. Which is the best Taxane? Intergroup, AC ® T(weekly; q-3 weekly) vs. AC ® P(weekly; q-3 weekly) 3. Which is the best schedule of a regimen containing Taxane and anthracycline ? Sequential vs. combination (only docetaxel studies) BCIRG 005, TAC (6) vs. AC (4) ® T (4) NSABP B-30, TAC (4) vs. AT (4) vs. AC ® T