TITLE: Systemic Therapy for Patients with Advanced HER2-Positive Breast Cancer: American Society of Clinical Oncology Clinical Practice Guideline

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1 TITLE: Systemic Therapy for Patients with Advanced HER2-Positive Breast Cancer: American Society of Clinical Oncology Clinical Practice Guideline Table of Contents Data Supplement 1: Additional Evidence Tables from Studies Identified in the Systematic Review Table 1: Study Characteristics Table 2: Participant and Disease Characteristics Data Supplement 2: Search Strategy string and dates Data Supplement 3: QUOROM Diagram Data Supplement 4: Clinical Questions Data Supplement 5: Multiple Chronic Conditions Table Data Supplement 6: Expanded Discussion: Literature Review and Analysis Data Supplement 7: Expanded Discussion on Patient and Clinician Communication Data Supplement 8: Glossary of Terms References ASCO HER2-Positive Advanced Breast Cancer Non-Brain Metastases Treatment Guideline - Data Supplement 1

2 DATA SUPPLEMENT 1: Additional Evidence Tables Table 1: Study Characteristics Study Interventions N randomized J. Baselga/S. M. Swain CLEOPATRA 2012 pertuzumab + trastuzumab + docetaxel trastuzumab + docetaxel + placebo N analyzed-efficacy N-safety Randomized Arm 1: 402, Arm 2: 406, Overall: 808 NOTE: Data for patients who did not have evidence of independently assessed progressive disease or who had not died within 18 wks. after the last tumor assessment were censored at the time of the last independent tumor assessment that provided results that could be evaluated Analyzed-Efficacy Arm 1: 402, Arm 2: 406, Overall: 808 Analyzed-Safety Arm 1: 407, Arm 2: 397, Study Duration (m/yyyy and total time) Feb/2008- July/2010, 2 yrs., 5 mos. (data cutoff 5/13/2011) Primary/Secondary Outcome(s) Primary PFS: determined on the basis of the assessment of tumors at an independent review facility (independently assessed progressionfree survival). NOTE: PFS = the time from randomization to the first documented radiographic evidence of progressive disease according to RECIST. Secondary OS, AEs, Objective Response rate, Other: investigator-assessed PFS Inclusion/Exclusion Criteria Inclusion Locally recurrent, unresectable, or metastatic HER2-positive breast cancer. HER2-positive status was confirmed centrally, by means of IHC (3+) or FISH (amplification ratio 2.0). 18 yrs., LVEF 50% at baseline, ECOG 0-1, 1 endocrine treatment, if previous trastuzumab, then 12 month interval between neo- or adjuvant and metastatic diagnosis. Exclusion CNS metastases, prior cumulative dose of doxorubicin >360 mg/square meter BSA or equivalent, previous decline in LVEF to <50% during or after previous trastuzumab, or "current uncontrolled medical conditions that could limit a patient s ability to undertake study therapy." Follow-Up Median 19.3 mos. RECIST assessment every 9 wks. by investigator and independent review (until time of DP or death), LVEF: up to 3 yrs. after discontinuation, pts. with cardiac events or serious AEs - up to 1 yr. after final dose or 1 yr. of such events after discontinuation of treatment. NOTE: Safety data reported for those who had received 1 ASCO HER2-Positive Advanced Breast Cancer Non-Brain Metastases Treatment Guideline - Data Supplement 2

3 Study Interventions N randomized N analyzed-efficacy N-safety dose Study Duration (m/yyyy and total time) Primary/Secondary Outcome(s) Inclusion/Exclusion Criteria Follow-Up J. Huober/N. Harbeck electra 2012 M. Andersson/S. T. Langkjer HERNATA 2011 trastuzumab + letrozole letrozole alone trastuzumab + docetaxel trastuzumab + vinorelbine Randomized Arm 1: 26, Arm 2: 31, Arm 3: 35, Overall (92) Analyzed-Efficacy Analyzed-Safety Randomized Arm 1: 143, Arm 2: 141, Overall 284 Analyzed-Efficacy Arm 1: 143, Arm 2: 141, Overall 284 Analyzed-Safety (closed prematurely in 2007) May 2004 to August 2008 Primary Other: TTP, NOTE: defined as date of randomization/start of treatment and earliest date of progression, or of breast cancer mortality Secondary OS, Response rate: objective/cbr, Other: TTF. Duration of response/cb - interval between. Randomization and earliest date of progression in subset w/ confirmed assessment of OR or CB, NOTE: ORR=CR + PR. CBR-CR, PR, or SD 24 wks. Primary Other: TTP Secondary OS, AEs, Response rate, Other: 1 yrs. survival, TTF Inclusion Women who were postmenopausal with newly dx HER+ MBC or LABC, Arms 1 and 2 primary tumor had to be HER2+l. No prior treatment for MBC or LABC, LVEF 50% baseline, adequate hepatic, renal, bone marrow function, ECOG PS 0-1, 1 measurable lesion Exclusion Clinical or radiological signs of CNS metastases, IBC, other concurrent or previous malignant disease, uncontrolled cardiac disease, prior anti-her2+ apart from adjuvant trastuzumab. Inclusion Eligible patients were 18 to 75 yrs. of age with MBC or LABC verified histologically or cytologically and HER2- positive status assessed locally by IHC (3) or FISH positivity on the primary cancer or from a biopsy of a metastatic lesion. The ASCO HER2-Positive Advanced Breast Cancer Non-Brain Metastases Treatment Guideline - Data Supplement 3 TTP was measured from random assignment to date of documented progression with censoring for (for patients alive) at last visit date or at date of death. OS was calculated from date of random assignment to

4 Study Interventions N randomized N analyzed-efficacy N-safety Arm 1: 139, Arm 2: 138 Study Duration (m/yyyy and total time) Primary/Secondary Outcome(s) Inclusion/Exclusion Criteria patients had to have measurable or nonmeasurable disease; performance status 2 according to WHO; adequate bone marrow, liver, renal, and cardiac function with normal LVEF as defined by each institution; and an estimated life expectancy of more than 12 wks.. Chemotherapy and HER2- targeted treatment was allowed as (neo-) adjuvant therapy (for taxanes, vinorelbine, and trastuzumab > 12 mos. before), but not for treatment of metastatic or locally advanced disease. Previous endocrine therapy was allowed for both early-stage and advanced disease. Follow-Up date of death with censoring for patients still alive at last visit date. TTF was defined as the time from date of random assignment to the date of the last study chemotherapy administration, with censoring for patients still on treatment. Note that this definition of TTF allows continued trastuzumab beyond TTF. Exclusion V. Valero/D. J. Slamon BCIRG docetaxel, carboplatin, and trastuzumab (TCH) docetaxel and trastuzumab (TH) Randomized Arm 1: TH n=131, Arm 2: TH n=131, Overall 263 Analyzed-Efficacy December March 2004 (accrual) Primary NOTE: TTP - interval from the day of random assignment to the date of disease progression, diagnosis of second primary malignancy, or Brain metastasis, dyspnea, second primary malignancy, and serious concomitant illness. Inclusion Women w/ MBC FISH+ from central lab, measurable lesions per RECIST or nonmeasurable 2 radiologically evident lytic bone lesions. Patients were Cutoff date 12/2008 (F/U 4-7 yrs.) ASCO HER2-Positive Advanced Breast Cancer Non-Brain Metastases Treatment Guideline - Data Supplement 4

5 Study Interventions N randomized V. Valero/D. J. Slamon BCIRG (cont d) N analyzed-efficacy N-safety Arm 1: TH n=131, Arm 2: TH n=131 Analyzed-Safety Arm 1: 131, Arm 2: 131, Overall 262 Study Duration (m/yyyy and total time) Primary/Secondary Outcome(s) death Secondary OS: definition interval between date of 1st does and date of allcause death, Response rate, Other: duration of response Inclusion/Exclusion Criteria between 18 and 75 yrs. of age, with a Karnofsky performance status 60%. Prior taxane-based adjuvant or neoadjuvant chemotherapy was permitted if relapse had occurred 6 mos. after the discontinuation of taxanebased therapy; prior trastuzumab adjuvant or neoadjuvant therapy (without prior taxane therapy) was permitted if 6 mos. had elapsed since the end of such therapy; prior taxane-trastuzumab based adjuvant or neoadjuvant therapy was permitted if 12 mos. had elapsed since the end of such therapy. Patients were eligible if neoadjuvant anthracycline dosages did not exceed 360mg/m 2 for doxorubicin or 720 mg/m 2 for epirubicin. Prior endocrine therapy was allowed if progressive disease was documented. Prior palliative radiation therapy was allowed if 4 wks. had elapsed since the end of radiation therapy. Follow-Up Exclusion Prior platinum salt therapy, chemotherapy, or trastuzumab for MBC. ASCO HER2-Positive Advanced Breast Cancer Non-Brain Metastases Treatment Guideline - Data Supplement 5

6 Study Interventions N randomized L. S. Schwartzberg/S. Johnston 2010 lapatinib + letrozole letrozole + placebo N analyzed-efficacy N-safety Randomized Arm 1: 111, Arm 2: 108, Overall 219 Analyzed-Efficacy Arm 1: 111, Arm 2: 108, Overall: 219 NOTE: For efficacy. Also for QOL 1 Analyzed-Safety Arm 1: 113, Arm 2: 106, Study Duration (m/yyyy and total time) Accrual December 9, 2003 and December 29, Data lock on 6/3/2008. Primary/Secondary Outcome(s) Primary PFS: RECIST, investigator-assessed, NOTE: "time from randomization until the earliest date of disease progression or death resulting from any cause." Secondary OS, AEs, Response rate: ORR, Other: CBR, NOTE: CBR=CR, PR, of SD 6 mos. Inclusion/Exclusion Criteria Inclusion Postmenopausal women with ER or progesterone receptor positive (i.e., HR), histologically confirmed, advanced breast cancer or MBC (stage IIIb/c or stage IV). Prior neoadjuvant/adjuvant chemotherapy, antiestrogens, and radiotherapy were allowed. ECOG PS, normal organ function, cardiac ejection fraction within the institutional range of normal. Follow-Up (Until DP or withdrawal) NOTE: 2 randomized to letrozole + placebo actually received letrozole + lapatinib Exclusion Prior therapy for advanced or metastatic disease was prohibited. Extensive symptomatic visceral disease and current or past central nervous system metastases were causes for exclusion. ASCO HER2-Positive Advanced Breast Cancer Non-Brain Metastases Treatment Guideline - Data Supplement 6

7 Study Interventions N randomized B. Kaufman/A. Jones TAnDEM 2009 anastrozole trastuzumab + anastrozole NOTE: Treatment was planned to continue until PD, at which point patients in the anastrozole alone arm could switch to a trastuzumabcontaining regimen. N analyzed-efficacy N-safety Randomized Arm 1: 104, Arm 2: 103, Overall 207 Analyzed-Efficacy Arm 1: 104, Arm 2: 103, Overall 207 Analyzed-Safety Study Duration (m/yyyy and total time) Primary Primary/Secondary Outcome(s) "With the exception of fatal AEs, which are reported both up to and after cross over, AE values for the anastrozole alone arm are only up to the point of cross over to trastuzumab," ORR, CBR, TTP, duration of response Secondary PFS Inclusion/Exclusion Criteria Inclusion Postmenopausal, HER2+ IHC 3+ or FISH 2 amplification, HR+, MBC. LVEF >50%, adequate baseline hepatic, renal, and bone marrow function, ECOG 0-1, and measurable or evaluable disease Exclusion Clinical or radiologic evidence of CNS metastases; history of another malignancy, CHF, or uncontrolled cardiac disease (angina, arrhythmias, hypertension); uncontrolled serious intercurrent illness; and severe dyspnea at rest. Patients who had received an investigational drug within 30 days of starting study medication or previous anti-her2 therapy were ineligible. Patients with previous radiotherapy to indicator lesions were excluded from the response evaluation. Follow-Up NR ASCO HER2-Positive Advanced Breast Cancer Non-Brain Metastases Treatment Guideline - Data Supplement 7

8 Study Interventions N randomized K. Inoue/S. Noguchi JO trastuzumab then trastuzumab + T: sequential: trastuzumab + T concurrent NOTE: 107/108 safety population included in modified-itt N analyzed-efficacy N-safety Randomized Arm 1: 56, Arm 2: 56 (1/56 assigned by not treated at time of data cutoff), Overall 112 (authors said assigned 111 assigned) Analyzed-Efficacy Arm 1: 55, Arm 2: 53, Overall, NOTE: 107/108 safety population included in modified-itt Analyzed-Safety Arm 1: 54, Arm 2: 53, Overall 108 Study Duration (m/yyyy and total time) Accrual 9/2004-5/2008 Primary/Secondary Outcome(s) Primary PFS: for trastuzumabmono stage of sequential, and Arm 2, OS: for both arms, NOTE: joint primary endpoints Secondary PFS: second PFS during trastuzumab + docetaxel of sequential, AEs, Response rate: ORR in trastuzumabmono stage of sequential, and Arm 2, ORR in trastuzumab+ docetaxel stage of sequential, Other: TTF in trastuzumab-mono stage of sequential, and Arm 2 Inclusion/Exclusion Criteria Inclusion Female with breast cancer confirmed by tissue and cytologic dx, HER2+ by IHC 3+ or FISH+ by local institution confirmed in primary or target met lesions, measurable lesions by RECIST, ECOG PS 0-1, LVEF >50% on EKG. Exclusion NR Follow-Up data cutoff 5/2/2008, OS data as of 9/1/2008 ASCO HER2-Positive Advanced Breast Cancer Non-Brain Metastases Treatment Guideline - Data Supplement 8

9 Study Interventions N randomized K. L. Blackwell/S. Verma EMILIA 2012 T-DM1 (3.6 mg/kg q3w) lapatinib (1250 mg/day)+ capecitabine (1000 mg/m 2, d 1-14, q3w) N analyzed-efficacy N-safety Randomized Arm 1: 495, Arm 2: 496, NOTE: 991 Analyzed-Efficacy Arm 1: 495, Arm 2: 496, NOTE: 991 Analyzed-Safety Arm 1: 490, Arm 2: 488 Study Duration (m/yyyy and total time) 2/ / yrs., clinical data cutoff 1/14/12 Primary/Secondary Outcome(s) Primary PFS: by independent review, OS, AEs, NOTE: co-primary endpoint Secondary PFS: by investigator, Response rate: ORR, duration of response, Other: time to symptom progression Inclusion/Exclusion Criteria Inclusion Required previous trastuzumab tx. PD on met tx or w/in 6 mos adjuvant tx, central confirmation of HER2+. Exclusion NR Follow-Up Median (range) Arm (0-34), Arm (0-35) K. A. Gelmon/W. Parulekar MA.31/GSK EGF lapatinib + taxane, then lapatinib trastuzumab + taxane, then trastuzumab Randomized Arm 1: 318, Arm 2: 318, Overall 636 Analyzed-Efficacy Arm 1: 318, Arm 2: 318, Overall wks. combo, then mono until PD. Accrual 10/ /2011. Primary PFS Secondary OS, AEs Inclusion Women, HER2+ central or local lab, no prior chemo or HER2 targeted tx in met setting. Mandatory tissue for central testing. Prior NACT chemo/h allowed in 12 mos. Median 13.6 mos. (12.9 mos. L, 14 mos. H). Database lock 4/13/12. 1 yr. planned. Median 13.6 mos. (12.9 mos. L, 14 mos. trastuzumab) Analyzed-Safety Exclusion Arm 1: 313, Arm 2: 317, NOTE: 630 "Standard" No CNS metastases ASCO HER2-Positive Advanced Breast Cancer Non-Brain Metastases Treatment Guideline - Data Supplement 9

10 Study Interventions N randomized Cameron/Geyer EGF lapatinib plus capecitabine (combo) capecitabine N analyzed-efficacy N-safety Randomized Arm 1: 207, Arm 2: 201, Overall 408, NOTE: QOL study 2 171/198 LC and 168/201 C patients at baseline (see Table 1) Analyzed-Efficacy NR Study Duration (m/yyyy and total time) 3/2004 until 10/2008 Primary/Secondary Outcome(s) Primary Other: TTP as determined by an independent review panel Secondary PFS, OS, AEs, Response rate, Other: BR=CR, PR, or SD 6 mos. Inclusion/Exclusion Criteria Follow-Up 3/2004 until 10/ ~4.5 yrs. Analyzed-Safety Blackwell, EGF /2012 lapatinib alone lapatinib and trastuzumab 3/29/2004-4/3/2006 3,4 2 yrs. (note: data lock 11/15/2005 [In 5 says data lock 4/3/2006]) Randomized Arm 1: 145, Arm 2: 146, Overall: 291 NOTE: for QOL scores only for patients 80% of times from the relevant questionnaire) 6. At withdrawal 132 and 137 available, 71 (54%) and 66 (48% completed [i.e. 1 question on FACT-B questionnaire completed. FACT-B 1 yr., 11/ /2006 Primary PFS: based on investigator assessments according to RECIST Secondary OS, AEs, QOL: By FACT-B, Response rate: ORR: CR + PR, Other: Clinical benefit response rate (CR + PR + SD 24 wks.) Inclusion Women 18 yrs. of age with histologically or cytologically confirmed BC, met disease progressed on their most recent treatment regimen, which must have contained trastuzumab. IHC3+ or FISH+. Prior anthracyclineor taxane-based tx in adjuvant or met setting. 1 met measurable lesion according to RECIST. ECOG PS 2 and adequate hematologic, renal, hepatic function; and a cardiac ejection fraction within the ASCO HER2-Positive Advanced Breast Cancer Non-Brain Metastases Treatment Guideline - Data Supplement 10

11 Study Interventions N randomized Blackwell, EGF /2012 (cont d) N analyzed-efficacy N-safety time to deterioration 141 and 141 Analyzed-Efficacy Arm 1: 146, Arm 2: 149, Overall: 291 Study Duration (m/yyyy and total time) Primary/Secondary Outcome(s) Inclusion/Exclusion Criteria institutional normal range. Exclusion NR Follow-Up Analyzed-Safety 1 yr., 11/ /2006 Abbreviations: AEs, adverse events; BSA, body surface area; CB, clinical benefit; CBR, clinical benefit rate; CHF, congestive heart failure; CNS, central nervous system; chemo, chemotherapy; DFS, disease-free survival; DP, disease progression; dx, diagnosis; ECOG, Eastern Cooperative Group; EKG, electrocardiogram; ER, estrogen receptor, FACT-B, Functional Assessment of Cancer Therapy Breast; FISH, fluorescent in situ hybridization; F/U, follow-up; H, Herceptin; HR, hazard ratio; IBC, inflammatory breast cancer; IHC, immunohistochemistry; LABC, locally advanced breast cancer; LVEF, left ventricular ejection fraction; MBC, metastatic breast cancer; met, metastatic; mos., months; NACT, neo-adjuvant chemotherapy; OR, overall response; ORR, overall response rate; OS, Overall Survival; PD, progressive disease; PFS, progression-free survival; PgR, progesterone receptor, PR, partial response; PFS, progression free survival; pts., patients, q, every; QOL, quality of life; RECIST, Response Evaluation Criteria in Solid Tumors; SD, standard deviation; TTF, time to treatment failure; TTP, time to progression; tx, treatment; w/, with; wks., weeks; w/in, within, WHO, World Health Organization; yrs., years ASCO HER2-Positive Advanced Breast Cancer Non-Brain Metastases Treatment Guideline - Data Supplement 11

12 Table 2: Participant and Disease Characteristics Study Interventions Demographics Diagnosis/Treatment Sample sizes J. Baselga/S. M. Swain CLEOPATRA 2012 pertuzumab + trastuzumab + docetaxel trastuzumab + docetaxel, placebo Arm 1: 402 Arm 2: 406 Overall: 808 Age Intervention 54 (22-82) Control 54 (27-89) Sex intervention 100% female control 99.5% female Ethnicity n (%). Intervention: Asian 128 (31.8), Black 10 (2.5), White 245 (60.9), Other 19 (4.7) Control: Asian 133 (32.8), Black 20 (4.9), White 235 (57.9), Other 18 (4.4) Disease % HER2+: 808, ER+ and/or PgR+: Arm (47), Arm (47), HER2+/ER-/PgR-: Arm (52.7), Arm (48.3), HER2 unknown: IHC 1(.2), 1(0.2), FISH 17 (4.2), 19 (4.7), ER/PgR unknown: 1 (.2), 11 (2.7) Metastatic %: 100 Treatment Arm 1 - adjuvant trastuzumab: or neoadjuvant: 47/402 (11.7) Arm 2 - adjuvant trastuzumab: or neoadjuvant: 41/406 (10.1) Arm 1 - other: anthracyclines: 150 (37.3), hormone 106 (26.4), taxane 91, (22.6) Arm 2 - anthracycline 164 (40.4), hormone 97 (23.9), taxane 94 (23.2) ASCO HER2-Positive Advanced Breast Cancer Non-Brain Metastases Treatment Guideline - Data Supplement 12

13 Study Interventions Demographics Diagnosis/Treatment Sample sizes J. Huober/N. Harbeck electra 2012 trastuzumab + letrozole letrozole alone Arm 1: 26, Arm 2: 31, Arm 3: 35, Overall (92) Age Let + trastuzumab 61.5 (39-87), Let alone 61 (47-88), Arm 3 70 (45-81) Sex NR Ethnicity Disease % HER2+: 57, HER2+/ER+/PgR+: let + trastuzumab: 26/26 (100%), Let 30/31 (97), HER2+/ER-/PgR-: 0, ER/PgR unknown: Let + trastuzumab n=0, Let alone n=1/31 (3%), NOTE: HER2- n=35, 100% HR+ Metastatic n (%): Let + trastuzumab 7/26 (27), Let 2/31 (7), Arm 3 15/35 (43), Locally Advanced % (n): let + trastuzumab 13/26 (50), Let 23/31 (74), Arm 3 18/35 (51), NOTE: Unknown: Let + trastuzumab 6/26 (23), Let 6/31 (19), Arm 3 2/35 (6) NR Treatment Arm 1 - adjuvant trastuzumab: 8/26 (31), Arm 2 - adjuvant trastuzumab: 16/31 (52), Arm 1 - other: any adjuvant let + trastuzumab 11/26 (42). TAM 8/26 (31), Arm 2 - other: Let 22/31 (71). TAM 20/31 (65) M. Andersson/S. T. Langkjer HERNATA 2011 trastuzumab + docetaxel trastuzumab + vinorelbine Arm 1: 143, Arm 2: 141, Overall 284. trastuzumab + T 56 (33-72), trastuzumab + V 57 (29-72) Age trastuzumab + docetaxel 56 (33-72), trastuzumab + vinorelbine 57 (29-72) Sex NR Disease % HER2+: 280 (note: IHC 3+ n= docetaxel 116 (81.1), vinorelbine 117 (83), total 233 (82). FISH + n= docetaxel 51 (35.7), vinorelbine 49 (34.8), total 100 (35.2), HER2 unknown: negative/unknown n= docetaxel 2 (91.4), vinorelbine 2 (1.4), total 4 (1.4), NOTE: HR+ n= docetaxel 76 (53.1), vinorelbine 85 (60.3), total 161 (56.7). HR- n=t 64 (44.8), vinorelbine 55 (39), total 119 (41.9). HR unknown n= docetaxel 3 (2.1), vinorelbine 1 (0.7), total 4 (1.4) Ethnicity Metastatic n (%): 100 NR Treatment Arm 1 - adjuvant trastuzumab: 1 (0.7), Arm 2 - adjuvant trastuzumab: 0, Arm 1 - other: chemo, adjuvant 59 (41.3), adjuvant anthracycline 49 (34.3), taxane 1 (0.7), adjuvant endocrine tx. 56 (39.2), locally advanced/met endocrine 17 (11.9), adjuvant RT 78 (54.5), locally advanced /met RT 18 (2.6), Arm 2 - other: chemo, adjuvant 70 (49.6), adjuvant anthracycline 58 (41.1), taxane 3 (2.1), adjuvant endocrine tx. 54 (38.3), locally advanced/met endocrine 24 (17), adjuvant RT 72 ASCO HER2-Positive Advanced Breast Cancer Non-Brain Metastases Treatment Guideline - Data Supplement 13

14 Study Interventions Demographics Diagnosis/Treatment Sample sizes (51.1), locally advanced/met RT 16 (11.3) V. Valero/D. J. Slamon BCIRG Trastuzumab + Chemo: docetaxel, carboplatin, and trastuzumab (TCH) Trastuzumab + Chemo: docetaxel and trastuzumab (TH) Arm 1: TH n=131, Arm 2: TH n=131tch 51, TH 52 Age TCH 51, TH 52 Sex 100% female Ethnicity Disease % HER2+/ER+/PgR+: TCH 86/132 (62.5), TH 95 (72.5) Metastatic n (%): TCH 130 (98.5), TH 128 (97.7), Locally Advanced % (n): 2 (1.5), 3 (2.3) Treatment ASCO HER2-Positive Advanced Breast Cancer Non-Brain Metastases Treatment Guideline - Data Supplement 14

15 Study Interventions Demographics Diagnosis/Treatment Sample sizes L. S. Schwartzberg /S. Johnston 2010 lapatinib + letrozole letrozole + placebo Arm 1: 111, Arm 2: 108, Overall 219, NOTE: For efficacy. Age Let + Lap 60 (44-85), Let + Placebo 59 (45-87) Sex Ethnicity NR Disease % HER2+: 219, HER2+/ER+/PgR+: 76/111 (68) + lapatinib, 75/108 (69) + placebo, HER2+/ER+/PgR-: 23/111 (21) + lapatinib, 27/108 (25) + placebo, ER/PgR unknown: 9 (8) + lapatinib, 4 (4) + placebo, NOTE: HER2+/ER-/PgR+ 3 (3) + lap, 2 (2) + placebo Metastatic n (%): 106 (95), 101 (94),Locally Advanced %(n): IIIb or IIIc 5 (5), 7 (6) Treatment Arm 1 - other: TAM or tormifene only 59 (53), AI only <1%, anthracycline only 41 (37), anthracycline and taxanes 9 (8), other 11 (10), any biologic <1%, Arm 2 - other: TAM or tormifene only 60 (56), AI only <1%, anthracycline only 38 (35), anthracycline and taxanes 9 (8), other 4 (4), any biologic <1% ASCO HER2-Positive Advanced Breast Cancer Non-Brain Metastases Treatment Guideline - Data Supplement 15

16 Study Interventions Demographics Diagnosis/Treatment Sample sizes B. Kaufman/A. Jones TAnDEM 2009 anastrozole, trastuzumab + anastrozole NOTE: "Treatment was planned to continue until progressive disease (PD), at which point patients in the anastrozole alone arm could switch to a trastuzumab-containing regimen." Arm 1: 104, Arm 2: 103, Overall 207A: 54 (27-77), trastuzumab + A: 56 (31-85) Age Anastrozole: 54 (27-77), trastuzumab + Anastrozole: 56 (31-85) Sex 100% female Ethnicity NR Disease % HER2+: 207, HER2+/ER+/PgR+: local: 100% v. 100%. central: A 73/104 (70.2), trastuzumab + A 77/103 (74.8), HER2+/ER-/PgR-: A: 23/104, trastuzumab + A: 21/103, ER/PgR unknown: central confirmation not possible A: 8/104, trastuzumab + A 5/103 Metastatic n (%): 100 Treatment Arm 1 - other: HT 69/14 (66.3), TAM for met 3/104 (2.9), chemo 62/104 (59.6), anthracycline 53/104 (51), bisphosphonates 27/104 (26), Arm 2 - other: HT 62/103 (60.2), TAM for met 5/103 (4.9), chemo 55/103 (53.4), anthracycline 46/103 (44.7), bisphosphonates 28/103 (27.2) K. Inoue/S. Noguchi JO trastuzumab alone: 4 mg/kg, first dose, then 2 mg/kg 2nd dose, trastuzumab + chemo: trastuzumab + T after disease progression, NOTE: trastuzumab then trastuzumab + T: sequential Age Sequential 57.5 (32-83), combo 54.3 (31-80) Sex Disease % HER2+: 100%, HER2+/ER+/PgR+: S 22/54 (41), C 29 (54), HER2+/ER- /PgR-: S 32 (59), C 23 (43), ER/PgR unknown: C 1 (2) trastuzumab + chemo: trastuzumab + T, NOTE: trastuzumab + T concurrent Arm 1: 55, Arm 2: 53, Overall, NOTE: 107/108 safety population included in modified-itt sequential 57.5 (32-83), combo 54.3 (31-80) 100% female Ethnicity Treatment Arm 1 - other: adjuvant chemo 20/54 (37), anthracyclines S 17/54 (31), paclitaxel 7/54 (13), Arm 2 - other: adjuvant chemo 29/53 (55), anthracyclines 17/53 (32), paclitaxel 6/53 (11) ASCO HER2-Positive Advanced Breast Cancer Non-Brain Metastases Treatment Guideline - Data Supplement 16

17 Study Interventions Demographics Diagnosis/Treatment Sample sizes K. L. Blackwell/S. Verma EMILIA 2012 other targeted tx + chemo: T-DM1 (3.6 mg/kg q3w) other targeted tx + chemo: lapatinib (1250 mg/day)+ capecitabine (1000 mg/m2, d 1-14, q3w) Arm 1: 495, Arm 2: 496, NOTE: 991T-DM1 53 (25-84), CL 53 (24-83) Age T-DM1 53 (25-84), CL 53 (24-83) Sex Female Ethnicity T-DM1, CL white 358 (72) v 374 (75), Asian 94 (19) v 86 (17), AA 29 (6) v 21 (4), other 7 (1) v 10 (2), NA 7 (1) v 5 (1) Disease % HER2+: 100%, HER2+/ER+/PgR+: T-DM1 282 (57), CL 263 (53), HER2+/ER-/PgR-: T-DM1 202 (41), CL 224 (45), ER/PgR unknown: T- DM1 11 (2), CL 9 (2), NOTE: ER+ and/or PgR+ Metastatic n (%): <3 T-DM1 298 (60), CL 307 (62), 3 T-DM1 189 (38), CL 175 (35), unknown T-DM1 8 (2), CL 9 (2) Treatment Arm 1 - adjuvant trastuzumab: 16% (100% when including met), Arm 2 - adjuvant trastuzumab: 16% (100% when including met), Arm 1 - other: taxane 100%, anthracyclines 61%, endocrine 41%, Arm 2 - other: 100%, 61% anthracycline, endocrine 41% K. A. Gelmon/W. Parulekar MA.31/GSK EGF lapatinib + taxane, then lapatinib trastuzumab + taxane, then trastuzumab Arm 1: 318, Arm 2: 318, Overall 636L 55.4 (27-87), trastuzumab 54.1 (29-84) Age lapatinib 55.4 (27-87), trastuzumab 54.1 (29-84) Sex 100% female Disease % Metastatic n (%): 42%, 43%, NOTE: metastatic at diagnosis Treatment Arm 1 - adjuvant trastuzumab: (Neo) adjuvant 18%, Arm 2 - adjuvant trastuzumab: 18%, Arm 1 - other: taxane 21%, Arm 2 - other: 22% Ethnicity NR ASCO HER2-Positive Advanced Breast Cancer Non-Brain Metastases Treatment Guideline - Data Supplement 17

18 Study Interventions Demographics Diagnosis/Treatment Sample sizes D. Cameron/C. E. Geyer EGF lapatinib plus capecitabine (combo) capecitabine Arm 1: 207, Arm 2: 201, Overall 408 Age See 696 Sex 100% Female Disease % HER2+/ER-/PgR-: 49 (101/207) vs. 50 (101/201), ER/PgR unknown: 7/207 (3) vs. 7 (3) Metastatic n (%): 191 (96) vs. 193 (96), Locally Advanced %(n): IIIB or IIIC 7 (4) vs. 8 (4) Ethnicity Treatment NR Arm 1 - adjuvant trastuzumab: 9 (5), Arm 2 - adjuvant trastuzumab: 7 (4), Arm 1 - other: trastuzumab Met 187 (95). anthracycline 194 (98).taxanes 198 (100), Arm 2 - other: trastuzumab Met 189 (94). anthracycline 199 (>99). taxane 199 (>99) K. L. Blackwell/J. O'Shaughnes sy EGF lapatinib alone lapatinib and trastuzumab Arm 1: 145, Arm 2: 146, Overall 291 Age lapatinib= 51 (29-78), lapatinib + trastuzumab 52 (26-81), total 51 (26-81) Sex 100% female Disease % HER2+: lapatinib n=146/148, lapatinib and trastuzumab n=147/148, total 293/296, HER2+/ER-/PgR-: mono 75/148 (51%), combo 75/148 (51%), ITT 150/293 (51%) Metastatic n (%): 100% Treatment Ethnicity NR Median # of prior chemo regimens: Lap 4, Combo: 5. Median # of prior trastuzumab for MBC: Lap 3, Combo: 3 Abbreviations: AI, aromatase inhibitor; chemo, chemotherapy; ER, estrogen receptor, FISH, fluorescent in situ hybridization; H, Herceptin; HR, hormone receptor; HT, hormonal treatment; IHC, immunohistochemistry; lap, lapatinib; Let, letrozole; MBC, metastatic breast cancer; met, metastasis, PD, progressive disease; PgR, progesterone receptor, q, every; TAM, tamoxifen; tx, treatment; ASCO HER2-Positive Advanced Breast Cancer Non-Brain Metastases Treatment Guideline - Data Supplement 18

19 DATA SUPPLEMENT 2: Literature Search Strategy Trastuzumab only searches - date parameters: 2009/01/01 to 2012/10/04 Trastuzumab plus other agents, endocrine therapy (Clinical Question 2) - date parameters: 1966 to 2012/10/04 Key PubMed terms Breast neoplasms[mh] AND Neoplasm metastasis [MH] AND ((Genes, erbb-2[mesh] OR Receptor, erbb- 2[MeSH] OR Her-2 [tiab] OR Her2 [tiab] OR HER2 [tiab] OR HER-2 [tiab] OR erbb-2 [tiab] OR erbb2 [tiab] OR epidermal growth factor receptor-2 [tiab] OR epidermal growth factor receptor 2 [tiab] OR receptor, epidermal growth factor[mh] OR epidermal growth factor receptor-neu [tiab] OR epidermal growth factor receptor-neu receptor[nm]) OR ( antibodies, monoclonal [MH] OR Trastuzumab[NM] OR lapatinib [NM] OR pertuzumab[nm] OR TDM-1 [tiab] OR TDM1[tiab] OR trastuzumab-dm1 [tiab] OR trastuzumab-dm1 conjugate [NM] OR trastuzumab-emtansine [TIAB]) AND randomized controlled trial [[PT] OR metaanalysis[pt] OR guideline[pt] NOT (editorial[pt] OR editorial[tiab] OR letter[pt] OR newspaper article[pt]) NOT (case reports[pt] OR case report[tiab]) NOT (animals[mesh] NOT humans[mesh]) AND ("1966/01/01"[PDat] :"2012/06/12"[PDat]) AND English[la] Added terms for Clinical Question 2: AND ("Antineoplastic Agents, Hormonal" [Pharmacological Action] OR (estrogen receptor modulator*[tiab] OR SERM[TIAB] OR estrogen antagonists[pharmacological Action] OR estrogen antagonists[nm] OR estrogen antagonist [TIAB] OR estrogen antagonists [TIAB]) OR (tamoxifen[mesh] OR tamoxifen[nm] OR tamoxifen[all FIELDS] OR nolvadex[tiab] OR novaldex[tiab] OR zitazonium[tiab] OR soltamox[tiab] OR Toremifene[MH]) OR (aromatase inhibitors[mesh] OR aromatase inhibitors[nm] OR aromatase inhibitor [TIAB] OR aromatase inhibitors [TIAB] OR aromatase inhibition [TIAB] OR aminoglutethimide[tiab] OR anastrozole[all FIELDS] OR exemestane[all FIELDS] OR fadrozole[tiab] OR formestane[tiab] OR letrozole[all FIELDS] OR femara[tiab] OR plomestane[tiab] OR vorozole[tiab] OR arimidex[tiab] OR aromasin[tiab] OR aromasine[tiab] OR aromasil[tiab]) OR fulvestrant [Supplementary Concept] OR Goserelin[MH] OR Leuprolide[MH] OR Medroxyprogesterone Acetate[MH]) ASCO HER2-Positive Advanced Breast Cancer Non-Brain Metastases Treatment Guideline - Data Supplement 19

20 DATA SUPPLEMENT 3: QUOROM Diagram 739 potentially relevant abstracts identified 40 papers selected for full-text review 40 papers identified through review of reference lists 40 papers reviewed in full-text 16 papers were excluded. 7not study design of interest 3 not population of interest of interest 5 date parameters incorrect 18 papers had data extracted (N.B. some multiple publications for a given study) ASCO HER2-Positive Advanced Breast Cancer Non-Brain Metastases Treatment Guideline - Data Supplement 20

21 DATA SUPPLEMENT 4: Clinical Questions Clinical Question 1. What is the optimal treatment for patients with HER2-positive advanced breast cancer? Clinical Question 1.a. Is HER2-targeted therapy recommended for all patients with HER2- positive advanced breast cancer? Question 1.a.i. In first-line? 1.a.ii. In second-line? Clinical Question 1.b. If HER2-targeted therapy is recommended, then which HER2-targeted therapy (trastuzumab, lapatinib, pertuzumab, and/or trastuzumab emtansine [TDM-1]) ± chemotherapy should be offered? Question 1.b.i. In first-line? Question 1.b.ii. In second-line? Question 1.b.iii. In third or greater-line? Question 1.b.iv. What is the optimal timing, dose, schedule, and duration of treatment? Question 1.b.v. How should any previous HER2 adjuvant therapy influence treatment? Question 1.b.v.a. If there is a recurrence 12 months? Question 1.b.v.b. If there is a recurrence >12 months? Clinical Question 2. For patients with HER2-positive advanced breast cancer, does ER/PgR status influence decisions about treatment of patients with HER2-positive and hormone receptor-positive advanced breast cancer? Clinical Question 2.a. What is the most appropriate first-line therapy? Clinical Question 2.b. If a clinician plans to offer endocrine therapy at some point during the woman s treatment, what is the appropriate sequencing? Clinical Question 2.c. In what circumstances could clinicians offer first-line endocrine therapy alone? ASCO HER2-Positive Advanced Breast Cancer Non-Brain Metastases Treatment Guideline - Data Supplement 21

22 DATA SUPPLEMENT 5: Multiple Chronic Conditions Table 10 Most Common Co-occurring Chronic Conditions Among Female Medicare beneficiaries with Breast Cancer (N = 905,843), 2011 Beneficiaries less than 65 years (N = 64,525) Beneficiaries 65 years and older (N = 841,318) N % N % Breast cancer prevalence 2.5 Breast cancer prevalence 5.6 Top 10 co-morbidities Top 10 co-morbidities Hypertension 35, Hypertension 591, Hyperlipidemia 27, Hyperlipidemia 467, Depression 25, Arthritis 345, Arthritis 22, Anemia 293, Anemia 22, Ischemic heart disease 268, Diabetes 21, Diabetes 244, Ischemic heart disease 15, Cataracts 218, COPD 10, Heart failure 162, Chronic kidney disease 10, Depression 155, Heart failure 9, Chronic kidney disease 150, Notes: Prepared by IPG/OIPDA on May 15, Data Source: CMS administrative claims data, January December 2011, from the Chronic Condition Warehouse (CCW), ccwdata.org. Population: Female Medicare beneficiaries enrolled in fee-for-service (FFS) coverage of both Parts A and B for the entire year. Beneficiaries who were enrolled at any point during the year in a Medicare Advantage (MA) plan were excluded as were beneficiaries who first became eligible for Medicare after January of the calendar year. Beneficiaries who died during the year were included up to their date of death if they meet the other inclusion criteria. Beneficiaries less than 65 years of age are primarily receiving Medicare due to a disability. Chronic Condition Measures: For these tables, chronic conditions were identified through Medicare administrative claims. Medicare beneficiaries were considered to have a chronic condition if the CMS administrative data had a claim indicating that they were receiving a service or treatment for the specific condition. The data tables include information for beneficiaries with one of twenty-eight chronic conditions identified in the CCW. Detailed information on the identification of chronic conditions in the CCW is available at The list of 28 conditions include: Acquired hypothyroidism, Acute myocardial infarction, Alzheimer's Disease (including related Disorders or senile dementia), Anemia, Asthma, Atrial fibrillation, Autism, Benign prostatic hyperplasia, Breast cancer, Colon cancer, Endometrial cancer, Lung cancer, Prostate cancer, Cataract, Chronic kidney disease, COPD, Depression, Diabetes, Glaucoma, Heart failure, Hip/pelvic fracture, Hypertension, Hyperlipidemia, Ischemic heart disease, Osteoporosis, Arthritis (OA and RA), Schizophrenia (and other psychotic disorders) and Stroke. Unpublished data provided by the Office of Information Products and Data Analytics, Centers for Medicare & Medicaid Services, May 2013 ASCO HER2-Positive Advanced Breast Cancer Non-Brain Metastases Treatment Guideline - Data Supplement 22

23 DATA SUPPLEMENT 6: Additional Discussion: Literature Review and Analysis This section is an expanded literature review and analysis suggestion of the published guideline. 9 Search Results A total of nine first-line, three second-line, and four beyond-second-line phase III randomized clinical trials were deemed eligible for inclusion in the ASCO systematic review (some trials provided evidence for more than one recommendation) and comprise the evidentiary basis of the guideline recommendations, in addition to the trials in a Cancer Care Ontario systematic review (2011). 10,11 The identified trials spanned from 2009 to In no case did more than one study found by the systematic review have the same comparisons. The primary outcome for all trials was therapeutic efficacy, measured primarily by progression-free survival (PFS) (n=7) 7,12-17 and time to progression (TTP) n=4. Data on key outcomes of interest are reported in Tables 2, 3, and The majority of studies also reported OS (either as a primary or secondary outcome). Adverse events and QOL were also reported. Data on key adverse events are reported in Tables 3 and 4 (in the JCO publication). Various agents were examined including, trastuzumab, endocrine therapies, lapatinib, pertuzumab, anthracyclines, taxanes, capecitabine, and T-DM1. Most studies included at least one arm of trastuzumab alone or in a combination (n=8). 12,13,15-20 The studies that did not include trastuzumab included a lapatinibcontaining arm (n=3 and one with both). 7,14,21 The three second-line studies include lapatinib in at least one arm. 7,15,21 One study directly addresses the sequence issue raised by Clinical Question I.b.iv. 17 To address the question of the role of hormonal/endocrine therapy, the systematic review identified three hormonal therapy plus HER2-targeted therapy studies, all in firstline. 14,16,18 No study compared different HER2-targeted therapies (with or without hormonal therapy). Two studies address questions of how prior adjuvant HER2-targeted therapy may influence subsequent treatment choices. 7,13 There was insufficient evidence to make evidencebased recommendations on some of these questions. Therefore, some were made on the basis of informal consensus recommendations, and are labeled as such. The original protocol for this guideline included a question about the management of patients with HER2-positive advanced breast cancer that metastasizes to the brain. However, upon review of the available evidence, the Expert Panel concluded that the majority of the evidence was insufficient to inform evidence-based recommendations for a traditional ASCO clinical practice guideline. Therefore, ASCO produced a separate, complementary guideline on that topic using formal consensus-based process. 22 Study Quality As seen in the Table 2 (Quality assessment) of the guideline, study quality was formally assessed for the eleven studies identified. Design aspects related to the individual study quality was assessed by one reviewer with factors such as blinding, allocation concealment, placebo control, intention to treat, funding sources, etc., generally indicating an intermediate to high potential risk of bias for most of the identified evidence. Refer to the Methodology Supplement for definitions of ratings for overall potential risk of bias. ASCO HER2-Positive Advanced Breast Cancer Non-Brain Metastases Treatment Guideline - Data Supplement 23

24 DISCUSSION Literature Review and Analysis Clinical Question 1. What is the optimal treatment for patients with HER2-positive advanced breast cancer? For patients with HER2-positive advanced breast cancer: Clinical Question 1.a. Is HER2-targeted therapy recommended for all in the first-line? Recommendation 1.a.i. Clinicians should recommend HER2-targeted therapy-based combinations for first-line treatment, except for highly selected patients with estrogen receptor-positive (ER+) or progesterone receptor-positive (PgR+) and HER2-positive disease for whom clinicians may use endocrine therapy alone (see Clinical Question 2). (Type: Evidence-based; Evidence Quality: High, Strength of Recommendation: Strong) Literature Review and Analysis This recommendation is based on a body of evidence regarding first-line therapy, found both in the ASCO and CCO systematic reviews. 10 CCO included the Slamon et al. pivotal trial and nine other trastuzumab RCTs. These trials found a benefit to HER2-targeted therapy combinations, specifically trastuzumab. Slamon et al. was the only first-line phase III trial that compared a HER2-targeted therapy plus chemotherapy to chemotherapy alone. 23 That trial found survival, TTP, and overall response rate (ORR) benefits in the trastuzumab arm (see CCO evidence table at: The CCO review found two phase III trials that compared HER2-targeted therapy plus endocrine therapy to endocrine therapy alone. 18,16 Both of those trials found a PFS/TTP benefit, but not overall survival (OS), in the combination arm, and will be discussed in the section on endocrine therapy (Clinical Question 2), with another, more recent trial. 14 All of the trials in the CCO systematic review results also included trials with trastuzumab plus or minus another agent versus a non-trastuzumab control. ASCO reviewed Phase III trials that CCO reviewed when presentations only were available (as published results subsequently became available). 15,24-27 The other four first-line trials CCO reviewed were phase II and because only phase III trials were specified in ASCO s protocol, they are not used to support recommendations in this ASCO guideline A separate ASCO Guideline addresses the definition of and testing for HER2-positivity for patients with breast cancer and its role in treatment selection for these patients. 34 The ASCO systematic review results included other first-line studies (n=5) of various trastuzumab-chemotherapy combinations. They had one or more HER2-targeted agents in both arms. 20,17,19,16,18 There were not statistically significant differences in OS/PFS/TTP in these trials. There was one arm of trastuzumab after trastuzumab/taxane in an additional study (versus lapatinib at progression after lapatinib/ taxane treatment). Finally, the ASCO systematic review included studies in which the interventional arms were lapatinib, pertuzumab, and/or T- DM1. 13,7,8,12,14 Selected results of these trials are in Table 1 and 3 (in the JCO publication); results from the trials on recommended agents are discussed below. Clinical Interpretation ASCO HER2-Positive Advanced Breast Cancer Non-Brain Metastases Treatment Guideline - Data Supplement 24

25 Overall, HER2-targeted therapy in combination with chemotherapy in the first-line setting is associated with improvements in response rate, progression-free survival, time to progression, and OS when compared to chemotherapy alone. In trials of endocrine therapy, the addition of HER2-targeted therapy is associated with improvements in response rates and progression-free survival, but not survival. These data support the use of HER2-targeted therapy in the first-line treatment of metastatic breast cancer. There are some contraindications to HER2-targeted therapy; due to its cardiovascular toxic effects (see Table 4 in guideline). The single most important contraindication is a decreased left ventricular ejection fraction (LVEF) and/or clinical evidence of congestive heart failure arising from a low LVEF. Among patients with congestive heart failure or low ejection fraction, the decision to use HER2-targeted therapy must be made on an individual basis, assessing the relative risks of cardiac dysfunction from a specific regimen versus disease progression. Therefore, the Panel recommended that clinicians should treat patients with clinical congestive heart failure or compromised LVEF on a case-by-case basis, assessing the relative risks of cardiac dysfunction versus disease progression. 35 For select patients with HER2-positive and hormone receptor-positive (ER+/PgR+-) breast cancer, endocrine treatment with either trastuzumab or lapatinib or endocrine therapy alone may be an acceptable first-line treatment. Endocrine therapy alone is included as an option because the trials of endocrine therapy with or without HER2-targeted therapy did not demonstrate a survival advantage. This recommendation is discussed with Clinical Question/Recommendation 2. Question: 1.a.ii. In second-line-general? Clinical Question: 1.a.ii. Is HER2-targeted therapy recommended for all in the secondline? Recommendation 1.a.ii. If a patient s HER2-positive advanced breast cancer has progressed during or after first-line HER2-targeted therapy, then clinicians should recommend second-line HER2-targeted therapybased treatment. (Type: Evidence-based; Evidence Quality: High, Strength of Recommendation: Strong) Literature Review and Analysis This recommendation is based on a body of evidence regarding second-line therapy, found both in the ASCO and CCO systematic reviews. The comparisons in three of the studies supporting this recommendation each included an intervention of a HER2-targeted therapy combination versus chemotherapy. 4,21,36-39 These three studies found a PFS or TTP and/or safety benefit for the HER2-targeted therapy combination arm. 21,36,37,39,38 The primary outcome for four studies was PFS/TTP. 7,15,21,36-38 In the Blackwell et al. study, OS and safety were co-primary endpoints. Four of the studies found a PFS or TTP benefit for the intervention arm. 7,15,21 The three studies with chemotherapy alone in the control arm 21,39 found benefit a benefit in PFS, 21 TTP, 36,37,38 and/or safety. 39 Two studies compared different HER-targeted therapies. The EMILIA (An Open-Label Study of Trastuzumab Emtansine (T-DM1) vs Capecitabine + Lapatinib in Patients with HER2-Positive Locally Advanced or Metastatic Breast Cancer) study showed a statistically significant OS benefit for those receiving the T-DM1 over the combination of capecitabine and lapatinib. 7,8 The study of lapatinib alone versus lapatinib plus trastuzumab showed an OS benefit for lapatinib plus ASCO HER2-Positive Advanced Breast Cancer Non-Brain Metastases Treatment Guideline - Data Supplement 25

26 trastuzumab, but most of the survival benefit was post-progression and the median number of prior therapies was four to five. 15,40 See Recommendation 1.b.ii. for further information. Clinical Interpretation Overall, all of the studies showed that there is a benefit to continuing some form of HER2- targeted therapy in the second-line setting, either a combination of HER2-targeted therapy and chemotherapy, a combination of two HER2-targeted therapies, or T-DM1. These were associated with improved outcomes. The EMILIA study showed both improvements in survival and a favorable toxicity profile for T-DM1 when compared to capecitabine and lapatinib and confirmed the benefit of T-DM1 in the second-line treatment of metastatic breast cancer. Clinical Question: 1.a.iii. Is HER2-targeted therapy recommended for all in the third-line and beyond? Recommendation 1.a.iii. If a patient s HER2-positive advanced breast cancer has progressed during or after second- or greater-line HER2-targeted treatment, then clinicians should recommend third- or greater-line HER2- targeted therapy based treatment. (Type: Evidence-based; Evidence Quality: Intermediate, Strength of Recommendation: Moderate) Literature Review and Analysis The lapatinib plus trastuzumab study 40 and the EMILIA study provide the evidence for this recommendation. 7,8,15 In neither of these studies were there survival differences based on the number of prior metastatic treatment regimens the participants had received. In the lapatinib versus trastuzumab study, patients had received a median of four (one-12) prior chemotherapy regimens for those receiving lapatinib, compared to four and a half (one-12) prior regimens for those receiving lapatinib and trastuzumab; 28 and 34 participants had six prior regimens, in those arms, respectively. An exploratory univariate analysis of that study of OS by number of prior trastuzumab regimens did not produce statistically significant results, e.g. two versus > two prior regimens (HR=0.99; 95% CI, 0.75 to 1.31, p=.96). In the EMILIA study, equal proportions of participants in both study arms had received >1 prior regimen (39%). In an independently-assessed PFS analysis by subgroup, those who received T-DM1 in third- and greater-line (n=512) received a PFS benefit from T-DM1 (HR=0.69; 95% CI, ]). 8 In other studies, results were not presented by numbers of prior regimens. 4,13,21,36-39 Clinical Interpretation The use of HER2-targeted therapies in the third-line and beyond was associated with improved progression free survival in subgroup analyses. However, neither of the two studies was specifically focused on this population, therefore the data are not as strong as the data supporting the use of HER2-targeted therapies in the first and second-line settings. A report from the TH3RESA study also showed an improvement in PFS with the use of T-DM1 versus physician s choice for patients previously treated with both trastuzumab and lapatinib. However, the results of this study were presented after ASCO s literature search cut-off date and so were not formally considered as the basis of this recommendation (ClinicalTrials.gov Identifier: NCT ) 41. The lapatinib plus trastuzumab study did include a heavily pretreated population and showed a benefit of continuing trastuzumab in combination with lapatinib after progression on previous trastuzumab-containing regimens. These data support the continuation of HER2-targeted therapy in the third- and greater-line. ASCO HER2-Positive Advanced Breast Cancer Non-Brain Metastases Treatment Guideline - Data Supplement 26

27 Clinical Question 1.b. Which HER2-targeted therapy (trastuzumab, lapatinib, pertuzumab, or TDM-1) ± chemotherapy should be offered? Clinical Question: 1.b.i. What is the specific recommended regimen in first-line? Recommendation 1.b.i. Clinicians should recommend the combination of trastuzumab, pertuzumab, and a taxane for first-line treatment, unless the patient has a contraindication to taxanes. (Type: Evidence-based; Evidence Quality: High, Strength of Recommendation: Strong) Literature Review and Analysis The Panel reviewed data on pertuzumab, trastuzumab, lapatinib, and T-DM1 in first-line based regimens (note: combinations with hormone receptor-targeted drugs are discussed below). The recommendation for the pertuzumab/trastuzumab/docetaxel combination is based on one phase III clinical trial, CLEOPATRA (Clinical Evaluation of Pertuzumab and Trastuzumab). This trial of 808 participants compared pertuzumab, trastuzumab, and docetaxel to trastuzumab and docetaxel. If patients had previously received trastuzumab, then a 12 month interval between neo-adjuvant or adjuvant and metastatic diagnosis was required. (See Clinical Question 1.b.v.b.) The published benefits included an increase in PFS 18.5 months versus 12.4 months (HR for progression or death=0.62; 95% CI, , p<0.001). There was also an increased OS, however, this was an interim analysis at which the study did not meet its stopping boundary, therefore was not statistically significant. There was an increased response rate, which was an exploratory endpoint. The major side effects seen more frequently in the pertuzumab arm were febrile neutropenia and diarrhea (grade 3 or higher). LVEF declines were numerically less frequent in the pertuzumab arm, but the difference was not tested for statistical significance (N.B. the safety population was all of the patients who had one dose of pertuzumab.) 13 The published benefits included an increase in PFS. There was also an increased OS. The second interim analysis of CLEOPATRA found that pertuzumab/trastuzumab/docetaxel was associated with an OS benefit (HR 0.66, p=0.0008); those data will be reviewed when published. 42 No increase in the risk of cardiac dysfunction was seen with addition of pertuzumab; LVEF declines were numerically less frequent in the pertuzumab arm, but the difference was not tested for statistical significance. As the CLEOPATRA regimen utilized a taxane, contraindications to the regimen include any contraindications to the use of a taxane including neuropathy, prior taxane hypersensitivity, etc. 43 (See drug labels for other contraindications). As the CLEOPATRA regimen included a taxane, the recommendation specifically refers to patients contraindications to taxanes; they include neuropathy, pain, fatigue, and severe hypersensitivity 43 (See drug labels for other contraindications). The exclusion criteria for this systematic review excluded lower levels of evidence to inform a recommendation for alternate chemotherapy agents to combine with pertuzumab plus trastuzumab. Therefore, there is no phase III RCT evidence to support a recommend to use other agents in combination with pertuzumab and trastuzumab. The overall risk of bias in this study was assessed as intermediate. Clinical Interpretation The Panel reviewed evidence on the agents listed above for patients considering first-line therapy. Pertuzumab plus trastuzumab and docetaxel was more effective than trastuzumab and docetaxel in CLEOPATRA, including OS. The Panel discussed whether the benefit of ASCO HER2-Positive Advanced Breast Cancer Non-Brain Metastases Treatment Guideline - Data Supplement 27