Perjeta

• Left Ventricular Dysfunction: PERJETA can cause subclinical and clinical cardiac failure manifesting as decreased LVEF and CHF. Evaluate cardiac function prior to and during treatment. Discontinue PERJETA treatment for a confirmed clinically significant decrease in left ventricular function

  [see

  2.3 Recommended Dosage and Administration

  The initial dose of PERJETA is 840 mg administered as a 60-minute intravenous infusion, followed every 3 weeks by a dose of 420 mg administered as an intravenous infusion over 30 to 60 minutes.

  When administered with PERJETA, the recommended initial dose of trastuzumab is 8 mg/kg administered as a 90-minute intravenous infusion, followed every 3 weeks by a dose of 6 mg/kg administered as an intravenous infusion over 30 to 90 minutes.

  When administered with PERJETA, the recommended initial dose of trastuzumab hyaluronidase-oysk is 600 mg/10,000 units (600 mg trastuzumab and 10,000 units hyaluronidase) administered subcutaneously over approximately 2 to 5 minutes once every three weeks irrespective of the patient's body weight.

  Administer PERJETA, trastuzumab or trastuzumab hyaluronidase-oysk, and taxane sequentially. PERJETA and trastuzumab or trastuzumab hyaluronidase-oysk can be given in any order. Administer taxane after PERJETA and trastuzumab or trastuzumab hyaluronidase-oysk. An observation period of 30 to 60 minutes is recommended after each PERJETA infusion and before commencement of any subsequent administration of trastuzumab or trastuzumab hyaluronidase-oysk, or taxane

  [see Warnings and Precautions (5.3)].

  In patients receiving an anthracycline-based regimen, administer PERJETA and trastuzumab or trastuzumab hyaluronidase-oysk after completion of the anthracycline.

  Metastatic Breast Cancer (MBC)

  When administered with PERJETA, the recommended initial dose of docetaxel is 75 mg/m²administered as an intravenous infusion. The dose may be escalated to 100 mg/m²administered every 3 weeks if the initial dose is well tolerated.

  Neoadjuvant Treatment of Breast Cancer

  Administer PERJETA every 3 weeks for 3 to 6 cycles as part of one of the following treatment regimens

  [see Clinical Studies (14.2, 14.3)]

  :

  • Four preoperative cycles of PERJETA in combination with trastuzumab or trastuzumab hyaluronidase-oysk and docetaxel followed by 3 postoperative cycles of fluorouracil, epirubicin, and cyclophosphamide (FEC)
  • Three or four preoperative cycles of FEC alone followed by 3 or 4 preoperative cycles of PERJETA in combination with docetaxel and trastuzumab or trastuzumab hyaluronidase-oysk
  • Six preoperative cycles of PERJETA in combination with docetaxel, carboplatin, and trastuzumab (TCH) or trastuzumab hyaluronidase-oysk (escalation of docetaxel above 75 mg/m²is not recommended)
  • Four preoperative cycles of dose-dense doxorubicin and cyclophosphamide (ddAC) alone followed by 4 preoperative cycles of PERJETA in combination with paclitaxel and trastuzumab or trastuzumab hyaluronidase-oysk

  Following surgery, administer PERJETA and trastuzumab or trastuzumab hyaluronidase-oysk to complete 1 year of treatment (up to 18 cycles) or until disease recurrence or unmanageable toxicity, whichever occurs first.

  Adjuvant Treatment of Breast Cancer

  As part of a regimen including standard anthracycline- and/or taxane-based chemotherapy, administer PERJETA in combination with trastuzumab or trastuzumab hyaluronidase-oysk every 3 weeks for a total of 1 year (up to 18 cycles) or until disease recurrence or unmanageable toxicity, whichever occurs first. Administer PERJETA on Day 1 of the first taxane-containing cycle

  [see Clinical Studies (14.3)]

  .

  ,

  5.1 Left Ventricular Dysfunction

  PERJETA can cause left ventricular dysfunction, including symptomatic heart failure. Decreases in LVEF have been reported with drugs that block HER2 activity, including PERJETA.

  Assess LVEF prior to initiation of PERJETA and at regular intervals during treatment to ensure that LVEF is within normal limits. If the LVEF declines and has not improved, or has declined further at the subsequent assessment, consider permanent discontinuation of PERJETA and trastuzumab

  [see Dosage Modification for Adverse Reactions (2.5)]

  .

  In the PERJETA-treated patients with MBC in CLEOPATRA, left ventricular dysfunction occurred in 4% of patients and symptomatic left ventricular systolic dysfunction (LVSD) (congestive heart failure) occurred in 1% of patients. Patients who received prior anthracyclines or prior radiotherapy to the chest area may be at higher risk of decreased LVEF or left ventricular dysfunction.

  In patients receiving PERJETA as a neoadjuvant treatment in combination with trastuzumab and docetaxel in NeoSphere, LVEF decline > 10% and a drop to < 50% occurred in 8% of patients and left ventricular dysfunction occurred in 3% of patients. LVEF recovered to ≥ 50% in all these patients.

  In patients receiving neoadjuvant PERJETA in TRYPHAENA, LVEF decline > 10% and a drop to < 50% occurred in 7% of patients treated with PERJETA plus trastuzumab and FEC followed by PERJETA plus trastuzumab and docetaxel, 16% of patients treated with PERJETA plus trastuzumab and docetaxel following FEC, and 11% of patients treated with PERJETA in combination with TCH. Left ventricular dysfunction occurred in 6% of patients treated with PERJETA plus trastuzumab and FEC followed by PERJETA plus trastuzumab and docetaxel, 4% of patients treated with PERJETA plus trastuzumab and docetaxel following FEC, and 3% of patients treated with PERJETA in combination with TCH. Symptomatic LVSD occurred in 4% of patients treated with PERJETA plus trastuzumab and docetaxel following FEC, 1% of patients treated with PERJETA in combination with TCH, and none of the patients treated with PERJETA plus trastuzumab and FEC followed by PERJETA plus trastuzumab and docetaxel. LVEF recovered to ≥ 50% in all but one patient.

  In patients receiving neoadjuvant PERJETA in BERENICE, in the neoadjuvant period, LVEF decline ≥ 10% and a drop to < 50% as measured by ECHO/MUGA assessment occurred in 7% of patients treated with PERJETA plus trastuzumab and paclitaxel following ddAC, and 2% of patients treated with PERJETA plus trastuzumab and docetaxel following FEC. Ejection fraction decreased (asymptomatic LVD) occurred in 7% of patients treated with PERJETA plus trastuzumab and paclitaxel following ddAC and 4% of the patients treated with PERJETA plus trastuzumab and docetaxel following FEC in the neoadjuvant period. Symptomatic LVSD (NYHA Class III/IV Congestive Heart Failure) occurred in 2% of patients treated with PERJETA plus trastuzumab and paclitaxel following ddAC and none of the patients treated with PERJETA plus trastuzumab and docetaxel following FEC in the neoadjuvant period.

  In patients receiving adjuvant PERJETA in APHINITY, the incidence of symptomatic heart failure (NYHA Class III/IV) with a LVEF decline ≥ 10% and a drop to < 50% was 0.6%. Of the patients who experienced symptomatic heart failure, 47% of PERJETA-treated patients had recovered (defined as 2 consecutive LVEF measurements above 50%) at the data cutoff. The majority of the events (86%) were reported in anthracycline-treated patients. Asymptomatic or mildly symptomatic (NYHA Class II) declines in LVEF ≥ 10% and a drop to < 50% were reported in 3% of PERJETA-treated patients, of whom 80% recovered at the data cutoff.

  PERJETA has not been studied in patients with a pretreatment LVEF value of < 50%, a prior history of CHF, decreases in LVEF to < 50% during prior trastuzumab therapy, or conditions that could impair left ventricular function such as uncontrolled hypertension, recent myocardial infarction, serious cardiac arrhythmia requiring treatment or a cumulative prior anthracycline exposure to > 360 mg/m²of doxorubicin or its equivalent.

  and

  6.1 Clinical Trials Experience

  Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.

  Metastatic Breast Cancer (MBC)

  CLEOPATRA

  The safety of PERJETA in combination with trastuzumab and docetaxel was evaluated in a randomized trial (CLEOPATRA) in patients with HER2-positive metastatic breast cancer

  [see Clinical Studies (14.1)]

  . Patients received either PERJETA administered at an initial dose of 840 mg followed by 420 mg every 3 weeks thereafter or placebo in combination with trastuzumab (initial dose of 8 mg/kg, followed by 6 mg/kg every 3 weeks thereafter) and docetaxel (75 mg/m2 by intravenous infusion every 3 weeks for 6 cycles). The median duration of study treatment was 18.1 months for patients in the PERJETA-treated group.

  Permanent discontinuation of PERJETA, trastuzumab, and docetaxel due to adverse reactions occurred in 6% of patients. Adverse reactions that led to permanent discontinuation of PERJETA, trastuzumab, and docetaxel in >1% of patients were left ventricular dysfunction.

  The safety profile of PERJETA remained unchanged with an additional 2.75 years of follow-up (median total follow-up of 50 months) in CLEOPATRA.

  The most common adverse reactions (> 30%) with PERJETA in combination with trastuzumab and docetaxel were diarrhea, alopecia, neutropenia, nausea, fatigue, rash, and peripheral neuropathy. The most common Grade 3 – 4 adverse reactions (> 2%) were neutropenia, febrile neutropenia, leukopenia, diarrhea, peripheral neuropathy, anemia, asthenia, and fatigue. An increased incidence of febrile neutropenia was observed for Asian patients in both treatment arms compared with patients of other races and from other geographic regions. Among Asian patients, the incidence of febrile neutropenia was higher in the pertuzumab-treated group (26%) compared with the placebo-treated group (12%).

  Table 3summarizes the adverse reactions in CLEOPATRA that occurred ≥ 10% of patients in the PERJETA-treated group.

  Table 3: Adverse Reactions (≥ 10%) in Patients Who Received PERJETA in Combination with Trastuzumab and Docetaxel in CLEOPATRA

  Adverse Reactions	PERJETA + trastuzumab + docetaxel n=407 %		Placebo + trastuzumab + docetaxel n=397 %
  	All Grades %	Grades 3 – 4 %	All Grades %	Grades 3 – 4 %
  Gastrointestinal disorders
  Diarrhea	67	8	46	5
  Nausea	42	1	42	0.5
  Vomiting	24	1	24	2
  Stomatitis	19	0.5	15	0.3
  Constipation	15	0	25	1
  Skin and subcutaneous tissue disorders
  Alopecia	61	0	60	0.3
  Rash	34	0.7	24	0.8
  Nail disorder	23	1	23	0.3
  Pruritus	14	0	10	0
  Dry skin	11	0	4	0
  Blood and lymphatic system disorders
  Neutropenia	53	49	50	46
  Anemia	23	2	19	4
  Leukopenia	18	12	20	15
  Febrile neutropeniaIn this table this denotes an adverse reaction that has been reported in association with a fatal outcome	14	13	8	7
  General disorders and administration site conditions
  Fatigue	37	2	37	3
  Mucosal inflammation	28	1	20	1
  Asthenia	26	2	30	2
  Peripheral edema	23	0.5	30	0.8
  Pyrexia	19	1	18	0.5
  Nervous system disorders
  Neuropathy peripheral	32	3	34	2
  Headache	21	1	17	0.5
  Dysgeusia	18	0	16	0
  Dizziness	13	0.5	12	0
  Metabolism and nutrition disorders
  Decreased appetite	29	2	26	2
  Musculoskeletal and connective tissue disorders
  Myalgia	23	1	24	0.8
  Arthralgia	15	0.2	16	0.8
  Infections and infestations
  Upper respiratory tract infection	17	0.7	13	0
  Nasopharyngitis	12	0	13	0.3
  Respiratory, thoracic, and mediastinal disorders
  Dyspnea	14	1	16	2
  Eye disorders
  Lacrimation increased	14	0	14	0
  Psychiatric disorders
  Insomnia	13	0	13	0

  Clinically relevant adverse reactions in < 10% of patients in the PERJETA-treated group in CLEOPATRA included paronychia (7%).

  Adverse Reactions Reported in Patients Receiving PERJETA and Trastuzumab After Discontinuation of Docetaxel

  In CLEOPATRA, adverse reactions that occurred after discontinuation of docetaxel included diarrhea (19%), upper respiratory tract infection (13%), rash (12%), headache (11%), and fatigue (11%).

  Neoadjuvant Treatment of Breast Cancer

  NeoSphere

  The safety of PERJETA was evaluated in a randomized trial (NeoSphere) in patients with operable, locally advanced, or inflammatory HER2-positive breast cancer (T2-4d) who were scheduled for neoadjuvant therapy

  [see Clinical Studies (14.2)]

  .

  In combination with trastuzumab and docetaxel, PERJETA was given intravenously at an initial dose of 840 mg, followed by 420 mg every 3 weeks for 4 cycles. After surgery, patients in the PERJETA plus trastuzumab arm received docetaxel every 3 weeks for 4 cycles prior to FEC.

  Permanent discontinuation of neoadjuvant PERJETA due to an adverse reaction occurred in 0.9% of patients.

  The most common adverse reactions (> 30%) were alopecia, neutropenia, diarrhea, and nausea. The most common Grade 3 – 4 adverse reactions (> 2%) were neutropenia, febrile neutropenia, leukopenia, and diarrhea.

  Table 4summarizes the adverse reactions in NeoSphere that occurred ≥ 10% of patients who received neoadjuvant PERJETA with trastuzumab and docetaxel followed by FEC.

  Table 4: Adverse Reactions (≥ 10%) in Patients who Received Neoadjuvant PERJETA in NeoSphere

  Adverse Reactions	Trastuzumab + docetaxel n=107 %		PERJETA + trastuzumab + docetaxel n=107 %
  	All Grades %	Grades 3 – 4 %	All Grades %	Grades 3 – 4 %
  Skin and subcutaneous tissue disorders
  Alopecia	66	0	65	0
  Rash	21	2	26	0.9
  Blood and lymphatic system disorders
  Neutropenia	64	59	50	45
  Leukopenia	21	11	9	5
  Gastrointestinal disorders
  Nausea	36	0	39	0
  Diarrhea	34	4	46	6
  Vomiting	12	0	13	0
  Stomatitis	7	0	18	0
  General disorders and administration site conditions
  Fatigue	27	0	26	0.9
  Mucosal inflammation	21	0	26	2
  Asthenia	18	0	21	2
  Pyrexia	10	0	17	0
  Peripheral edema	10	0	3	0
  Musculoskeletal and connective tissue disorders
  Myalgia	22	0	22	0
  Arthralgia	8	0	10	0
  Nervous system disorders
  Peripheral Sensory Neuropathy	12	0.9	8	0.9
  Headache	11	0	11	0
  Dysgeusia	10	0	15	0
  Psychiatric disorders
  Insomnia	11	0	8	0
  Metabolism and nutrition disorders
  Decreased appetite	7	0	14	0

  Clinically relevant adverse reactions in < 10% of patients receiving neoadjuvant PERJETA with trastuzumab and docetaxel followed by FEC included anemia, febrile neutropenia, dizziness, upper respiratory tract infection, and increased lacrimation.

  Neoadjuvant Treatment of Breast Cancer

  TRYPHAENA

  The safety of PERJETA was evaluated in patients with HER2-positive locally advanced, operable, or inflammatory (T2-4d) breast cancer in TRYPHAENA

  [see Clinical Studies (14.2)].

  Adverse reactions resulting in permanent discontinuation of any component of neoadjuvant treatment occurred in 7% of patients receiving PERJETA in combination with trastuzumab and docetaxel following FEC and 8% for patients receiving PERJETA in combination with TCH.

  The most common adverse reactions (>2%) resulting in permanent discontinuation of PERJETA were left ventricular dysfunction, drug hypersensitivity, and neutropenia.

  For PERJETA administered in combination with trastuzumab and docetaxel for 3 cycles following 3 cycles of FEC, the most common adverse reactions (> 30%) were diarrhea, nausea, alopecia, neutropenia, vomiting, and fatigue. The most common Grade 3 – 4 adverse reactions (> 2%) were neutropenia, leukopenia, febrile neutropenia, diarrhea, left ventricular dysfunction, anemia, dyspnea, nausea, and vomiting.

  For PERJETA administered in combination with docetaxel, carboplatin, and trastuzumab (TCH) for 6 cycles, the most common adverse reactions (> 30%) were diarrhea, alopecia, neutropenia, nausea, fatigue, vomiting, anemia, and thrombocytopenia. The most common Grade 3 – 4 adverse reactions (> 2%) were neutropenia, febrile neutropenia, anemia, leukopenia, diarrhea, thrombocytopenia, vomiting, fatigue, ALT increased, hypokalemia, and hypersensitivity.

  Table 5summarizes the adverse reactions in TRYPHAENA that occurred in > 10% of patients who received neoadjuvant PERJETA with trastuzumab and docetaxel following FEC or who received neoadjuvant PERJETA in combination with TCH.

  Table 5: Adverse Reactions (≥ 10%) in Patients Receiving Neoadjuvant Treatment with PERJETA in TRYPHAENA

  Adverse Reactions	PERJETA + trastuzumab + docetaxel following FEC		PERJETA + TCH
  	n=75 %		n=76 %
  	All Grades %	Grades 3 – 4 %	All Grades %	Grades 3 – 4 %
  Gastrointestinal disorders
  Diarrhea	61	5	72	12
  Nausea	53	3	45	0
  Vomiting	36	3	39	5
  Dyspepsia	8	0	22	0
  Constipation	23	0	16	0
  Stomatitis	17	0	12	0
  Skin and subcutaneous tissue disorders
  Alopecia	52	0	55	0
  Rash	11	0	21	1
  Palmar-Plantar Erythrodysaesthesia Syndrome	11	0	8	0
  Dry skin	9	0	11	0
  Blood and lymphatic system disorders
  Neutropenia	47	43	49	46
  Leukopenia	16	12	17	12
  Anemia	9	4	38	17
  Febrile neutropenia	9	9	17	17
  Thrombocytopenia	1	0	30	12
  General disorders and administration site conditions
  Fatigue	36	0	42	4
  Mucosal inflammation	20	0	17	1
  Pyrexia	9	0	16	0
  Asthenia	15	1	13	1
  Edema peripheral	4	0	9	0
  Psychiatric disorders
  Insomnia	13	0	21	0
  Nervous system disorders
  Headache	15	0	17	0
  Dysgeusia	13	0	21	0
  Dizziness	8	1	16	0
  Neuropathy peripheral	1	0	11	0
  Metabolism and nutrition disorders
  Decreased appetite	11	0	21	0
  Respiratory, thoracic, and mediastinal disorders
  Epistaxis	11	0	16	1
  Dyspnea	8	3	11	1
  Oropharyngeal pain	7	0	12	0
  Cough	5	0	12	0
  Musculoskeletal and connective tissue disorders
  Myalgia	11	1	11	0
  Arthralgia	12	0	7	0
  Eye disorders
  Lacrimation increased	5	0	8	0
  Investigations
  ALT increased	3	0	11	4
  Immune system disorders
  Hypersensitivity	1	0	12	3

  Clinically relevant adverse reactions in < 10% of patients who received neoadjuvant PERJETA with trastuzumab and docetaxel following FEC or who received neoadjuvant PERJETA in combination with TCH included nail disorder, paronychia, pruritus, upper respiratory tract infection, and nasopharyngitis.

  Neoadjuvant Treatment of Breast Cancer

  BERENICE

  The safety of PERJETA was evaluated in a two-arm non-randomized study (BERENICE) in patient with HER2-positive locally advanced, inflammatory, or early-stage HER2-positive breast cancer

  [see Clinical Studies (14.2)].

  Adverse reactions resulting in permanent discontinuation of any component of neoadjuvant treatment were 14% for patients receiving PERJETA in combination with trastuzumab and paclitaxel following ddAC and 8% for patients receiving PERJETA in combination with trastuzumab and docetaxel following FEC. The most common adverse reactions (>1%) resulting in permanent discontinuation of any component of neoadjuvant treatment were peripheral neuropathy, decreased ejection fraction, diarrhea, neutropenia and infusion-related reaction.

  For PERJETA administered in combination with trastuzumab and paclitaxel for 4 cycles following 4 cycles of ddAC, the most common adverse reactions (> 30%) were nausea, diarrhea, alopecia, fatigue, constipation, peripheral neuropathy and headache. The most common Grade 3 – 4 adverse reactions (> 2%) were neutropenia, febrile neutropenia, decreased neutrophil count, decreased white blood cell count, anemia, diarrhea, peripheral neuropathy, increased ALT, and nausea.

  For PERJETA administered in combination with trastuzumab and docetaxel for 4 cycles following 4 cycles of FEC, the most common adverse reactions (> 30%) were diarrhea, nausea, alopecia, asthenia, constipation, fatigue, mucosal inflammation, vomiting, myalgia, and anemia. The most common Grade 3 – 4 adverse reactions (> 2%) were febrile neutropenia, diarrhea, neutropenia, decreased neutrophil count stomatitis, fatigue, vomiting, mucosal inflammation, neutropenic sepsis and anemia.

  Table 6summarizes the adverse reactions in BERENICE that occurred in ≥ 10% of patients who received neoadjuvant PERJETA with trastuzumab and paclitaxel following ddAC or who received neoadjuvant PERJETA with trastuzumab and docetaxel following FEC.

  Table 6: Adverse Reactions (≥ 10%) of Patients Receiving Neoadjuvant PERJETA in Combination with Trastuzumab and Taxane Chemotherapy Following ddAC or FEC in BERENICE

  Adverse Reactions	PERJETA + trastuzumab + paclitaxel following ddAC n=199 %		PERJETA + trastuzumab + docetaxel following FEC n=198 %
  	All Grades %	Grades 3 – 4 %	All Grades %	Grades 3 – 4 %
  Gastrointestinal disorders
  Nausea	71	3	69	2
  Diarrhea	67	3	69	10
  Constipation	35	0.5	38	0.5
  Vomiting	23	1	35	4
  Stomatitis	25	0	27	5
  Dyspepsia	19	0	16	0
  Upper abdominal pain	6	0	13	0
  Abdominal pain	5	0	10	0
  Gastroesophageal reflux disease	12	0	2	0
  Skin and subcutaneous tissue disorders
  Alopecia	62	0	59	0
  Rash	14	0	11	0
  Dry skin	14	0	10	0
  Nail discoloration	15	0	2	0
  Palmar-Plantar Erythrodysaesthesia Syndrome	6	0	10	0.5
  General disorders and administration site conditions
  Fatigue	58	1	38	5
  Asthenia	19	2	41	0
  Mucosal inflammation	22	1	37	4
  Pyrexia	15	0	18	0
  Peripheral edema	9	0	12	1
  Nervous system disorders
  Peripheral neuropathy	42	3	26	0.5
  Headache	30	0.5	14	0.5
  Dysgeusia	20	0	19	0.5
  Paresthesia	15	0	9	0
  Dizziness	12	0	8	0
  Blood and lymphatic system disorders
  Anemia	27	3	30	3
  Neutropenia	22	12	16	9
  Febrile neutropenia	7	7	17	17
  Musculoskeletal and connective tissue disorders
  Myalgia	20	0	33	1
  Arthralgia	20	0	21	1
  Back pain	10	0	9	0
  Pain in extremity	10	0	8	0
  Bone pain	12	0.5	5	0
  Respiratory, thoracic, and mediastinal disorders
  Epistaxis	25	0	19	0
  Dyspnea	15	0.5	15	0.5
  Cough	20	0.5	9	0
  Oropharyngeal pain	10	0	8	0.5
  Metabolism and nutrition disorders
  Decreased appetite	20	0	23	0
  Psychiatric disorders
  Insomnia	19	0	13	0
  Vascular disorders
  Hot flush	19	0	13	0
  Injury, poisoning and procedural complications
  Infusion-related reaction	16	1	13	1
  Eye disorders
  Increased lacrimation	9	0	18	0
  Investigations
  Decreased white blood cell count	11	4	3	2
  Infections and infestations
  Urinary tract infection	11	1	2	0

  Clinically relevant adverse reactions in < 10% of patients who received PERJETA in combination with trastuzumab and paclitaxel following ddAC or patients receiving PERJETA in combination with trastuzumab and docetaxel following FEC included pruritus, nail disorder, paronychia, upper respiratory tract infection, and nasopharyngitis.

  Adjuvant Treatment of Breast Cancer

  APHINITY

  The safety of PERJETA was evaluated in a multicenter, randomized, double-blind, placebo-controlled study (APHINITY) conducted in patients with HER2-positive early breast cancer who had their primary tumor excised prior to randomization

  [see Clinical Studies (14.3)].

  Patients were randomized to receive either PERJETA in combination with trastuzumab and chemotherapy or placebo in combination with trastuzumab and chemotherapy. Investigators selected one of three anthracycline-based or non-anthracycline-based chemotherapy regimens for patients. PERJETA and trastuzumab were administered intravenously every 3 weeks starting on Day 1 of the first taxane-containing cycle, for a total of 52 weeks (up to 18 cycles) or until recurrence, withdrawal of consent, or unmanageable toxicity.

  Serious adverse reactions (hospitalization) due to diarrhea in the PERJETA-treated group was 2.4%. The incidence of diarrhea was higher when chemotherapy was administered with PERJETA (61%) and was higher when administered with non-anthracycline based therapy (85%) than with anthracycline based therapy (67%). The median duration of diarrhea was 8 days. The median duration of Grade ≥3 diarrhea was 20 days. The incidence of diarrhea during the period PERJETA and trastuzumab were administered without chemotherapy was 18% in the PERJETA-treated group.

  Adverse reactions resulting in permanent discontinuation of any study therapy were 13% for patients in the PERJETA-treated group. Adverse reactions resulting in permanent discontinuation of PERJETA was 7%. The most common adverse reactions (>0.5%) resulting in permanent discontinuation of any study treatment were ejection fraction decreased, neuropathy peripheral, diarrhea, and cardiac failure.

  When PERJETA was administered in combination with trastuzumab and chemotherapy, the most common adverse reactions (> 30%) were diarrhea, nausea, alopecia, fatigue, peripheral neuropathy, and vomiting. The most common Grade 3 – 4 adverse reactions (> 2%) were neutropenia, febrile neutropenia, diarrhea, neutrophil count decreased, anemia, white blood cell count decreased, leukopenia, fatigue, nausea, and stomatitis.

  Table 7summarizes the adverse reactions that occurred in ≥ 10% of patients who received adjuvant PERJETA in combination with trastuzumab and chemotherapy followed by PERJETA and trastuzumab for a total of 52 weeks (up to 18 cycles) or until recurrence, withdrawal of consent, or unmanageable toxicity.

  Table 7: Adverse Reactions (≥ 10%) of Patients Receiving Adjuvant PERJETA in Combination with Trastuzumab and Chemotherapy Followed by PERJETA and Trastuzumab in APHINITY

  Adverse Reactions	PERJETA + trastuzumab + chemotherapy n=2364 %		Placebo + trastuzumab + chemotherapy n=2405 %
  	All Grades %	Grades 3 – 4 %	All Grades %	Grades 3 – 4 %
  Gastrointestinal disorders
  Diarrhea	71	10	45	4
  Nausea	69	2	65	2
  Vomiting	32	2	30	2
  Constipation	29	0.5	32	0.3
  Stomatitis	28	2	24	1
  Dyspepsia	14	0	14	0
  Abdominal pain	12	0.5	11	0.6
  Abdominal pain upper	10	0.3	9	0.2
  Skin and subcutaneous tissue disorders
  Alopecia	67	<0.1	67	<0.1
  Rash	26	0.4	20	0.2
  Pruritus	14	0.1	9	<0.1
  Dry skin	13	0.1	11	<0.1
  Nail disorder	12	0.2	12	0.1
  General disorders and administration site conditions
  Fatigue	49	4	44	3
  Mucosal inflammation	23	2	19	0.7
  Asthenia	21	1	21	2
  Pyrexia	20	0.6	20	0.7
  Edema peripheral	17	0	20	0.2
  Musculoskeletal and connective tissue disorders
  Arthralgia	29	0.9	33	1
  Myalgia	26	0.9	30	1
  Pain in extremity	10	0.2	10	0.2
  Blood and lymphatic system disorders
  Anemia	28	7	23	5
  Neutropenia	25	16	23	16
  Febrile neutropeniaIn this table this denotes an adverse reaction that has been reported in association with a fatal outcome	12	12	11	11
  Nervous system disorders
  Dysgeusia	26	0.1	22	<0.1
  Neuropathy peripheral	33	1	32	1
  Headache	22	0.3	23	0.4
  Paresthesia	12	0.5	10	0.2
  Dizziness	11	0	11	0.2
  Metabolism and nutrition disorders
  Decreased appetite	24	0.8	20	0.4
  Vascular disorders
  Hot flush	20	0.2	21	0.4
  Respiratory, thoracic, and mediastinal disorders
  Epistaxis	18	<0.1	14	0
  Cough	16	<0.1	15	<0.1
  Dyspnea	12	0.4	12	0.5
  Psychiatric disorders
  Insomnia	17	0.3	17	<0.1
  Investigations
  Neutrophil count decreased	14	10	14	10
  Eye disorders
  Lacrimation increased	13	0	13	<0.1
  Infections and infestations
  Nasopharyngitis	13	<0.1	12	0.1
  Injury, poisoning and procedural complications
  Radiation skin injury	13	0.3	11	0.3

  Clinically relevant

  adverse reactions in

  <

  10% of patients

  who received

  PERJETA

  in combination with trastuzumab

  and

  anthracycline-based or non-anthracycline-based

  chemotherapy regimens included

  l

  eukopenia, upper respiratory tract infection, and paronychia

  Adverse Reactions in Patients Receiving PERJETA and Trastuzumab After Discontinuation of Chemotherapy

  In APHINITY, adverse reactions that occurred after discontinuation of chemotherapy in >10% included diarrhea (18%), arthralgia (15%), radiation skin injury (12%), and hot flush (12%).

  ].
• Embryo-fetal Toxicity: Exposure to PERJETA can cause embryo-fetal death and birth defects. Advise patients of these risks and the need for effective contraception

  [see

  5.2 Embryo-Fetal Toxicity

  Based on its mechanism of action and findings in animal studies, PERJETA can cause fetal harm when administered to a pregnant woman. PERJETA is a HER2/neu receptor antagonist. Cases of oligohydramnios and oligohydramnios sequence manifesting as pulmonary hypoplasia, skeletal abnormalities, and neonatal death have been reported with use of another HER2/neu receptor antagonist (trastuzumab) during pregnancy. In an animal reproduction study, administration of pertuzumab to pregnant cynomolgus monkeys during the period of organogenesis resulted in oligohydramnios, delayed fetal kidney development, and embryo-fetal death at exposures 2.5 to 20 times the exposure in humans at the recommended dose, based on C_max.

  Verify the pregnancy status of females of reproductive potential prior to the initiation of PERJETA. Advise pregnant women and females of reproductive potential that exposure to PERJETA in combination with trastuzumab during pregnancy or within 7 months prior to conception can result in fetal harm, including embryo-fetal death or birth defects. Advise females of reproductive potential to use effective contraception during treatment and for 7 months following the last dose of PERJETA in combination with trastuzumab

  [see Use in Specific Populations (8.1, 8.3)]

  .

  and

  8.1 Pregnancy

  Pregnancy Pharmacovigilance Program

  There is a pregnancy pharmacovigilance program for PERJETA. If PERJETA is administered during pregnancy, or if a patient becomes pregnant while receiving PERJETA or within 7 months following the last dose of PERJETA in combination with trastuzumab, health care providers and patients should immediately report PERJETA exposure to Genentech at 1-888-835-2555.

  Risk Summary

  Based on its mechanism of action and findings in animal studies, PERJETA can cause fetal harm when administered to a pregnant woman. There are no available data on the use of PERJETA in pregnant women. However, in post-marketing reports, use of another HER2/neu receptor antagonist (trastuzumab) during pregnancy resulted in cases of oligohydramnios and oligohydramnios sequence manifesting as pulmonary hypoplasia, skeletal abnormalities, and neonatal death. In an animal reproduction study, administration of pertuzumab to pregnant cynomolgus monkeys during the period of organogenesis resulted in oligohydramnios, delayed fetal kidney development, and embryo-fetal deaths at clinically relevant exposures that were 2.5 to 20-fold greater than exposures in humans receiving the recommended dose, based on C_max

  [see Data].

  Apprise the patient of the potential risks to a fetus. There are clinical considerations if PERJETA in combination with trastuzumab is used during pregnancy or within 7 months prior to conception

  [see Clinical Considerations]

  .

  The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.

  Clinical Considerations

  Fetal/Neonatal Adverse Reactions

  Monitor women who received PERJETA in combination with trastuzumab during pregnancy or within 7 months prior to conception for oligohydramnios. If oligohydramnios occurs, perform fetal testing that is appropriate for gestational age and consistent with community standards of care.

  Data

  Animal Data

  Pregnant cynomolgus monkeys were treated on Gestational Day (GD)19 with loading doses of 30 to 150 mg/kg pertuzumab, followed by bi-weekly doses of 10 to 100 mg/kg. These dose levels resulted in clinically relevant exposures of 2.5 to 20-fold greater than exposures in humans receiving the recommended dose, based on C_max. Intravenous administration of pertuzumab from GD19 through GD50 (period of organogenesis) was embryotoxic, with dose-dependent increases in embryo-fetal death between GD25 to GD70. The incidences of embryo-fetal loss were 33, 50, and 85% for dams treated with bi-weekly pertuzumab doses of 10, 30, and 100 mg/kg, respectively (2.5 to 20-fold greater than the recommended human dose, based on C_max). At Caesarean section on GD100, oligohydramnios, decreased relative lung and kidney weights, and microscopic evidence of renal hypoplasia consistent with delayed renal development were identified in all pertuzumab dose groups. Pertuzumab exposure was reported in offspring from all treated groups, at levels of 29% to 40% of maternal serum levels at GD100.

  8.3 Females and Males of Reproductive Potential

  Pregnancy Testing

  Verify the pregnancy status of females of reproductive potential prior to the initiation of PERJETA.

  Contraception

  Females

  Based on the mechanism of action and animal data, PERJETA can cause embryo-fetal harm when administered during pregnancy. Advise females of reproductive potential to use effective contraception during treatment and for 7 months following the last dose of PERJETA in combination with trastuzumab

  [see Use in Specific Populations (8.1)].

  ].

PERJETA is a HER2/neu receptor antagonist indicated for:

• Use in combination with trastuzumab and docetaxel for treatment of adults with HER2-positive metastatic breast cancer (MBC) who have not received prior anti-HER2 therapy or chemotherapy for metastatic disease. (
  1.1 Metastatic Breast Cancer (MBC)

  PERJETA is indicated for use in combination with trastuzumab and docetaxel for the treatment of adults with HER2-positive metastatic breast cancer who have not received prior anti-HER2 therapy or chemotherapy for metastatic disease

  [see Dosage and Administration (2.2)and Clinical Studies (14.1)]

  .
  )
• Use in combination with trastuzumab and chemotherapy as
  • neoadjuvant treatment of adults with HER2-positive, locally advanced, inflammatory, or early stage breast cancer (either greater than 2 cm in diameter or node positive) as part of a complete treatment regimen for early breast cancer. (
    1.2 Early Breast Cancer (EBC)

    PERJETA is indicated for use in combination with trastuzumab and chemotherapy for

    • the neoadjuvant treatment of adults with HER2-positive, locally advanced, inflammatory, or early stage breast cancer (either greater than 2 cm in diameter or node positive) as part of a complete treatment regimen for early breast cancer
      [see Dosage and Administration (2.2)and Clinical Studies (14.2)]
      .
    • the adjuvant treatment of adults with HER2-positive early breast cancer at high risk of recurrence
      [see Dosage and Administration (2.2)and Clinical Studies (14.3)]
      .
    ,
    2.2 Patient Selection

    Select patients based on HER2 protein overexpression or HER2 gene amplification in tumor specimens

    [see Indications and Usage (1)and Clinical Studies (14)]

    . Assessment of HER2 protein overexpression and HER2 gene amplification should be performed using FDA-approved tests specific for breast cancer by laboratories with demonstrated proficiency.

    Information on the FDA-approved tests for the detection of HER2 protein overexpression and HER2 gene amplification is available at: http://www.fda.gov/CompanionDiagnostics.

    Improper assay performance, including use of suboptimally fixed tissue, failure to utilize specified reagents, deviation from specific assay instructions, and failure to include appropriate controls for assay validation, can lead to unreliable results.
    ,
    14.2 Neoadjuvant Treatment of Breast Cancer

    NeoSphere

    NeoSphere (NCT00545688) was a multicenter, randomized trial conducted in 417 patients with operable, locally advanced, or inflammatory HER2-positive breast cancer (T2-4d) who were scheduled for neoadjuvant therapy. HER2 overexpression was defined as a score of 3+ IHC or FISH amplification ratio of 2.0 or greater as determined by a central laboratory. Patients were randomly allocated to receive 1 of 4 neoadjuvant regimens prior to surgery as follows: trastuzumab plus docetaxel, PERJETA plus trastuzumab and docetaxel, PERJETA plus trastuzumab, or PERJETA plus docetaxel. Randomization was stratified by breast cancer type (operable, locally advanced, or inflammatory) and estrogen receptor (ER) or progesterone receptor (PgR) positivity.

    PERJETA was given intravenously at an initial dose of 840 mg, followed by 420 mg every 3 weeks for 4 cycles. Trastuzumab was given intravenously at an initial dose of 8 mg/kg, followed by 6 mg/kg every 3 weeks for 4 cycles. Docetaxel was given as an initial dose of 75 mg/m²by intravenous infusion every 3 weeks for 4 cycles. The docetaxel dose could be escalated to 100 mg/m²at the investigator's discretion if the initial dose was well tolerated. Following surgery all patients received 3 cycles of 5-fluorouracil (600 mg/m²), epirubicin (90 mg/m²), and cyclophosphamide (600 mg/m²) (FEC) given intravenously every 3 weeks and trastuzumab administered intravenously every 3 weeks to complete 1 year of therapy. After surgery, patients in the PERJETA plus trastuzumab arm received docetaxel every 3 weeks for 4 cycles prior to FEC.

    The major efficacy outcome measure was pathological complete response (pCR) rate in the breast (ypT0/is) defined as the absence of invasive cancer in the breast and lymph nodes (ypT0/is ypN0) for the efficacy analysis.

    Demographics were balanced (median age was 49 – 50 years old, the majority were White (71%) and all were female. Overall, 7% of patients had inflammatory cancer, 32% had locally advanced cancer, and 61% had operable cancer. Approximately half the patients in each treatment group had hormone receptor-positive disease (defined as ER-positive and/or PgR-positive).

    Statistically significant improvements in pCR rates were observed in patients receiving PERJETA plus trastuzumab and docetaxel compared to patients receiving trastuzumab plus docetaxel. The pCR rates and magnitude of improvement with PERJETA were lower in the subgroup of patients with hormone receptor-positive tumors compared to patients with hormone receptor-negative tumors. The efficacy results are summarized in Table 9.

    Table 9: Efficacy Results from NeoSphere

    Endpoint	H+T N=107	Ptz+H+T N=107	Ptz+H N=107	Ptz+T N=96
    T=docetaxel, Ptz=PERJETA, H=trastuzumab CI=Confidence Interval
    pCRypT0/is ypN0 (absence of invasive cancer in the breast and lymph nodes) based on intention-to-treat population, n (%) [95% CI]95% CI for one sample binomial using Pearson-Clopper method.	23 (21.5%) [14.1, 30.5]	42 (39.3%) [30.0, 49.2]	12 (11.2%) [5.9, 18.8]	17 (17.7%) [10.7, 26.8]
    p-value (with Simes correction for CMH test)p-value from Cochran-Mantel-Haenszel (CMH) test, with Simes multiplicity adjustment		0.0063 (vs. H+T)	0.0223 (vs. H+T)	0.0018 (vs. Ptz+H+T)
    Hormone receptor-positive subgroup	N=50	N=50	N=51 One patient had unknown hormone receptor status. The patient did not achieve a pCR.	N=46
    pCR , n (%) [95% CI]	6 (12.0%) [4.5, 24.3]	11 (22.0%) [11.5, 36.0]	1 (2.0%) [0.1, 10.5]	4 (8.7%) [2.4, 20.8]
    Hormone receptor-negative subgroup	N=57	N=57	N=55	N=50
    pCR , n (%) [95% CI]	17 (29.8%) [18.4, 43.4]	31 (54.4%) [40.7, 67.6]	11 (20.0%) [10.4, 33.0]	13 (26.0%) [14.6, 40.3]

    TRYPHAENA

    TRYPHAENA(NCT00976989) was a three-arm, randomized (1:1:1) study in the neoadjuvant setting conducted in 225 patients with HER2-positive locally advanced, operable, or inflammatory (T2-4d) breast cancer designed primarily to assess cardiac safety. HER2 overexpression was defined as a score of 3+ IHC or FISH amplification ratio of 2.0 or greater as determined by a central laboratory.

    Patients were randomly allocated to receive 1 of 3 neoadjuvant regimens prior to surgery as follows: 3 cycles of FEC followed by 3 cycles of docetaxel all in combination with PERJETA and trastuzumab, 3 cycles of FEC alone followed by 3 cycles of docetaxel and trastuzumab in combination with PERJETA, or 6 cycles of docetaxel, carboplatin, and trastuzumab (TCH) in combination with PERJETA. Randomization was stratified by breast cancer type (operable, locally advanced, or inflammatory) and ER and/or PgR positivity.

    PERJETA was given by intravenous infusion at an initial dose of 840 mg, followed by 420 mg every 3 weeks. Trastuzumab was given by intravenous infusion at an initial dose of 8 mg/kg, followed by 6 mg/kg every 3 weeks. 5-Fluorouracil (500 mg/m²), epirubicin (100 mg/m²), and cyclophosphamide (600 mg/m²) [FEC] were given intravenously every 3 weeks for 3 cycles. In the PERJETA plus trastuzumab, docetaxel, and FEC arms, docetaxel was given as an initial dose of 75 mg/m²by intravenous infusion every 3 weeks for 3 cycles with the option to escalate to 100 mg/m²at the investigator's discretion if the initial dose was well tolerated. However, in the PERJETA plus TCH arm, docetaxel was given intravenously at 75 mg/m²(no escalation was permitted) and carboplatin (AUC 6) was given intravenously every 3 weeks for 6 cycles. Following surgery all patients received trastuzumab to complete 1 year of therapy, which was administered intravenously every 3 weeks.

    Demographics were balanced (median age was 49-50 years old, the majority were White [76%]) and all were female. Overall 6% of patients had inflammatory cancer, 25% had locally advanced cancer and 69% had operable cancer, with approximately half the patients in each treatment group having ER-positive and/or PgR-positive disease.

    The pCR (ypT0/is ypN0) rates were 56.2% (95% CI: 44.1%, 67.8%), 54.7% (95% CI: 42.7%, 66.2%), and 63.6% (95% CI: 51.9%, 74.3%) for patients treated with PERJETA plus trastuzumab and FEC followed by PERJETA plus trastuzumab and docetaxel, PERJETA plus trastuzumab and docetaxel following FEC, or PERJETA plus TCH, respectively

    .

    The pCR rates were lower in the subgroups of patients with hormone receptor-positive tumors: 41.0% (95% CI: 25.6%, 57.9%), 45.7% (95% CI: 28.8%, 63.4%), and 47.5% (95% CI: 31.5%, 63.9%) than with hormone receptor-negative tumors: 73.5% (95% CI: 55.6%, 87.1%), 62.5% (95% CI: 45.8%, 77.3%), and 81.1% (95% CI: 64.8%, 92.0%), respectively.

    BERENICE

    A two-arm non-randomized study (BERENICE, NCT02132949) was conducted in 401 patients with HER2-positive locally advanced, inflammatory, or early-stage HER2-positive breast cancer. HER2 overexpression was defined as a score of 3+ IHC or ISH amplification ratio of 2.0 or greater as determined by a central laboratory.

    Patients received 1 of 2 neoadjuvant regimens prior to surgery as follows: 4 cycles of dose dense doxorubicin and cyclophosphamide (ddAC) followed by 4 cycles of PERJETA in combination with trastuzumab and weekly paclitaxel for 12 weeks or 4 cycles of 5-fluorouracil, epirubicin and cyclophosphamide (FEC) followed by 4 cycles of PERJETA in combination with trastuzumab and docetaxel. The choice of neoadjuvant treatment regimen was made by the Investigator on a site-specific basis. Dosing for the regimens was as follows:

    • PERJETA was given by intravenous infusion at an initial dose of 840 mg, followed by 420 mg every 3 weeks. Trastuzumab was given by intravenous infusion at an initial dose of 8 mg/kg, followed by 6 mg/kg every 3 weeks.
    • In the ddAC cohort, (doxorubicin 60 mg/m²and cyclophosphamide 600 mg/m²) were given intravenously every 2 weeks (ddAC) for 4 cycles with G-CSF (granulocyte colony stimulating factor) support at investigator discretion, followed by paclitaxel 80 mg/m²given intravenously weekly for 12 weeks, with PERJETA and trastuzumab every 3 weeks from the start of paclitaxel for 4 cycles.
    • In the FEC cohort, 5-Fluorouracil (5-FU) (500 mg/m²), epirubicin (100 mg/m²), and cyclophosphamide (600 mg/m²) were given intravenously every 3 weeks for 4 cycles, followed by docetaxel given as an initial dose of 75 mg/m²by intravenous infusion every 3 weeks for 4 cycles with PERJETA and trastuzumab, and with the option to escalate to 100 mg/m²at the investigator's discretion if the initial dose was well tolerated.

    Following surgery, all patients received PERJETA and trastuzumab administered intravenously every 3 weeks to complete 1 year of therapy.

    The median age was 49 years old (range 21-78), 12% of patients were 65 or older, 83% were White, and all but one patient was female (99.8%). Overall 3% of patients had inflammatory cancer, 23% had locally advanced cancer (Stage 3A or greater), 5% were not classified per TNM staging, with approximately two thirds of the patients in each treatment group having ER-positive and/or PgR-positive disease. All patients had an ECOG performance status of 0 or 1.

    The pCR (ypT0/is ypN0) rates were 61.8% (95% CI: 54.7, 68.6) and 60.7% (95% CI: 53.6, 67.5) for patients treated with ddAC followed by PERJETA plus trastuzumab and paclitaxel, or FEC followed by PERJETA plus trastuzumab and docetaxel, respectively

    .

    The pCR rates were lower in the subgroups of patients with hormone receptor-positive tumors: 51.6% (95% CI: 42.6, 60.5%) and 57.3% (95% CI: 48.1, 66.1%) than with hormone receptor-negative tumors: 81.5% (95% CI: 70.0, 90.1%) and 68.0% (95% CI: 56.2, 78.3%), respectively.
    )
  • adjuvant treatment of adults with HER2-positive early breast cancer at high risk of recurrence (
    1.2 Early Breast Cancer (EBC)

    PERJETA is indicated for use in combination with trastuzumab and chemotherapy for

    • the neoadjuvant treatment of adults with HER2-positive, locally advanced, inflammatory, or early stage breast cancer (either greater than 2 cm in diameter or node positive) as part of a complete treatment regimen for early breast cancer
      [see Dosage and Administration (2.2)and Clinical Studies (14.2)]
      .
    • the adjuvant treatment of adults with HER2-positive early breast cancer at high risk of recurrence
      [see Dosage and Administration (2.2)and Clinical Studies (14.3)]
      .
    ,
    2.2 Patient Selection

    Select patients based on HER2 protein overexpression or HER2 gene amplification in tumor specimens

    [see Indications and Usage (1)and Clinical Studies (14)]

    . Assessment of HER2 protein overexpression and HER2 gene amplification should be performed using FDA-approved tests specific for breast cancer by laboratories with demonstrated proficiency.

    Information on the FDA-approved tests for the detection of HER2 protein overexpression and HER2 gene amplification is available at: http://www.fda.gov/CompanionDiagnostics.

    Improper assay performance, including use of suboptimally fixed tissue, failure to utilize specified reagents, deviation from specific assay instructions, and failure to include appropriate controls for assay validation, can lead to unreliable results.
    ,
    14.3 Adjuvant Treatment of Breast Cancer

    APHINITY (NCT01358877) was a multicenter, randomized, double-blind, placebo-controlled study conducted in 4804 patients with HER2-positive early breast cancer who had their primary tumor excised prior to randomization. Patients were then randomized to receive PERJETA or placebo, in combination with adjuvant trastuzumab and chemotherapy. Randomization was stratified by the following factors: region, nodal status, protocol version, central hormone receptor status, and adjuvant chemotherapy regimen.

    Investigators selected one of the following anthracycline-based or non-anthracycline-based chemotherapy regimens for individual patients:

    • 3 or 4 cycles of FEC (5-FU 500-600 mg/m², epirubicin 90-120 mg/m², cyclophosphamide 500-600 mg/m²) or FAC (5-FU 500-600 mg/m², doxorubicin 50 mg/m², cyclophosphamide 500-600 mg/m²), followed by 3 or 4 cycles of docetaxel (75 mg/m²which could be escalated to 100 mg/m²every 3 weeks) or 12 cycles of weekly paclitaxel (80 mg/m²).
    • 4 cycles of AC (doxorubicin 60 mg/m²and cyclophosphamide 500-600 mg/m²) or EC (epirubicin 90-120 mg/m²and cyclophosphamide 500-600 mg/m²) either every 3 weeks or every 2 weeks with GCSF support, followed by docetaxel (100 mg/m²for 3 cycles or 75 mg/m²for first cycle and 100 mg/m²for subsequent three cycles, or 75 mg/m²for four cycles) or 12 cycles of weekly paclitaxel (80 mg/m²).
    • 6 cycles of docetaxel (75 mg/m²) in combination with carboplatin (AUC 6)

    PERJETA and trastuzumab were administered intravenously every 3 weeks starting on Day 1 of the first taxane-containing cycle, for a total of 52 weeks (up to 18 cycles) or until recurrence, withdrawal of consent, or unmanageable toxicity.

    After completion of chemotherapy, patients received radiotherapy and/or hormone therapy as per investigator's discretion.

    The major efficacy outcome of the study was invasive disease-free survival (IDFS), defined as the time from randomization to first occurrence of ipsilateral local or regional invasive breast cancer recurrence, distant recurrence, contralateral invasive breast cancer, or death from any cause. Additional efficacy endpoints were IDFS including second primary non-breast cancer, disease-free survival (DFS), and overall survival (OS).

    Demographics were balanced between the two treatment arms. The median age was 51 years (range 18-86), 13% of patients were 65 or older, and over 99% of patients were female. Sixty-three percent of patients had node-positive disease, 64% had hormone receptor-positive disease, and 71% were White. All patients had an ECOG performance status of 0 or 1. Seventy-eight percent received an anthracycline containing regimen.

    PERJETA-treated patients and placebo-treated patients both received a median number of 18 cycles of anti-HER2 therapy. After a median follow-up of 45.4 months, a statistically significant improvement in IDFS was demonstrated in patients randomized to receive PERJETA compared with patients randomized to receive placebo. The efficacy results from APHINITY are summarized in Tables 10and 11and in Figure 3.

    Table 10: Efficacy Results from APHINITY

    	PERJETA + trastuzumab + chemotherapy N=2400	Placebo + trastuzumab + chemotherapy N=2404
    HR=Hazard Ratio, CI=Confidence Interval
    Invasive Disease Free Survival (IDFS)
    Number (%) of patients with event	171 (7.1%)	210 (8.7%)
    HR [95% CI]All analyses stratified by nodal status, protocol version, central hormone receptor status, and adjuvant chemotherapy regimen. Stratification factors are defined according to the randomization data for IDFS.	0.82 [0.67, 1.00]
    p-value (Log-Rank test, stratified )	0.047
    3 year event-free rate3-year event-free rate derived from Kaplan-Meier estimates, % [95% CI]	94.1 [93.1, 95.0]	93.2 [92.2, 94.3]
    IDFS including second primary non-breast cancer
    Number (%) of patients with event	189 (7.9%)	230 (9.6%)
    HR [95% CI]	0.83 [0.68, 1.00]
    3 year event-free rate , % [95% CI]	93.5 [92.5, 94.5]	92.5 [91.4, 93.6]
    Disease Free Survival (DFS)
    Number (%) of patients with event	192 (8.0%)	236 (9.8%)
    HR [95% CI]	0.82 [0.68, 0.99]
    3 year event-free rate , % [95% CI]	93.4 [92.4, 94.4]	92.3 [91.2, 93.4]
    Overall Survival (OS)Data from first interim analysis
    Number (%) of patients with event	80 (3.3%)	89 (3.7%)
    HR [95% CI]	0.89 [0.66, 1.21]
    3 year event-free rate , % [95% CI]	97.7 [97.0, 98.3]	97.7 [97.1, 98.3]

    Figure 3 Kaplan-Meier Curve of Invasive Disease Free Survival from APHINITY (ITT Population)

    

    Table 11 Efficacy Results by Baseline Disease Characteristics and Adjuvant Chemotherapy from APHINITYExploratory analyses without adjusting multiple comparisons, therefore, results are considered descriptive.

    Population	Number of events/Total N (%)		IDFS at 3 year (%, 95% CI)		Unstratified HR (95% CI)
    	PERJETA + trastuzumab + chemotherapy	Placebo + trastuzumab + chemotherapy	PERJETA + trastuzumab + chemotherapy	Placebo + trastuzumab + chemotherapy
    Hormone Receptor Status
    Negative	71/864 (8.2%)	91/858 (10.6%)	92.8 (90.8, 94.3)	91.2 (89.0, 92.9)	0.76 (0.56, 1.04)
    Positive	100/1536 (6.5%)	119/1546 (7.7%)	94.8 (93.5, 95.8)	94.4 (93.1, 95.4)	0.86 (0.66, 1.13)
    Nodal Status
    Negative	32/897 (3.6%)	29/902 (3.2%)	97.5 (96.3, 98.4)	98.4 (97.3, 99.0)	1.13 (0.68, 1.86)
    Positive	139/1503 (9.2%)	181/1502 (12.1%)	92.0 (90.5, 93.3)	90.2 (88.5, 91.6)	0.77 (0.62, 0.96)
    Adjuvant Chemotherapy Regimen
    Anthracycline	139/1865 (7.4%)	171/1877 (9.1%)	93.8 (92.6, 94.8)	93.0 (91.8, 94.1)	0.82 (0.66, 1.03)
    Non-Anthracycline	32/535 (6.0%)	39/527 (7.4%)	94.9 (92.6, 96.6)	94.0 (91.5, 95.8)	0.82 (0.51, 1.31)

    

    )

• For intravenous infusion only.
  Do not administer as an intravenous push or bolus. (
  2.5 Dosage Modification for Adverse Reactions

  Left Ventricular Dysfunction

  Assess left ventricular ejection fraction (LVEF) prior to initiation of PERJETA and at regular intervals during treatment. The recommended dosage modifications for LVEF decrease are listed in Table 2

  [see Warnings and Precautions (5.1)].

  Table 2: Dose Modifications for Left Ventricular Dysfunction

  	Pre-treatment LVEF:	Monitor LVEF every:	Withhold PERJETA and trastuzumab or trastuzumab hyaluronidase-oysk for at least 3 weeks for an LVEF decrease to:		Resume PERJETA and trastuzumab or trastuzumab hyaluronidase-oysk after 3 weeks if LVEF has recovered to:
  Metastatic Breast Cancer	≥ 50%	~12 weeks	Either		Either
  			<40%	40%-45% with a fall of ≥10%-points below pre-treatment value	>45%	40%-45% with a fall of <10%-points below pre-treatment value
  Early Breast Cancer	≥ 55%For patients receiving anthracycline-based chemotherapy, a LVEF of ≥ 50% is required after completion of anthracyclines, before starting PERJETA and trastuzumab or trastuzumab hyaluronidase-oysk.	~12 weeks (once during neoadjuvant therapy)	<50% with a fall of ≥10%-points below pre-treatment value		Either
  					≥50%	<10% points below pre-treatment value

  Infusion-Related Reactions

  The infusion rate of PERJETA may be slowed or interrupted if the patient develops an infusion-related reaction

  [see Warnings and Precautions (5.3)]

  .

  Hypersensitivity Reactions/Anaphylaxis

  The infusion should be discontinued immediately if the patient experiences a serious hypersensitivity reaction

  [see Warnings and Precautions (5.4)]

  .
  )
• HER2 testing: Perform using FDA-approved tests by laboratories with demonstrated proficiency. (
  2.1 Evaluation and Testing Before Initiating Perjeta

  Assess left ventricular ejection fraction (LVEF) prior to initiation of PERJETA and at regular intervals during treatment

  [see Boxed Warning, Dosage and Administration (2.4), Warnings and Precautions (5.1)].

  Verify the pregnancy status of females of reproductive potential prior to the initiation of PERJETA

  [see Warnings and Precautions (5.2), Use in Specific Populations (8.1, 8.3)].
  )
• The initial PERJETA dose is 840 mg administered as a 60-minute intravenous infusion, followed every 3 weeks thereafter by 420 mg administered as a 30 to 60 minute intravenous infusion. (
  2.3 Recommended Dosage and Administration

  The initial dose of PERJETA is 840 mg administered as a 60-minute intravenous infusion, followed every 3 weeks by a dose of 420 mg administered as an intravenous infusion over 30 to 60 minutes.

  When administered with PERJETA, the recommended initial dose of trastuzumab is 8 mg/kg administered as a 90-minute intravenous infusion, followed every 3 weeks by a dose of 6 mg/kg administered as an intravenous infusion over 30 to 90 minutes.

  When administered with PERJETA, the recommended initial dose of trastuzumab hyaluronidase-oysk is 600 mg/10,000 units (600 mg trastuzumab and 10,000 units hyaluronidase) administered subcutaneously over approximately 2 to 5 minutes once every three weeks irrespective of the patient's body weight.

  Administer PERJETA, trastuzumab or trastuzumab hyaluronidase-oysk, and taxane sequentially. PERJETA and trastuzumab or trastuzumab hyaluronidase-oysk can be given in any order. Administer taxane after PERJETA and trastuzumab or trastuzumab hyaluronidase-oysk. An observation period of 30 to 60 minutes is recommended after each PERJETA infusion and before commencement of any subsequent administration of trastuzumab or trastuzumab hyaluronidase-oysk, or taxane

  [see Warnings and Precautions (5.3)].

  In patients receiving an anthracycline-based regimen, administer PERJETA and trastuzumab or trastuzumab hyaluronidase-oysk after completion of the anthracycline.

  Metastatic Breast Cancer (MBC)

  When administered with PERJETA, the recommended initial dose of docetaxel is 75 mg/m²administered as an intravenous infusion. The dose may be escalated to 100 mg/m²administered every 3 weeks if the initial dose is well tolerated.

  Neoadjuvant Treatment of Breast Cancer

  Administer PERJETA every 3 weeks for 3 to 6 cycles as part of one of the following treatment regimens

  [see Clinical Studies (14.2, 14.3)]

  :

  • Four preoperative cycles of PERJETA in combination with trastuzumab or trastuzumab hyaluronidase-oysk and docetaxel followed by 3 postoperative cycles of fluorouracil, epirubicin, and cyclophosphamide (FEC)
  • Three or four preoperative cycles of FEC alone followed by 3 or 4 preoperative cycles of PERJETA in combination with docetaxel and trastuzumab or trastuzumab hyaluronidase-oysk
  • Six preoperative cycles of PERJETA in combination with docetaxel, carboplatin, and trastuzumab (TCH) or trastuzumab hyaluronidase-oysk (escalation of docetaxel above 75 mg/m²is not recommended)
  • Four preoperative cycles of dose-dense doxorubicin and cyclophosphamide (ddAC) alone followed by 4 preoperative cycles of PERJETA in combination with paclitaxel and trastuzumab or trastuzumab hyaluronidase-oysk

  Following surgery, administer PERJETA and trastuzumab or trastuzumab hyaluronidase-oysk to complete 1 year of treatment (up to 18 cycles) or until disease recurrence or unmanageable toxicity, whichever occurs first.

  Adjuvant Treatment of Breast Cancer

  As part of a regimen including standard anthracycline- and/or taxane-based chemotherapy, administer PERJETA in combination with trastuzumab or trastuzumab hyaluronidase-oysk every 3 weeks for a total of 1 year (up to 18 cycles) or until disease recurrence or unmanageable toxicity, whichever occurs first. Administer PERJETA on Day 1 of the first taxane-containing cycle

  [see Clinical Studies (14.3)]

  .
  )
• MBC: Administer PERJETA, trastuzumab or trastuzumab hyaluronidase-oysk, and docetaxel every 3 weeks. (
  2.3 Recommended Dosage and Administration

  The initial dose of PERJETA is 840 mg administered as a 60-minute intravenous infusion, followed every 3 weeks by a dose of 420 mg administered as an intravenous infusion over 30 to 60 minutes.

  When administered with PERJETA, the recommended initial dose of trastuzumab is 8 mg/kg administered as a 90-minute intravenous infusion, followed every 3 weeks by a dose of 6 mg/kg administered as an intravenous infusion over 30 to 90 minutes.

  When administered with PERJETA, the recommended initial dose of trastuzumab hyaluronidase-oysk is 600 mg/10,000 units (600 mg trastuzumab and 10,000 units hyaluronidase) administered subcutaneously over approximately 2 to 5 minutes once every three weeks irrespective of the patient's body weight.

  Administer PERJETA, trastuzumab or trastuzumab hyaluronidase-oysk, and taxane sequentially. PERJETA and trastuzumab or trastuzumab hyaluronidase-oysk can be given in any order. Administer taxane after PERJETA and trastuzumab or trastuzumab hyaluronidase-oysk. An observation period of 30 to 60 minutes is recommended after each PERJETA infusion and before commencement of any subsequent administration of trastuzumab or trastuzumab hyaluronidase-oysk, or taxane

  [see Warnings and Precautions (5.3)].

  In patients receiving an anthracycline-based regimen, administer PERJETA and trastuzumab or trastuzumab hyaluronidase-oysk after completion of the anthracycline.

  Metastatic Breast Cancer (MBC)

  When administered with PERJETA, the recommended initial dose of docetaxel is 75 mg/m²administered as an intravenous infusion. The dose may be escalated to 100 mg/m²administered every 3 weeks if the initial dose is well tolerated.

  Neoadjuvant Treatment of Breast Cancer

  Administer PERJETA every 3 weeks for 3 to 6 cycles as part of one of the following treatment regimens

  [see Clinical Studies (14.2, 14.3)]

  :

  • Four preoperative cycles of PERJETA in combination with trastuzumab or trastuzumab hyaluronidase-oysk and docetaxel followed by 3 postoperative cycles of fluorouracil, epirubicin, and cyclophosphamide (FEC)
  • Three or four preoperative cycles of FEC alone followed by 3 or 4 preoperative cycles of PERJETA in combination with docetaxel and trastuzumab or trastuzumab hyaluronidase-oysk
  • Six preoperative cycles of PERJETA in combination with docetaxel, carboplatin, and trastuzumab (TCH) or trastuzumab hyaluronidase-oysk (escalation of docetaxel above 75 mg/m²is not recommended)
  • Four preoperative cycles of dose-dense doxorubicin and cyclophosphamide (ddAC) alone followed by 4 preoperative cycles of PERJETA in combination with paclitaxel and trastuzumab or trastuzumab hyaluronidase-oysk

  Following surgery, administer PERJETA and trastuzumab or trastuzumab hyaluronidase-oysk to complete 1 year of treatment (up to 18 cycles) or until disease recurrence or unmanageable toxicity, whichever occurs first.

  Adjuvant Treatment of Breast Cancer

  As part of a regimen including standard anthracycline- and/or taxane-based chemotherapy, administer PERJETA in combination with trastuzumab or trastuzumab hyaluronidase-oysk every 3 weeks for a total of 1 year (up to 18 cycles) or until disease recurrence or unmanageable toxicity, whichever occurs first. Administer PERJETA on Day 1 of the first taxane-containing cycle

  [see Clinical Studies (14.3)]

  .
  )
• Neoadjuvant: Administer PERJETA, trastuzumab or trastuzumab hyaluronidase-oysk, and chemotherapy preoperatively every 3 weeks for 3 to 6 cycles. (
  2.3 Recommended Dosage and Administration

  The initial dose of PERJETA is 840 mg administered as a 60-minute intravenous infusion, followed every 3 weeks by a dose of 420 mg administered as an intravenous infusion over 30 to 60 minutes.

  When administered with PERJETA, the recommended initial dose of trastuzumab is 8 mg/kg administered as a 90-minute intravenous infusion, followed every 3 weeks by a dose of 6 mg/kg administered as an intravenous infusion over 30 to 90 minutes.

  When administered with PERJETA, the recommended initial dose of trastuzumab hyaluronidase-oysk is 600 mg/10,000 units (600 mg trastuzumab and 10,000 units hyaluronidase) administered subcutaneously over approximately 2 to 5 minutes once every three weeks irrespective of the patient's body weight.

  Administer PERJETA, trastuzumab or trastuzumab hyaluronidase-oysk, and taxane sequentially. PERJETA and trastuzumab or trastuzumab hyaluronidase-oysk can be given in any order. Administer taxane after PERJETA and trastuzumab or trastuzumab hyaluronidase-oysk. An observation period of 30 to 60 minutes is recommended after each PERJETA infusion and before commencement of any subsequent administration of trastuzumab or trastuzumab hyaluronidase-oysk, or taxane

  [see Warnings and Precautions (5.3)].

  In patients receiving an anthracycline-based regimen, administer PERJETA and trastuzumab or trastuzumab hyaluronidase-oysk after completion of the anthracycline.

  Metastatic Breast Cancer (MBC)

  When administered with PERJETA, the recommended initial dose of docetaxel is 75 mg/m²administered as an intravenous infusion. The dose may be escalated to 100 mg/m²administered every 3 weeks if the initial dose is well tolerated.

  Neoadjuvant Treatment of Breast Cancer

  Administer PERJETA every 3 weeks for 3 to 6 cycles as part of one of the following treatment regimens

  [see Clinical Studies (14.2, 14.3)]

  :

  • Four preoperative cycles of PERJETA in combination with trastuzumab or trastuzumab hyaluronidase-oysk and docetaxel followed by 3 postoperative cycles of fluorouracil, epirubicin, and cyclophosphamide (FEC)
  • Three or four preoperative cycles of FEC alone followed by 3 or 4 preoperative cycles of PERJETA in combination with docetaxel and trastuzumab or trastuzumab hyaluronidase-oysk
  • Six preoperative cycles of PERJETA in combination with docetaxel, carboplatin, and trastuzumab (TCH) or trastuzumab hyaluronidase-oysk (escalation of docetaxel above 75 mg/m²is not recommended)
  • Four preoperative cycles of dose-dense doxorubicin and cyclophosphamide (ddAC) alone followed by 4 preoperative cycles of PERJETA in combination with paclitaxel and trastuzumab or trastuzumab hyaluronidase-oysk

  Following surgery, administer PERJETA and trastuzumab or trastuzumab hyaluronidase-oysk to complete 1 year of treatment (up to 18 cycles) or until disease recurrence or unmanageable toxicity, whichever occurs first.

  Adjuvant Treatment of Breast Cancer

  As part of a regimen including standard anthracycline- and/or taxane-based chemotherapy, administer PERJETA in combination with trastuzumab or trastuzumab hyaluronidase-oysk every 3 weeks for a total of 1 year (up to 18 cycles) or until disease recurrence or unmanageable toxicity, whichever occurs first. Administer PERJETA on Day 1 of the first taxane-containing cycle

  [see Clinical Studies (14.3)]

  .
  )
• Adjuvant: Administer PERJETA, trastuzumab or trastuzumab hyaluronidase-oysk, and chemotherapy postoperatively every 3 weeks for a total of 1 year (up to 18 cycles). (
  2.3 Recommended Dosage and Administration

  The initial dose of PERJETA is 840 mg administered as a 60-minute intravenous infusion, followed every 3 weeks by a dose of 420 mg administered as an intravenous infusion over 30 to 60 minutes.

  When administered with PERJETA, the recommended initial dose of trastuzumab is 8 mg/kg administered as a 90-minute intravenous infusion, followed every 3 weeks by a dose of 6 mg/kg administered as an intravenous infusion over 30 to 90 minutes.

  When administered with PERJETA, the recommended initial dose of trastuzumab hyaluronidase-oysk is 600 mg/10,000 units (600 mg trastuzumab and 10,000 units hyaluronidase) administered subcutaneously over approximately 2 to 5 minutes once every three weeks irrespective of the patient's body weight.

  Administer PERJETA, trastuzumab or trastuzumab hyaluronidase-oysk, and taxane sequentially. PERJETA and trastuzumab or trastuzumab hyaluronidase-oysk can be given in any order. Administer taxane after PERJETA and trastuzumab or trastuzumab hyaluronidase-oysk. An observation period of 30 to 60 minutes is recommended after each PERJETA infusion and before commencement of any subsequent administration of trastuzumab or trastuzumab hyaluronidase-oysk, or taxane

  [see Warnings and Precautions (5.3)].

  In patients receiving an anthracycline-based regimen, administer PERJETA and trastuzumab or trastuzumab hyaluronidase-oysk after completion of the anthracycline.

  Metastatic Breast Cancer (MBC)

  When administered with PERJETA, the recommended initial dose of docetaxel is 75 mg/m²administered as an intravenous infusion. The dose may be escalated to 100 mg/m²administered every 3 weeks if the initial dose is well tolerated.

  Neoadjuvant Treatment of Breast Cancer

  Administer PERJETA every 3 weeks for 3 to 6 cycles as part of one of the following treatment regimens

  [see Clinical Studies (14.2, 14.3)]

  :

  • Four preoperative cycles of PERJETA in combination with trastuzumab or trastuzumab hyaluronidase-oysk and docetaxel followed by 3 postoperative cycles of fluorouracil, epirubicin, and cyclophosphamide (FEC)
  • Three or four preoperative cycles of FEC alone followed by 3 or 4 preoperative cycles of PERJETA in combination with docetaxel and trastuzumab or trastuzumab hyaluronidase-oysk
  • Six preoperative cycles of PERJETA in combination with docetaxel, carboplatin, and trastuzumab (TCH) or trastuzumab hyaluronidase-oysk (escalation of docetaxel above 75 mg/m²is not recommended)
  • Four preoperative cycles of dose-dense doxorubicin and cyclophosphamide (ddAC) alone followed by 4 preoperative cycles of PERJETA in combination with paclitaxel and trastuzumab or trastuzumab hyaluronidase-oysk

  Following surgery, administer PERJETA and trastuzumab or trastuzumab hyaluronidase-oysk to complete 1 year of treatment (up to 18 cycles) or until disease recurrence or unmanageable toxicity, whichever occurs first.

  Adjuvant Treatment of Breast Cancer

  As part of a regimen including standard anthracycline- and/or taxane-based chemotherapy, administer PERJETA in combination with trastuzumab or trastuzumab hyaluronidase-oysk every 3 weeks for a total of 1 year (up to 18 cycles) or until disease recurrence or unmanageable toxicity, whichever occurs first. Administer PERJETA on Day 1 of the first taxane-containing cycle

  [see Clinical Studies (14.3)]

  .
  )

Injection: 420 mg/14 mL (30 mg/mL) clear to slightly opalescent and colorless to pale brown solution in a single-dose vial

Females and Males of Reproductive Potential: Verify the pregnancy status of females prior to initiation of PERJETA. (