NEOADJUVANT TRIAL DESIGNS

PERJETA, in combination with Herceptin® (trastuzumab) and chemotherapy, has been studied in multiple clinical trials for the neoadjuvant treatment of adults with HER2‑positive breast cancer.1

Learn more about the trial designs, endpoints, and baseline patient characteristics.

HER2=human epidermal growth factor receptor 2.

NeoSphere trial TRYPHAENA trial BERENICE trial
NeoSphere trial

The NeoSphere trial design

A multicenter, randomized, open-label Phase II clinical trial evaluating the efficacy and safety of PERJETA-based neoadjuvant therapy.1,2

NeoSphere trial schema1

FEC=5-fluorouracil, epirubicin, and cyclophosphamide.
*Randomization stratified by breast cancer type (operable, locally advanced, or inflammatory) and estrogen receptor (ER) or progesterone receptor (PR) status ([ER+ and/or PR+] vs [ER– and PR–]).1

Treatment cycles were received every 3 weeks. During the neoadjuvant period, all patients received 4 cycles of their respective therapies. PERJETA dosing: 840 mg loading dose, 420 mg for subsequent 3 cycles; Herceptin dosing: 8 mg/kg loading dose, 6 mg/kg for subsequent 3 cycles (administered to complete one year of treatment); docetaxel dosing: 75 mg/m2 every 3 weeks for 4 cycles. Docetaxel dose could be escalated to 100 mg/m2 at investigator’s discretion if initial dose was well tolerated. FEC dosing: 5-fluorouracil (600 mg/m2), epirubicin (90 mg/m2), and cyclophosphamide (600 mg/m2) every 3 weeks for 3 cycles.1

NeoSphere trial endpoints included pCR and safety

Primary endpoint

  • Pathological complete response (pCR) in the breast (ypT0/is)1
    • ypT0/is=no invasive cells in the breast by microscopic examination at surgery, in situ lesions permitted2

Additional pCR endpoint (FDA preferred definition of pCR)

  • pCR in the breast and lymph nodes (ypT0/is ypN0)1
    • ypT0/is ypN0=the absence of invasive cancer in the breast and lymph nodes, in situ lesions permitted

Select secondary endpoints included safety2

Learn more about the NeoSphere trial outcomes and safety profile.

Patient demographics in NeoSphere

Demographics were balanced across treatment arms.1

Select baseline patient characteristics in NeoSphere2

†Data missing for one patient.

NeoSphere outcomes
TRYPHAENA trial

The TRYPHAENA trial design

TRYPHAENA was an additional open-label Phase II trial of neoadjuvant PERJETA-based therapy with and without an anthracycline.1,3

  • 225 patients with locally advanced, operable, or inflammatory HER2+ breast cancer (T2-4d)
  • Designed primarily to assess cardiac safety; all arms included PERJETA
  • All treatments administered in 3-week cycles

TRYPHAENA trial schema1

TCH=docetaxel, carboplatin, and Herceptin.
*Randomization stratified by breast cancer type (operable, locally advanced, or inflammatory) and estrogen receptor (ER) or progesterone receptor (PR) status ([ER+ and/or PR+] vs [ER– and PR–]).1

Treatment cycles were received every 3 weeks. PERJETA dosing: 840 mg loading dose, 420 mg for subsequent cycles; Herceptin dosing: 8 mg/kg loading dose, 6 mg/kg for subsequent cycles (administered to complete one year of treatment); docetaxel dosing: 75 mg/m2 each cycle, escalated to 100 mg/m2 at investigator’s discretion if initial dose was well tolerated (not escalated in the PERJETA + TCH arm); carboplatin dosing: AUC 6; FEC dosing: 5-fluorouracil (500 mg/m2), epirubicin (100 mg/m2), and cyclophosphamide (600 mg/m2) every 3 weeks for 3 cycles.1

TRYPHAENA endpoints included cardiac safety and tolerability

Primary endpoints1,3

  • Cardiac safety and tolerability during neoadjuvant treatment
    • Incidence of symptomatic left ventricular systolic dysfunction (LVSD)
    • Decline in left ventricular ejection fraction (LVEF) of ≥10% from baseline to <50%

Select secondary endpoints1,3

  • pCR in breast (ypT0/is) assessed at surgery
    • Additional pCR endpoint (FDA preferred): pCR in breast and nodes (ypT0/is ypN0) assessed at surgery

ypT0/is=no invasive cells in the breast by microscopic examination at surgery, in situ lesions permitted 3 ; ypT0/is ypN0=the absence of invasive cancer in the breast and lymph nodes, in situ lesions permitted.1

Learn more about the TRYPHAENA trial outcomes and safety profile.

Patient demographics in TRYPHAENA4

Demographics were balanced across treatment arms.

Select baseline patient characteristics in TRYPHAENA4

TRYPHAENA outcomes
BERENICE trial

The BERENICE trial design

A multicenter, nonrandomized, open-label Phase II clinical trial evaluating the cardiac safety profile of PERJETA-based neoadjuvant therapies.1,5

BERENICE trial schema1,5

ddAC=dose-dense doxorubicin and cyclophosphamide; GCSF=granulocyte colony–stimulating factor.
*One patient with HER2-negative disease was enrolled in error and was not included in the intent-to-treat and safety populations.

Treatment cycles with PERJETA and Herceptin were received every 3 weeks. PERJETA dosing: 840 mg loading dose, 420 mg for subsequent cycles; Herceptin dosing: 8 mg/kg loading dose, 6 mg/kg for subsequent cycles; ddAC dosing: doxorubicin (60 mg/m2) and cyclophosphamide (600 mg/m2) every 2 weeks with GCSF support at investigator discretion; paclitaxel dosing: 80 mg/m2 weekly; FEC dosing: 5-fluorouracil (500 mg/m2), epirubicin (100 mg/m2), and cyclophosphamide (600 mg/m2) every 3 weeks; docetaxel dosing: 75 mg/m2 every 3 weeks. Docetaxel dose could be escalated to 100 mg/m2 at investigator's discretion if initial dose was well tolerated.1

BERENICE endpoints included cardiac safety and pCR

Primary endpoints5

  • Cardiac safety during neoadjuvant treatment
    • Incidence of symptomatic LVSD (NYHA Class III/IV CHF)
    • Incidence of decline in LVEF of ≥10% from baseline to <50%

Select secondary endpoints5

  • General safety during the neoadjuvant period
  • pCR in the breast and lymph nodes (ypT0/is ypN0)*

*ypT0/is ypN0=the absence of invasive cancer in the breast and lymph nodes; in situ lesions permitted.1
CHF=congestive heart failure.

Learn more about the BERENICE trial outcomes and safety profile.

Patient demographics in BERENICE1,5

Baseline demographics were balanced across treatment arms.

Select baseline patient characteristics in BERENICE1,5

†Hormone receptor status was unknown in 8 patients.
‡Two patients had primary tumors that were misdiagnosed.

  • The overall patient age range was 21 to 78 years1
  • All patients had an ECOG performance status of 0 or 11
  • 3% of patients had inflammatory cancer, 23% had locally advanced cancer, and 5% were not classified per TNM staging1

ECOG=Eastern Cooperative Oncology Group; TNM=tumor, node, and metastasis.

BERENICE outcomes
  1. PERJETA Prescribing Information. Genentech, Inc. 2025.
  2. Gianni L, Pienkowski T, Im Y-H, et al. Efficacy and safety of neoadjuvant pertuzumab and trastuzumab in women with locally advanced, inflammatory, or early HER2-positive breast cancer (NeoSphere): a randomised multicentre, open-label, phase 2 trial. Lancet Oncol. 2012;13(1):25-32.
  3. Schneeweiss A, Chia S, Hickish T, et al. Pertuzumab plus trastuzumab in combination with standard neoadjuvant anthracycline-containing and anthracycline-free chemotherapy regimens in patients with HER2-positive early breast cancer: a randomized phase II cardiac safety study (TRYPHAENA). Ann Oncol. 2013;24:2278-2284. doi:10.1093/annonc/mdt182.
  4. Data on file. Genentech, Inc.
  5. Swain SM, Ewer MS, Viale G, et al. Pertuzumab, trastuzumab, and standard anthracycline- and taxane-based chemotherapy for the neoadjuvant treatment of patients with HER2-positive localized breast cancer (BERENICE): a phase II, open-label, multicenter, multinational cardiac safety study. Ann Oncol. 2018;29(3):646-653. doi:10.1093/annonc/mdx773.

Important Safety Information & Uses

Indications:

PERJETA® (pertuzumab) 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 (EBC)
  • the adjuvant treatment of adults with HER2-positive early breast cancer (EBC) at high risk of recurrence

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

Important Safety Information

BOXED WARNINGS: Left Ventricular Dysfunction and Embryo-Fetal Toxicity

  • PERJETA can cause subclinical and clinical cardiac failure manifesting as decreased left ventricular ejection fraction (LVEF) and congestive heart failure (CHF). Evaluate cardiac function prior to and during treatment. Discontinue PERJETA treatment for a confirmed clinically significant decrease in left ventricular function
  • Exposure to PERJETA can cause embryo-fetal death and birth defects. Advise patients of these risks and the need for effective contraception
    • 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
    • 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, healthcare providers and patients should immediately report PERJETA exposure to Genentech at 1-888-835-2555

Contraindications

PERJETA is contraindicated in patients with known hypersensitivity to pertuzumab or to any of its excipients.

Warnings and Precautions

Left Ventricular Dysfunction

  • PERJETA can cause left ventricular dysfunction, including symptomatic heart failure
  • 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
  • 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 fluorouracil, epirubicin, and cyclophosphamide (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 docetaxel, carboplatin, and trastuzumab (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 1 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 dose-dense doxorubicin and cyclophosphamide (ddAC) and 4% of the patients treated with PERJETA plus trastuzumab and docetaxel following FEC in the neoadjuvant period. Symptomatic LVSD (New York Heart Association [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/m2 of doxorubicin or its equivalent

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

Infusion-Related Reactions

  • PERJETA can cause serious infusion reactions, including fatal events
  • In CLEOPATRA, on the first day, when only PERJETA was administered, infusion-related reactions occurred in 13% of patients and <1% were Grade 3 or 4. The most common infusion reactions (≥1%) were pyrexia, chills, fatigue, headache, asthenia, hypersensitivity, and vomiting. During the second cycle when all drugs were administered on the same day, the most common infusion reactions in the PERJETA-treated group (≥1%) were fatigue, dysgeusia, hypersensitivity, myalgia, and vomiting
  • In APHINITY, when PERJETA was administered in combination with trastuzumab and chemotherapy on the same day, infusion-related reactions occurred in 21% of patients with <1% of patients experiencing Grade 3-4 events
  • Observe patients closely for 60 minutes after the first infusion and for 30 minutes after subsequent infusions of PERJETA. If a significant infusion-related reaction occurs, slow or interrupt the infusion and administer appropriate medical therapies. Monitor patients carefully until complete resolution of signs and symptoms. Consider permanent discontinuation in patients with severe infusion reactions

Hypersensitivity Reactions/Anaphylaxis

  • PERJETA can cause hypersensitivity reactions, including anaphylaxis
  • In CLEOPATRA, the overall frequency of hypersensitivity/anaphylaxis reactions was 11% in PERJETA-treated patients, with Grade 3-4 hypersensitivity reactions and anaphylaxis occurring in 2% of patients
  • In NeoSphere, TRYPHAENA, BERENICE, and APHINITY, hypersensitivity/anaphylaxis events were consistent with those observed in CLEOPATRA. In APHINITY, the overall frequency of hypersensitivity/anaphylaxis was 5% in the PERJETA-treated group. The incidence was highest in the PERJETA plus TCH treated group (8%) with 1% Grade 3-4 events
  • Observe patients closely for hypersensitivity reactions. Severe hypersensitivity, including anaphylaxis and fatal events, have been observed in patients treated with PERJETA. Angioedema has been described in post-marketing reports. Medications to treat such reactions, as well as emergency equipment, should be available for immediate use prior to administration of PERJETA

Most Common Adverse Reactions

Neoadjuvant Treatment of Breast Cancer

  • The most common adverse reactions (>30%) with PERJETA in combination with trastuzumab and docetaxel were alopecia, diarrhea, nausea, and neutropenia
  • The most common adverse reactions (>30%) with PERJETA in combination with trastuzumab and docetaxel when given for 3 cycles following 3 cycles of FEC were fatigue, alopecia, diarrhea, nausea, vomiting, and neutropenia
  • The most common adverse reactions (>30%) with PERJETA in combination with docetaxel, carboplatin, and trastuzumab (TCH) were fatigue, alopecia, diarrhea, nausea, vomiting, neutropenia, thrombocytopenia, and anemia
  • The most common adverse reactions (>30%) with PERJETA in combination with trastuzumab and paclitaxel when given for 4 cycles following 4 cycles of ddAC were nausea, diarrhea, alopecia, fatigue, constipation, peripheral neuropathy, and headache
  • The most common adverse reactions (>30%) with PERJETA in combination with trastuzumab and docetaxel when given for 4 cycles following 4 cycles of FEC were diarrhea, nausea, alopecia, asthenia, constipation, fatigue, mucosal inflammation, vomiting, myalgia, and anemia

Adjuvant Treatment of Breast Cancer

  • The most common adverse reactions (>30%) with PERJETA in combination with trastuzumab and chemotherapy were diarrhea, nausea, alopecia, fatigue, peripheral neuropathy, and vomiting

Treatment of Metastatic Breast Cancer

  • The most common adverse reactions (>30%) with PERJETA in combination with trastuzumab and docetaxel were diarrhea, alopecia, neutropenia, nausea, fatigue, rash, and peripheral neuropathy

You may report side effects to the FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. You may also report side effects to Genentech at 1-888-835-2555.

Please see the full Prescribing Information for additional Important Safety Information, including BOXED WARNINGS.