Pertuzumab, Trastuzumab, and Hyaluronidase-zzxf (Phesgo)

Number: 0977

Table Of Contents

Policy
Applicable CPT / HCPCS / ICD-10 Codes
Background
References


Policy

Scope of Policy

This Clinical Policy Bulletin addresses pertuzumab, trastuzumab, and hyaluronidase-zzxf (Phesgo) for commercial medical plans. For Medicare criteria, see Medicare Part B Criteria.

Note: Requires Precertification:

Precertification of pertuzumab, trastuzumab, and hyaluronidase-zzxf (Phesgo) is required of all Aetna participating providers and members in applicable plan designs. For precertification of pertuzumab, trastuzumab, and hyaluronidase-zzxf (Phesgo), call (866) 752-7021, or fax (888) 267-3277. For Statement of Medical Necessity (SMN) precertification forms, see Specialty Pharmacy Precertification

  1. Criteria for Initial Approval

    Aetna considers pertuzumab, trastuzumab, and hyaluronidase-zzxf (Phesgo) medically necessary for the following indication:

    1. Breast cancer

      1. Pre-operative (neoadjuvant) treatment of HER2-positive breast cancer in combination with chemotherapy for locally advanced, inflammatory, or early stage breast cancer (either greater than 2 cm in diameter or node positive); or
      2. Adjuvant treatment of HER2-positive breast cancer that is either node-positive or at high risk for recurrence in combination with chemotherapy; or
      3. Treatment of HER2-positive recurrent or metastatic breast cancer or HER2-positive breast cancer with no response to preoperative systemic therapy.

      Aetna considers all other indications as experimental, investigational, or unproven.

  2. Continuation of Therapy

    Aetna considers continuation of pertuzumab, trastuzumab, and hyaluronidase-zzxf (Phesgo) medically necessary in members reauthorization for an indication listed in Section I when there is no evidence of unacceptable toxicity or disease progression while on the current regimen. Adjuvant and neoadjuvant treatment of breast cancer will be approved for a total of 12 months of therapy.

Dosage and Administration

Note: Phesgo injection for subcutaneous use has different dosage and administration instructions than intravenous pertuzumab and trastuzumab products.

Phesgo is supplied as:

  • 1,200 mg pertuzumab, 600 mg trastuzumab, and 30,000 units hyaluronidase/15mL (80 mg, 40 mg, and 2,000 units/mL) of solution in a single-dose vial. 
  • 600 mg pertuzumab, 600 mg trastuzumab, and 20,000 units hyaluronidase/10 mL (60 mg, 60 mg, and 2,000 units/mL) of solution in a single-dose vial

For subcutaneous use in the thigh only. Not to be administered intravenously.

Breast Cancer

  • The initial dose of Phesgo is 1,200 mg pertuzumab, 600 mg trastuzumab, and 30,000 units hyaluronidase administered subcutaneously over approximately 8 minutes, followed every 3 weeks by a dose of 600 mg pertuzumab, 600 mg trastuzumab, and 20,000 units hyaluronidase administered subcutaneously over approximately 5 minutes.
  • Neoadjuvant: administer Phesgo by subcutaneous injection every 3 weeks and chemotherapy by intravenous infusion preoperatively for 3 to 6 cycles.
  • Adjuvant: administer Phesgo by subcutaneous injection every 3 weeks and chemotherapy by intravenous infusion postoperatively for a total of 1 year (up to 18 cycles).
  • Metastatic Breast Cancer: administer Phesgo by subcutaneous injection and docetaxel by intravenous infusion every 3 weeks.

Source: Genentech 2020.


Table:

CPT Codes / HCPCS Codes / ICD-10 Codes

Code Code Description

Other CPT codes related to the CPB:

96401 Chemotherapy administration, subcutaneous or intramuscular; non-hormonal anti-neoplastic

HCPCS codes covered if selection criteria are met:

J9316 Injection, pertuzumab, trastuzumab, and hyaluronidase-zzxf, per 10 mg

ICD-10 codes covered if selection criteria are met:

C50.011 - C50.929 Malignant neoplasm of breast

Background

U.S. Food and Drug Administration (FDA)-Approved Indications

  • Neoadjuvant treatment of breast cancer
    For use in combination with chemotherapy for the neoadjuvant treatment of adult patients 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.
  • Adjuvant treatment of breast cancer
    For use in combination with chemotherapy for the adjuvant treatment of adult patients with HER2-positive early breast cancer at high risk of recurrence.
  • Metastatic breast cancer (MBC)
    For use in combination with docetaxel for the treatment of adult patients with HER2-positive metastatic breast cancer who have not received prior anti-HER2 therapy or chemotherapy for metastatic disease. 

Compendial Uses

  • HER2-positive breast cancer: May be substituted anywhere that the combination of intravenous pertuzumab and intravenous trastuzumab are given as part of systemic therapy.

The human epidermal growth factor receptor 2 (HER2) protein promotes the growth of cancer cells. HER2-positive breast cancer makes up approximately one-fifth of breast cancers.  Pertuzumab and trastuzumab bind to sites on HER2 and disrupt signaling to stop cancer cell growth. On June 29, 2020, the U.S. Food and Drug Administration approved Phesgo, a fixed-dose combination of two HER2/neu receptor antagonists (pertuzumab and trastuzumab), and hyaluronidase–zzxf, an endoglycosidase. Phesgo is indicated for use in combination with chemotherapy as neoadjuvant treatment of patients 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; as adjuvant treatment of patients with HER2-positive early breast cancer at high risk of recurrence; and in combination with docetaxel for treatment of patients with HER2- positive metastatic breast cancer (MBC) who have not received prior anti-HER2 therapy or chemotherapy for metastatic disease.

Phesgo’s initial loading dose is administered over approximately 8 minutes compared to 150 minutes for sequential infusion of loading doses for IV Perjeta and Herceptin. Maintenance doses of Phesgo are administered over approximately 5 minutes compared with 60 to 150 minutes for IV Perjeta and Herceptin.

Neoadjuvant and Adjuvant Treatment of Breast Cancer

The effectiveness of Phesgo for use in combination with chemotherapy is supported by evidence from adequate and well-controlled studies conducted with intravenous pertuzumab and intravenous trastuzumab administered in combination with chemotherapy in adults with HER2-overexpressing early breast cancer (NCT00545688, NCT00976989, NCT02132949, NCT01358877) and an additional study to evaluate the pharmacokinetics, efficacy, and safety of subcutaneous administration of the fixed-dose combination of pertuzumab and trastuzumab in combination with chemotherapy in participants with HER2-positive early breast cancer (FeDeriCa study; NCT03493854). 

The NeoSphere trial (Gianni 2012; NCT00545688) investigated the combination of pertuzumab or trastuzumab, or both, with docetaxel and the combination of pertuzumab and trastuzumab without chemotherapy in the neoadjuvant setting in a multicentre, open-label, phase 2 study. Treatment-naive women with HER2-positive breast cancer were randomly assigned (1:1:1:1) centrally and stratified by operable, locally advanced, and inflammatory breast cancer, and by hormone receptor expression to receive four neoadjuvant cycles of: trastuzumab (8 mg/kg loading dose, followed by 6 mg/kg every 3 weeks) plus docetaxel (75 mg/m2), escalating, if tolerated, to 100 mg/m2) every 3 weeks; group A) or pertuzumab (loading dose 840 mg, followed by 420 mg every 3 weeks) and trastuzumab plus docetaxel (group B) or pertuzumab and trastuzumab (group C) or pertuzumab plus docetaxel (group D). The primary endpoint, examined in the intention-to-treat population, was pathological complete response in the breast. Neither patients nor investigators were masked to treatment. Of 417 eligible patients, 107 were randomly assigned to group A, 107 to group B, 107 to group C, and 96 to group D. Patients given pertuzumab and trastuzumab plus docetaxel (group B) had a significantly improved pathological complete response rate (49 of 107 patients; 45·8% [95% CI 36·1-55·7]) compared with those given trastuzumab plus docetaxel (group A; 31 of 107; 29·0% [20·6-38·5]; p=0·0141). 23 of 96 (24·0% [15·8-33·7]) women given pertuzumab plus docetaxel (group D) had a pathological complete response, as did 18 of 107 (16·8% [10·3-25·3]) given pertuzumab and trastuzumab (group C). The most common adverse events of grade 3 or higher were neutropenia (61 of 107 women in group A, 48 of 107 in group B, one of 108 in group C, and 52 of 94 in group D), febrile neutropenia (eight, nine, none, and seven, respectively), and leucopenia (13, five, none, and seven, respectively). The number of serious adverse events was similar in groups A, B, and D (15-20 serious adverse events per group in 10-17% of patients) but lower in group C (four serious adverse events in 4% of patients). The authors concluded that patients given pertuzumab and trastuzumab plus docetaxel (group B) had a significantly improved pathological complete response rate compared with those given trastuzumab plus docetaxel, without substantial differences in tolerability. Pertuzumab and trastuzumab without chemotherapy eradicated tumours in a proportion of women and showed a favourable safety profile. In the 5-year analysis of the NeoSphere trial (Gianni 2016) the investigators concluded that progression-free survival and disease-free survival at 5-year follow-up show large and overlapping confidence intervals, but support the primary endpoint (pathological complete response) and suggest that neoadjuvant pertuzumab is beneficial when combined with trastuzumab and docetaxel. Additionally, they suggest that total pathological complete response could be an early indicator of long-term outcome in early-stage HER2-positive breast cancer.

In TRYPHAENA trial (Schneeweiss 2013; NCT00976989), the authors assessed the tolerability, with particular focus on cardiac safety, of trastuzumab (H) and pertuzumab (P) with chemotherapy in the neoadjuvant treatment of HER2-positive early breast cancer.  In this multicenter, open-label phase II study, patients with operable, locally advanced, or inflammatory breast cancer were randomized 1 : 1 : 1 to receive six neoadjuvant cycles q3w (Arm A: 5-fluorouracil, epirubicin, cyclophosphamide [FEC] + H + P ×3 → docetaxel [T] + H + P ×3; Arm B: FEC ×3 → T + H + P ×3; Arm C: T + carboplatin + H [TCH]+P ×6). pCR was assessed at surgery and adjuvant therapy given to complete 1 year of H. Two hundred twenty-five patients were randomized. During neoadjuvant treatment, two patients (2.7%; Arm B) experienced symptomatic left ventricular systolic dysfunction (LVSD) and 11 patients (Arm A: 4 [5.6%]; Arm B: 4 [5.3%]; Arm C: 3 [3.9%]) had declines in left ventricular ejection fraction of ≥10% points from baseline to <50%. Diarrhea was the most common adverse event. pCR (ypT0/is) was reported for 61.6% (Arm A), 57.3% (Arm B), and 66.2% (Arm C) of patients. The authors concluded that the combination of P with H and standard chemotherapy resulted in low rates of symptomatic LVSD. The authors later reported that the three-year Kaplan-Meier survival estimates for disease-free survival (DFS) and progression-free survival (PFS) were similar between treatment groups. Patients who achieved total pathological complete response had improved DFS. No new safety signals were identified (Schneeweiss 2018).

In the BERENICE trial (Swain 2018; NCT02132949), the study investigators report cardiac safety of pertuzumab, trastuzumab, and chemotherapy in the neoadjuvant treatment of HER2-positive early breast cancer. This was a nonrandomized, phase II, open-label, multicenter, multinational study in patients with normal cardiac function. In the neoadjuvant period, cohort A patients received four cycles of dose-dense doxorubicin and cyclophosphamide, then 12 doses of standard paclitaxel plus four standard trastuzumab and pertuzumab cycles. Cohort B patients received four standard fluorouracil/epirubicin/cyclophosphamide cycles, then four docetaxel cycles with four standard trastuzumab and pertuzumab cycles. The primary end point was cardiac safety during neoadjuvant treatment, assessed by the incidence of New York Heart Association class III/IV heart failure and of left ventricular ejection fraction declines (≥10 percentage-points from baseline and to a value of <50%). The main efficacy end point was pathologic complete response (pCR, ypT0/is ypN0). Results are descriptive. Safety populations were 199 and 198 patients in cohorts A and B, respectively. Three patients [1.5%; 95% confidence interval (CI) 0.31% to 4.34%] in cohort A experienced four New York Heart Association class III/IV heart failure events. Thirteen patients (6.5%; 95% CI 3.5% to 10.9%) in cohort A and four (2.0%; 95% CI 0.6% to 5.1%) in cohort B experienced at least one left ventricular ejection fraction decline. No new safety signals were identified. pCR rates were 61.8% and 60.7% in cohorts A and B, respectively. The highest pCR rates were in the HER2-enriched PAM50 subtype (75.0% and 73.7%, respectively). The authors concluded that treatment with pertuzumab, trastuzumab, and common anthracycline-containing regimens for the neoadjuvant treatment of early breast cancer resulted in cardiac and general safety profiles, and pCR rates, consistent with prior studies with pertuzumab.

The APHINITY trial (von Minckwitz 2017; NCT01358877) investigated whether pertuzumab, when added to adjuvant trastuzumab and chemotherapy, improves outcomes among patients with HER2-positive early breast cancer. Patients with node-positive or high-risk node-negative HER2-positive, operable breast cancer were randomly assigned to receive either pertuzumab or placebo added to standard adjuvant chemotherapy plus 1 year of treatment with trastuzumab. The authors assumed a 3-year invasive-disease-free survival rate of 91.8% with pertuzumab and 89.2% with placebo. In the trial population, 63% of the patients who were randomly assigned to receive pertuzumab (2400 patients) or placebo (2405 patients) had node-positive disease and 36% had hormone-receptor-negative disease. Disease recurrence occurred in 171 patients (7.1%) in the pertuzumab group and 210 patients (8.7%) in the placebo group (hazard ratio, 0.81; 95% confidence interval [CI], 0.66 to 1.00; P=0.045). The estimates of the 3-year rates of invasive-disease-free survival were 94.1% in the pertuzumab group and 93.2% in the placebo group. In the cohort of patients with node-positive disease, the 3-year rate of invasive-disease-free survival was 92.0% in the pertuzumab group, as compared with 90.2% in the placebo group (hazard ratio for an invasive-disease event, 0.77; 95% CI, 0.62 to 0.96; P=0.02). In the cohort of patients with node-negative disease, the 3-year rate of invasive-disease-free survival was 97.5% in the pertuzumab group and 98.4% in the placebo group (hazard ratio for an invasive-disease event, 1.13; 95% CI, 0.68 to 1.86; P=0.64). Heart failure, cardiac death, and cardiac dysfunction were infrequent in both treatment groups. Diarrhea of grade 3 or higher occurred almost exclusively during chemotherapy and was more frequent with pertuzumab than with placebo (9.8% vs. 3.7%). The authors concluded that pertuzumab significantly improved the rates of invasive-disease-free survival among patients with HER2-positive, operable breast cancer when it was added to trastuzumab and chemotherapy. Diarrhea was more common with pertuzumab than with placebo. 

The FeDeriCa study (NCT03493854) was an open-label, multicenter, randomized study conducted in 500 patients with operable or locally advanced (including inflammatory) HER2- positive breast cancer with a tumor size > 2 cm or node-positive. HER2 overexpression was defined as IHC 3+ in > 10% of immunoreactive cells or HER2 gene amplification by ISH (ratio of HER2 gene signals to centromere 17 signals > 2.0) using an FDA-approved test. Patients were randomized to receive 8 cycles of neoadjuvant chemotherapy with concurrent administration of 4 cycles of either subcutaneous Phesgo or intravenous pertuzumab and trastuzumab during cycles 5-8, followed by surgery. Patients received one of the of the following two neoadjuvant chemotherapy regimens: (A) 4 cycles of doxorubicin (60 mg/m2) and cyclophosphamide (600 mg/m2) every 2 weeks followed by paclitaxel (80 mg/m2) weekly for 12 weeks; or (B) 4 cycles of doxorubicin (60 mg/m2) and cyclophosphamide (600 mg/m2) every 3 weeks followed by 4 cycles of docetaxel (75 mg/m2 for the first cycle and then 100 mg/m2 at subsequent cycles at the investigator’s discretion) every 3 weeks. Patients received HER2- targeted therapy every 3 weeks as follows: (A) Phesgo (SC): 1200 mg/600 mg (initial); 600mg/600 mg (maintenance); (B) Pertuzumab (IV): 840 mg (initially); 420 mg (maintenance); (C) Trastuzumab (IV): 8 mg/kg (initially); 6 mg/kg (maintenance); (D) Trastuzumab-oysk (SC): 600 mg, where substitution of intravenous trastuzumab for subcutaneous trastuzumab in the adjuvant period was permitted at investigator discretion. Following surgery, patients continued therapy with Phesgo or intravenous pertuzumab and trastuzumab as treated prior to surgery, for an additional 14 cycles, to complete 18 cycles of antiHER2 therapy. Patients also received adjuvant radiotherapy and endocrine therapy as per investigator’s discretion.  FeDeriCa was designed to demonstrate non-inferiority of the Cycle 7 (i.e., pre-dose Cycle 8) pertuzumab serum C (trough) from Phesgo pertuzumab to the intravenous pertuzumab (primary endpoint). Secondary endpoints included Cycle 7 serum trastuzumab C (trough), efficacy (pathological complete response [pCR], defined as the absence of invasive neoplastic cells in the breast and in the axillary lymph nodes), and safety. The median age was 51 years (range: 25-81), and the majority of patients were White (66%). The majority of patients had hormone receptor-positive disease (61%) or node-positive disease (58%). The pCR rate was 59.7% (95% CI: 53.3, 65.8) in the Phesgo arm and 59.5% (95% CI: 53.2, 65.6) in the intravenous pertuzumab and trastuzumab arm.

Metastatic Breast Cancer

The effectiveness of Phesgo for use in combination with docetaxel has been established for the treatment of patients with HER2-positive metastatic breast cancer who have not received prior anti-HER2 therapy or chemotherapy for metastatic disease. Use of Phesgo for this indication is supported by evidence from adequate and well-controlled studies conducted with intravenous pertuzumab and intravenous trastuzumab administered in combination with chemotherapy in adults with HER2-overexpressing metastatic breast cancer (CLEOPATRA study; Swain 2020; NCT00567190) and additional pharmacokinetic and safety data that demonstrated comparable pharmacokinetics and safety profiles between Phesgo and intravenous pertuzumab and intravenous trastuzumab (FeDeriCa). 

The CLEOPATRA study was a phase 3 study comparing the efficacy and safety of pertuzumab, trastuzumab, and docetaxel with placebo, trastuzumab, and docetaxel in patients with HER2-positive metastatic breast cancer. In the primary analysis and subsequent reports, progression-free and overall survival were significantly improved in the pertuzumab group compared with the placebo group. This was a double-blind, randomized, placebo-controlled, phase 3 trial that was done at 204 centres in 25 countries. Eligible patients were 18 years or older, had HER2-positive, metastatic breast cancer, had not received previous chemotherapy or biological treatment for their metastatic disease, and had an Eastern Cooperative Oncology Group performance status of 0 or 1. All study drugs were given intravenously, every 3 weeks. Patients were assigned to receive either pertuzumab or placebo at a loading dose of 840 mg, and 420 mg thereafter; plus trastuzumab at 8 mg/kg loading dose and 6 mg/kg thereafter; and docetaxel at 75 mg/m2, escalating to 100 mg/m2 if tolerated. Pertuzumab or placebo and trastuzumab were given until disease progression; docetaxel was given for six cycles, or longer at the investigators' discretion. Randomisation (1:1) was done by use of an interactive voice-response system and was stratified by geographical region (Asia, Europe, North America, or South America) and previous treatment (previous adjuvant or neoadjuvant chemotherapy vs none). The primary endpoint was independent review facility-assessed progression-free survival, which has been reported previously. Since the confirmatory overall survival analysis had also occurred before this prespecified end-of-study analysis, analyses presented here are descriptive. Overall survival analyses were based on the intention-to-treat population with crossover patients analysed in the placebo group; analyses were not adjusted for crossover to the pertuzumab group and are likely to be conservative. Safety analyses were based on treatment received; crossover patients were counted in the placebo group up to the day before first pertuzumab dose. Between Feb 12, 2008, and July 7, 2010, 1196 patients were assessed for eligibility, of whom 808 were enrolled and randomly assigned. 402 patients were assigned to receive docetaxel plus trastuzumab plus pertuzumab, and 406 patients were assigned to receive docetaxel plus trastuzumab plus placebo. Clinical cutoff for this analysis was Nov 23, 2018. Between July 2012 and clinical cutoff, 50 patients crossed from the placebo to the pertuzumab group. Median follow-up was 99·9 months in the pertuzumab group (IQR 92·9-106·4) and 98·7 months (90·9-105·7) in the placebo group. Median overall survival was 57·1 months (95% CI 50-72) in the pertuzumab group and 40·8 months (36-48) in the placebo group (hazard ratio 0·69, 95% CI 0·58-0·82); 8-year landmark overall survival rates were 37% (95% CI 31-42) in the pertuzumab group and 23% (19-28) in the placebo group. The most common grade 3-4 adverse event was neutropenia (200 [49%] of 408 patients in the pertuzumab group, 183 [46%] of 396 patients in the placebo group). Five (1%) of 408 patients in the pertuzumab group and six (2%) of 396 patients in the placebo group had treatment-related deaths. One new serious adverse event suggestive of congestive heart failure (pertuzumab group) and one new symptomatic left ventricular systolic dysfunction (post-crossover) occurred since the previous analysis. In this end-of-study analysis of CLEOPATRA, the authors state that their analysis shows that the previously observed improvements in overall survival with pertuzumab, trastuzumab, and docetaxel versus placebo, trastuzumab, and docetaxel were maintained after a median of more than 8 years of follow-up. The long-term safety and cardiac safety profiles of pertuzumab, trastuzumab, and docetaxel were maintained in the overall safety population and within crossover patients. HER2-targeted therapy has changed the natural history of HER2-positive metastatic breast cancer, with the dual blockade of pertuzumab and trastuzumab, with docetaxel, demonstrating an 8-year landmark overall survival rate of 37%.

Patient Experience

The PHranceSCa study (NCT03674112) was a randomized, multi-center, open-label cross-over trial conducted in 160 patients with HER2-positive breast cancer undergoing adjuvant treatment. All patients completed neoadjuvant treatment with pertuzumab, trastuzumab and chemotherapy and had surgery before randomization. Following randomization, 80 patients in arm A received 3 cycles of intravenous pertuzumab and trastuzumab followed by 3 cycles of Phesgo and 80 patients in arm B received 3 cycles of PHESGO followed by 3 cycles of intravenous pertuzumab and trastuzumab. All patients received 18 total cycles of HER2-targeted therapy. After Cycle 6, 136 out of 160 patients (85%) reported preferring subcutaneous administration of Phesgo over intravenous pertuzumab and trastuzumab and the most common reason was that administration required less time in the clinic. After Cycle 6, 22 out of 160 patients (14%) reported preferring intravenous pertuzumab and trastuzumab over Phesgo and the most common reason was feels more comfortable during administration. Two out of 160 patients (1%) had no preference for the route of administration. All 160 patients (100%) completed the preference questionnaire.


References

The above policy is based on the following references:

  1. Gao JJ, Osgood CL, Gong Y, et al. FDA approval summary: Pertuzumab, trastuzumab, and hyaluronidase-zzxf injection for subcutaneous use in patients with HER2-positive breast cancer. Clin Cancer Res. 2021;27(8):2126-2129.
  2. Genentech, Inc. Phesgo (pertuzumab, trastuzumab, and hyaluronidase-zzxf) injection, for subcutaneous use. Prescribing Information. South San Francisco, CA: Genentech, Inc; June 2020.
  3. Gianni L, Pienkowski T, Im YH, 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.
  4. Gianni L, Pienkowski T, Im YH, et al. 5-year analysis of neoadjuvant pertuzumab and trastuzumab in patients with locally advanced, inflammatory, or early-stage HER2-positive breast cancer (NeoSphere): A multicentre, open-label, phase 2 randomised trial. Lancet Oncol. 2016;17(6):791-800.
  5. National Comprehensive Cancer Network (NCCN). Pertuzumab, trastuzumab, and hyaluronidase-zzxf. NCCN Drugs & Biologics Compendium. Plymouth Meeting, PA: NCCN; December 2023.
  6. 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(9):2278-2284.
  7. Schneeweiss A, Chia S, Hickish T, et al. Long-term efficacy analysis of the randomised, phase II TRYPHAENA cardiac safety study: Evaluating pertuzumab and trastuzumab plus standard neoadjuvant anthracycline-containing and anthracycline-free chemotherapy regimens in patients with HER2-positive early breast cancer. Eur J Cancer. 2018;89:27-35.
  8. 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.
  9. Swain SM, Miles D, Kim SB, et al. Pertuzumab, trastuzumab, and docetaxel for HER2-positive metastatic breast cancer (CLEOPATRA): End-of-study results from a double-blind, randomised, placebo-controlled, phase 3 study. Lancet Oncol. 2020;21(4):519-530.
  10. Tan AR, Im S-A, Mattar A, et al; FeDeriCa study group. Fixed-dose combination of pertuzumab and trastuzumab for subcutaneous injection plus chemotherapy in HER2-positive early breast cancer (FeDeriCa): A randomised, open-label, multicentre, non-inferiority, phase 3 study. Lancet Oncol. 2021;22(1):85-97.
  11. von Minckwitz G, Procter M, de Azambuja E, et al. Adjuvant pertuzumab and trastuzumab in early HER2-positive breast cancer. N Engl J Med. 2017;377(2):122-131.
  12. Wang B, Deng R, Hennig S, et al. Population pharmacokinetic and exploratory exposure-response analysis of the fixed-dose combination of pertuzumab and trastuzumab for subcutaneous injection in patients with HER2-positive early breast cancer in the FeDeriCa study. Cancer Chemother Pharmacol. 2021;88(3):499-512.