Pertuzumab (Perjeta)

Number: 0973

Table Of Contents

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

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Policy

Scope of Policy

This Clinical Policy Bulletin addresses pertuzumab (Perjeta) for commercial medical plans. For Medicare criteria, see Medicare Part B Criteria.

Note: Requires Precertification:

Precertification of pertuzumab (Perjeta) is required of all Aetna participating providers and members in applicable plan designs. For precertification of pertuzumab (Perjeta), 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 (Perjeta) medically necessary for use in members with one of the following conditions:

   1. Breast Cancer

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

   2. Colorectal Cancer

      For treatment of colorectal cancer, including appendiceal adenocarcinoma and anal adenocarcinoma, with HER2-amplified and RAS and BRAF wild-type disease not previously treated with HER2 inhibitor in combination with trastuzumab when either of the following are met:

      1. Member is not appropriate for intensive therapy; or
      2. Perjeta will be used as subsequent therapy for progression of advanced or metastatic disease;

   3. Hepatobiliary Cancers

      For subsequent treatment of unresectable or metastatic HER2-positive hepatobiliary cancers (including intrahepatic and extrahepatic cholangiocarcinoma and gallbladder cancer) when used in combination with trastuzumab.

   4. Salivary Gland Tumor 

      For treatment of recurrent HER2-positive salivary gland tumors in combination with trastuzumab.

   Aetna considers all other indications as experimental and investigational (for additional information, see Experimental and Investigational and Background sections).

2. Continuation of Therapy

   Aetna considers continuation of pertuzumab (Perjeta) therapy medically necessary in members requesting 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.

3. Related Policies

   1. CPB 313 - Trastuzumab (Herceptin and biosimilars), Trastuzumab and Hyaluronidase-oysk (Herceptin Hylecta)

Dosage and Administration

Pertuzumab is available as Perjeta 420 mg/14 mL (30 mg/mL) in a single‐use vial.

For intravenous infusion only. Do not administer as an intravenous push or bolus.

Breast Cancer

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.

• MBC: Administer Perjeta, trastuzumab or trastuzumab hyaluronidase-oysk, and docetaxel every 3 weeks.
• Neoadjuvant: Administer Perjeta, trastuzumab or trastuzumab hyaluronidase-oysk, and chemotherapy preoperatively every 3 weeks for 3 to 6 cycles. 

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

Source: Genentech, 2021

Experimental and Investigational

Aetna considers pertuzumab, alone or in combination with chemotherapy, experimental and investigational for the treatment of the following types of cancer (not an all-inclusive list) and all other indications because pertuzumab has not been proven to be effective for these indications:

• Gastric cancer
• Hepatobiliary cancers (cholangiocarcinoma and gallbladder cancer)
• Lung cancer (including non-small-cell lung cancer)
• Ovarian cancer
• Pancreatic cancer
• Prostate cancer
• Salivary duct cancer
• Uterine cancer.

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Table:

CPT Codes / HCPCS Codes / ICD-10 Codes

Code	Code Description
Other CPT codes related to the CPB:
96413 - 96417	Chemotherapy administration
HCPCS codes covered if selection criteria are met:
J9306	Injection, pertuzumab, 1 mg
Other HCPCS codes related to the CPB:
J8530	Cyclophosphamide, oral, 25 mg
J9000	Injection, doxorubicin HCl, 10 mg
J9045	Injection, carboplatin, 50 mg
J9070	Cyclophosphamide, 100 mg
J9171	Injection, docetaxel, 1 mg
J9172	Injection, docetaxel (ingenus) not therapeutically equivalent to j9171, 1 mg
J9178	Injection, epirubicin HCl, 2 mg
J9190	Injection, fluorouracil, 500 mg
J9205	Injection, irinotecan liposome, 1 mg
J9206	Injection, irinotecan, 20 mg
J9263	Injection, oxaliplatin, 0.5 mg
J9267	Injection, paclitaxel, 1 mg
J9355	Injection, trastuzumab, excludes biosimilar, 10 mg
Q5112	Injection, trastuzumab-hyphendttb, biosimilar, (Ontruzant), 10 mg
Q5113	Injection, trastuzumab-hyphenpkrb, biosimilar, (Herzuma), 10 mg
Q5114	Injection, Trastuzumab-hyphendkst, biosimilar, (Ogivri), 10 mg
Q5116	Injection, trastuzumab-hyphenqyyp, biosimilar, (Trazimera), 10 mg
Q5117	Injection, trastuzumab-hyphenanns, biosimilar, 10 mg (Kanjinti)
ICD-10 codes covered if selection criteria are met:
C08.0 - C08.9	Malignant neoplasm of other and unspecified major salivary glands
C18.0 - C18.9	Malignant neoplasm of colon
C20	Malignant neoplasm of rectum
C21.0 - C21.8	Malignant neoplasm of anus and anal canal
C22.0 - C22.9	Malignant neoplasm of liver and intrahepatic bile ducts
C23	Malignant neoplasm of gallbladder
C24.0 - C24.9	Malignant neoplasm of other and unspecified parts of biliary tract
C50.011 - C50.929	Malignant neoplasm of breast [HER2 positive]
ICD-10 codes not covered for indications listed in the CPB (not all-inclusive):
C16.0 - C16.9	Malignant neoplasm of stomach
C25.0 - C25.9	Malignant neoplasm of pancreas
C34.00 - C34.92	Malignant neoplasm of bronchus and lung
C54.1 - C54.9	Malignant neoplasm of corpus uteri, except isthmus
C56.1 - C56.9	Malignant neoplasm of ovary
C61	Malignant neoplasm of prostate

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Background

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

• Metastatic Breast Cancer

  In combination with trastuzumab and docetaxel for the treatment of patients with human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer who have not received prior anti-HER2 therapy or chemotherapy for metastatic disease.

• Neoadjuvant Treatment of Breast Cancer

  In combination with trastuzumab and 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.

• Adjuvant Treatment of Breast Cancer

  In combination with trastuzumab and chemotherapy as adjuvant treatment of patients with HER2-positive early breast cancer at high risk of recurrence.

Compendial Uses

• Treatment of recurrent or stage IV (M1) human epidermal growth factor receptor 2 (HER2)-positive breast cancer
• Adjuvant treatment of locally advanced HER2-positive breast cancer
• HER2-amplified and RAS and BRAF wild-type colorectal cancer (including appendiceal adenocarcinoma and anal adenocarcinoma) in combination with trastuzumab
• HER2-positive recurrent salivary gland tumors
• HER2-positive hepatobiliary cancers

Perjeta (pertuzumab) is a humanized monoclonal antibody that targets the extracellular dimerization domain (Subdomain II) of the human epidermal growth factor receptor 2 protein (HER2) and, thereby, blocks ligand‐dependent heterodimerization of HER2 with other HER family members, including EGFR, HER3 and HER4. As a result, Perjeta (pertuzumab) inhibits ligand‐initiated intracellular signaling through two major signal pathways, mitogen‐activated protein (MAP) kinase and phosphoinositide 3‐kinase (PI3K). Inhibition of these signaling pathways can result in cell growth arrest and apoptosis, respectively. In addition, Perjeta (pertuzumab) mediates antibody‐dependent cell-mediated cytotoxicity (ADCC).

Perjeta carries a black box warning to include left ventricular (LV) dysfunction and embryo‐fetal toxicity. Cardiac failure manifesting as decreased LVEF and CHF can result from administration of pertuzumab. Evaluate LV function in all patients prior to and during treatment with pertuzumab. Discontinue treatment for confirmed clinically significant decrease in LV function. Embryo-fetal death and birth defects can occur when administered to a pregnant woman. Patients are to be advised of these risks and the need for effective contraception.

Infusion‐Associated Reactions, Hypersensitivity Reactions/Anaphylaxis: Monitor for signs and symptoms. If a significant infusion‐associated reaction occurs, slow or interrupt the infusion and administer appropriate medical therapies.

Pertuzumab has also been studied for the treatment of other types of solid tumors (e.g., colon, gastric, lung, ovarian, prostate, rectal, and uterine cancers); however, its effectiveness for these types of cancer has not been established.

Perjeta (pertuzumab) should be withheld or discontinued if trastuzumab treatment is withheld or discontinued.

If docetaxel is discontinued, treatment with Perjeta (pertuzumab) and trastuzumab may continue. Dose reductions are not recommended for Perjeta (pertuzumab).

Breast Cancer

On June 8, 2012, the FDA approved pertuzumab (Perjeta) for the treatment of patients with HER2-positive metastatic breast cancer.  Pertuzumab, in combination with trastuzumab and docetaxel, is indicated for patients who have not received prior treatment for metastatic breast cancer with an anti-HER2 therapy or chemotherapy. On September 30, 2013, the FDA granted accelerated approval to Perjeta (pertuzumab) for use in combination with trastuzumab and chemotherapy for the 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. The indication is based on demonstration of an improvement in pathological complete response rate. No data are available demonstrating improvement in event‐free survival or overall survival.

The safety and effectiveness of Perjeta were evaluated in a single clinical trial involving 808 patients with HER2-positive metastatic breast cancer who were tested prior to treatment to determine if the HER2 protein was increased.  Patients were randomly assigned to receive Perjeta, trastuzumab and docetaxel or trastuzumab and docetaxel with a placebo.  The study was designed to measure the length of time a patient lived without the cancer progressing, progression-free survival (PFS).  Those treated with the combination containing Perjeta had a median PFS of 18.5 months, while those treated with the combination containing placebo had a median PFS of 12.4 months.  The most common side effects observed in patients receiving Perjeta in combination with trastuzumab and docetaxel were diarrhea, fatigue, hair loss, leukopenia, nausea, rash, and peripheral sensory neuropathy. 

Neoadjuvant systemic therapy is frequently used option for the systemic treatment for breast cancer.  Inclusion in the regimen of targeted drugs (e.g., trastuzumab and pertuzumab) significantly improves outcomes in HER2-positive breast cancer patients (Semiglazov et al, 2013).  O'Sullivan and Swain (2013) noted thatHER2 over-expression or amplification is present in approximately 1/5 of breast cancers and historically was associated with aggressive disease and poorer prognosis.  The introduction of the humanized monoclonal antibody trastuzumab dramatically improved DFS and OS in this subgroup.  As the majority of patients with metastatic disease ultimately develop resistance to trastuzumab, a need exists for more effective targeted therapies.  Pertuzumab is an anti-HER2/neu-targeted therapy in the late stages of clinical development.  The combination of pertuzumab, trastuzumab and docetaxel has been found to have an OS benefit in patients with HER2 positive metastatic breast cancer (MBC) when used in the first-line setting.  This reflects a new standard of care, and pertuzumab was recently approved for this indication by the FDA. The effectiveness of pertuzumab and trastuzumab in conjunction with chemotherapy is currently being evaluated in the adjuvant setting.

Zagouri et al (2013) carried out the first systematic review according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines to synthesize all available data of pertuzumab in breast cancer.  The search strategy retrieved 11 studies that evaluated pertuzumab.  One study was conducted in the neoadjuvant setting (417 patients), whereas all the others dealt with patients with recurrent, metastatic, or refractory disease (1,023 patients).  Six studies were conducted in HER2(+) breast cancer population (1,354 patients), whereas 5 studies (86 patients) were conducted in HER2(-) (or unknown HER2 status) disease.  Pertuzumab is the most recent agent approved by the FDA in combination with trastuzumab and docetaxel for the treatment of patients with HER2(+) metastatic breast cancer who have not received prior anti-HER2 therapy or chemotherapy for metastatic disease.  This approval has been based on data from a phase III Clinical Evaluation of Pertuzumab and Trastuzumab (CLEOPATRA) study.  The anti-tumor activity with the significant reduction in the risk of progression or death, as reflected upon the increase of 6.1 months in median PFS, indicates that pertuzumab may provide an avenue for achieving additional benefit for patients with HER2(+).  Moreover, pertuzumab seems to have a putative role in the management of patients with HER2 who are resistant to trastuzumab.  The promising role of pertuzumab in the neoadjuvant and adjuvant settings remains to be further investigated and established in the future.

In a randomized, multi-center, open-label, phase II study, Gianni et al (2012) examined the combination of pertuzumab or trastuzumab, or both, with docetaxel and the combination of pertuzumab and trastuzumab without chemotherapy in the neoadjuvant setting.  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 4 neoadjuvant cycles of: trastuzumab (8 mg/kg loading dose, followed by 6 mg/kg every 3 weeks) plus docetaxel (75 mg/m(2), escalating, if tolerated, to 100 mg/m(2) 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 end-point, examined in the intention-to-treat population, was pathological complete response (pCR) 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 pCR rate (49 of 107 patients; 45.8 % [95 % CI: 36.1 to 55.7]) compared with those given trastuzumab plus docetaxel (group A; 31 of 107; 29.0 % [20.6 to 38.5]; p = 0.0141); 23 of 96 (24.0 % [15.8 to 33.7]) women given pertuzumab plus docetaxel (group D) had a pCR, as did 18 of 107 (16.8 % [10.3 to 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, 1 of 108 in group C, and 52 of 94 in group D), febrile neutropenia (8, 9, 0, and 7, respectively), and leucopenia (13, 5, 0, and 7, respectively).  The number of serious adverse events was similar in groups A, B, and D (15 to 20 serious adverse events per group in 10 to 17 % of patients) but lower in group C (4 serious adverse events in 4 % of patients).  The authors concluded that patients given pertuzumab and trastuzumab plus docetaxel (group B) had a significantly improved pCR rate compared with those given trastuzumab plus docetaxel, without substantial differences in tolerability.  Pertuzumab and trastuzumab without chemotherapy eradicated tumors in a proportion of women and showed a favorable safety profile.  The authors stated that these findings justified further exploration in adjuvant trials and support the neoadjuvant approach for accelerating drug assessment in early breast cancer.

In a randomized phase II clinical trial, Schneeweiss et al (2013) evaluated the tolerability, with particular focus on cardiac safety, of trastuzumab and pertuzumab (P) with chemotherapy in the neoadjuvant treatment of HER2-positive early breast cancer.  In this multi-center, open-label phase II study, patients with operable, locally advanced, or inflammatory breast cancer were randomized 1 : 1 : 1 to receive 6 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).  Pathologic complete response was assessed at surgery and adjuvant therapy given to complete 1 year of H.  A total of 225 patients were randomized.  During neoadjuvant treatment, 2 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 greater than or equal to 10 % points from baseline to less than 50 %.  Diarrhea was the most common adverse event.  Pathologic complete response (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.

On September 30, 2013, the FDA granted accelerated approval to Perjeta (pertuzumab) as part of a complete treatment regimen for patients with early stage breast cancer before surgery (neoadjuvant setting).  Perjeta is the 1st FDA-approved drug for the neoadjuvant treatment of breast cancer.  Perjeta’s new indication is intended for patients with HER2-positive, locally advanced, inflammatory or early stage breast cancer (tumor greater than 2 cm in diameter or with positive lymph nodes) who are at high risk of having their cancer return or metastasize or of dying from the disease.  It is to be used in combination with trastuzumab and other chemotherapy prior to surgery and, depending upon the treatment regimen used, may be followed by chemotherapy after surgery.  Following surgery, patients should continue to receive trastuzumab to complete 1 year of treatment.  Perjeta’s accelerated approval for neoadjuvant treatment is based on a study designed to measure pCR.  In the study, 417 subjects were randomly assigned to receive 1 of 4 neoadjuvant treatment regimens:

1. trastuzumab plus docetaxel,
2. Perjeta plus trastuzumab and docetaxel,
3. Perjeta plus trastuzumab, or
4. Perjeta plus docetaxel.

About 39 % of subjects who received Perjeta plus trastuzumab and docetaxel achieved pCR, compared to about 21 % who received trastuzumab plus docetaxel.  The confirmatory trial for this accelerated approval is being conducted in patients with HER2-positive breast cancer who had prior breast cancer surgery and are at high risk of having their cancer return.  More than 4,800 participants are enrolled in this trial, which will provide further data on safety, effectiveness, and long-term outcomes.  Results are expected in 2016.Swain et al (2013) noted that CLEOPATRA is a phase III study to compare the safety and effectiveness of pertuzumab, trastuzumab, and docetaxel with placebo, trastuzumab, and docetaxel in patients with HER2-positive first-line metastatic breast cancer.  The results of the primary analysis showed significantly longer median PFS in the pertuzumab group than in the placebo group.  Interim analysis of OS favored the pertuzumab group but was not significant.  These researchers reported results for OS after an additional year of follow-up.  The study was a double-blind randomized trial undertaken at 204 centers in 25 countries.  Patients with HER2-positive metastatic breast cancer who had not received previous chemotherapy or biological treatment for their metastatic disease were randomly assigned to receive either pertuzumab, trastuzumab plus docetaxel (n = 402); or the same regimen with a matching placebo replacing pertuzumab (n = 406).

Randomization was in a 1:1 ratio, stratified by geographical region and previous treatment status.  The primary end-point was PFS (assessed independently), which has been reported previously; no follow-up data were gathered for the primary end-point.  Secondary end-points included OS, PFS (assessed by investigator), objective response rate, and safety.  Median follow-up was 30 months in both groups.  Effectiveness end-points were analyzed in the intention-to-treat population and safety was analyzed by treatment received.  The study was completed but safety and survival data continue to be followed-up.  In the intention-to-treat population, 267 patients died by data cut-off (May 14, 2012), 154 (38 %) of 406 in the placebo group and 113 (28 %) of 402 in the pertuzumab group.  Median OS was 37.6 months (95 % CI: 34. To -NE [not estimable]) in the placebo group but had not been reached (95 % CI: 42.4 to NE) in the pertuzumab group (HR 0.66, 95 % CI: 0.52 to 0.84; p = 0.0008).  Investigator-assessed median PFS was 12.4 months (95 % CI: 10.4 to 13.5) in the placebo group and 18.7 months (16.6 to 21.6) in the pertuzumab group (HR 0.69, 95 % CI: 0.58 to 0.81).  Serious adverse events were reported in 115 (29 %) of 396 patients who received placebo, trastuzumab, and docetaxel and 148 (36 %) of 408 who received pertuzumab, trastuzumab, and docetaxel, and included febrile neutropenia, neutropenia, diarrhea, pneumonia, and cellulitis.  Overall, adverse events were similar to those reported at the primary analysis with respect to frequency, severity, and specificity.  The authors concluded that their analysis showed a significant improvement in OS with pertuzumab, trastuzumab, and docetaxel in patients with HER2-positive metastatic breast cancer, compared with placebo, trastuzumab, and docetaxel.  Moreover, they stated that since this effect was not achieved at the expense of adverse events, this regimen represents a substantial improvement on the standard of care for this population of patients.

Kumler et al (2014) stated that HER2 is over-expressed in 15 to 20 % of all breast cancers.  Treatment with trastuzumab has led to an improved outcome and prolonged survival of HER2-positive breast cancer patients and today the drug is established as standard of care in both the adjuvant and metastatic settings.  However, trastuzumab resistance is common and a major focus in the treatment of HER2-positive breast cancer has been developing therapeutic agents to either potentiate the effect of trastuzumab or to target cells which have become resistant to trastuzumab.  These investigators examined the effectiveness and toxicity of dual targeting in HER2-positive breast cancer.  A computer-based literature search was carried out using PubMed; data reported at international meetings and clinicaltrials.gov was included.  This paper described safety and effectiveness of lapatinib, pertuzumab or trastuzumab-DM1 in combination with trastuzumab in the (neo)adjuvant and metastatic settings.  Furthermore, combinations of trastuzumab and drugs targeting the downstream pathway were described.  The authors concluded that dual blockade is likely to represent a substantial advance for patients with HER2-positive breast cancer.  However, the relevant subpopulation remains to be defined and side effects including cardiotoxicity might be a limiting factor to the use.  They stated that there is an urgent need for prospective biomarker-driven trials to identify patients for whom dual targeting is cost-effective.

Colorectal Cancer

Pohl et al (2009) examined the anti-tumor activity of pertuzumab as a single agent or in combination with erlotinib or irinotecan in human colon cancer cells in-vitro and in-vivo.  Colon cancer cell lines were tested for HER1/HER2 expression by western blot analysis.  The effect of pertuzumab on cell cycle distribution was analyzed by FACS.  Nude mice bearing xenograft tumors were treated with pertuzumab alone, or in combination either with irinotecan or with erlotinib.  Tumor volume was measured repeatedly.  Tumor histology was analyzed for necrosis.  Six of nine cell lines showed high expression of HER1/HER2.  Pertuzumab inhibited cell cycle progression in various cell lines.  Pertuzumab showed minor anti-tumor activity in xenograft tumors, but significantly inhibited tumor growth when combined with erlotinib (p < 0.001).  Combination of pertuzumab with irinotecan had no additional effect on growth of additional tumors.  Pertuzumab treated DLD-1 xenograft tumors did not show enhanced necrosis, which, however, was found in HCT116 derived xenografts.  The authors concluded that pertuzumab has some anti-tumor activity on human colon cancer cells in-vitro and in-vivo, in particular when combined with erlotinib.  In-vivo, pertuzumab combination treatment was not superior to irinotecan monotherapy.  These data warrant further investigation of simultaneous HER1/EGFR TKI inhibition and HER1/HER2 dimerization inhibition for colorectal cancer therapy.

Gastric Cancer

Pazo Cid and Anton (2013) stated that the prognostic value of HER2 in gastric cancer is controversial.  Consensus guidelines have standardized the testing of HER2 status in gastric cancer.  Over-expression of this receptor occurs in approximately 20 % of gastric and gastro-esophageal junction adenocarcinomas, predominantly those of the intestinal type.  Recently, trastuzumab has emerged as the first targeted drug to improve OS when combined with chemotherapy in advanced HER2-positive gastric cancer.  Primary and secondary resistance to trastuzumab has become a major problem and new strategies to overcome this resistance are needed.  A high percentage of advanced HER2-positive gastric cancer patients who progress on trastuzumab therapy are candidates for second-line therapy.  New families of targeted drugs, including tyrosine kinase inhibitors (TKIs) such as lapatinib and PF-00299804, mammalian target of rapamycin (mTOR) pathway inhibitors such as everolimus, heat-shock protein 90 (HSP90) inhibitors such as AUY922, HER dimerization inhibitors such as pertuzumab, and antibody-chemotherapy conjugates such as trastuzumab-emtansine (T-DM1), could offer alternative second-line treatments when trastuzumab-based first-line therapy fails.

Non-Small Cell Lung Cancer

Felip et al (2012) stated that pertuzumab has demonstrated pharmacodynamics activity with stable disease in non-small-cell lung cancer (NSCLC).  Combining erlotinib and pertuzumab may enhance antitumor activity.   These researchers aimed to establish the recommended dosing of the erlotinib and pertuzumab combination; assessed safety, preliminary efficacy, and pharmacokinetics; and analyzed biomarkers.  A total of 15 patients with stage IIIb/IV NSCLC who failed chemotherapy were recruited.  The patients received erlotinib (days -8 to -1), then combination therapy (21-day cycles for 6 cycles).  Pertuzumab was given intravenous at 840 mg, then 420 mg once every 3 weeks, with erlotinib given daily (100 or 150 mg).  No dose-limiting toxicities were observed.  Adverse events were generally grade 1/2 and manageable.  The objective response rate was 20 % (3/15 patients; 2 responders had mutant HER1, 1 responder had wild-type HER1), median overall PFS was 9.3 weeks.  High HER1, HER2, and HER3 messenger RNA expression correlated with increased PFS.  Combination therapy did not affect erlotinib's pharmacokinetics; however, pertuzumab mean exposures (maximum concentration, 231 mg/L; area under the concentration-time curve from 0 to 21 days, 1,780 mg d/L) were slightly higher than in previous studies.  The authors concluded that combination therapy was well-tolerated in patients with good performance status, with encouraging efficacy.

Mazieres and colleagues (2022) noted that HER2 exon 20 insertions and point mutations are oncogenic drivers found in 1 % to 2 % of patients with NSCLC.  No targeted therapy is approved for this subset of patients.  In a multi-center, non-randomized, phase-II clinical trial, these researchers examined the effectiveness of the combination of 2 antibodies against (trastuzumab and pertuzumab) with docetaxel.  Patients with HER2-mutated, advanced NSCLC who progressed after greater than or equal to 1 platinum-based treatment were enrolled.  Patients received pertuzumab at a loading dose of 840 mg and 420 mg thereafter; trastuzumab at an 8 mg/kg loading dose and 6 mg/kg thereafter; and docetaxel at a dose of 75 mg/m2 every 3 weeks.  The primary outcome was the objective response rate (ORR); other endpoints included the duration of response, PFS, and safety.  A total of 45 patients were enrolled and treated.  The median age was 64.5 years (range of 31 to 84 years), 35 % were smokers, 72 % were women, 15 % had an Eastern Cooperative Oncology Group (ECOG) performance status of 2, and 30 % had brain metastases.  The ORR was 29 % (n = 13), and 58 % had stable disease (SD; n = 26).  The median PFS was 6.8 months (95 % CI: 4.0 to 8.5).  The median duration of response in patients with a confirmed response (n = 13) was 11 months (95 % C: 2.9 to 14.9).  Grade-3/4 treatment-related adverse events (AEs) were observed in 64 % of the patients.  No patient discontinued treatment because of toxicity.  The most frequent grade greater than or equal to 3 treatment-related AEs were neutropenia (33 %), diarrhea (13 %), and anemia (9 %).  The authors concluded that triple therapy with trastuzumab, pertuzumab, and docetaxel was feasible and effective for HER2-mutated pre-treated advanced NSCLC.  Moreover, these researchers stated that since there is no standard of care (SOC) regarding targeted therapy in patients presenting HER2 mutated NSCLC, this combined therapy could be considered as a potential therapeutic option.

Ovarian Cancer

Kurzeder and colleagues (2016) noted that the AGO-OVAR 2.29/ENGOT-ov14/PENELOPE, a prospective, randomized phase III clinical trial, evaluated the addition of pertuzumab to chemotherapy in patients with platinum-resistant ovarian carcinoma with low tumor HER3 mRNA expression.  These investigators reported the results of the primary efficacy analysis.  Eligible patients had ovarian carcinoma that progressed during or within 6 months of completing 4 or more platinum cycles, centrally tested low tumor HER3 mRNA expression (concentration ratio less than or equal to 2.81 by quantitative reverse transcriptase polymerase chain reaction on cobas z480 [Roche Molecular Diagnostics, Pleasanton, CA]), and no more than 2 prior lines of chemotherapy.  After investigators' selection of the chemotherapy backbone (single-agent topotecan, weekly paclitaxel, or gemcitabine), patients were randomly assigned to also receive either placebo or pertuzumab (840-mg loading dose followed by 420 mg every 3 weeks).  Stratification factors were selected chemotherapy, prior anti-angiogenic therapy, and platinum-free interval.  The primary end-point was independent review committee-assessed PFS.  Additional end-points included OS, investigator-assessed PFS, ORR, safety, patient-reported outcomes, and translational research.  Overall, a total of 156 patients were randomly assigned.  Adding pertuzumab to chemotherapy did not significantly improve independent review committee-assessed PFS for the primary analysis (stratified HR, 0.74; 95 % CI: 0.50 to 1.11; p = 0.14; median PFS, 4.3 months for pertuzumab plus chemotherapy v 2.6 months for placebo plus chemotherapy).  Sensitivity analyses and secondary efficacy end-point results were consistent with the primary analysis.  The effect on PFS favoring pertuzumab was more pronounced in the gemcitabine and paclitaxel cohorts.  No new safety signals were seen.  The authors concluded that although the primary objective was not met, subgroup analyses showed trends in PFS favoring pertuzumab in the gemcitabine and paclitaxel cohorts, meriting further exploration of pertuzumab in ovarian cancer
.
In a Cochrane review, Haldar et al (2011) compared the effectiveness and toxicities of epidermal growth factor receptor (EGFR) inhibitors alone or in combination with standard chemotherapy in the treatment of ovarian cancer.  These investigators searched the Cochrane Gynaecological Cancer Group Trials Register, The Cochrane Central Register of Controlled Trials (CENTRAL) Issue 4, 2010, MEDLINE and EMBASE up to October 2010.  They also searched registers of clinical trials, abstracts of scientific meetings, and reference lists of included studies, and contacted experts in the field.  Randomized controlled trials (RCTs) comparing anti-EGFR agents with or without conventional chemotherapy versus conventional chemotherapy alone or no treatment in women with histologically proven ovarian cancer.  Two review authors independently abstracted data and assessed risk of bias.  They reported adjusted HRs for OS and PFS and risk ratios (RRs) comparing adverse events in women who received gemcitabine plus pertuzumab and gemcitabine plus placebo.  These researchers found only 1 completed and 3 ongoing RCTs that met their inclusion criteria.  The completed trial randomized 131 women with relapsed ovarian cancer to receive gemcitabine and pertuzumab or placebo and gemcitabine (control).  There was no statistically significant difference in OS, PFS and response between women who received gemcitabine and pertuzumab and those who received control, although PFS approached borderline significance (adjusted HR = 0.66, 95 % CI: 0.43 to 1.03; p = 0.06).  The trial reported a higher rate of adverse events in the gemcitabine and pertuzumab arm for most outcomes, but most were not statistically significant (although many approached borderline significance) because the trial lacked statistical power due to its relatively small size and the low number of observed events.  The trial was at moderate risk of bias.  The authors concluded that EGFR inhibitors, including pertuzumab, may add activity to conventional chemotherapy for treatment of platinum-resistant ovarian cancer.  Certain subsets of women with particularly aggressive tumors resistant to conventional chemotherapy may benefit from EGFR inhibitor treatment.  They stated that further RCTs are needed before EGFR inhibitors are introduced as first- or second-line treatment of ovarian cancer.

In a phase II clinical trial, Kaye et al (2013) evaluated the safety and effectiveness of pertuzumab in combination with carboplatin-based chemotherapy in patients with platinum-sensitive, recurrent advanced ovarian cancer.  Patients were randomized to receive 6 cycles of chemotherapy (carboplatin and either paclitaxel (Taxol) or gemcitabine) with or without pertuzumab.  The primary end point was PFS as determined by Response Evaluation Criteria in Solid Tumors and/or by CA 125 measurements.  Secondary end points evaluated the response rate, safety profile, duration of response, time to PFS and OS for both treatment arms.  A total of 149 patients received either chemotherapy with pertuzumab (arm A, n = 74) or chemotherapy alone (arm B, n = 75).  There was no significant difference either in median PFS or in the secondary end points between the 2 arms.  No differences were seen in an exploratory biomarker analysis of HER3 mRNA expression between the 2 arms.  Pertuzumab was well-tolerated, with no increase in cardiac adverse events compared with chemotherapy alone.  The authors concluded that addition of pertuzumab to carboplatin-based chemotherapy did not substantially prolong PFS in unselected patients with platinum-sensitive ovarian cancer.

Pancreatic Cancer

Thomas et al (2014) noted that the anti-HER2 antibody pertuzumab inhibits HER2 dimerization and affects HER2/HER3 dimer formation and signaling.  As HER3 and its ligand neuregulin are implicated in pancreatic tumorigenesis, these researchers investigated whether HER3 expression could be a predictive biomarker of pertuzumab efficacy in HER2low-expressing pancreatic cancer.  They correlated in-vitro and in-vivo HER3 expression and neuregulin dependency with the inhibitory effect of pertuzumab on cell viability and tumor progression.  HER3 knockdown in BxPC-3 cells led to resistance to pertuzumab therapy.  Pertuzumab treatment of HER3-expressing pancreatic cancer cells increased HER3 at the cell membrane, whereas the anti-HER3 monoclonal antibody 9F7-F11 down-regulated it.  Both antibodies blocked HER3 and AKT phosphorylation and inhibited HER2/HER3 hetero-dimerization but affected differently HER2 and HER3 homo-dimers.  The pertuzumab/9F7-F11 combination enhanced tumor inhibition and the median survival time in mice xenografted with HER3-expressing pancreatic cancer cells.  Furthermore, HER2 and HER3 were co-expressed in 11 % and HER3 alone in 27 % of the 45 pancreatic ductal adenocarcinomas analyzed by immunohistochemistry.  HER3 is essential for pertuzumab efficacy in HER2 low-expressing pancreatic cancer and HER3 expression might be a predictive biomarker of pertuzumab efficacy in such cancers.  The authors concluded that further studies in clinical samples are needed to confirm these findings and the interest of combining anti-HER2 and anti-HER3 therapeutic antibodies. 

Prostate Cancer

Malara et al (2012) noted that prostate cancer is the most commonly diagnosed malignancy in men in developed countries.  ErbB2, a tyrosine kinase receptor over-expressed in many human cancer types, contributes to prostate cancer progression by activating the androgen receptor in a steroid poor environment, thus promoting androgen-independent cell growth.  The consequent development of hormone refractory tumors is a major obstacle in prostate cancer therapy.  The inhibition of ErbB2 signal transduction pathways by the use of human antibodies could be a valuable alternative strategy for cancer therapy.  These investigators performed a comparative analysis in-vitro and in-vivo of the anti-tumor effects of 3 different antibodies targeting different epitopes of ErbB2: Herceptin (trastuzumab), 2C4 (pertuzumab) and Erb-hcAb (human anti-ErbB2-compact antibody), a novel fully human compact antibody.  These researchers demonstrated that the growth of both androgen-dependent and independent prostate cancer cells was efficiently inhibited by Erb-hcAb.  The anti-tumor effects induced by Erb-hcAb on some cell lines were more potent than those observed for either Herceptin or 2C4.  Thus, Erb-hcAb could be a promising candidate in the immunotherapy of prostate cancer for which no obvious treatment has been reported so far.

Uterine Cancer

El-Sahwi et al (2010) evaluated pertuzumab activity separately or in combination with trastuzumab against primary uterine serous papillary adenocarcinoma (USPC) cell lines expressing different levels of HER2/neu.  Six USPC cell lines were assessed by immunohistochemistry (IHC), flow cytometry, and real-time polymerase chain reaction for HER2/neu expression.  c-erbB2 gene amplification was evaluated using fluorescent in-situ hybridization (FISH).  Sensitivity to pertuzumab and trastuzumab-induced antibody-dependent cell-mediated cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC) was evaluated in 5 h chromium release assays.  Pertuzumab cytostatic activity was evaluated using proliferation-based assays.  Three USPC cell lines stained heavily for HER2/neu by IHC and showed amplification of the c-erbB2 gene by FISH.  The remaining FISH-negative USPCs expressed HER2/neu at 0/1+ levels.  In cytotoxicity experiments against USPC with a high HER2/neu expression, pertuzumab and trastuzumab were similarly effective in inducing strong ADCC.  The addition of complement-containing plasma and interleukin-2 increased the cytotoxic effect induced by both mAbs.  In low HER2/neu USPC expressors, trastuzumab was more potent than pertuzumab in inducing ADCC.  Importantly, in this setting, the combination of pertuzumab with trastuzumab significantly increased the ADCC effect induced by trastuzumab alone (p = 0.02).  Finally, pertuzumab induced a significant inhibition in the proliferation of all USPC cell lines tested, regardless of their HER-2/neu expression.  The authors concluded that pertuzumab and trastuzumab induce equally strong ADCC and CDC in FISH-positive USPC cell lines.  Pertuzumab significantly increases trastuzumab-induced ADCC against USPC with a low HER2/neu expression and may represent a new therapeutic agent in patients harboring advanced/recurrent and/or refractory USPC.

Pertuzumab Plus Trastuzumab 

Ina phase-III clinical trial, Tabernero and colleagues (2018) examined the safety and efficacy of pertuzumab versus placebo in combination with trastuzumab and chemotherapy in 1st-line HER2-positive metastatic gastric or gastro-esophageal junction cancer.  JACOB was a double-blind, placebo-controlled, randomized, multi-center, phase-III trial in patients aged 18 years or older with HER2-positive metastatic gastric or gastro-esophageal junction cancer.  Eligible patients had measurable or evaluable non-measurable disease at baseline, ECOG performance status of 0 or 1, and baseline LVEF of 55 % or more.  Patients at 197 oncology clinics (in 30 countries) were randomly assigned (1:1) to receive either pertuzumab (840 mg intravenously) or placebo every 3 weeks, with trastuzumab (8 mg/kg loading dose, then 6 mg/kg every 3 weeks intravenously), plus chemotherapy (cisplatin 80 mg/m2 every 3 weeks intravenously, oral capecitabine 1,000 mg/m2 twice-daily [2,000 mg/m2 every 24 hours] for 28 doses every 3 weeks, or 5-fluorouracil 800 mg/m2 every 24 hours intravenously [120 hours continuous infusion] every 3 weeks).  Randomization was by a central permuted block randomization scheme (block size of 4) with an interactive voice or web response system, stratified by geographical region, previous gastrectomy, and HER2 positivity.  The primary end-point was OS in the intention-to-treat population.  Between June 10, 2013, and January 12, 2016, of 3,287 patients assessed, 780 eligible patients were randomly assigned to receive either pertuzumab plus trastuzumab and chemotherapy (pertuzumab group, n = 388) or placebo plus trastuzumab and chemotherapy (control group, n = 392).  Median duration of follow-up was 24.4 months (95 % CI: 22.3 to 26.1) in the pertuzumab group and 25.0 months (22.3 to 28.9) in the control group.  After 242 deaths in the pertuzumab group and 262 deaths in the control group (the study was not stopped at this point), OS was not significantly different between treatment groups (median OS 17.5 months [95 % CI: 16.2 to 19.3] in the pertuzumab group and 14.2 months [12.9 to 15.5] in the control group; HR 0.84 [95 % CI: 0.71 to 1.00]; p = 0.057).  Serious AEs occurred in 175 (45 %) of 385 patients in the pertuzumab group and 152 (39 %) of 388 patients in the control group.  Diarrhea was the most common serious AE in both groups (17 [4 %] patients in the pertuzumab group versus 20 [5 %] patients in the control group).  The most common grade 3 to 5 AEs were neutropenia (116 [30 %] patients in the pertuzumab group versus 108 [28 %] patients in the control group), anemia (56 [15 %] versus 65 [17 %]), and diarrhea (51 [13 %] versus 25 [6 %]).  Treatment-related deaths occurred in 7 (2 %) patients in the control group; no treatment-related deaths occurred in the pertuzumab group.  The authors concluded that adding pertuzumab to trastuzumab and chemotherapy did not significantly improve OS in patients with HER2-positive metastatic gastric or gastro-esophageal junction cancer compared with placebo.  These researchers stated that further studies are needed to identify improved 1st-line therapeutic options in these types of cancer and to identify patients with HER2-driven tumors who might benefit from dual HER2-targeted therapy.

Park and colleagues (2018) noted that alterations in the HER2 pathway have been identified in a subset of salivary duct carcinomas.  Dual HER2 inhibition with trastuzumab and pertuzumab has superior anti-tumor efficacy to trastuzumab monotherapy in HER2-positive breast cancer, yet its efficacy in HER2-positive salivary duct carcinoma is unknown.  These investigators reported 2 cases of exceptional responses of HER2-positive salivary duct carcinomas to dual HER2 blockade and docetaxel combination and their molecular characteristics.  A 54-year old man with recurrent metastatic HER2 expressing salivary duct carcinoma of the parotid gland after definitive concurrent chemo-radiation achieved a CR after 6 cycles of trastuzumab, pertuzumab, and docetaxel (TPH).  A 42-year old woman with HER2-positive salivary duct carcinoma of the parotid gland with bone and liver metastases had CR with TPH and remained in remission on maintenance trastuzumab and pertuzumab.  The authors concluded that dual HER2 blockage resulted in CR in patients with HER expressing salivary duct carcinoma and warrants further evaluation in this patient population.

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References