Breast Cancer Vol. 8 No. 4 October 2001

Sat elli Symposium II

Compassionate Use of Humanized Anti-HER2/neu Protein, Trastuzumab for Metastatic Breast Cancer in Japan

Yutaka Tokuda .1, Yasuhiro Suzuki .1, Masatoshi Ohta *~, Yuki Saito *~, Mitsuhiro Kubota *~, Tomoo Tajima .1, Shinobu Umemura .2, and R. Yoshiyuki Osamura .2

The HER-2/neu protein is thought to be a unique and useful target for antibody therapy of cancers overex- pressing the HER-2/neu gene. The recombinant humanized anti-HER-2 monoclonal antibody, trastuzumab (Herceptin | was approved for clinical use in the US in 1998. In Japan, it was approved and later became available in June, 2001. We have treated 41 patients with metastatic breast cancer with trastuzumab pur- chased from the US. In this paper, the details of the patients we experienced are reviewed.

Breast Cancer 8:310-315, 2001.

Key words: HER2/neu, Humanized monoclonal antibody, Trastuzumab, Breast cancer

In 1998, two papers presented at the Annual Meeting of the American Society of Clinical Oncol- ogy (ASCO) encouraged patients with breast can- cer via the news media. Both papers concerned clinical trials with trastuzumab (Herceptin | which is a humanized monoclonal antibody against the HER-2/neu oncoprotein. The day after the meeting, USA Today reported the statement of Dr. L. Nor- ton, Memorial-Sloan Kettering Cancer Center, that "it is an opening of a new cancer treatment". In the autumn of 1998, the FDA approved Herceptin ~ unusually quickly. Since then, we have treated metastatic breast cancer patients with Herceptin *~ purchased from the US under the approval of the Institutional Review Board of the Tokai University School of Medicine. In June, 2001, Herceptin | was finally approved and became available in Japan. In this paper, such compassionate use experience with Herceptin | is presented.

Patients and Methods

Patients Patients with metastatic breast cancer refracto-

ry to conventional chemo- or endocrine therapies and overexpressing the HER2 gene product were

*Department of Surgery and *~Department of Pathology, Tokai Universily School of Medicine, Japan. Reprint requests to Yutaka Tokuda, Department of Surgery, Tokai Univer- siV School of Medicine, Bohseidai, Isehara, Kanagawa 259-1193, Japan. E-mail: tokuda@is.icc.u-tokai.ac, jp

eligible for this study. The expression of HER2 was determined by immunohistochemical staining of paraffin-embedded thin sections of the primary or metastatic tumors using a rabbit polyclonal anti- body against the human HER2 product (DAKO, Glostrup, Denmark). Expression was scored as 0, 1 +, 2 +, or 3 + using standardized criteria. Eligible patients had 2 + or 3 + overexpression (weak to strong complete membrane staining observed in more than 10% of tumor cells).

Treatment Herceptin | was purchased from the US by the

patients and administered according to the protocol approved by the Institutional Review Board of the Tokai University School of Medicine. Patients received a loading dose of 4 mg/kg, followed by weekly administration of 2 mg/kg as a mainte- nance dose. The infusion was administered over 90 minutes. Thirty minutes before the initial adminis- tration, the majority of the patients were given a suppository of a non-steroidal anti-inflammatory drug (NSAID). Weekly paclitaxel 80 mg/m ~, tri- weekly docetaxel 60 mg/m 2, weekly vinorelbine 25 mg/m ~, or cyclophosphamide 100 rag/body/day and 5'-deoxy-5-fluorouridine (5'DFUR) 800-1,200 rag/body/day for 14 days were given in conjunc- tion with Herceptin | for some patients.

Evaluation of Response A complete response (CR) was defined as the

complete resolution of all measurable tumors for a

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duration of at least 4 weeks. Partial response (PR) was defined as _~ 50% reduction in the sum of the products of the two longest perpendicular dimen- sions of all measurable tumors for a duration of at least 4 weeks, and progressive disease (PD) was defined as a _~ 25% increase in any measurable lesions or the appearance of any new lesion.

Results

Forty-one patients were registered from May, 1999 to May, 2001. Patient characteristics are listed in Table 1. Two patients with unknown HER2 sta- tus were examined in the US. They showed 3 + HER2 overexpression on immunohistochemical staining.

Toxicity We examined the effect of NSAID pretreatment

on infusion reaction after the loading dose of Her-

Table 1. Patient Characteristics

Characteristic No. of Patients

A g e , years Median (Range) 51 (26-68)

HER2 overexpression 2+ 7 34- 32 Unknown 2

Herceptin | Single use 21 Combination 20

Table 2. Effects of Pretreatment on Infusion Reaction during Loading Dosage of Herceptin |

Fever or Chills Pretreatment Rate

-t-

4- 2 31 6.1% - - 1 7 1 2 . 5 %

ceptin ~'>. As shown in Table 2, 6.1% of 33 patients undergoing pretreatment had fever or chills of grade 1 or more within 24 hours after initiation of Herceptin ~'. On the contrary, 12.5% of 8 patients not undergoing pretreatment had an infusion reaction.

Cardiotoxicity of grade 2 manifested in 3 patients as shown in Table 3. Case 002 had bilateral supra- clavictilar lymph node and paraaortic lymph node metastasis with CR, case 005 had liver metastases with CR, and case 015 had liver and lung metas- tases with PR. Thus, when left ventricular ejection fraction (EF) deteriorated, anticancer drugs only were discontinued. Although Herceptin | was still continued, EF gradually improved (Fig 1).

Tumor Response Twenty-one patients as shown in Table 4 were

treated with Herceplin | alone. High-dose chemother- apy was given to 9 patients. Two patients (10%) responded to the treatment. Interestingly, case 007 had liver metastasis showing PR, but bone metas- tases progressed.

Twenty patients treated with Herceptin | and anticancer drugs are listed in Table 5. Eighteen patients were evaluable for response. Among them, 15 patients (83%) responded to the treatment. Among 5 patients treated with docetaxel, 3 patients had CR or PR in 4 patients evaluable for response.

---e--Case 002

E F ( % ) ~ Case o05

90" --41--Case 015

80

70

60

50

40"

3 0 '

2 0 '

10 '

0 Pre Minimum 2 ~ ~ 1'0 1"2

W e e k s

Time plotted against ejection fraction. Fig 1.

Table 3. Grade 2 Cardiotoxicily

Case Age Cumulative dose of

doxorubicin (mg/m 2) Combined drugs

Ejection fraction (%)

Prior Minimal

002 53 005 60 015 66

80 0

40

2 Docetaxel 60mg/m/3w 56 38 Docetaxel 60mg/m2/3w 77 59 Paclitaxel 80mg/m2/w 66 50

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Tokuda Y, et al

Table 4. Patients Treated with Herceptin ~ alone

Compassionate Use of Trastuzumab

Case Age HER2 HDC* Disease sites

003 56 3+ -k Liver 006 46 2+ -I- Bone 007 53 3+ Liver 008 58 3+ -f- Liver

010 30 3+ -t- Liver 011 33 3+ Pleura, Soft tissue 013 49 2+ -Jr- Breast, Liver

014 43 3+ Pleura, Soft tissue

016 60 3+ Liver 019 48 3-t- -I-- Chest wall 020 40 3+ -t- Bone, Pleura 025 59 3+ Chest wall 027 54 2+ Lung, Liver, Bone 028 51 3+ + Soft tissue

029 51 3+ Lung 031 42 3+ Pleura, Liver, Bone

032 54 3+ Breast, Liver 033 68 2+ Breast, Soft tissue

036 27 3+ Breast, Soft tissue 037 51 3+ Bone, Chest wall

039 35 3+ + Liver, Bone

Response 2nd-line

PD PD PR

PD H** -f- CY -I- 5'DFUR

PD

SD NF***

PD

PD PD SD PD PD SD H -f- Paclitaxel PD H + Vinorelbine

NE

SD PD

SD PR PD

Response Comments

Liver: PR, Bone: PD

PR

PR PR

*HDC: high-dose chemotherapy **H: Herceptin |

***NE: not evaluable

Table 5. Patients Treated with Herceptin ~ plus Chemotherapeutic Drugs

Case Age HER2 Disease sites

001 43 2+ Liver 002 53 3+ Soft tissue 004 51 unknown Soft tissue 005 60 3-1- Liver 009 52 unknown Chest wall 012 43 2-1- Lung, Liver 015 66 3+ Lung, Liver 017 47 3+ Breast, Liver

018 64 3+ Liver 021 61 3-t- Breast, Liver, Bone

022 35 3+ Liver, Bone 023 65 3+ Lung, Bone 024 55 3-'1- Chest wall, Soft tissue

026 41 3+ Liver 030 26 3+ Liver 034 49 3-1- Liver, Bone 035 64 3+ Liver 038 51 3+ Bone 040 53 2-t- Lung, Liver, Bone, Chest wall

041 54 3-1- Liver, Bone

Combined d rugs Response

Docetaxel PD Docetaxel NE* Docetaxel -f- CBDCA CR Docetaxel CR CBDCA PD Paclitaxel/weekly PR Paclitaxel/weekly CR Docetaxel PR Paclitaxel/weekly PR Paclitaxel/weekly CR

Paclitaxel/weekly PR Paclitaxel/weekly PR

Paclitaxel/weekly CR Docetaxel PR Paclitaxel/weekly PR Paclitaxel/weekly NE Vinorelbine PR Paclitaxel/weekly NE Paclitaxel/weekly SD Paclitaxel/weekly PR

2nd-line Response

CY -t- 5'DFUR PR

Vinorelbine PR Vinorelbine PR

Vinorelbine NE

*NE: not evaluable

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Breast Cancer Vol. 8 No. 4 October 2001

Table 6. Patients with CNS Metastasis

Case Age HER2 Disease sites

005 60 3-k Liver 007 53 3-1- Liver 012 43 2+ Lung, Liver 017 47 3 if- Breast, Liver 019 48 3-k- Chest wall 021 61 3-t- Breast, Liver, Bone 027 54 2-t- Lung, Liver, Bone 029 51 3-}- Lung

Combined d rugs Response

Docetaxel CR None PR Vinorelbine PR Docetaxel PR None PD Paclitaxel CR None PD Vinorelbine PR

Fig 2. Case 001, a 43 year~ld woman, had multiple liver metas- tasis (A) responding to Herceptin ~' combined with cyclophos- phamide and 5'DFUR (B).

Weekly paclitaxel was used for 12 patients. Among an evaluable 11 patients, 3 patients had CR and 7 patients had PR. Interestingly, 3 of 4 patients treat- ed with Herceptiff': plus vinorelbine responded in contrast to prior taxane treatment. One patient refractory to Herceptin" plus docetaxel responded to cyclophosphamide plus 5'DFUR together with Herceptiff '~ (Fig 2).

Eight patients showed CNS metastasis during

the Herceptin ~'~ treatments (Table 6). Among them, 6 patients were responding to the treatments. Case 021 had liver and bone metastases. Her liver metas- tases responded to weekly administration of Her- ceptin ~'' and paclitaxel. However, she had multiple brain metastases during the response (Fig 3).

Discussion

The efficacy of pretreatment for alleviating infu- sion reactions during the loading dose of Herceptin ': has not been examined yet. Infusion reaction was observed in 6.1% and 12.5% of the pretreatment group and non-pretreatment group, respectively. There was no statistically significant difference between the two groups, but manifestation rate in the pretreatment group was lower than the 30 to 40% reported previously ') .

Concurrent treatment with an anthracycline, cyclophosphamide, and Herceptin" significantly increased the risk of cardiac dysfunction, as com- pared with therapy with only an anthracycline and cyclophosphamide ~). Thus, Herceptin ' should not be concurrently used with an anthracycline. Car- diotoxicity was also identified in ten (4.7%) of 213 patients treated with Hercepfin '~ alone t). Nine had received anthracycline therapy and 6 had a cumula- tive doxorubicin dose of more than 400 mg /m ~. The cumulative dose of anthracycline has not been identified as a risk factor as yet, but patients who have received a high cumulative dose should be treated with special caution. We had three patients with grade 2 cardiotoxicity, although their cumula- tive doxorubicin doses were low. Continued use of only Herceptin ~' did not cause further cardiac dete- rioration and cardiac function improved without specific treatment.

We encountered one patient with PR to liver metastases but PD of bone metastases. Until now,

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Tokuda Y, et al Compassionate Use of Trastuzumab

Fig 3. Case 021, a 61 year-old woman, had multiple liver metastasis (A) responding to Herceptin | combined with weekly paclitaxel (B). However, she had multiple brain metastases during the response (C, D).

there have been no published data on response rates according to disease site. Detailed analysis will be published after world-wide use of this drug.

Herceptin | plus vinorelbine treatment was report- ed to be effective in patients refractory to anthracy- clines and taxanes 3). We treated 5 patients refracto- ry to taxane t rea tment . All of three evaluable patients responded to the combination. We also had 2 patients t reated with Herceptin | cyclophos- phamide and 5'DFUR after more than 3 regimens which included taxanes. Interestingly, both patients had PR. According to a previous in vitro study 4), 5- FU is antagonistic to Herceptiff ~>. However, Bange- mann et al. ~ reported in the 23rd Annual San Anto- nio Breast Cancer Sympos ium in 2000, a 53% response rate in patients refractory to Herceptin | alone or Herceptin | in combination with paclitaxel, either weekly or every 3 weeks. Thus, Herceptin | in combination with 5-FU derivatives should be worth examined with regard to its efficacy in patients refractory to Herceptin | and taxanes.

One of the most important issues during Her-

ceptin | treatment was CNS metastasis. Eight patients manifested CNS metastasis during Herceptin | treatment. Six had other metastatic sites respond- ing to the treatment. According to a paper regard- ing a patient with meningeal carcinomatosis +, only minimal amounts of Herceptin + penetrate the CSE Therefore, it is unlikely that intravenous Herceptin | would be useful to treat meningeal or cerebral dis- ease of breast cancer. As a potential t reatment method to resolve this issue, the safety and efficacy of intrathecal administration of Hercepfin | should be determined.

References

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2) Slamon D J, Leyland-Jones B, Shak S, et al: Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses

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