Stratification Factors for Randomization

1. Age at registration: 70-75/76-802. PS: 0/13. Hormone receptor status*: +/4. Pathological nodal status: +/-5. Institution

*≥10% positive by IHC method

Masataka Sawaki, M.D.,Ph.D.

Evaluation of Trastuzumab without Chemotherapy as a Postoperative Adjuvant Therapy in HER2-Positive Elderly Breast Cancer Patients: Randomized Controlled Trial (RESPECT)Masataka Sawaki1*, Tsuyoshi Saito2, Shinichi Baba3, Kokoro Kobayashi4, Hiroaki Kawashima5, Michiko Tsuneizumi6, Noriko Sagara7, Hiroko Bando8, Masato Takahashi9, Miki Yamaguchi10, Tsutomu Takashima11, Takahiro Nakayama12, Masahiro Kashiwaba3, Toshiro Mizuno13, Yutaka Yamamoto14, Naruto Taira15, Hiroji Iwata1, Yukari Uemura16, Yasuo Ohashi17 and Hirofumi Mukai181Department of Breast Oncology, Aichi Cancer Center, 2Japanese Red Cross Saitama hospital, 3Sagara Hospital, Kagoshima, 4Department of Breast Medical Oncology, Cancer Institute Hospital of the Japanese Foundation for Cancer Research, 5Aomori City Hospital, 6Department of Breast Surgery, Shizuoka General Hospital, 7Kameda Medical Center, 8Faculty of Medicine, University of Tsukuba, 9Department of Breast Surgery, NHO Hokkaido Cancer Center, 10JCHO Kurume General Hospital, 11Department of Surgical Oncology, Osaka City University Graduate School of Medicine, 12Osaka International Cancer Institute, 13Department of Medical Oncology, Mie University Hospital, 14Department of Breast and Endocrine Surgery, Graduate School of Medical Sciences, Kumamoto University, 15Okayama University Hospital, 16Department of Biostatistics, Tokyo University Hospital, 17Department of Integrated Science and Engineering for Sustainable society Chuo University, 18Department of Breast and Medical Oncology, National Cancer Center Hospital East.

On behalf of National Surgical Adjuvant Study of Breast Cancer 07 (N-SAS BC 07) steering committee, Japan. *Correspondence to Masataka Sawaki, M. D., Ph.D ; m-sawaki@aichi-cc.jp

Objective

Background Results Monotherapy of trastuzumab as an adjuvant treatment without

concurrent or preceding chemotherapy is not used in clinical practice since its benefit has not been investigated.

It has clinical significance to demonstrate benefit of trastuzumab without toxicity induced by chemotherapy, especially in elderly patients.

Then, we designed a randomized controlled trial to investigate the efficacy of trastuzumab monotherapy compared to trastuzumab and chemotherapy combination therapy in women over 70 years of age with human epidermal growth factor receptor type-2 (HER2)-positive primary breast cancer (Sawaki M, et al. Jpn J Clin Oncol 2011;41:709-12).

To investigate the relative value of trastuzumab monotherapy as an adjuvant treatment compared to the standard combination treatment with chemotherapy in elderly breast cancer patients.

Primary endpoint: Disease-free survival (DFS)

Secondary endpoints: Overall survival (OS), recurrence-free survival (RFS), adverse events, health-related quality of life (HRQOL), comprehensive geriatric assessment (CGA), cost-effectiveness (utility)

Conclusion

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Methods

Trastuzumab monotherapyTrastuzumab (1 year)

Randomization

HER2-positive elderly patientAge: 70 - 80 years old

Stage: I (pT>0.5cm), IIA, IIB, IIIA / M0

Trastuzumab + ChemotherapyTrastuzumab (1 year) + Chemotherapy

（Investigator’s choice from PTX/DTX/AC/EC/FEC/CMF/TC/TCbH）

Fig.1. Trial design (NCT01104935)

The small number of events precluded the evaluation of trastuzumab monotherapy based on HR of DFS, and comparison of RMSTs revealed that the lost survival due to omitting chemotherapy was less than 1 month at 3 years.

In light of less toxicity and a better QOL profile, trastuzumab monotherapy can be an option as an adjuvant therapy for elderly HER2-positive Breast Cancer patients.

Fig. 2A. DFS (n=266) DFS at 3 yrs was 94.8% in H+CT group vs 89.2% in H group (HR=1.42; 95% CI, 0.68 to 2.95, P=0.35). The difference in RMST between arms at 3 years was -0.45 months (95% CI, -1.71 to 0.80).

Table 1. Patient Characteristics

We randomly assigned patients over 70 years old with HER2-positive invasive Breast Cancer who received curative surgery into either trastuzumab (Herceptin®; H) (H group) or H plus chemotherapy (CT) (H+CT group) selected from pre-specified regimens (Fig.1).

Major inclusion criteria• Histologically diagnosed as HER2-positive (3+ overexpression or positive by

fluorescence in situ hybridization) invasive breast cancer and who received curative operation for primary breast cancer

• Stage I (pT>0.5cm), IIA, IIB or IIIA/M0• A woman ≥70 and <81 years of age at time of registration and PS 0-1 (ECOG)• Baseline left ventricular ejection fraction ≥ 55%• Organ function is preserved• No treatment history of endocrine therapy or chemotherapy for breast cancer• Consent obtained from the patient herself using the consent form Major exclusion criteria• Active double cancer (synchronous double cancer or invasive cancer of another organ)• Postoperative pathological axillary lymph node metastasis in ≥4 sites• History of complicating cardiac disease and/or uncontrolled diabetes

Acknowledgement: We wish to thank all of our patients who participated in the RESPECT study. This study was funded by the Comprehensive Support Project of the Public Health Research Foundation, Japan.Clinical trial information: NCT01104935

Definition of protocol treatment• Trastuzumab: The loading administration dose was 8 mg/kg, and the maintenance dose was 6 mg/kg every three weeks for 1year.• Chemotherapy: The regimen with starting dose was prescribed as below.i. Paclitaxel (PTX) 80mg/m2 weekly for 12 cyclesii. Docetaxel (DTX) 75mg/m2 every 3 weeks for 4 cyclesiii. AC (DXR/CPM) 60/600mg/m2 every 3 weeks for 4 cyclesiv. EC (EPI/CPA) 90/600mg/m2 every 3 weeks for 4 cyclesv. FEC (5-FU/EPI/CPA) 500/75/500mg/m2 every 3 weeks for 6 cyclesvi. FEC (5-FU/EPI/CPA) 500/100/500mg/m2 every 3 weeks for 4-6 cyclesvii. CMF(CPA/MTX/5-FU) 75-100mg orally from day 1 to day 14, 40mg/m2 on day 1 and day 8

intravenously, and 500-600mg/m2 intravenously on day 1 and day 8, every 4 weeks for 6 cyclesviii. TCbH (DTX/CBDCA/H) 60-75mg/m2 day 1/5-6AUC day1/4mg/kg→2mg/kg day 1, 8, 15 every 3

weeks for 6 cycles• Combined trastuzumab treatment was initiated sequentially after the end of

chemotherapy. However, concomitant administration was allowed when combining trastuzumab with PTX, DTX and CMF.

• Dosage for subsequent cycles was implemented according to the pre-defined dose reduction criteria and levels of dose reduction.

If hormone receptor was positive, standard hormone therapy was indicated. In case of after breast conservative operation, irradiation for breast was indicated after chemotherapy.

Statistical Consideration• The total required numbers of events and patients were set to 120 and 260,

respectively, for assuring a statistical power of 80% for a 95% confidence interval (CI) with a hazard ratio (HR) of H to H+CT not to exceed 1.69. The clinical positioning of each treatment was examined by comparing the calculated HR with the threshold for “the addition of chemotherapy is determined a definite advantage” (1.69) based on the questionnaire of physicians in the trial group.

• Restricted mean survival time (RMST) was calculated as a supplementary endpoint for interpreting the relative benefit of H, because the blinded interim analysis showed that the number of events was much fewer than expected, and the statistical power of the non-inferiority test based on HR is not assured. The restricted time for RMST is three-, five-, and seven years.

Table 4. Adverse events (CTCAE v.3.0)

Table 3. The events in DFS Table 2. Regimen received and Relative Dose Intensity (RDI)

Fig. 2B. RFS (n=266) RFS at 3 yrs was 95.6% (9 events with 4 deaths) in H+CT group vs 91.7% (13 events with 5 deaths) in H group. The difference in RMST between arms at 3 years was -0.41 months (95% CI, -1.51 to 0.68).

A total of 275 patients were randomized from 2009 October to 2014 October. Of 275 patients, 9 patients (3.3%) was excluded before initiation of protocol treatment

because of withdrawal (n=8) and difficulty of attending to the hospital (n=1), then, 266 included in the full set analysis (n=131 in H+CT group, n=135 in H group).

The patient’s characteristics are shown in Table 1. They were well balanced in two groups. Stage I (pT>0.5cm): 43.6%, IIA: 41.7%, IIB: 13.5%, IIIA: 1.1%.

The median age was 73.5 (70-80) years. The median follow up time was 3.52 yrs. The chemotherapy regimen received and relative dose intensity are shown in Table 2. The planned analysis showed that DFS at 3 yrs was 94.8% in H+CT group (n=131, 12

events) vs 89.2% in H group (n=135, 18 events) (HR=1.42; 95% CI, 0.68 to 2.95, P=0.35) (Fig.2A). The events in DFS are shown in Table 3.

The difference in RMST between arms at 3 years was -0.45 months (95% CI, -1.71 to 0.80). Relapse-free survival (RFS) at 3 years was 95.6% (9 events with 4 deaths) in H+CT group

vs 91.7% (13 events with 5 deaths) in H group (Fig.2B). Common adverse events are shown in Table 4. The grade 3/4 non-hematological AE were

seen more in H+CT group than H group (29.8% vs 11.9%, P=0.0003). The total score of FACT-G improved (with 5 points or more) more in H group (H: 42.9% vs

H+CT: 25.3%, P=0.021) at 1 year (Fig.3A), and deteriorated more in H+CT group (H: 19.0% vs H+CT: 38.0%, P=0.009) at 1 year (Fig.3B).

Fig. 3. The total score of FACT-G Compared with the score at baseline, 5 point or more decrease (increase) are defined as A) clinically meaningful HRQOL improvement and B) deterioration.

28% 19% 31%48% 38% 36%0%

20%

40%

60%

80%

100%

2 months 1year 3years

B) Rate of clinically meaningful HRQOL deterioration

H group H+CT group

p=0.006 p=0.009 p=0.613

38% 43% 37%15% 25% 36%0%

20%

40%

60%

80%

100%

2 months 1year 3years

A) Rate of clinically meaningful HRQOL improvement

H group H+CT group

p<0.001 p=0.021 p=0.870