NEJM. Volume 344:783-792, March 15, 2001, Number 11

1. Use of Chemotherapy plus a Monoclonal Antibody (Trastuzumab) against HER2 for Metastatic Breast Cancer That Overexpresses HER2 Dennis J. Slamon, M.D., Ph.D., Brian Leyland-Jones, M.D., Steven Shak, M.D., Hank Fuchs, M.D., Virginia Paton, Pharm.D., Alex Bajamonde, Ph.D., Thomas Fleming, Ph.D., Wolfgang Eiermann, M.D., Janet Wolter, M.D., Mark Pegram, M.D., Jose Baselga, M.D., and Larry Norton, M.D. NEJM. Volume 344:783-792, March 15, 2001, Number 11

2. The Facts • HER2neu: amplified in 25-30% of malignant breast CA • F w/breast CA that overexpress HER2 • Aggressive disease with significantly shortened disease-free survivaland overall survival • Lab studies: amplification of HER2 has a direct role in the pathogenesisof these cancers; therapeutic drug development

3. Trastuzumab • Trastuzumab was noted to inhibit tumor growth when usedalone • synergistic when used in combination with • Cisplatin, carboplatin,docetaxel and ionizingradiation • additive effects when used with • Doxorubicin,cyclophosphamide, methotrexate and paclitaxel

4. Clinical Question • Is there a significant difference in the time to disease progression, incidence of adverse effects, rates and duration of responses, time to treatment failure and overall survival of female patients (ages 25-77, with breast CA that overexpressedHER2) that underwent chemotherapy alone and chemotherapy w/ trastuzumab?

5. The Objective of the Study • The objective of the study is to compare the time to disease progression, incidence of adverse effects, rates and duration of responses, time to treatment failure and overall survival of female patients (ages 25-77, with breast CA that overexpressedHER2) that underwent chemotherapy alone and chemotherapy w/ trastuzumab.

6. Main Outcome Measures • End points • Time to disease progression • Incidenceof adverse effects • Rates andthe duration of responses • Time to treatment failure • Overall survival

7. Methodology

8. Patients • Women with progressive metastatic breast cancer that overexpressedHER2 who had not previously received chemotherapy for metastaticdisease were eligible for the study. • The level of expression of HER2was determined by immunohistochemical analysis in a centrallaboratory. • Only patients who had weak-to-moderate stainingof the entire tumor-cell membrane for HER2 (referred to as ascore of 2+) or more than moderate staining (referred to asa score of 3+) in more than 10 percent of tumor cells on immunohistochemicalanalysis were eligible for the study.

9. Excluded • Women with: • Bilateral breast cancer • Untreated brain metastases • Osteoblastic bone metastases • Pleuraleffusion or ascites as the only evidence of disease • A secondtype of primary cancer, or a Karnofsky score of less than 60. • Pregnant • Receivedany type of investigational agent within 30 days before thestudy began.

10. Treatment: Chemotherapy Alone Chemotherapy Plus Trastuzumab Trastuzumab was administered intravenously in aloading dose of 4 mg per kilogram of body weight, followed bya dose of 2 mg per kilogram once a week, until there was evidenceof disease progression. • Consistedof an anthracycline: • Doxorubicin = 60 mg per squaremeter of body-surface area or • Epirubicin = 75 mgper square meter) • Cyclophosphamide = 600 mgper square meter) for patients who had never before receivedan anthracycline, or • Paclitaxel = 175 mg per squaremeter) for patients who had received adjuvant (postoperative)anthracycline. • Administered once every three weeks for sixcycles, and additional cycles were administered at the investigator'sdiscretion.

11. Treatment • On the detection of disease progression,patients were given the option of entering a nonrandomized,open-label study in which trastuzumab was administered at thesame doses alone or in combination with other therapies. Sixty-sixpercent of such patients elected to do so

12. Efficacy • Patients were evaluated for a response at weeks 8 and 20 andthen at 12-week intervals by themembers of an independent response-evaluation committee, whowere unaware of the patients' treatment assignments. • A completeresponse was defined as the disappearance of all tumor on thebasis of radiographic evidence, visual inspection, or both. • A partial response was defined as a decrease of more than 50percent in the dimensions of all measurable lesions.

13. Efficacy • Diseaseprogression was defined as an increase of more than 25%in the dimensions of any measurable lesion. • The primary studyend point was the time to disease progression. • Pre-specifiedsecondary end points were the rate of objective response, theduration of a response, the time to treatment failure (a compositeof disease progression, death, discontinuation of treatment,and the use of other types of antitumor therapy), and survivalas of October 1999.

14. Adverse Events • Clinical assessments were performed at base line, at specifiedtimes , and at the time the patient was removed from the study by an independent cardiac evaluation committee whose members wereunaware of patients' treatment assignments. • Adverse events were classified as mild, moderate, or severe. • Abnormalitiesin laboratory values were classified by the grading system ofthe World Health Organization and cardiac dysfunction by thecriteria of the New York Heart Association.

15. Statistical Analysis • Estimated that 450 patients would be needed in order forthe study to detect at a power of 90 percent a 50 percent increasein the median time to disease progression, given a median timeto progression of eight months in the subgroups receiving chemotherapyalone and a significance level of 0.05 with the use of a two-tailedlog-rank test. • All end points were analyzed according to theintention-to-treat principle. • The primary analysis of all efficacyvariables was performed on data pooled from both chemotherapyregimens.

16. Statistical Analysis • Additional analyses were performed within each chemotherapygroup. • The time to the various end points was analyzed withthe use of Kaplan–Meier methods, and a two-sided log-ranktest was used to compare the groups. • The rate of objective responsewas analyzed with the use of normal approximation methods; atwo-sided chi-square test was used to compare the groups.

17. Results

18. Results • 469 patients enrolled between June 1995 and March 1997 • 5 patients were never treated • 2 declined treatment • 1 diedbefore treatment was begun • 1 had disease progression at enrollment • 1 was enrolled inadvertently. • chemotherapyplus trastuzumab - median time in the study was 40 weeks. • chemotherapy alone – median time in study was 25 weeks • a reflection of the longertime to disease progression in the group that received combinationtreatment trastuzumab.

19. Baseline Characteristics of Patients

20. Efficacy • Chemotherapy plus trastuzumab - median time to disease progression was 7.4 months • anthracycline, cyclophosphamide,and trastuzumab median time to progression 7.8 months • paclitaxel and trastuzumab median time to progression, 6.9months • Chemotherapy alone - median time to disease progression was 4.6 months. • 6.1 month median time progression in the subgroup given only anthracyclineand cyclophosphamide • 3.0 months in the group given paclitaxelalone

21. Results of an Intention-to-Treat Analysis of the End Points

22. Results • Chemotherapy plustrastuzumab compared to chemotherapy alone associated with: • a significantly higherrate of overall response (50 percent vs. 32 percent) • a longer duration of response (median 9.1 vs. 6.1 months) • a longer time to treatment failure (median, 6.9 vs. 4.5months).

24. Results • Chemotherapy plus trastuzumab also associated with a significantlylower rate of death at one year • (22 percent, as compared with33 percent in the group given chemotherapy alone) • The median survival was 25.1 months in the group given chemotherapyplus trastuzumab and 20.3 months in the group that receivedchemotherapy alone. • The calculationincluded patients in the group given chemotherapy alone whoreceived open-label trastuzumab after the occurrence of diseaseprogression. • The risk of death was reduced by 18 to 20 percentin the subgroups given trastuzumab. • The efficacy oftrastuzumab was consistently observed in both subgroups who were given trastuzumab; however,patients with a score of 3+ for the overexpression of HER2 benefitedto a greater degree from such treatment than those with a scoreof 2+.

26. Results: Deaths • 314 patients had died • 149 in the groupgiven chemotherapy plus trastuzumab and 165 in the group givenchemotherapy alone • As of October 2009 • 95 percent of these deaths were attributedto progressive disease. • Two deaths, both in patients who hadreceived an anthracycline, cyclophosphamide, and trastuzumab,were possibly related to trastuzumabtherapy • one patient diedof sepsis after 2 doses of trastuzumab • the second diedof hepatitis B–related hepatorenal syndrome after 11 dosesof trastuzumab.

27. Results: Adverse Events • Approximately 25 percent of patients had chills, fever, or bothduring the initial infusion of trastuzumab. Slowing the infusionrate ameliorated these symptoms. • No episodes of frank anaphylaxisoccurred, but one patient had moderate hypotension, and threehad mild bronchospasm, all of which resolved without treatment. • Infection occurred in 47 percent of patients who were givenchemotherapy plus trastuzumab and in 29 percent of those treatedwith chemotherapy alone (Table 4).

29. Results: Adverse Events • These infections consistedof: • mild-to-moderate infections of the upper respiratory tract (72 percent% • catheter-related infections (9 %) • viral syndrome (3%) • other types of infections(16 %). • The addition of trastuzumab to the chemotherapy regimen increasedthe frequency of leukopenia and anemia (Table 4). • These casesof cytopenia were mild to moderate in severity and did not necessitatethe discontinuation of trastuzumab or withdrawal from the study.

30. Results: Adverse Events • Eighteen patients (15 in the subgroup givenan anthracycline, cyclophosphamide, and trastuzumab and 3 inthe subgroup given paclitaxel and trastuzumab) had clinicalsigns of cardiac dysfunction. • Two additional adverse eventswere attributed to trastuzumab therapy: • embolic stroke asa possible complication of cardiac dysfunction • chest painafter 49 doses of trastuzumab and six cycles of an anthracyclineand cyclophosphamide

31. Results: Cardiotoxicity • This review identified 63 patientswith symptomatic or asymptomatic cardiac dysfunction • 39 of143 patients had received an anthracycline, cyclophosphamide,and trastuzumab (accounting for 27 percent of this subgroup) • 11 of 135 had received an anthracycline and cyclophosphamidealone (incidence, 8 percent) • 12 of 91 had received paclitaxeland trastuzumab (incidence, 13 percent) • 1 of 95 had receivedpaclitaxel alone (incidence, 1 percent

32. Results: Cardiotoxicity • Incidence of cardiac dysfunction of New York Heart Associationclass III or IV was highest among patients who had receivedan anthracycline, cyclophosphamide, and trastuzumab • 16 percent,as compared with 3 percent among patients who had received ananthracycline and cyclophosphamide alone, 2 percent among thosewho had received paclitaxel and trastuzumab, and 1 percent amongthose who had received paclitaxel alone

33. Results: Cardiotoxicity • Of the 63 patients with cardiac dysfunction, 44 received standardmedical treatment. • The condition improved in 33 of these 44patients, did not change in 5, and worsened in 4. • Among the five patientswith persistent class III or IV cardiac dysfunction, three werein the group given an anthracycline, cyclophosphamide, and trastuzumab. • Increasing age was the only base-line characteristic that wasa significant risk factor for cardiac dysfunction in patientswho were receiving the combination of an anthracycline, cyclophosphamide,and trastuzumab.

34. Discussion • Trastuzumab-based combination therapy was effective; it reduced the relative risk of death by 20% at a median follow-up of 30 mos. • Few studies of metastaticbreast cancer have demonstrated a survival advantage of thismagnitude in association with the addition of a single agent.

35. Discussion • Particularly noteworthy is that 2/3 of patients who wereinitially assigned to receive chemotherapy alone began, afterdisease progression, to receive open-label trastuzumab aloneor with chemotherapy. Such a crossover design would generallyreduce the likelihood that a survival advantage would be found. • Significant increases in the time to disease progression, therates of response, the duration of responses, and the time totreatment failure were observed in both subgroups that weregiven chemotherapy plus trastuzumab

36. Toxic Effects • Adverse effect: cardiacdysfunction • Greater risk of cardiacdysfunction • concurrent tx w/ TZM, anthracycline, cyclophosphamideVS treatment with anthracycline, cyclophosphamide • Drug discontinued in 18/235 patients (8%); patients initially received anthracycline, cyclophosphamide and TZM.

37. Toxic Effects • Continued use of trastuzumab did not cause further cardiac deteriorationin most patients, and cardiac function improved in 75%of patients after the initiation of standard medical care • Old age: significant risk factor for cardiac dysfunction. • Mechanismof cardiotoxicity: unknown.

38. Can the results help me in caring for the patient? • Yes

39. Will the reproducibility of the test and its interpretation be satisfactory in my setting ? • Yes, however, the price of the drug has to be considered; it is very expensive and it might not be accessible to all patients here in our country

40. Are the results applicable to my patient ? • Yes, the subjects of the study were female patients, ages 25-77, with breast CA that overexpressedHER2

41. Will the results change my management ? • Yes, considering the efficacy of trastuzumab in improving overall survival, increasing time to disease progression, therates of response, the duration of responses, and the time totreatment failure • The incidence of adverse effects of the drug is minimal; benefits outweight risks

42. Resolution of the Problem • Given the extremely poor prognosis of patients with HER2-(+)metastatic breast cancer, the cardiotoxicity of trastuzumabmust be weighed against its potential clinical benefit. • Risks will necessitate great caution in its use, especiallywhen it is combined with an anthracycline

43. Resolution of the Problem • Benefits outweigh risks • Concurrent treatmentwith trastuzumab and first-line chemotherapy was associatedwith a significantly longer time to disease progression, a higherrate of response, a longer duration of response, and improvedoverall survival.