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Originally published as JCO Early Release 10.1200/JCO.2005.12.903 on May 23 2005 © 2005 American Society of Clinical Oncology.
Trastuzumab Plus Chemotherapy: Convincing Survival Benefit or Not?Cancer Research Network Inc, Plantation, FL Trastuzumab has altered the lives of many women with Her-2/neu–amplified metastatic breast cancer (MBC). Within our clinical practice, we have several women who continue receiving trastuzumab 5 to 9 years after the initiation of therapy. Long survival durations in MBC are not uncommon for patients with hormonally sensitive tumors, but for Her-2/neu–amplified tumors the prognosis was dismal before the use of this agent.1 Improvements in survival from first relapse with MBC have occurred during the last decades2,3 secondary to the development of new hormonal and cytotoxic agents. Despite these gradual improvements in survival from first relapse, there are few trials demonstrating convincing benefits in overall survival for a novel regimen compared with a more standard comparator. The article by Marty et al4 in this issue of the Journal of Clinical Oncology confirms an overall survival benefit produced by a trastuzumab plus chemotherapy combination over chemotherapy alone. The survival benefit for a combination of trastuzumab plus chemotherapy was originally described by Slamon et al5 in one of the pivotal clinical trials of trastuzumab. In the trial by Marty et al,4 weekly trastuzumab plus docetaxel 100 mg/m2 every 3 weeks proved superior to the same dose of single-agent docetaxel in all end points including response rate, response duration, time to progression, treatment failure, and most importantly, overall survival (31.2 v 22.7 months; P = .0062). In the pivotal trial,5 there was also a statistically significant survival benefit when patients treated with chemotherapy plus trastuzumab (n = 235) were compared with those treated with chemotherapy alone (n = 234; 25.1 v 20.3 months; P = .046). In that trial, women with no prior anthracycline adjuvant therapy received an anthracycline plus cyclophosphamide (AC) alone or in combination with trastuzumab. Women with prior anthracycline adjuvant therapy were randomly assigned to paclitaxel 175 mg/m2 every 3 weeks alone or with trastuzumab. The overall survival advantage for AC + trastuzumab over AC alone was 26.8% v 21.4% (P = .16). An unexpected high cardiotoxicity rate led to the recommendation to avoid concomitant anthracycline use with trastuzumab outside of clinical trials. These recommendations are being challenged by provocative trials, such as the neoadjuvant trial by Buzdar,6 in which paclitaxel followed by an epirubicin-containing regimen was administered with concurrent trastuzumab, resulting in a 65% pathologic complete response rate with no cardiotoxicity. Other trials are re-exploring anthracyclines plus trastuzumab, also with encouraging efficacy results and a relative lack of cardiotoxicity. Examples include the liposomal doxorubicins7-10 and epirubicin.11 However, such combinations should still be limited to clinical trials. Although the anthracycline plus trastuzumab clinical trials cited above are of interest for future development, data by Marty et al4 are more relevant to current practice, given that taxane plus trastuzumab combinations are commonly used worldwide for the treatment of MBC. This practice is based on the results from the paclitaxel plus trastuzumab subset of the pivotal trial,5 which reported an overall survival benefit compared with paclitaxel alone (22.1 v 18.4 months), although this result was not statistically significant (P = .17). We believe that paclitaxel administered on a 3-week schedule is unlikely to be the most effective combination for Her-2/neu–amplified MBC for three reasons. First, efficacy seems less for administration of paclitaxel on a 3-week schedule than on a weekly schedule.12,13 Second, a recent phase III trial of paclitaxel compared with docetaxel every 3 weeks14 showed superiority for docetaxel in all end points, including overall survival (15.4 v 12.7 months; P = .03). Third, the trial by Marty et al4 showed a statistically significant survival benefit, whereas the pivotal trial5 using paclitaxel plus trastuzumab did not. The efficacy data reported in the study by Marty et al4 are quite similar to other previously reported docetaxel plus trastuzumab trials. All suggest good and reasonably durable responses, whether the docetaxel was given on a schedule every 3 weeks (four trials) or weekly (six trials), or as part of triplet combinations (four trials). Although no definitive data have yet been presented to determine whether a schedule of docetaxel administration weekly or every 3 weeks would be more efficacious or less toxic, it is of interest that in two different trials of the weekly schedule, 23%15 and 27%16 of patients, were withdrawn from study because of toxicity, whereas only 10% withdrew because of toxicity in the study by Marty et al.4 Interestingly, the only two septic deaths in the latter trial occurred in patients randomly assigned to docetaxel alone. It is anticipated that the risk of septic death in this setting could be reduced in the future with the use of prophylactic growth factors. Thus, in a recent phase III trial of docetaxel 100 mg/m2 every 3 weeks, with or without pegfilgrastim,17,18 the rate of febrile neutropenia was reduced from 17% without pegfilgrastim to 1% with pegfilgrastim. In addition to the docetaxel-based trastuzumab doublet and triplet combinations, many other trastuzumab combinations have shown promise in Her-2/neu–amplified MBC. These include paclitaxel (administered weekly), vinorelbine, gemcitabine, and capecitabine,19 and other combinations, as suggested by the in vitro work of Pegram et al.20 Certainly, the triplet of carboplatin, docetaxel, and trastuzumab seems to produce exciting results, based on in vitro synergy,20 preliminary phase II data,21 pending phase III data (Breast Cancer International Research Group [BCIRG] protocol 007, which randomly assigned patients to docetaxel plus trastuzumab, with or without carboplatin), and even in the adjuvant setting (BCIRG 006).22 Other nonplatinum-based triplet combinations with trastuzumab are also under development with promising results, but that research goes beyond the scope of this editorial. This editorial deals with the overall survival benefit for the taxane plus trastuzumab combinations. Few chemotherapy clinical trials in MBC during the last three decades have claimed an overall survival benefit for a particular regimen compared with another.23 Recently, two studies showed an advantage in overall survival: docetaxel plus capecitabine compared with docetaxel alone,24 and gemcitabine plus paclitaxel compared with paclitaxel alone.25 Considerable controversy has been generated about the survival benefit conclusions in both of these studies.23,26 Neither included a mandatory crossover to capecitabine24 or gemcitabine25 for patients randomly assigned to the single-agent arm. Miles et al26 analyzed the overall survival for the 46 of 256 (18%) patients who actually crossed over from docetaxel to capecitabine in the trial originally reported by O'Shaughnessy.24 They found an overall survival of 21 months, contrasted with the 14.5 months reported for the combination of docetaxel plus capecitabine therapy from the original analysis. Their hypothesis-generating subset analysis has led to a trial of combination versus sequential docetaxel and capecitabine. Updated survival data beyond the abstract of Reyes et al27 are eagerly awaited. Similar questions could be raised for both of the trastuzumab trials. Neither included a mandatory crossover to single-agent trastuzumab for the chemotherapy arm, although 154 of 234 (66%) of patients randomly assigned to chemotherapy alone in the pivotal trial subsequently received trastuzumab. However, even this crossover was confounded, given that 68% of these 154 patients received alternative chemotherapy plus trastuzumab rather than trastuzumab alone.27 Regardless, 27 of 138 AC-treated patients and 22 of 96 paclitaxel-treated patients received single-agent trastuzumab at crossover, with median survivals of 27.4 and 9 months, contrasted with 21.4 and 18.4 months, respectively, for the original randomly assigned cohort of the respective chemotherapies alone (G. Lieberman, R. Mass, and Genentech Inc, personal communications, December 2004). In the trial by Marty et al,4 53 of 94 (57%) patients crossed over from docetaxel to trastuzumab. Although the overall survival for the combination was 31.2 months, and the overall survival for the docetaxel arm was 22.7 months, the latter was further subdivided into those who did (30.3 months) and did not cross over (16.6 months). Neither of the retrospective subset analyses for the pivotal trial5 and the trial by Marty et al4 shed any real light on the question of combination versus sequential therapy. At this point, another cross-trial comparison may also be of interest (albeit with all the negative caveats implied by cross-trial comparisons). A clinical trial was performed with trastuzumab used as first-line therapy for MBC29 in parallel with the pivotal trial.5 Eligibility and patient characteristics for both trials were similar, but not identical. Although the 41% overall response rates for paclitaxel plus trastuzumab seemed superior to the 26% response rate in the single-agent trial, the overall survivals were 22.1 months for the paclitaxel plus trastuzumab combination and 24.4 months for single-agent therapy. Although the authors of this editorial fully endorse first-line trastuzumab in hormone receptor–negative and hormone-refractory patients with MBC, a lingering question remains regarding the survival benefit of trastuzumab combination therapy compared with a sequential approach. This may never be tested directly in a properly designed trial. Regardless of the academic interest of this question, we are convinced that trastuzumab has made an impact on overall survival in MBC; in addition, we hope for increased cure rates if ongoing adjuvant trials show a benefit with the addition of trastuzumab.22 Authors' Disclosures of Potential Conflicts of Interest The following authors or their immediate family members have indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. Consultant/Advisory Role: Charles L. Vogel, Roche; Elizabeth Tan-Chiu, Genentech. Honoraria: Charles L. Vogel, Aventis, Roche; Elizabeth Tan-Chiu, Genentech. Research Funding: Charles L. Vogel, Aventis, Roche. For a detailed description of these categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and Disclosures of Potential Conflicts of Interest found in Information for Contributors in the front of each issue. Acknowledgment We thank Dr Carter, PhD, who humanized the mouse monoclonal now known as trastuzumab,30 Dr Slamon, MD, PhD, for his perseverance from observations to proof of principle,1,5 and M. Marty, MD, and coworkers for providing additional confirmatory evidence for the use of trastuzumab early in the course of MBC. These successes with trastuzumab have further stimulated the development of investigational anti-Her-2 vaccine strategies31 and exciting new molecules such as pertuzumab,32 lapatinib,33 and others. We also thank those valiant women who in the mid-1990s elected to sail uncharted waters and join the initial trastuzumab clinical trials that opened the doors to improved survival for the next generation of patients with MBC. REFERENCES 1. Slamon D, Clark G, Wong S, et al: Human breast cancer: Correlation of relapse and survival with amplification of the Her2 neu oncogene. Science 235:177-182, 1997[CrossRef] 2. Vogel CL, Azevedo SJ, Ayub J, et al: Breast cancer survival after first recurrence: The Miami experience. Cancer 70:129-135, 1992[CrossRef][Medline] 3. Giordano SH, Buzdar AU, Smith TL, et al: Is breast cancer survival improving? Trends in survival for patients with recurrent breast cancer diagnosed from 1974 through 2000. Cancer 100:44-52, 2004[CrossRef][Medline]
4. Marty M, Cognetti D, Maraninchi D, et al: Efficacy and safety of trastuzumab combined with docetaxel in patients with human epidermal growth factor receptor 2–positive metastatic breast cancer given as first-line treatment: Results of a randomized phase II trial by the M77001 Study Group. J Clin Oncol 23:4265-4274, 2005
5. Slamon DJ, Leyland-Jones B, Shak S, et al: Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic beast cancer that overexpresses HER2. N Engl J Med 344:783-792, 2001 6. Buzdar AU, Hunt K, Smith T, et al: Significantly higher pathological complete remission rate following neoadjuvant therapy with trastuzumab, paclitaxel and anthracycline-containing chemotherapy: Initial results of a randomized trial in operable breast cancer with Her2 positive disease. Proc Am Soc Clin Oncol 22:7S, 2004 (abstr 520) 7. Wolff AC, Bonetti M, Sparano JA, et al: Cardiac safety of trastuzumab in combination with pegylated liposomal doxorubicin and docetaxel in HER2-positive metastatic breast cancer: Preliminary results of the Eastern Cooperative Oncology Group trial E3198. Proc Am Soc Clin Oncol 22:18, 2000 (abstr 70) 8. Chia SK, Clemons M, Martin LA, et al: A multi-center phase II trial of pegylated liposomal doxorubicin and trastuzumab in HER-2 over-expressing metastatic breast cancer. Proc Am Soc Clin Oncol 23:34, 2004 (abstr 630) 9. Theodoulou M, Campos SM, Baptist G, et al: TLC D99 (D, Myocet) and Herceptin (H) is safe in advanced breast cancer (ABC): Final cardiac safety and efficacy analysis. Proc Am Soc Clin Oncol 21:49b, 2002 (abstr 216) 10. Trigo J, Climent MA, Gil M, et al: Cardiac safety and activity of a phase I study of 3-weekly Myocet in combination with weekly Herceptin and paclitaxel in HER2-positive locally advanced or metastatic breast cancer. Proc Am Soc Clin Oncol 21:61a 2002 (abstr 242) 11. Eidtmann H, Thomssen CH, Untch M, et al: Herceptin in combination with epirubicin plus cyclophosphamide: Interim results on cardiac safety and efficacy in patients with metastatic breast cancer. Proc Am Soc Clin Oncol 21:60a 2002 (abstr 236) 12. Perez EA, Rowland KM, Suman VJ, et al: N98-32-52: Efficacy and tolerability of two schedules of paclitaxel, carboplatin and trastuzumab in women with HER2 positive metastatic breast cancer: A North Central Cancer Treatment Group randomized phase II trial. Breast Cancer Res Treat 82:S47, 2003 (abstr 216; suppl 1) 13. Green MC, Buzdar AU, Smith T, et al: Weekly paclitaxel followed by FAC as primary systemic chemotherapy of operable breast cancer improves pathologic complete remission rates when compared to every 3-week paclitaxel therapy followed by FAC: Final results of a prospective phase III randomized trial. Proc Am Soc Clin Oncol 21:38a 2002 (abstr 135) 14. Jones S, Erban J, Overmoyer B, et al: Randomized trial comparing docetaxel and paclitaxel in patients with metastatic breast cancer. Breast Cancer Res Treat 82:S9 2003 (abstr 10; suppl 1)
15. Esteva FJ, Valero V, Booser D, et al: Phase II study of weekly docetaxel and trastuzumab for patients with Her-2-overexpressing metastatic breast cancer. J Clin Oncol 20:1800-1808, 2002
16. Tedesco KL, Thor AD, Johnson Y, et al: Docetaxel combined with trastuzumab is an active regimen in Her2 3+ overexpressing and fluorescent in situ hybridization-positive metastatic breast cancer: A multi-institutional phase II trial. J Clin Oncol 22:1071-1077, 2004 17. Schwartzberg LS, Tjulandin SA, Wojtukiewicz MZ, et al: Prophylactic pegfilgrastim significantly reduces the incidence of febrile neutropenia, hospitalizations, and IV anti-infection use in patients receiving docetaxel: A phase III, randomized, double-blind placebo controlled study. Support Care Cancer 12:382, 2004 (abstr A-52) 18. Vogel CL: Febrile neutropenia in docetaxel-treated breast cancer: Evaluating pegfilgrastim. Chemotherapy Foundation Symposium XXII 61, 2004 (abstr 51) 19. Vogel CL, Franco SX: Clinical experience with trastuzumab (Herceptin). Breast J 6:452-462, 2003 20. Pegram MD, Lopez A, Konecny G, et al: Trastuzumab and chemotherapeutics: Drug interactions and synergies. Semin Oncol 27:21-25, 2000 (suppl 11)[Medline] 21. Slamon D, Yeon CH, Pienkowski D, et al: Survival analysis from two open-label, non-randomized phase II trials of trastuzumab combined with docetaxel and platinums (cisplatin or carboplatin) in women with Her2 + advanced breast cancer. Proc Am Soc Clin Oncol 22:37S, 2004 (abstr 642) 22. Tan-Chiu E, Piccart M: Moving forward: Herceptin in the adjuvant setting. Oncology 63:57-63, 2002 (suppl 1)
23. Miles D, von Minckwitz G, Seidman AD: Combination versus sequential therapy in metastatic breast cancer. Oncologist 7:13-19, 2002 (suppl 6)
24. O'Shaughnessy J, Miles D, Vukelja S, et al: Superior survival with capecitabine plus docetaxel combination therapy in anthracycline-pretreated patients with advanced breast cancer: Phase III trial results. J Clin Oncol 20:2812-2823, 2002 25. Albain KS, Nag S, Calderillo-Ruiz, et al: Global phase III study of gemcitabine plus paclitaxel vs. paclitaxel as front-line therapy for metastatic breast cancer: First report of overall survival. Proc Am Soc Clin Oncol 22:5S, 2004 (abstr 510) 26. Miles D, Vukelja S, Moiseyenko JA, et al: Survival benefit with capecitabine plus docetaxel versus docetaxel alone: Analysis of therapy in a randomized phase III trial. Clin Breast Cancer 5:273-278, 2004[Medline] 27. Reyes S, Torrecillas L, Acosta A, et al: Capecitabine and taxanes: Combinations versus sequential therapy in anthracycline-pretreated metastatic breast cancer—Findings from the Mexican Oncology Study Group phase III trial. Eur J Cancer 1:136, 2003 (suppl 5; abstr 447)[CrossRef]
28. Tripathy D, Slamon D, Coleigh M, et al: Safety of treatment of metastatic breast cancer with trastuzumab beyond disease progression. J Clin Oncol 22:1063-1070, 2004
29. Vogel CL, Cobleigh MA, Tripathy D, et al: Efficacy and safety of trastuzumab as a singe agent in first line treatment of HER2 overexpressing metastatic breast cancer. J Clin Oncol 20:719-726, 2002
30. Carter P, Presta L, Groman CM: Humanization of an anti-p185 HER2 antibody for human cancer therapy. Proc Natl Acad Sci U S A 89:4285-4289, 1992
31. Disis ML, Schiffman K, Guthrie K: Effect of dose on immune response in patients vaccinated with an her-2/neu intracellular domain protein–based vaccine. J Clin Oncol 22:1916-1925, 2004 32. Agus DB, Gordon M, Taylor C: Clinical activity in a phase I trial of HER-2-targeted rhuMAb 2C4 (pertuzumab) in patients with advanced solid malignancies. Proc Am Soc Clin Oncol 22:192, 2003 (abstr 771) 33. Burris HA, Hurwitz H, Dees C, et al: EGF10004: A randomized, multicenter, phase II study of the safety, biologic activity and clinical efficacy of the dual kinase inhibitor GW572016. Breast Cancer Res Treat 82: 2003 (abstr 39)
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Copyright © 2005 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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