Originally published as JCO Early Release 10.1200/JCO.2008.20.8215 on March 16 2009

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Continuing Trastuzumab Beyond Progression

Division of Hematology Oncology, College of Medicine, University of Tennessee, Memphis, TN, and Aptium Oncology, Lynn Cancer Institute, West Campus, Boca Raton, FL

During the last decade, most oncologists empirically adopted the practice of continuing trastuzumab beyond progression of disease in patients with human epidermal growth factor 2 (HER-2) –positive metastatic breast cancer (H2MBC), deviating from the established paradigm of stopping and switching drugs or interventions when patients develop disease progression. With trastuzumab, they simply switched the cytotoxic agent paired with this monoclonal anti–HER-2 antibody. Although a whole host of considerations may have facilitated this trend, ranging from virulence of HER-2–positive disease, tolerability of trastuzumab, and lack of other available agents for HER-2 blockade, this practice was not based on any prospective randomized data establishing benefit. The pivotal randomized trial in first-line H2MBC that established the benefit of adding trastuzumab to chemotherapy allowed patients to cross over from the chemotherapy alone arm to receive trastuzumab with a different chemotherapeutic regimen. However, it did not have a postprogression randomization in the experimental arm to continue or stop trastuzumab, which unfortunately left this critical question unanswered.¹ The data on subsequent treatment chosen at investigators' discretion were nevertheless captured, showing the safety and feasibility of continuing trastuzumab beyond progression.² There have been subsequent efforts to explore the worth of this strategy that were unsuccessful due to poor accrual, including an attempt by a US cooperative group to randomly assign patients who had experienced progression while receiving a taxane-trastuzumab regimen to vinorelbine with or without trastuzumab (L. Puztai, personal communication, April 2005). As often happens, practice had moved beyond the question. There have been attempts to analyze retrospectively the outcome of patients who stopped or continued trastuzumab that seem to indicate a benefit of continuation in the British Columbia registry and in Europe.^4–7 These analyses were useful to support the continuation hypothesis but could not be deemed definitive because of their retrospective design.

More recently, a randomized trial examined the role of lapatinib, a dual kinase (HER-1 and HER-2) inhibitor in patients who had experienced progression after receiving trastuzumab, in addition to being exposed to an anthracycline and a taxane.⁸ This study randomly assigned patients to receive capecitabine alone in approved doses (1,250 mg/m² twice daily for 2 of 3 weeks) or a lower dose (1,000 mg/m² twice daily) on the same schedule, combined with once-daily lapatinib at 1,250 mg throughout the treatment period. With 324 eligible patients, this trial met its primary end point of median time to disease progression, in favor of the doublet (8.4 v 4.4 months; P = .0019). Although the US Food and Drug Administration's approval of lapatinib has added another option for this patient population, oncologists and patients have been faced with the dilemma of taking a fork in the road when they encounter progression in patients receiving trastuzumab: should they follow the evidence and switch to lapatinib or follow their habit, based on preclinical data and retrospective analyses, and continue trastuzumab?

In this issue of Journal of Clinical Oncology, von Minckwitz et al⁹ report the first randomized trial, to our knowledge, assigning patients who experience progression while receiving a trastuzumab-containing regimen to stop or continue this antibody with the institution of capecitabine therapy. The authors need to be congratulated and commended for attempting to answer this critical question, and successfully enrolling more than 150 patients. They enrolled patients with H2MBC who had experienced progression while receiving first-line trastuzumab-based chemotherapy and randomly assigned 78 patients per arm (far fewer than the intended 482 total) to receive capecitabine with or without continuation of trastuzumab. They showed a better time to disease progression in favor of the continuation (5.6 v 8.2 months; P = .0338); response rates were also better with the doublet therapy (27% v 48%; P = .0115) but overall survival was not statistically significantly different. No significant incremental grade 3 to 4 toxicities were noted in the trastuzumab-containing arm.

The open-label design with no independent assessment of response or progression subjects these results to investigator bias; one is struck by the high response rates in both arms despite the use of RECIST (Response Evaluation Criteria in Solid Tumors) criteria (which usually result in lower response rates compared with the WHO criteria used in the older trials). Patient numbers are small, and the study accrued slowly (during 45 months from 2003 to 2007) before it was closed because of the availability of the lapatinib plus capecitabine data, limiting the statistical power of its observations. Despite these limitations, the study von Minckwitz et al⁹ reached statistical significance for its primary end point. In comparing their results to those of the lapatinib trial, the authors argue for a similar benefit from their approach with less toxicity. However, this comparison has its limitations, as the authors themselves observe. In addition to the many differences in the patient populations in the two trials, the lapatinib trial had a larger sample size with independently assessed response rate and time to progression. Without a randomized trial, it is difficult to predict how trastuzumab plus capecitabine would compare to lapatinib plus capecitabine. Preliminary data have been reported from a randomized trial of 291 patients that compared a switch to single-agent lapatinib versus lapatinib plus continued trastuzumab beyond progression on multiple lines of trastuzumab-based chemotherapy regimens. The study showed the superiority of the doublet (progression-free survival, 12 v 8.1 weeks; P = .008),¹⁰ suggesting dissimilar, perhaps complementary, contributions of these two compounds to HER-2 blockade, as also evidenced by a recently reported neoadjuvant study with molecular correlates on serial biopsies. This possibility is now being explored in a large randomized trial in the adjuvant setting (ALLTO [Adjuvant Lapatinib and/or Trastuzumab Treatment Optimisation]). Patients enrolled onto this four-arm study receive standard chemotherapy from an approved list of regimens and 12 months of anti–HER-2 therapy with random assignment as follws: trastuzumab alone; lapatinib alone; both in combination concurrently; or both in sequence (12 weeks of trastuzumab followed by a 6-week washout period, then 34 weeks of lapatinib).¹¹

The National Comprehensive Cancer Network believes that the best management of any cancer patient is in a clinical trial.¹² The online version currently in use (v1.2009), recommends the use of capecitabine plus lapatinib in patients who experience progression after treatment with an anthracycline, a taxane and trastuzumab as a preferred treatment. However, it also lists additional options allowing for combining trastuzumab with other first-line cytotoxic agents, or with lapatinib (without cytotoxic therapy) in this setting. It is likely that the next version, expected to be online by January 2009, will take into account the results from recently released reports. Many practitioners following the National Comprehensive Cancer Network guideline now face patients who have experienced progression after receiving the capecitabine and lapatinib doublet. With the evidence now accumulating, it is becoming increasingly clear that continued HER-2 blockade is important in patients with H2MBC, and clinicians may find it prudent to reinstitute trastuzumab beyond lapatinib, given that there is more experience with combining various cytotoxic agents with trastuzumab, while keeping in mind that definitive data in this setting are lacking. The choice of therapy needs to take into account the risk-benefit ratios of these agents. Unlike trastuzumab, lapatinib has rash and diarrhea as its prominent toxicities. Conversely, it has the convenience of oral administration, and crosses the blood-brain barrier with some evidence of efficacy in treating brain metastases,¹³ which develop in up to one third of patients with H2MBC. There are perhaps also some differences in cardiotoxicity, which may need to be considered.

The current dichotomous dilemma of switching to lapatinib or continuing trastuzumab is about to get much more complicated if the current body of clinical investigation is any guide to the future. With preliminary evidence of activity for newer compounds such as pertuzumab,¹⁴ trastuzumab-DM1 (T-DM1),^15,16 tanespimycin,¹⁷ everolimus,¹⁸ and antiangiogenic strategies¹⁹ (some of which have entered phase III testing), we will struggle with the appropriate sequencing and combinations of these interventions. It bodes well for our patients to have an expanding menu of options, but it also puts the onus on us to use them judiciously. Given that the vast majority of patients with H2MBC develop progressive disease, we need to not only develop a better understanding of mechanisms of resistance but to also find ways to individualize therapy. Several potential mechanisms of resistance are being explored, including alterations in the PI3-kinase pathway, phosphatase and tensin homologue (PTEN), insulin-like growth factor 1 receptor (IGF-1R), and truncated HER-2 receptor. A lot more work will need to be done before the practitioners can apply this knowledge in clinical decision making. Until then, we should maximize our efforts to support the current ongoing trials as they struggle to meet their accrual goals.

AUTHOR'S DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

Although all authors completed the disclosure declaration, the following author(s) indicated a financial or other interest that is relevant to the subject matter under consideration in this article. Certain relationships marked with a "U" are those for which no compensation was received; those relationships marked with a "C" were compensated. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors.

Employment or Leadership Position: None Consultant or Advisory Role: Mohammad Jahanzeb, GlaxoSmithKline (C), Genetech BioOncology (U) Stock Ownership: None Honoraria: Mohammad Jahanzeb, GlaxoSmithKline, Genetech BioOncology, Roche Research Funding: Mohammad Jahanzeb, Genetech BioOncology Expert Testimony: None Other Remuneration: None

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