2009 San Antonio Breast Cancer Symposium: Potentially Practice-Changing Studies, Pt 2

[Hopeful]

2010 Feb 18, Lee Schwartzberg, MD, Editor-in-Chief

The 32nd San Antonio Breast Cancer Symposium, held December 9−13, 2009, brought together more than 8000 clinicians, scientists, medical oncologists, surgeons, and radiation oncologists, as well as professionals from a host of other disciplines, to hear several hundred oral and poster presentations on every aspect of breast cancer. Of the many important studies presented, some of the potentially practice-changing trials are summarized in this commentary.

Part I, posted previously, reviewed highlights of adjuvant hormonal therapy, hormonal therapy for metastatic disease, and bone-related issues.

Part II, presented here, reviews biologic therapy, particularly antiangiogenic therapy and anti-HER2 therapy in breast cancer.

Antiangiogenic Therapy in Metastatic Breast Cancer

A very active area of breast cancer research involves the addition of antiangiogenic therapy to chemotherapy. The ECOG E2100 trial firmly established the benefit of adding bevacizumab to paclitaxel in the first-line setting, reporting a near-doubling of progression-free survival (PFS), although there was no improvement in overall survival (OS).¹ At the 2009 annual meeting of the American Society of Clinical Oncology (ASCO), further evidence supporting the use of bevacizumab with other chemotherapeutic agents was established in the RIBBON-1 trial.² Such data led to the Food and Drug Administration’s approval of the use of bevacizumab with chemotherapy, and to its widespread use in the first-line setting.

Many questions remain, however, regarding the use of antiangiogenic agents in breast cancer, including the applicability of bevacizumab beyond the first line. To begin to address these questions, an entire oral session at San Antonio was devoted to trial results exploring antiangiogenic therapy.

Bevacizumab

An update of the AVADO trial, a randomized trial in which bevacizumab was added to docetaxel in first-line treatment of metastatic breast cancer, was presented at this session.³ This study evaluated 2 different doses of bevacizumab (7.5 and 15 mg/kg), compared with placebo, added to full-dose docetaxel (100 mg/m²) in patients with HER2-negative, untreated metastatic breast cancer. The overall response rate (ORR) was significantly higher for patients receiving bevacizumab 15 mg/kg than for those receiving docetaxel alone (64.1% vs 46.4%; P = .0003). PFS was 8.1 months for placebo, 9.0 months for bevacizumab 7.5 mg/kg, and 10 months for bevacizumab 15 mg/kg (hazard ratio [HR] = .67; P = .0002). Although the 1-year survival rate was significantly higher for bevacizumab 15 mg/kg vs placebo (84% vs 76%), there was no difference in median OS: 31.9 months for docetaxel and 30.8 and 30.2 months for bevacizumab 7.5 and 15 mg/kg, respectively. Adverse events (AEs), particularly neutropenia and thrombocytopenia, were modestly increased by bevacizumab, although the rate of venous thromboembolism (VTE) was actually lower in the bevacizumab arms.

The RIBBON-2 study was presented by Brufsky and colleagues.⁴ The study involved HER2-negative patients and those with unknown HER2 status who were being treated in the second-line setting without prior exposure to bevacizumab. The patients were randomized to chemotherapy (choice of paclitaxel, docetaxel, gemcitabine, capecitabine, or vinorelbine) plus placebo or to chemotherapy plus bevacizumab 15 mg/kg. The primary endpoint, an improvement in PFS was met, with bevacizumab improving PFS to 7.2 months vs 5.1 months for chemotherapy plus placebo (P = .007). However, there was no improvement in OS (18.0 vs 16.4 months for bevacizumab vs placebo). ORR increased from 29.6% to 39.5% with the addition of bevacizumab (P = .02).

Serious AEs occurred in 24% of bevacizumab-treated patients vs 17% of placebo patients and mostly consisted of neutropenia, hypertension, proteinuria, and bleeding in a small number of patients.

Comment on bevacizumab

These studies add to the accumulated knowledge of bevacizumab’s place in the treatment of metastatic breast cancer. The strength of evidence now firmly supports the addition of bevacizumab to chemotherapy in the first- and second-line settings, essentially regardless of the agent selected. This suggests that the mechanism of bevacizumab is relatively independent of the chemotherapy mechanism. With 3 randomized trials completed, it appears clear that the benefit of bevacizumab is confined to response rate and PFS, with no impact on OS. There are several reasons for this, including, most likely, a dilution of benefit when multiple, other active lines of treatment are added after bevacizumab failure. However, the possibility of tumor rebound upon withdrawal of antiangiogenic therapy cannot be completely discounted. More research into the mechanisms of disease progression after treatment with bevacizumab is indicated.

The absolute benefit of bevacizumab in the first-line setting appears to be more modest than initially observed, averaging out to a clinically and statistically significant 2-month improvement in PFS; the early E2100 results now appear to be the outlier. RIBBON-2 supports the use of bevacizumab in the second-line setting, providing patients unexposed to bevacizumab in the first-line setting with a similar improvement in PFS as for those treated first-line, and no alteration in OS. AVADO firmly supports the use of the now-established 15 mg/kg dose of bevacizumab every 3 weeks, rather than a lower dose, to achieve benefit. Whether treatment with bevacizumab should be continued past the progression of breast cancer, as has been suggested in other tumor types, will require further prospective trials for a definitive answer.

Antiangiogenic TKIs

A host of small-molecule antiangiogenic tyrosine kinase inhibitors (TKIs), which have demonstrated activity in other oncologic settings, are of intense interest in breast cancer. Results of several studies involving multitargeted receptor TKIs were also reported at the special San Antonio session. Sorafenib, a small-molecule TKI inhibiting vascular endothelial growth factor (VEGF) receptors 1 through 3, as well as B-RAF and several other targets, was the subject of 2 interesting reports.

Sorafenib

Baselga et al performed a randomized, phase 2 study evaluating the addition of sorafenib to capecitabine in first- or second-line treatment of metastatic breast cancer.⁵ This all-oral regimen yielded a significant improvement in median PFS, from 4.1 months to 6.4 months (HR = 0.576; P = .0006), but no significant increase in response rate. Subgroup analysis demonstrated benefit from sorafenib in all prespecified subgroups. Additionally, both first- and second-line patients had a significant improvement in PFS, which was particularly striking in the first-line patients, in whom median PFS improved by 3.5 months. The addition of sorafenib to capecitabine increased the incidence of hand-foot syndrome, as expected, since this toxicity occurs commonly with both drugs. The incidence of grade 3 hand-foot syndrome was 45% for capecitabine plus sorafenib, compared with 13% for capecitabine alone. Other grade 3 toxicities, including diarrhea, were similar in incidence in both arms. These promising phase II findings are the foundation for a phase III trial, which will soon be launched.

A similarly designed trial employing weekly paclitaxel in the same schedule as used in E2100, with addition of sorafenib or placebo in the first-line setting, was reported by Gradishar et al.⁶ (Disclosure: I am an author on this abstract.) This phase II study was conducted multinationally and included sites in the United States, Brazil, and India. There was a trend toward an improvement in PFS, the primary endpoint, from 5.6 months with placebo to 6.9 months with sorafenib (HR = 0.79; P = .0857). ORR was significantly increased, and a prespecified secondary endpoint of time to progression was also significantly increased, from 5.6 months with placebo to 8.1 months with sorafenib (HR = 0.67; P = .0171).

Again, hand-foot syndrome was the major toxicity associated with the combination, occurring in 30% of patients receiving paclitaxel plus sorafenib compared with 3% of those receiving paclitaxel alone. Grade 3 to 4 neutropenia and anemia were seen more often in the combination arm, but there was no difference in the incidence of neuropathy between the arms. In the paclitaxel plus sorafenib group, 16 deaths were reported during the study, compared with 4 deaths in the placebo arm. Many of these deaths occurred in Indian patients, and the causes were somewhat unusual by Western standards, as they included tuberculosis, meningitis, and malaria.

Together, these studies suggest that clinically meaningful benefit is obtained from adding sorafenib to chemotherapy in breast cancer. Additional phase II trials evaluating sorafenib with chemotherapy in other breast cancer settings are being performed and will be reported in the future.

Sunitinib

Another small-molecule TKI, sunitinib, is also being actively investigated in breast cancer. Reported this year at San Antonio were results of a study comparing single-agent sunitinib with capecitabine in taxane- and anthracycline-resistant metastatic breast cancer.⁷ In this phase III global trial, the primary endpoint, PFS, was shorter with sunitinib than with capecitabine (2.8 months vs 4.2 months; HR = 1.47; P < .001). The response rate and clinical benefit rate were better in the control arm. Sunitinib was more toxic, causing grade 3 to 4 neutropenia, thrombocytopenia, and fatigue at higher rates than with capecitabine; capecitabine increased the risk of grade 3 to 4 hand-foot syndrome. Based on these findings of reduced efficacy and increased toxicity, it is unlikely that sunitinib as a single agent will be explored further in breast cancer.

A different study design was employed for a randomized, phase II-b trial exploring the addition of motesanib to paclitaxel. Motesanib is another multitargeted small-molecule TKI demonstrating activity against VEGF and other kinases.⁸ In this trial, paclitaxel for 3 out of 4 weeks plus placebo was compared with paclitaxel plus motesanib or with paclitaxel plus bevacizumab in a 3-arm trial. The primary endpoint, an improvement in response rate for motesanib plus paclitaxel over that for placebo plus paclitaxel, was not realized (P = 0.31), although, numerically, the response rate with motesanib was higher (49% vs 41%). Median PFS was 9.5 months for motesanib compared with 9.0 months for placebo and 11.5 months for bevacizumab.

Motesanib was associated with an increased rate of severe toxicity, compared with the toxicity rates for either placebo or bevacizumab, particularly with regard to diarrhea, hypertension, and a unique toxicity consisting of hepatobiliary disorder and/or abdominal pain; bevacizumab was associated with an increase in peripheral sensory neuropathy. The hepatobiliary toxicity was primarily cholecystitis with gallbladder enlargement requiring surgery. This appears to be an agent-specific effect, and it has been observed also in other disease settings during treatment with motesanib. Both motesanib and bevacizumab were associated with similar rates of treatment delay due to AEs.

Comment on antiangiogenic therapy

In summary, the use of antiangiogenic therapy in metastatic breast cancer is well established. Bevacizumab demonstrates activity in both the first- and second-line settings, manifested as significant improvement in PFS. Somewhat disappointingly, bevacizumab did not provide an OS advantage in any of the several completed studies. However, the benefit of bevacizumab appears to extend across multiple chemotherapeutic agents in breast cancer.
The situation is not yet clarified for small-molecule antiangiogenic TKIs. Single-agent therapy, as evidenced by the sunitinib trial, is not likely to be a fruitful clinical development pathway for any of these agents. This is similar to the situation for single-agent bevacizumab. Based on the findings to date, sorafenib is the most promising TKI, as it produced a clear-cut PFS benefit in one study and a trend toward benefit in another. Nonetheless, the hand-foot syndrome toxicity associated with this drug must be considered. Further studies, ongoing and planned, will determine the ultimate worth of sorafenib in breast cancer.

Anti-HER2 Therapy

Anti−HER2-directed therapy has transformed the treatment of HER2-positive breast cancer, and its use is well established in both the metastatic and adjuvant settings. Nonetheless, despite a decade of experience, many questions remain regarding the treatment of HER2-positive disease. This year’s San Antonio conference shed important light on a number of those questions.

In the metastatic setting, there are 2 approved anti−HER2-targeted agents: trastuzumab, a monoclonal antibody directed against the extracellular-domain HER2, and lapatinib, a small-molecule TKI that is a dual inhibitor of both epithelial growth factor receptor (EGFR) and HER2 that is directed against an intracellular-binding domain.

Trastuzumab and lapatinib in metastatic disease

One of the most important presentations at San Antonio was a report of the final results of a trial comparing single-agent lapatinib against the combination of lapatinib plus trastuzumab in heavily pretreated, trastuzumab-refractory, HER2-positive patients.⁹ These patients had received a median of 3 trastuzumab-containing regimens for metastatic breast cancer, and a third of the patients had received at least 6 prior regimens. The updated report concerned the secondary endpoint of OS, which was significantly prolonged in the combination arm to 14.0 months, from 9.5 months for lapatinib alone (HR = 0.74; P = .026). After adjustment for baseline factors, lapatinib plus trastuzumab improved OS by 29%. In a multivariate analysis, significant factors for improved OS were combination therapy, ECOG performance status of 0, nonvisceral disease, <3 metastatic sites, and longer time from initial diagnosis to randomization. AEs were modest in both arms, with no difference in incidence between treatments. Cardiac events occurred more commonly in the combination arm, but the overall rate was <10%.

This study proves the worth of continued HER2 blockade even in the setting of highly advanced disease. Blocking HER2 molecules both extracellularly and intracellularly yielded a remarkable clinical benefit. Combination anti-HER2 therapy is the focus of a large adjuvant trial, the Adjuvant Lapatinib And/Or Trastuzumab Treatment Optimisation trial (ALLTO), currently being conducted globally.

Trastuzumab has markedly improved the outcome of many patients with HER2-positive breast cancer. Yet some patients do not respond to it, and all ultimately progress. Can trastuzumab be improved upon? Trastuzumab-DM1 (T-DM1) is an antibody drug conjugate coupling the trastuzumab molecule to a highly toxic small molecule. The concept is to use trastuzumab as a targeting agent, which can then deliver the toxin intracellularly to HER2-positive cells specifically without incurring systemic toxicity. This strategy improves the therapeutic index of an agent that would otherwise be difficult to use in its native state.

Previous phase I studies of T-DM1 established a tolerable dose and showed promising activity. Results of a phase II trial of single-agent T-DM1 were presented at San Antonio. All of the participants were heavily pretreated patients with prior exposure to adriamycin, taxanes, cyclophosphamide, and trastuzumab and with good ECOG performance status.¹⁰ A response rate of 30% and a clinical benefit rate of 40% were reported; PFS was 7.3 months. The most frequently occurring AEs were fatigue, nausea, and thrombocytopenia, but the incidence of grade 3 to 4 toxicity was modest, with only thrombocytopenia being observed at a rate >5%. These encouraging results will serve as a reference for phase III trials investigating T-DM1 in less heavily pretreated patients.

Adjuvant treatment of HER2-positive disease

Considerable debate has arisen regarding the adjuvant treatment of HER2-positive breast cancer and whether to use anthracycline-containing regimens plus trastuzumab or move to a non−anthracycline-containing program, which reduces the synergistic cardiotoxicity of anthracyclines and trastuzumab. Consequently, presentation of the results of the third planned analysis of BCIRG 006, presented by Slamon et al at San Antonio, was eagerly awaited.¹¹ This study compared docetaxel, carboplatin, and trastuzumab (TCH) against a standard regimen of doxorubicin and cyclophosphamide (AC) followed by taxotere plus trastuzumab (AC-TH) and against a nontrastuzumab arm (AC-T).

The longer-term follow-up of this trial, now at a median of 65 months, confirmed again the benefit of adding trastuzumab in HER2-positive patients. The 5-year DFS rate was 75% for AC-T, 84% for AC-TH, and 81% for TCH. Benefit was seen for both node-positive and node-negative patients, although only AC-TH was superior in node-negative patients. The 5-year OS rate was 87% for AC-T, 92% for AC-TH, and 91% for TCH. TCH-treated patients generally experienced less toxicity than did those treated with AC-T or AC-TH; they specifically experienced a lower incidence overall of myalgia, nail changes, and neuropathy, and a lower incidence of grade 3 vomiting, myalgias, stomatitis, arthralgias, and hand-foot syndrome. With AC-TH, the rate of severe cardiac toxicity was significantly higher than with the other regimens, although absolute numbers of patients affected were small, amounting to <1%.

The investigators for the BCIRG 06 study looked carefully at the expression of topoisomerase 2 in these cancers, since this enzyme is often coamplified along with HER2, based on its proximity to HER2 on chromosome 17 and the fact that it is the putative target for anthracyclines. Approximately 35% of patients in BCIRG 06 had coamplification of topoisomerase 2, along with HER2. In the group in which there was no coamplification, there was a strong benefit for the addition of trastuzumab to chemotherapy (AC-TH: HR = 0.53; P < .001; TCH: HR = 0.61; P < .001). In contrast, in the coamplified subgroup, AC-T yielded similar benefit as with the trastuzumab-containing regimens (AC-TH: HR = 0.9; TCH: HR = 1.2), raising the question of whether anti-HER2 therapy is necessary when topoisomerase 2 is amplified.

These results leave open the question of using anthracyclines in HER2-positive breast cancer, since the results are numerically better for the anthracycline-containing regimen. Certainly, TCH remains an option in the treatment of HER2-positive breast cancer and might be particularly useful in node-positive patients and in those who are predisposed to cardiac events.

Another unanswered question in the adjuvant setting is whether to administer trastuzumab together with chemotherapy or whether to deliver it sequentially after chemotherapy is completed. The intergroup study N9831 had previously reported a large benefit associated with combination taxane plus trastuzumab given after anthracycline and cyclophosphamide. This year’s report added long-term follow-up data (median, 5.5 years in the sequential arm) and the results for the first planned comparison of sequential trastuzumab (AC-T-H) vs concurrent trastuzumab (AC-TH).¹² Sequential trastuzumab improved DFS by one-third (HR = 0.67; P < .0001). DFS was longer with concurrent trastuzumab than without trastuzumab (HR = 0.77), although the P-value of .019 did not cross the prespecified boundary for significance. The 5-year DFS rate was 71.9% for AC-T, 80% for AC-T-H, and 84.2% for AC-TH. OS at 5 years was not significantly different, however, between AC-T and AC-T-H.

Comment on anti-HER2 therapy

These findings suggest that trastuzumab should be administered along with taxanes when given as part of an adjuvant, sequential regimen of doxorubicin and cyclophosphamide followed by taxane. The longer follow-up time of both the BCIRG 06 and the N9831 trials has revealed a somewhat reduced benefit from trastuzumab as compared with the benefit initially reported. Nonetheless, adjuvant anti-HER2 therapy remains a critically important part of the treatment of both node-negative and node-positive HER2-positive breast cancer.

Conclusions

In the metastatic setting, the use of antiangiogenic agents is growing, and the role of bevacizumab is firmly established. Newer TKIs, particularly sorafenib, hold some promise, although more trials are needed to establish the worth of this class of agent. For HER2-positive tumors, combined HER2 blockade is now established as a new clinical treatment paradigm. This foundation offers a platform from which to conduct a variety of studies in an attempt to improve on the already impressive results from HER2 blockade. The best chemotherapy partners for trastuzumab as adjuvant treatment remain debatable, but concurrent use of chemotherapy and trastuzumab appears to be superior to sequential therapy.

By presenting the results of some practice-changing trials and an explosion of new biologic data, San Antonio 2009 again challenges us to apply the lessons of the laboratory in the clinic. Thankfully, the success rate of translational therapy is increasing, and the future of breast cancer treatment appears promising indeed.

References

1. Miller K, Wang M, Gralow J, et al. Paclitaxel plus bevacizumab versus paclitaxel alone for metastatic breast cancer. N Engl J Med. 2007; 357(26):2666-2676.
2. Robert NJ, Dieras V, Glaspy J, et al. RIBBON-1: Randomized double-blind, placebo-controlled, phase III trial of chemotherapy with or without bevacizumab (B) for first-line treatment of HER2-negative locally recurrent or metastatic breast cancer (MBC). J Clin Oncol. 2009;27(15 suppl):abstract 1005.
3. Miles D, Chan A, Romieu G, et al. Final overall survival results from the randomized, double-blind, placebo-controlled, phase III AVADO study of bevacizumab plus docetaxel compared with placebo plus docetaxel for the first-line treatment of locally recurrent or metastatic breast cancer. Program and abstracts of the 32nd Annual San Antonio Breast Cancer Symposium; December 9-13, 2009; San Antonio, Texas. Abstract 41.
4. Brufsky A, Bondarenko I, Smirnov V, et al. RIBBON-2: a randomized, double-blind, placebo-controlled phase III trial evaluating the efficacy and safety of bevacizumab in combination with chemotherapy for second-line treatment of HER2-negative metastatic breast cancer. Program and abstracts of the 32nd Annual San Antonio Breast Cancer Symposium; December 9-13, 2009; San Antonio, Texas. Abstract 42.
5. Baselga J, Grupo Español de Estudio Tratamiento y Otras Experimentales en Tumores Sólidos, Roché H, et al. SOLTI-0701: a multinational double-blind, randomized phase 2b study evaluating the efficacy and safety of sorafenib compared to placebo when administered in combination with capecitabine in patients with locally advanced or metastatic breast cancer (BC). Program and abstracts of the 32nd Annual San Antonio Breast Cancer Symposium; December 9-13, 2009; San Antonio, Texas. Abstract 45.
6. Gradishar W, Kaklamani V, Prasad Sahoo T, et al. A double-blind, randomized placebo-controlled, phase 2b study evaluating the efficacy and safety of sorafenib in combination with paclitaxel as a first-line therapy in patients with locally recurrent or metastatic breast cancer. Program and abstracts of the 32nd Annual San Antonio Breast Cancer Symposium; December 9-13, 2009; San Antonio, Texas. Abstract 44.
7. Barrios C, Liu M, Lee S, et al. Phase III randomized trial of sunitinib (SU) vs. capecitabine (C) in patients (pts) with previously treated HER2-negative advanced breast cancer. Program and abstracts of the 32nd Annual San Antonio Breast Cancer Symposium; December 9-13, 2009; San Antonio, Texas. Abstract 46.
8. Mackey J, Hurvits S, Crown J, et al. CIRG/TORI 010: 10-month analysis of a randomized phase II trial of motesanib plus weekly paclitaxel as first line therapy in HER2-negative metastatic breast cancer (MBC). Program and abstracts of the 32nd Annual San Antonio Breast Cancer Symposium; December 9-13, 2009; San Antonio, Texas. Abstract 47.
9. Blackwell K, Burstein H, Sledge G, et al. Updated survival analysis of a randomized study of lapatinib alone or in combination with trastuzumab in women with HER2-positive metastatic breast cancer progressing on trastuzumab therapy. Program and abstracts of the 32nd Annual San Antonio Breast Cancer Symposium; December 9-13, 2009; San Antonio, Texas. Abstract 61.
10. Krop I, LoRusso P, Miller K, et al. A phase II study of trastuzumab-DMI (T-DM1), a novel HER2 antibody-drug conjugate, in patients previously treated with lapatinib, trastuzumab, and chemotherapy. Program and abstracts of the 32nd Annual San Antonio Breast Cancer Symposium; December 9-13, 2009; San Antonio, Texas. Abstract 5090.
11. Slamon D, Eiermann W, Robert N, et al. Phase III randomized trial comparing doxorubicin and cyclophosphamide followed by docetaxel (AC→T) with doxorubicin and cyclophosphamide followed by docetaxel and trastuzumab (AC→TH) with docetaxel, carboplatin and trastuzumab (TCH) in HER2neu positive early breast cancer patients: BCIRG 006 Study. Program and abstracts of the 32nd Annual San Antonio Breast Cancer Symposium; December 9-13, 2009; San Antonio, Texas. Abstract 62.
12. Perez E, Suman V, Davidson N, et al. Results of chemotherapy alone, with sequential or concurrent addition of 52 weeks of trastuzumab in the NCCTG N9831 HER2-positive Adjuvant Breast Cancer Trial. Program and abstracts of the 32nd Annual San Antonio Breast Cancer Symposium; December 9-13, 2009; San Antonio, Texas. Abstract 80.

Hopeful