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1 Interviews are based on data presented at the 2012 American Society of Clinical Oncology Annual Meeting, June 1-5, 2012, Chicago, Illinois* *PeerVoice is an independent publisher of conference news and medical education programmes. The following is a transcript from a multimedia activity, which may be found at: Note: This is a downloadable version of a Web-based presentation. Programme interactivity only applies when viewing the activity online. Featured Presentations Setting the Neoadjuvant Stage for Patients With Breast Cancer: What Are the Benefits of Combination Therapy? Antonio Llombart, MD Fundacion Instituto Valenciano de Oncologia Valencia, Spain Novel Therapeutic Approaches for Triple-Negative Breast Cancer: What Do the Data Tell Us So Far? Joyce O Shaughnessy, MD Baylor-Sammons Cancer Center Texas Oncology and US Oncology Dallas, Texas, USA A Fresh Look at First-Line Taxane-Containing Combination Therapies for HER2-Negative Metastatic Breast Cancer Prof. Xichun Hu, PhD Fudan University Shanghai Cancer Center Shanghai, China This activity is supported by an educational grant from Celgene International Sàrl. Go online to participate in this activity:

2 Presentation 1 Slide 1 Dr. Llombart: Hello, my name is Antonio Llombart. Welcome to this PeerVoice educational activity on breast cancer. Narrator: Throughout this activity, you will be asked to answer several PeerVoice Challenge Questions. Your answer selection will be compared with your peers responses, and when appropriate, the best answer will be discussed in the subsequent slides and commentary. This activity comprises 3 separate presentations highlighting data from the American Society of Clinical Oncology 2012 Annual Meeting. To download this activity's audio, transcripts, and slides, click the downloadable icons shown below. These presentations are available in English and Chinese. Please select the Languages menu on the right. Go online to participate in this activity: 2

3 Presentation 1 Slide 2 Dr. Llombart: It s clear that neoadjuvant therapy for early breast cancer has taken on great importance in breast cancer research over the last several years. Our best advances have been in patients with HER2-positive disease, whereas HER2-negative disease and particularly triple-negative breast cancer remain difficult to treat. New data presented at the American Society of Clinical Oncology s 2012 Annual Meeting explore some advances in the neoadjuvant setting. Go online to participate in this activity: 3

4 Presentation 1 Slide 3 A: doxorubicin; C: cyclophosphamide; HER2: human epidermal growth factor receptor 2; HR: hormone receptor; L: lapatinib; NSABP: National Surgical Adjuvant Breast and Bowel Project; pcr: pathological complete response; T: paclitaxel; TZ; trastuzumab. Robidoux A et al. American Society of Clinical Oncology 2012 Annual Meeting (ASCO 2012). Abstract LBA506. Dr. Llombart: First, I d like to present the NSABP B-41 study. The trial analysed the value of adding lapatinib to trastuzumab for HER2-positive locally advanced breast cancer. Interestingly in this trial, we didn t find any difference in terms of pathological complete remission between the lapatinib and the trastuzumab [treatment] arms. The combination of lapatinib with standard chemotherapy increased the pathological complete response rate, but just by 10% to 12%, not being statistically significant. Go online to participate in this activity: 4

5 Presentation 1 Slide 4 D: docetaxel; DFS: disease-free survival; P: pemetrexed. Schneeweiss A et al. ASCO Abstract Schneeweiss A et al. Ann Oncol. 2011;22: Dr. Llombart: [Next] I d like to present this randomised phase 2 study from Schneeweiss and colleagues that compares 2 similar regimens that substitute cyclophosphamide for pemetrexed in one of the treatment arms. Preliminary findings from this study were published 2 years ago, wherein the authors found that the cyclophosphamide-containing regimen had a higher pathological complete response rate in hormone-receptor negative tumours, but the pemetrexed-containing regimen had more activity in the hormone-receptor positive population. An interesting finding at ASCO was that the 3-year disease-free survival followed a similar trend. Although the trial was not powered to detect differences in disease-free survival, this supports the notion that cyclophosphamide can be a beneficial drug in the neoadjuvant setting, particularly for triple-negative breast cancer, whereas pemetrexed may be better suited in the hormone-receptor positive setting. Go online to participate in this activity: 5

6 Presentation 1 Slide 5 CT: chemotherapy; E: epirubicin; ER: oestrogen receptor; MDARCB: MD Anderson residual cancer burden (RCB); MRI: magnetic resonance imaging; NAX: vinorelbine (V) / bevacizumab (B) / C; NTX: V / TZ / C; PR: progesterone receptor; TNBC: triple-negative breast cancer. Albino ME et al. ASCO Abstract Dr. Llombart: Another phase 2 study of neoadjuvant chemotherapy by Albino and colleagues has explored a very aggressive approach with the combination of docetaxel, epirubicin, and cyclophosphamide. And following the fourth cycle, and depending on the response, the patients could be switched to alternate regimens in the absence of complete clinical response. Here, it s interesting to see that there is a significant trend towards a higher rate of pathological responders for the triple-negative and HER2-positive phenotypes. And these populations are the ones that tend to have higher KI-67 scores, suggesting that KI-67 and receptor status are good markers for response to chemotherapy in these patient types. Go online to participate in this activity: 6

7 Presentation 1 Slide 6 AE: adverse event; Cb: carboplatin; ccr: clinical complete response; cpr: clinical partial response; dd: dose-dense; nt: albumin-bound (or nab-)paclitaxel. Faye Sinclair N et al. ASCO Abstract Dr. Llombart: There was a presentation at ASCO concerning bevacizumab with 2 different regimens of neoadjuvant chemotherapy. Faye and coworkers presented their study in which they combined bevacizumab with nab-paclitaxel and carboplatin with or without AC, and the complete response achieved in triple-negative patients was always greater than 80%. Dr. O Shaughnessy will also take a look at this study when she explores the key ASCO abstracts for triple-negative breast cancer. There are additional studies evaluating nab-paclitaxel with bevacizumab and carboplatin alone or followed by AC the hypothesis being that this combination will have a higher pathological complete response that leads to an improved disease-free survival. This is interesting to see at a time when bevacizumab has been so strongly criticised. Go online to participate in this activity: 7

8 Presentation 1 Slide 7 Go online to participate in this activity: 8

9 Presentation 1 Slide 8 LABC: locally advanced breast cancer. Tan R et al. ASCO Abstract Dr. Llombart: Another exploratory study presented was the NSABP FB-6 study, which consisted of single-arm therapy, introducing pazopanib in combination with weekly paclitaxel following AC as neoadjuvant therapy. Although the pathological complete remission rate was low in the triple-negative subgroup, the toxicity profile seems reasonable. Therefore, I think that this is a regimen that could continue to be explored mostly in the triple-negative population. Go online to participate in this activity: 9

10 Presentation 1 Slide 9 Shinde AM et al. ASCO Abstract Dr. Llombart: Finally, a retrospective review study by Shinde and colleagues looked at a popular regimen used in the US for the neoadjuvant setting: The combination of carboplatin and paclitaxel. The study was small, but the results did show that the hormone-receptor negative populations had high response rates that ranged from 70% to 100%. This should be explored further in the triple-negative population, wherein high response rates could translate into increased disease-free or overall survival. Go online to participate in this activity: 10

11 Presentation 1 Slide 10 Go online to participate in this activity: 11

12 Presentation 1 Slide 11 Dr. Llombart: So, in conclusion, at ASCO this year, these data evaluating therapeutic strategies in the neoadjuvant setting increase our knowledge about how to manage patients in this therapeutic setting. Because patients are generally only receiving 6 to 8 cycles in the neoadjuvant setting, for the most part, the acute toxicities aren t a major concern; so we really focus on the efficacies of these new treatments, which show promise in combination regimens. Triple-negative breast cancer represents an important patient population that can possibly benefit from neoadjuvant therapy. However, we will need more advanced trial data to be able to confirm benefit in terms of pathological complete response, especially when looking ahead to adjuvant or metastatic first-line treatment options. Go online to participate in this activity: 12

13 Presentation 2 Slide 1 Narrator: Here, Dr. Joyce O Shaughnessy takes a closer look at novel combination therapies for triple-negative breast cancer (TNBC), both in the neoadjuvant and adjuvant setting. Dr. O Shaughnessy: Triple-negative breast cancer accounts for about 15% of all breast cancers, and when it recurs as metastatic triple-negative breast cancer, it s associated with a very poor prognosis. I m going to be reviewing novel therapeutic approaches for triple-negative breast cancer from ASCO 2012 and I ll try to address some factors to be clarified in determining which patients with triple-negative breast cancer should receive which therapies. I think where we are with triple-negative breast cancer at this time is that we are doing pilot studies in the neoadjuvant setting, looking for important hypotheses that are worthy of taking into the metastatic or adjuvant setting. Go online to participate in this activity: 13

14 Presentation 2 Slide 2 A: doxorubicin; AE: adverse event; B: bevacizumab; C: cyclophosphamide; Cb: carboplatin; dd: dose-dense; ER: oestrogen receptor; HER2: human epidermal growth factor receptor 2; nt: albumin-bound (or nab-)paclitaxel; pcr: pathological complete response; RBC: residual cancer burden; TNBC: triple-negative breast cancer. Faye Sinclair N et al. American Society of Clinical Oncology 2012 Annual Meeting (ASCO 2012). Abstract von Minckwitz G et al. N Engl J Med. 2012;366: Dr. O Shaughnessy: An interesting abstract from ASCO that looked at the triple-negative population was by Faye and colleagues, and looked at administering neoadjuvant weekly nab-paclitaxel plus carboplatin with or without bevacizumab in patients with ER-positive/HER2-negative and triple-negative breast cancer. This was a small study; however, it is intriguing in suggesting a higher pathological complete response rate in the triple-negative population with the addition of bevacizumab. This is in keeping with the published GeparQuinto trial, so we do have studies now showing the improvement in pathological complete response rates with bevacizumab added to chemotherapy preoperatively in the triple-negative population. Go online to participate in this activity: 14

15 Presentation 2 Slide 3 ccr: clinical complete response; cpr: clinical partial response; D: docetaxel; EGFR: epidermal growth factor receptor; CEF: C / epirubicin (E) / 5-fluorouracil (5-FU); PD: progressive disease; SD: stable disease. Nabholtz JM et al. ASCO Abstract Carey LA et al. J Clin Oncol. 2008;26(15S):1009. Dr. O Shaughnessy: At ASCO this year, we saw a very interesting trial by Nabholtz and colleagues for a phase 2, neoadjuvant anti-egfr therapy strategy for triple-negative breast cancer. This was for a combination of the anti-egfr monoclonal antibody panitumumab plus FEC 100 followed by docetaxel. The pathological response rate was about 50% in this population, with patients with higher KI-67s having a higher chance of achieving a pathological complete response rate. A low staining for EGFR, high p53, and high cytokeratine 5-6 staining tended to be associated with a poor response. This study is very interesting because it does suggest that there may be a subset of triple-negative breast cancer patients who may particularly benefit from an anti-egfr therapy strategy. This is in keeping with a study that Lisa Carey and I presented, suggesting, indeed, that in metastatic triple-negative breast cancer patients, there was a subgroup that benefited from IV cetuximab antibody in combination with a platinum-based regimen. Go online to participate in this activity: 15

16 Presentation 2 Slide 4 Go online to participate in this activity: 16

17 Presentation 2 Slide 5 I: iniparib; T: paclitaxel. Llombart A et al. ASCO Abstract O Shaughnessy J et al. N Engl J Med. 2011;364: Dr. O Shaughnessy: Llombart and colleagues brought an interesting SOLTI neoadjuvant trial to ASCO this year. This was a randomised, phase 2 study of two schedules of the IV inhibitor iniparib which is no longer felt to be a PARP inhibitor, but does lead to double-strand DNA breakage and interferes with DNA repair. And iniparib was put in combination with paclitaxel IV preoperatively versus paclitaxel alone in patients with triple-negative breast cancer. So there were not big differences with iniparib with regard to pathological complete response with paclitaxel in the triple-negative population. We need larger numbers, certainly, particularly in the metastatic setting, to look at the combination of paclitaxel with iniparib. Iniparib in combination with DNA-damaging agents may be more interesting at this time, and we await further data from Dr. Telli from Stanford who has looked at gemcitabine-carboplatin together with iniparib in the preoperative setting in triple-negative breast cancer. Go online to participate in this activity: 17

18 Presentation 2 Slide 6 CMF: C / methotrexate (M) / 5-FU; CT: chemotherapy; OS: overall survival. Hur MH et al. ASCO Abstract Cheang M et al. J Clin Oncol. 2009;27(15S):519. Dr. O Shaughnessy: Looking at adjuvant chemotherapy in triple-negative breast cancer, one study that was quite interesting from ASCO this year was by Hur and colleagues. This was a retrospective review comparing the outcome of triple-negative versus non triple-negative breast cancer patients. Interestingly, about half of the patients had received oral classical CMF as their adjuvant chemotherapy, as opposed to anthracycline-based or taxane-based regimens.. First, the overall survival for the triple-negative breast cancer patients at 5 years was significantly inferior to the non triple-negative breast cancer patients, and then furthermore, there was a significant improvement in outcome, with 5-year overall survival in favour of classical CMF compared to an anthracycline- or taxane-based regimen. Now these data, of course, are retrospective, but they do, in fact, line up with published data, showing no difference in the anthracycline-based versus the CMF regimen with regard to recurrence-free or overall survival, comparing the basal breast cancers to the non-basal breast cancers. So we have a couple of datasets suggesting that oral classical CMF is a reasonable therapy for patients with triple-negative breast cancer. Go online to participate in this activity: 18

19 Presentation 2 Slide 7 Go online to participate in this activity: 19

20 Presentation 2 Slide 8 Dr. O Shaughnessy: So in summary, what we saw at ASCO this year, with regard to the treatment of triple-negative breast cancer, is that the bevacizumab hypothesis, the anti-egfr hypothesis, as well as focusing on platinum-based regimens (perhaps with other DNA-damaging agents in the basal breast cancers), are all important hypotheses, but we need additional data before we move these opportunities into clinical practice. Go online to participate in this activity: 20

21 Presentation 2 Slide 9 Narrator: For more information and resources on breast cancer, please access the educational series webpage at Go online to participate in this activity: 21

22 Presentation 2 Slide 10 Narrator: This has been an educational activity published by PeerVoice. Please click the Evaluation tab to share your thoughts on this activity. Go online to participate in this activity: 22

23 Presentation 3 Slide 1 Dr. Hu: Hello, this is Xichun Hu from the Fudan University Shanghai Cancer Center. Welcome to this PeerVoice educational activity on breast cancer. Throughout this activity, you will be asked to answer several PeerVoice Challenge Questions. Your answer selection will be compared with your peers responses, and when appropriate, the best answer will be discussed in the subsequent slides and commentary. This activity comprises 3 separate presentations highlighting data from the American Society of Clinical Oncology 2012 Annual Meeting. To download this activity's audio, transcripts, and slides, click the downloadable icons shown below. These presentations are available in English and Chinese. Please select the Languages menu on the right. Go online to participate in this activity: 23

24 Presentation 3 Slide 2 Dr. Hu: The previous 2 presentations explored combination chemotherapy for triple-negative breast cancer in the neoadjuvant setting, and in China, combination chemotherapy is also the preferred approach for first-line, HER2-negative metastatic breast cancer. In this presentation, I ll explain the rationale for focusing on taxane-containing combination regimens in this setting, and present to you some new data coming out with novel taxanes. Finally, I will provide my opinions on when and for which patients a combination chemotherapy approach is most beneficial. Go online to participate in this activity: 24

25 Presentation 3 Slide 3 AC: doxorubicin (A) / cyclophosphamide (C); AD: A / docetaxel (D); AT: A / paclitaxel (T); FAC: A / C / 5-fluorouracil (5-FU); GT: gemcitabine (G) / T; HER2: human epidermal growth factor receptor 2; MBC: metastatic breast cancer; OS: overall survival; PFS: progression-free survival; TTP: time to progression; TZ: trastuzumab. 1. Ghersi D et al. Br J Cancer. 2005;93: Chan A et al. Ann Oncol. 2010;21: Dr. Hu: Many studies support an anthracycline- or taxane-based approach in the first-line treatment of metastatic breast cancer, but the evidence seems a little better for a taxane-based approach. A 2005 meta-analysis comparing taxane-containing regimens with non taxane-containing regimens for metastatic breast cancer showed an overall survival benefit for the taxane-containing regimen, with a hazard ratio of Another meta-analysis from 2010 also showed that taxane-containing regimens were more effective than non taxane-containing regimens for increasing the progression-free survival or time to progression. This same meta-analysis further showed that combination therapies with taxanes improve these endpoints as compared with single-agent taxane therapy. But really, we need to Go online to participate in this activity: 25

26 Presentation 3 individualise: If time to recurrence is several years, or if patients have few disease-related symptoms, single-agent chemotherapy may be best. But, if patients have symptomatic visceral metastases, I always recommend combination taxane therapy in the first-line setting; patients with a large tumour burden or extensive skin invasion would also be candidates for first-line combination chemotherapy. In the following slides, we ll address how emerging taxanes for HER2-negative metastatic breast cancer in the first-line setting are faring in phase 2 clinical trials. Go online to participate in this activity: 26

27 Presentation 3 Slide 4 Go online to participate in this activity: 27

28 Presentation 3 Slide 5 Cap: capecitabine; CR: complete response; nt: albumin-bound (or nab-)paclitaxel; PD: progressive disease; PR: partial response; SD: stable disease. Adapted from: Schwartzberg LS et al. Clin Breast Cancer. 2012;12: Dr. Hu: In this first small phase 2 study, the investigators examined albumin-bound, or nab-, paclitaxel in combination with capecitabine. Nab-paclitaxel differs from paclitaxel in its drug delivery method, which allows for a higher concentration in the tumour cells. In addition, it does not require premedication with corticosteroids. The study found a 61% overall response rate; complete response was obtained in 2 patients [4%]. Additionally, the median progression-free survival was 10.6 months and the median overall survival was approximately 20 months. Go online to participate in this activity: 28

29 Presentation 3 Slide 6 NR: not reached; RECIST: Response Evaluation Criteria In Solid Tumours. Based on: Roy V et al. Ann Oncol. 2009;20: Dr. Hu: There has been a second phase 2 study investigating nab-paclitaxel combined with gemcitabine, again in previously untreated HER2-negative patients with metastatic breast cancer. Here, the median duration of response was 6.9 months. And although the median overall survival was not reached, the study did find a median progression-free survival of 7.9 months. Go online to participate in this activity: 29

30 Presentation 3 Slide 7 B: bevacizumab. Adapted from: Lobo C et al. Breast Cancer Res Treat. 2010;123: Dr. Hu: Finally, there has been a third, small phase 2 trial with nab-paclitaxel published, this one with the triplet combination of nab-paclitaxel, gemcitabine, and bevacizumab. Here the median progression-free survival was 10.4 months. The clinical benefit rate was higher in this study at 93.1%. So although these 3 studies were small and caution is warranted when making cross-trial comparisons it is clear that nab-paclitaxel is an effective taxane in combination treatment regimens. Go online to participate in this activity: 30

31 Presentation 3 Slide 8 CT: chemotherapy; ECOG: Eastern Cooperative Oncology Group; PS: performance status. Seidman AD et al. American Society of Clinical Oncology 2012 Annual Meeting (ASCO 2012). Abstract Dr. Hu: Another emerging taxane, tesetaxel, has been investigated for first-line metastatic breast cancer and results from a small phase 2 trial were presented at ASCO Tesetaxel is an oral drug that, like nab-paclitaxel, does not require premedication. This study demonstrated an overall response rate of 45%, and a disease control rate of 82%, with 1 patient achieving complete response. So these preliminary data suggest this agent is also effective in the first-line setting and weekly dosing will be evaluated in a new cohort of patients. Go online to participate in this activity: 31

32 Presentation 3 Slide 9 Go online to participate in this activity: 32

33 Presentation 3 Slide 10 AE: adverse event; HFS: hand-foot syndrome. 1. Schwartzberg LS et al. Clin Breast Cancer. 2012;12: Roy V et al. Ann Oncol. 2009;20: Lobo C et al. Breast Cancer Res Treat. 2010;123: Seidman AD et al. ASCO Abstract Dr. Hu: When considering the safety of the taxanes, all agents can be associated with some common adverse events, such as neutropenia and neurotoxicity. But when combined with other agents, the toxicity profile will change and perhaps even have an additive toxic effect. For instance, when nab-paclitaxel is combined with capecitabine, patients may experience more pain and hand-foot syndrome, whereas its combination with gemcitabine may lead to more neutropenia, fatigue, anaemia, and dyspnoea. And then when nab-paclitaxel is combined with both gemcitabine and bevacizumab, more patients may develop a neutropenic fever, grade 3 infections, or leucopenia or thrombocytopenia. Regarding tesetaxel, it also has some of the common taxane-associated adverse events, such as neutropenia, febrile neutropenia, fatigue, and peripheral neuropathy. And we try to individualise therapy based on these side-effect profiles. Go online to participate in this activity: 33

34 Presentation 3 Slide Schwartzberg LS et al. Clin Breast Cancer. 2012;12: Roy V et al. Ann Oncol. 2009;20: Lobo C et al. Breast Cancer Res Treat. 2010;123: Seidman AD et al. ASCO Abstract Dr. Hu: So in conclusion, when deciding on a taxane-containing combination therapy, emerging agents such as nab-paclitaxel and tesetaxel show potential. From my viewpoint, nab-paclitaxel can replace paclitaxel or docetaxel in any chemotherapeutic doublet. In addition, neither of these agents require premedication with steroids, making them more patient-friendly. Go online to participate in this activity: 34

35 Presentation 3 Slide 12 Dr. Hu: For more information and resources on breast cancer, please access the educational series webpage at Go online to participate in this activity: 35

36 Presentation 3 Slide 13 Dr. Hu: This has been an educational activity published by PeerVoice. Please click the Evaluation tab to share your thoughts on this activity. Go online to participate in this activity: 36