Subtipo triple negativo: debe de ser Nab-Paclitaxel un estándar?

Transcripción

1 Tratamiento: con qué y para quién? Subtipo triple negativo: debe de ser Nab-Paclitaxel un estándar? Miquel Àngel Seguí Palmer

2 Despite a better response to neoadjuvant treatments over non-tnbc tumours, the long-term prognosis of TNBC patients overall is poorer than that of other breast cancer subtypes, particularly in the first 3 years after treatment. Patients achieving pcr have an at least similar survival compared with non-tnbc patients, but survival for TNBC patients with residual disease remains poor in comparison. This paradox may be explained by the presence of residual, resistant disease remaining in the majority of patients (>60%)

3 Long-term outcomes in TNBC. pcr vs. no pcr This suggests that additions or alterations to standard NACT that significantly increase the pcr rate could improve long-term outcomes. Cortazar P, et al. Lancet. 2014

4 Overlap of Triple-Negative, Basal-like, and BRCA1-Mutant Breast Cancers

5 Distribution of clinical groups in the Claudin-low, Basal-like, HER2-enriched, Luminal B, and Luminal A within each subtype Prat A, Perou CM. Mol Oncol. 201

6 Given the association between achievement of a pcr and superior long-term outcomes in TNBC, should the standard neoadjuvant regimen for TNBC be updated to reflect results from trials that report higher pcr rates, or should any revision await demonstration of improvements in recurrence-free or overall survival?

7 Answering this question is especially challenging in TNBC, given its aggressive biology and limited treatment options.

8 While patients with HER2 + disease can benefit from anti-her2 therapy and patients with ER + disease can benefit from endocrine therapy, the only recommended treatment for TNBC is standard chemotherapy; there is no targeted therapy specifically recommended for patients with TNBC. Efforts so far to identify targeted therapy for TNBC have not been successful.

9 Efficacy of neoadjuvant regimens in TNBC Liedtke C, et al. J Clin Oncol 2008

10 Anthracycline/taxane based regimen are standard of care for neoadjuvant therapy in TNBC Nab-paclitaxel is a solvent-free formulation of paclitaxel encapsulated in albumin which might further improve the pcr rate in breast cancer patients receiving neoadjuvant treatment and cause lower toxicity.

11 Untch M, el al. Lancet Oncol. 2016

12 Untch M, el al. Lancet Oncol. 2016

13 276 Untch M, el al. Lancet Oncol. 2016

14 GeparSepto: Primary Endpoint (pcr: ypt0 ypn0) Untch M, el al. Lancet Oncol. 2016

15 GeparSepto: pcr in Stratified Subgroups Untch M, el al. Lancet Oncol. 2016

16 GeparSepto: pcr in TNBC % pcr Overall TNBC PACLITAXEL NAB-PACLITAXEL

17 pcr rates acccording to np dose in TNBC Von Minckwitz G, et al. SABCS 2015

18 GeparSepto: Selected Toxicities Untch M, el al. Lancet Oncol. 2016

19 Time to resolve peripheral sensory neuropathy Von Minckwitz G, et al. SABCS 2015

20 The study met its primary endpoint overall, with an increase in pcr from nab-paclitaxel (OR 1.53; p<0.001); TN subset greatest benefit (OR 2.69). Dose reduction amendment was required. Greater hematologic toxicity and sensory neuropathy. Not clear that the pcr will be enough to translate into DFS and OS benefit, especially taking into account the toxicity differential.

21 Gianni L, el al. ASCO 2016

22 ETNA: Phase III Study of Neoadjuvant nab-paclitaxel vs Paclitaxel Both Followed y Anthra y line in HER2 High-Risk Breast Cancer Gianni L, el al. ASCO 2016

23 ETNA: Phase III Study of Neoadjuvant nab-paclitaxel vs Paclitaxel Both Followed y Anthra y line in HER2 High-Risk Breast Cancer Baseline Characteristics Parameter, n (%) Disease stage Non locally advanced Locally advanced Tumor subtype Luminal B intermediate Luminal B high Triple-negative Median age (range), years Tumor stage ct2 ct3 ct4a - c ct4d Nodal status cn0 cn1 cn2 cn3 P n = 349 nab-p n = 346 Total N = (75) 88 (25) 264 (76) 82 (24) 525 (75.5) 170 (24.5) 50 (14) 189 (54) 49 (14) 188 (54) 99 (14) 377 (54) 110 (31.5) 109 (31.5) 219 (31.5) 50 (25-79) 50 (26-77) 50 (25-79) 245 (70) 76 (22) 18 (5) 8 (2) 258 (75) 56 (16) 24 (7) 7 (2) 503 (72) 132 (19) 42 (6) 15 (2) 167 (48) 153 (44) 29 (8) 6 (2) 181 (52) 138 (40) 27 (8) 8 (2) 348 (50) 291 (42) 56 (8) 14 (2) Gianni L, el al. ASCO 2016

24 ETNA: Phase III Study of Neoadjuvant nab-paclitaxel vs Paclitaxel Both Followed y Anthra y line in HER2 High-Risk Breast Cancer Primary End-Point: pcr rate Gianni L, el al. ASCO 2016

25 ETNA: Phase III Study of Neoadjuvant nab-paclitaxel vs Paclitaxel Both Followed y Anthra y line in HER2 High-Risk Breast Cancer Subgroup Analysis: pcr rate Gianni L, el al. ASCO 2016

26 ETNA: pcr in TNBC % pcr PACLITAXEL NAB-PACLITAXEL Overall TNBC

27 ETNA: Phase III Study of Neoadjuvant nab-paclitaxel vs Paclitaxel Both Followed y Anthra y line in HER2 High-Risk Breast Cancer Safety: Select TEAEs and RD Grade 3 TEAE, % Any TEAE, % TEAE P n = 335 nab-p n = 337 RD (P - nab-p) P n = 335 nab-p n = 337 RD (P - nab-p) Peripheral neuropathy Nausea Neutrophil count decreased Asthenia Fatigue Vomiting Diarrhea WBC count decreased Rash ALT increased Lacrimation increased AST increased Hypersensitivity Gianni L, el al. ASCO 2016

28 ETNA: Phase III Study of Neoadjuvant nab-paclitaxel vs Paclitaxel Both Followed y Anthra y line in HER2 High-Risk Breast Cancer Improved pcr rate after nab-p did not reach statistical significance. At these schedules and doses, nab-p caused an overall rate of grade 3 neuropathy of 4.5% (2.7% more than the P regimen). In this study, the taxane schedule (qw 3/4 vs continuous) and the dose of P (90 vs 80 mg/m2) were different from those in GeparSepto.

29 GEPARSEPTO & ETNA: pcr in TNBC % pcr GEPARSEPTO ETNA PACLITAXEL NAB-PACLITAXEL

30 Reconciling results of GeparSepto with ETNA One possible explanation is the lower dose intensity of nabpaclitaxel used (125 mg/m2 QW 3/4 equivalent to mg/m2/week, compared with 125 mg/m2/week in GeparSepto). Although the dose intensity of paclitaxel was also lower in ETNA (90 mg/m2 QW 3/4 equivalent to 67.5 mg/m2/ week, compared with 80 mg/m2/week in GeparSepto), the relative reduction in dose intensity between the two trials was greater for nab-paclitaxel (25% reduction in dose intensity with nab-paclitaxel compared with a 16% reduction in dose intensity with paclitaxel).

31 Gluz O, el al. SABCS 2015

32 WSG-ADAPT TN Gluz O, el al. SABCS 2015

33 How high a bar to change neoadjuvant therapy for triple-negative breast cancer? The answer relies on the quantity and quality of available data and the risks and costs associated with the proposed treatment

34 Both Carboplatin and Bevacizumab Improve pcr in Neoadjuvant Treatment of TNBC pcr: carboplatin versus no-carboplatin Chen XS, et al. PLoS One. 2014

35 Both Carboplatin and Bevacizumab Improve pcr in Neoadjuvant Treatment of TNBC pcr: bevacizumab versus no-bevacizumab Chen XS, et al. PLoS One. 2014

36 How high a bar to change neoadjuvant therapy for triple-negative breast cancer? Nab-Paclitaxel, Bevacizumab & Carboplatin: pcr in TNBC

37 How high a bar to change neoadjuvant therapy for triple-negative breast cancer? Nab-Paclitaxel, Bevacizumab & Carboplatin: pcr in TNBC

38 How high a bar to change neoadjuvant therapy for triple-negative breast cancer? Nab-Paclitaxel, Bevacizumab & Carboplatin: pcr in TNBC

39 How high a bar to change neoadjuvant therapy for triple-negative breast cancer? Nab-Paclitaxel, Bevacizumab & Carboplatin: pcr in TNBC

40 How high a bar to change neoadjuvant therapy for triple-negative breast cancer? Nab-Paclitaxel, Bevacizumab & Carboplatin: pcr in TNBC

41 nabtune Trial

42 So, are we ready to add nabpaclitaxel to the standard neoadjuvant regimen for TNBC? Without RFS or OS data, the answer may have to be not yet.

43 So, are we ready to add nab-paclitaxel to the standard neoadjuvant regimen for TNBC? Questions before nab-paclitaxel is incorporated into standard clinical practice: 1) the relative dose intensity needed of nab-paclitaxel to achieve an improved pcr. 2) translation of the improved pcr leading to an improved efficacy outcomes (e.g. disease free survival) in GeparSepto. 3) demonstration of resolution of the grade 3-4 peripheral sensory neuropathy to grade 0-1, is needed.

44 On the other hand, in patients with larger tumors, and those with axillary nodal involvement, we must seriously consider the use of nab-paclitaxel in the hope of improving locoregional response, and discuss the pros and cons of this approach with the patient, while awaiting further data on its impact on distant recurrence and death. So..

45 Thank you!!

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48 Nab-Paclitaxel, Bevacizumab & Carboplatin: pcr in TNBC % pcr

49 Phase II trial CALGB Sikov WM, et al. J Clin Oncol 2015