Dataset Information

A randomized, 3-arm, neoadjuvant, phase 2 study comparing docetaxel?+?carboplatin?+?trastuzumab?+?pertuzumab (TCbHP), TCbHP followed by trastuzumab emtansine and pertuzumab (T-DM1+P), and T-DM1+P in HER2-positive primary breast cancer.

ABSTRACT: PURPOSE:The standard of care in the neoadjuvant setting for human epidermal growth factor receptor 2 (HER2)-positive breast cancer is dual HER2-targeted therapy. However, a need to minimize treatment-related toxicity and improve pathological complete response (pCR) rates, particularly in luminal HER2-positive disease, exists. METHODS:Neopeaks, a randomized, phase 2 study, compared docetaxel?+?carboplatin?+?trastuzumab?+?pertuzumab (TCbHP; 6 cycles; group A), TCbHP (4 cycles) followed by trastuzumab emtansine?+?pertuzumab (T-DM1+P; 4 cycles; group B), and T-DM1+P (4 cycles; group C) regimens in HER2-positive primary breast cancer patients; concurrent hormone therapy with T-DM1+P was administered in case of estrogen receptor positivity (ER+). Based on tumor shrinkage, nonresponders in group C were switched to 5-fluorouracil?+?epirubicin?+?cyclophosphamide (FEC; 4 cycles). Primary endpoint was pCR (comprehensive pCR ypN0 [ypT0-TisypN0]). RESULTS:Of 236 patients enrolled, 204 were randomized to groups A (n?=?51), B (n?=?52), and C (n?=?101). In group C, 80 (79%) patients continued T-DM1+P following favorable response, whereas 21 (21%) nonresponders switched to FEC. pCR rate was numerically higher with the TCbHP??? T-DM1+P regimen (71%) versus the standard TCbHP (57%) and T-DM1+P (57%) regimens. The rate in group C was higher among responders continuing T-DM1+P (63%) versus nonresponders who switched to FEC (38%). pCR rates after initial 4 cycles of T-DM1+P (group C; 57%) and standard TCbHP regimen (57%) were equivalent. pCR rate in patients with ER+ was significantly higher in group B (69%) than groups A (43%) and C (51%), but was comparable in patients with ER- (67-76%). Compared with the T-DM1-based arm, the incidence of adverse events was higher in the taxane-based arms. CONCLUSION:In the neoadjuvant setting, the pCR rate with the standard TCbHP??? T-DM1+P regimen was numerically better than the TCbHP regimen alone and significantly better in patients with ER+. Personalization of the T-DM1+P regimen could serve as a reasonable approach to minimize toxicity while maintaining efficacy. Trial registration ID: UMIN-CTR: UMIN000014649.

SUBMITTER: Masuda N

PROVIDER: S-EPMC7031180 | biostudies-literature | 2020 Feb

REPOSITORIES: biostudies-literature

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A randomized, 3-arm, neoadjuvant, phase 2 study comparing docetaxel + carboplatin + trastuzumab + pertuzumab (TCbHP), TCbHP followed by trastuzumab emtansine and pertuzumab (T-DM1+P), and T-DM1+P in HER2-positive primary breast cancer.

Masuda Norikazu N Ohtani Shoichiro S Takano Toshimi T Inoue Kenichi K Suzuki Eiji E Nakamura Rikiya R Bando Hiroko H Ito Yoshinori Y Ishida Kazushige K Yamanaka Takashi T Kuroi Katsumasa K Yasojima Hiroyuki H Kasai Hiroi H Takasuka Tsuyoshi T Sakurai Takaki T Kataoka Tatsuki R TR Morita Satoshi S Ohno Shinji S Toi Masakazu M

Breast cancer research and treatment 20200117 1

<h4>Purpose</h4>The standard of care in the neoadjuvant setting for human epidermal growth factor receptor 2 (HER2)-positive breast cancer is dual HER2-targeted therapy. However, a need to minimize treatment-related toxicity and improve pathological complete response (pCR) rates, particularly in luminal HER2-positive disease, exists.<h4>Methods</h4>Neopeaks, a randomized, phase 2 study, compared docetaxel + carboplatin + trastuzumab + pertuzumab (TCbHP; 6 cycles; group A), TCbHP (4 cycles) follo ...[more]

PMID: 31953696

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Project description:BACKGROUND:NeoSphere showed significantly higher pathologic complete response (pCR) with neoadjuvant pertuzumab, trastuzumab, and docetaxel compared with trastuzumab plus docetaxel, pertuzumab plus trastuzumab, or pertuzumab plus docetaxel. We assessed associations between human epidermal growth factor receptor 2 (HER2) pathway-related biomarkers and clinical outcome in response to these regimens. METHODS:Tumor, serum, and whole blood samples were collected at baseline and post neoadjuvant treatment before surgery. Associations between biomarkers and pCR, and between biomarkers and clinical variables were assessed in the overall and estrogen receptor (ER)-positive and ER-negative populations. Changes in serum marker levels between baseline and post-neoadjuvant treatment were examined. RESULTS:No markers were associated with pCR across all groups; however, significant associations were observed for two markers in individual groups. High HER2 was significantly associated with higher pCR rates (P?=?0.001) and a significant treatment interaction (P?=?0.0236) with pertuzumab, trastuzumab, and docetaxel (odds ratio 2.07, P?=?0.01). Low serum transforming growth factor alpha (TGF?) was associated with higher pCR rates with pertuzumab plus trastuzumab (P?=?0.04) without a significant treatment interaction. Presence of truncated HER2 did not affect pCR. A non-significant decreased pCR benefit was observed consistently across groups in patients with mutated PIK3CA while the treatment benefit from pertuzumab was maintained when comparing the trastuzumab plus docetaxel and pertuzumab, trastuzumab, and docetaxel groups. Notably, PIK3CA exon 9 mutations were associated with residual disease (pooled groups), which was not found for exon 20 mutations. Serum HER2 extracellular domain levels were significantly increased between baseline and post-neoadjuvant treatment in the non-trastuzumab-treated group, and decreased in the trastuzumab-containing groups (likely due to trastuzumab's mechanism of action). Differences in biomarker profiles according to ER status were observed. CONCLUSIONS:The observed associations of HER2 protein levels with sensitivity to pertuzumab, and of PIK3CA exon 9 mutation to lack of sensitivity to HER2-targeted monoclonal antibody treatment, warrant further investigation. Previously reported findings of truncated forms of HER2 as resistance markers to HER2-targeted treatment could not be confirmed in NeoSphere. Conventional HER2 assessment should continue and HER2 remains the only biomarker suitable for patient selection in this population. TRIAL REGISTRATION:Clinicaltrials.gov, NCT00545688 . Registered on 16 October 2007.

Project description:In patients with metastatic breast cancer that is positive for human epidermal growth factor receptor 2 (HER2), progression-free survival was significantly improved after first-line therapy with pertuzumab, trastuzumab, and docetaxel, as compared with placebo, trastuzumab, and docetaxel. Overall survival was significantly improved with pertuzumab in an interim analysis without the median being reached. We report final prespecified overall survival results with a median follow-up of 50 months.We randomly assigned patients with metastatic breast cancer who had not received previous chemotherapy or anti-HER2 therapy for their metastatic disease to receive the pertuzumab combination or the placebo combination. The secondary end points of overall survival, investigator-assessed progression-free survival, independently assessed duration of response, and safety are reported. Sensitivity analyses were adjusted for patients who crossed over from placebo to pertuzumab after the interim analysis.The median overall survival was 56.5 months (95% confidence interval [CI], 49.3 to not reached) in the group receiving the pertuzumab combination, as compared with 40.8 months (95% CI, 35.8 to 48.3) in the group receiving the placebo combination (hazard ratio favoring the pertuzumab group, 0.68; 95% CI, 0.56 to 0.84; P<0.001), a difference of 15.7 months. This analysis was not adjusted for crossover to the pertuzumab group and is therefore conservative. Results of sensitivity analyses after adjustment for crossover were consistent. Median progression-free survival as assessed by investigators improved by 6.3 months in the pertuzumab group (hazard ratio, 0.68; 95% CI, 0.58 to 0.80). Pertuzumab extended the median duration of response by 7.7 months, as independently assessed. Most adverse events occurred during the administration of docetaxel in the two groups, with long-term cardiac safety maintained.In patients with HER2-positive metastatic breast cancer, the addition of pertuzumab to trastuzumab and docetaxel, as compared with the addition of placebo, significantly improved the median overall survival to 56.5 months and extended the results of previous analyses showing the efficacy of this drug combination. (Funded by F. Hoffmann-La Roche and Genentech; CLEOPATRA ClinicalTrials.gov number, NCT00567190.).

Dataset Information

A randomized, 3-arm, neoadjuvant, phase 2 study comparing docetaxel?+?carboplatin?+?trastuzumab?+?pertuzumab (TCbHP), TCbHP followed by trastuzumab emtansine and pertuzumab (T-DM1+P), and T-DM1+P in HER2-positive primary breast cancer.

Publications

A randomized, 3-arm, neoadjuvant, phase 2 study comparing docetaxel + carboplatin + trastuzumab + pertuzumab (TCbHP), TCbHP followed by trastuzumab emtansine and pertuzumab (T-DM1+P), and T-DM1+P in HER2-positive primary breast cancer.

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