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A phase IIa dose-finding and safety study of first-line pertuzumab in combination with trastuzumab, capecitabine and cisplatin in patients with HER2-positive advanced gastric cancer.

ABSTRACT: Pertuzumab plus trastuzumab provides a more comprehensive blockade of HER2 signalling than trastuzumab alone. Therefore, we conducted a phase IIa study of the pharmacokinetics and safety of pertuzumab plus trastuzumab and chemotherapy in advanced gastric cancer (aGC).Patients received pertuzumab 840 mg for cycle 1 and 420 mg q3w for cycles 2-6 (Arm A) or pertuzumab 840 mg q3w for six cycles (Arm B). Trastuzumab, cisplatin and capecitabine were also given for six cycles, then trastuzumab q3w until disease progression or unmanageable toxicity. The co-primary endpoints were day 43 pertuzumab serum trough concentration (Cmin) and safety.Thirty patients were randomised. Mean pertuzumab Cmin at day 43 was 40.0 ?g ml(-1) (s.d.: 17.3) in Arm A and 62.7 ?g ml(-1) (29.1) in Arm B. Mean day 43 Cmin in Arm A was ~37% lower than that seen in metastatic breast cancer. The safety profiles were similar between arms and treatment was well tolerated. Partial responses were achieved by 86% and 55% of patients in Arms A and B, respectively.On the basis of the pharmacokinetic and safety data, the 840 mg q3w pertuzumab dose has been selected for a phase III study of pertuzumab, trastuzumab and chemotherapy in HER2-positive aGC.

SUBMITTER: Kang YK

PROVIDER: S-EPMC4134501 | biostudies-literature | 2014 Aug

REPOSITORIES: biostudies-literature

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A phase IIa dose-finding and safety study of first-line pertuzumab in combination with trastuzumab, capecitabine and cisplatin in patients with HER2-positive advanced gastric cancer.

Kang Y-K YK Rha S Y SY Tassone P P Barriuso J J Yu R R Szado T T Garg A A Bang Y-J YJ

British journal of cancer 20140624 4

<h4>Background</h4>Pertuzumab plus trastuzumab provides a more comprehensive blockade of HER2 signalling than trastuzumab alone. Therefore, we conducted a phase IIa study of the pharmacokinetics and safety of pertuzumab plus trastuzumab and chemotherapy in advanced gastric cancer (aGC).<h4>Methods</h4>Patients received pertuzumab 840 mg for cycle 1 and 420 mg q3w for cycles 2-6 (Arm A) or pertuzumab 840 mg q3w for six cycles (Arm B). Trastuzumab, cisplatin and capecitabine were also given for si ...[more]

PMID: 24960402

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Project description:BackgroundThe ToGA study showed that trastuzumab plus chemotherapy prolonged median survival in patients with human epidermal growth factor receptor 2 (HER2)-positive advanced gastric cancer. Among chemotherapy options, oxaliplatin might be as effective as cisplatin but has shown to be more tolerable. To further improve treatment options for patients with advanced gastric cancer, we initiated a study to evaluate the efficacy and safety of trastuzumab plus oxaliplatin/capecitabine in patients with HER2-positive advanced gastric cancer.MethodsCGOG1001 was an open-label, multicenter, prospective phase II study. Patients with chemotherapy-naive HER2-positive advanced gastric cancer were eligible. Trastuzumab was administered at a loading dose of 8 mg/kg followed by 6 mg/kg infusion every 3 weeks (q3w). Oxaliplatin was administrated as a 130 mg/m(2) infusion, q3w, for up to 6 cycles. Capecitabine 1000 mg/m(2) was given orally twice daily on days 1-14 followed by a 7-day rest interval. Trastuzumab and capecitabine were continued until disease progression or intolerable toxicity. The primary endpoint was objective response rate. Simon two-stage design (H0 = 40%, H1 = 60%, α = 0.05, β = 0.2) by Response Evaluation Criteria In Solid Tumors 1.0 was applied.ResultsFifty-one patients were enrolled. Confirmed response was recorded in 46 patients. One patient achieved complete response and 33 patients achieved partial response (response rate 34/51 [66.7%] in the intent-to-treat population). Median follow-up time was 28.6 months, with a median progression-free survival of 9.2 months (95% confidence interval [CI]: 6.5-11.6) and a median overall survival (OS) of 19.5 months (95% CI: 15.5-26.0). Patients with a HER2/CEP17 ratio of greater than five achieved improved OS (20.9 vs 19.5 months, p = 0.001). The most common adverse events of grade 3 or above were thrombocytopenia (21.6%), neutropenia (13.7%), anemia (5.9 %) and leucopenia (3.9%).ConclusionThe addition of trastuzumab to oxaliplatin/capecitabine was well tolerated and the results demonstrated encouraging efficacy.Trial registrationClinicalTrials.gov NCT01364493.

Project description:Pertuzumab (Perjeta) is an anti-HER2 monoclonal antibody that is used for treatment of HER2-positive breast cancers in combination with trastuzumab (Herceptin) and docetaxel and showed promising clinical outcomes. Pertuzumab is suggested to block heterodimerization of HER2 with EGFR and HER3 that abolishes canonical function of HER2. However, evidence on the exact mode of action of pertuzumab in homodimerization of HER2 are limited. In this study, we investigated the effect of pertuzumab and its combination with trastuzumab on HER2 homodimerization, phosphorylation and whole gene expression profile in Chinese hamster ovary (CHO) cells stably overexpressing human HER2 (CHO-K6). CHO-K6 cells were treated with pertuzumab, trastuzumab, and their combination, and then HER2 homodimerization and phosphorylation at seven pY sites were investigated. The effects of the monoclonal antibodies on whole gene expression and the expression of cell cycle stages, apoptosis, autophagy, and necrosis were studied by cDNA microarray. Results showed that pertuzumab had no significant effect on HER2 homodimerization, however, trastuzumab increased HER2 homodimerization. Interestingly, pertuzumab increased HER2 phosphorylation at Y1127, Y1139, and Y1196 residues, while trastuzumab increased HER2 phosphorylation at Y1196. More surprisingly, combination of pertuzumab and trastuzumab blocked the phosphorylation of Y1005 and Y1127 of HER2. Our results also showed that pertuzumab, but not trastuzumab, abrogated the effect of HER2 overexpression on cell cycle in particular G1/S transition, G2/M transition, and M phase, whereas trastuzumab abolished the inhibitory effect of HER2 on apoptosis. Our findings confirm that pertuzumab is unable to inhibit HER2 homodimerization but induces HER2 phosphorylation at some pY sites that abolishes HER2 effects on cell cycle progress. These data suggest that the clinical effects of pertuzumab may mostly through the inhibition of HER2 heterodimers, rather than HER2 homodimers and that pertuzumab binding to HER2 may inhibit non-canonical HER2 activation and function in non-HER-mediated and dimerization-independent pathway(s).

Project description:BackgroundIn 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.MethodsWe 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.ResultsThe 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.ConclusionsIn 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.).

Project description:BackgroundPertuzumab increases the rate of pathological complete response in the preoperative context and increases overall survival among patients with metastatic disease when it is added to trastuzumab and chemotherapy for the treatment of human epidermal growth factor receptor 2 (HER2)-positive breast cancer. In this trial, we investigated whether pertuzumab, when added to adjuvant trastuzumab and chemotherapy, improves outcomes among patients with HER2-positive early breast cancer.MethodsWe randomly assigned patients with node-positive or high-risk node-negative HER2-positive, operable breast cancer to receive either pertuzumab or placebo added to standard adjuvant chemotherapy plus 1 year of treatment with trastuzumab. We assumed a 3-year invasive-disease-free survival rate of 91.8% with pertuzumab and 89.2% with placebo.ResultsIn the trial population, 63% of the patients who were randomly assigned to receive pertuzumab (2400 patients) or placebo (2405 patients) had node-positive disease and 36% had hormone-receptor-negative disease. Disease recurrence occurred in 171 patients (7.1%) in the pertuzumab group and 210 patients (8.7%) in the placebo group (hazard ratio, 0.81; 95% confidence interval [CI], 0.66 to 1.00; P=0.045). The estimates of the 3-year rates of invasive-disease-free survival were 94.1% in the pertuzumab group and 93.2% in the placebo group. In the cohort of patients with node-positive disease, the 3-year rate of invasive-disease-free survival was 92.0% in the pertuzumab group, as compared with 90.2% in the placebo group (hazard ratio for an invasive-disease event, 0.77; 95% CI, 0.62 to 0.96; P=0.02). In the cohort of patients with node-negative disease, the 3-year rate of invasive-disease-free survival was 97.5% in the pertuzumab group and 98.4% in the placebo group (hazard ratio for an invasive-disease event, 1.13; 95% CI, 0.68 to 1.86; P=0.64). Heart failure, cardiac death, and cardiac dysfunction were infrequent in both treatment groups. Diarrhea of grade 3 or higher occurred almost exclusively during chemotherapy and was more frequent with pertuzumab than with placebo (9.8% vs. 3.7%).ConclusionsPertuzumab significantly improved the rates of invasive-disease-free survival among patients with HER2-positive, operable breast cancer when it was added to trastuzumab and chemotherapy. Diarrhea was more common with pertuzumab than with placebo. (Funded by F. Hoffmann-La Roche/Genentech; APHINITY ClinicalTrials.gov number, NCT01358877 .).

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.

Dataset Information

A phase IIa dose-finding and safety study of first-line pertuzumab in combination with trastuzumab, capecitabine and cisplatin in patients with HER2-positive advanced gastric cancer.

Publications

A phase IIa dose-finding and safety study of first-line pertuzumab in combination with trastuzumab, capecitabine and cisplatin in patients with HER2-positive advanced gastric cancer.

Similar Datasets

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