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Dual targeting of HER1/EGFR and HER2 with cetuximab and trastuzumab in patients with metastatic pancreatic cancer after gemcitabine failure: results of the "THERAPY"phase 1-2 trial.

Assenat E, Azria D, Mollevi C, Guimbaud R, Tubiana-Mathieu N, Smith D, Delord JP, Samalin E, Portales F, Larbouret C, Robert B, Bibeau F, Bleuse JP, Crapez E, Ychou M, Pèlegrin A - Oncotarget (2015)

Bottom Line: The higher dose level was defined as the trastuzumab recommended dose.Conventional phase 1 dose-escalation schedules are unsuitable for targeted therapies because most cutaneous toxicities are not considered dose-limiting toxicities.The compliance issues caused by skin toxicities were particularly detrimental because of the toxicity-response correlation.

View Article: PubMed Central - PubMed

Affiliation: Centre Hospitalier Régional Universitaire (CHU) de Montpellier, Montpellier, France.

ABSTRACT
To improve treatment efficacy, we decided to simultaneously target HER1 and HER2 with trastuzumab and cetuximab. Following promising preclinical results, we conducted a phase 1-2 trial in advanced pancreatic cancer patients after first-line gemcitabine-based chemotherapy failure. In this single-arm, non-randomized, multicenter trial, patients received weekly cetuximab (400mg/m², then 250mg/m²). They were sequentially included in two trastuzumab dose levels: 3.0 or 4.0mg/kg, then 1.5 or 2.0mg/kg/weekly. Endpoints were the objective response rate, safety, progression-free (PFS) and overall survival (OS). During phase 1 (n=10 patients), toxicities were evenly distributed except for skin toxicities that frequently caused compliance issues. The higher dose level was defined as the trastuzumab recommended dose. During phase 2 (n=39 patients), toxicities were mainly cutaneous reactions and asthenia. No objective response was observed. Nine patients were stabilized but arrested treatment due to toxicity. Median PFS was 1.8 months (95%CI: 1.7-2.0 months) and median OS was 4.6 months (95%CI: 2.7-6.6 months). Both were positively correlated with skin toxicity severity (P=0.027 and P=0.001, respectively). Conventional phase 1 dose-escalation schedules are unsuitable for targeted therapies because most cutaneous toxicities are not considered dose-limiting toxicities. The compliance issues caused by skin toxicities were particularly detrimental because of the toxicity-response correlation.

No MeSH data available.


Related in: MedlinePlus

Kaplan Meier progression-free survival and overall survival curves of all patients, and progression-free survival and overall survival curves of patients who experienced grade 0-1 or grade ≥ 2 cutaneous toxicities (all types)
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Figure 2: Kaplan Meier progression-free survival and overall survival curves of all patients, and progression-free survival and overall survival curves of patients who experienced grade 0-1 or grade ≥ 2 cutaneous toxicities (all types)

Mentions: For the survival analysis, the data of all evaluable patients included in the phase 2 study (n=38) were pooled with those of the phase 1 patients who received the same TRA dose (cohort 2, n=6). The median follow-up for the pooled patients (n=44) was 3.7 months (range: 0.4-22.9 months). The median PFS was 1.8 months (95% CI: 1.7 - 2.0 months), while the median OS was 4.6 months (95% CI: 2.7 – 6.6 months) (Fig. 2A and 2B). Both PFS and OS were significantly (and positively) correlated with the severity of skin toxicities (Fig. 2C and 2D), as detailed in Table 4B.


Dual targeting of HER1/EGFR and HER2 with cetuximab and trastuzumab in patients with metastatic pancreatic cancer after gemcitabine failure: results of the "THERAPY"phase 1-2 trial.

Assenat E, Azria D, Mollevi C, Guimbaud R, Tubiana-Mathieu N, Smith D, Delord JP, Samalin E, Portales F, Larbouret C, Robert B, Bibeau F, Bleuse JP, Crapez E, Ychou M, Pèlegrin A - Oncotarget (2015)

Kaplan Meier progression-free survival and overall survival curves of all patients, and progression-free survival and overall survival curves of patients who experienced grade 0-1 or grade ≥ 2 cutaneous toxicities (all types)
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4494975&req=5

Figure 2: Kaplan Meier progression-free survival and overall survival curves of all patients, and progression-free survival and overall survival curves of patients who experienced grade 0-1 or grade ≥ 2 cutaneous toxicities (all types)
Mentions: For the survival analysis, the data of all evaluable patients included in the phase 2 study (n=38) were pooled with those of the phase 1 patients who received the same TRA dose (cohort 2, n=6). The median follow-up for the pooled patients (n=44) was 3.7 months (range: 0.4-22.9 months). The median PFS was 1.8 months (95% CI: 1.7 - 2.0 months), while the median OS was 4.6 months (95% CI: 2.7 – 6.6 months) (Fig. 2A and 2B). Both PFS and OS were significantly (and positively) correlated with the severity of skin toxicities (Fig. 2C and 2D), as detailed in Table 4B.

Bottom Line: The higher dose level was defined as the trastuzumab recommended dose.Conventional phase 1 dose-escalation schedules are unsuitable for targeted therapies because most cutaneous toxicities are not considered dose-limiting toxicities.The compliance issues caused by skin toxicities were particularly detrimental because of the toxicity-response correlation.

View Article: PubMed Central - PubMed

Affiliation: Centre Hospitalier Régional Universitaire (CHU) de Montpellier, Montpellier, France.

ABSTRACT
To improve treatment efficacy, we decided to simultaneously target HER1 and HER2 with trastuzumab and cetuximab. Following promising preclinical results, we conducted a phase 1-2 trial in advanced pancreatic cancer patients after first-line gemcitabine-based chemotherapy failure. In this single-arm, non-randomized, multicenter trial, patients received weekly cetuximab (400mg/m², then 250mg/m²). They were sequentially included in two trastuzumab dose levels: 3.0 or 4.0mg/kg, then 1.5 or 2.0mg/kg/weekly. Endpoints were the objective response rate, safety, progression-free (PFS) and overall survival (OS). During phase 1 (n=10 patients), toxicities were evenly distributed except for skin toxicities that frequently caused compliance issues. The higher dose level was defined as the trastuzumab recommended dose. During phase 2 (n=39 patients), toxicities were mainly cutaneous reactions and asthenia. No objective response was observed. Nine patients were stabilized but arrested treatment due to toxicity. Median PFS was 1.8 months (95%CI: 1.7-2.0 months) and median OS was 4.6 months (95%CI: 2.7-6.6 months). Both were positively correlated with skin toxicity severity (P=0.027 and P=0.001, respectively). Conventional phase 1 dose-escalation schedules are unsuitable for targeted therapies because most cutaneous toxicities are not considered dose-limiting toxicities. The compliance issues caused by skin toxicities were particularly detrimental because of the toxicity-response correlation.

No MeSH data available.


Related in: MedlinePlus