POSEIDON Trial Phase 1b Results: Safety, Efficacy and Circulating Tumor DNA Response of the Beta Isoform-Sparing PI3K Inhibitor Taselisib (GDC-0032) Combined with Tamoxifen in Hormone Receptor Positive Metastatic Breast Cancer Patients.

PURPOSE: The strategy of combining endocrine therapy with PI3K-mTOR inhibition has shown promise in estrogen receptor (ER)-positive breast cancer, but new agents and combinations with a better therapeutic index are urgently needed. Taselisib is a potent, selective, beta-isoform-sparing PI3 kinase inhibitor. PATIENTS AND METHODS: 30 patients with ER-positive, metastatic breast cancer who had failed prior endocrine therapy were treated with escalating doses of taselisib (2 or 4 mg in an intermittent or continuous schedule) combined with tamoxifen 20 mg once daily in this phase 1b study using a "rolling six" design. RESULTS: Taselisib combined with tamoxifen was generally well tolerated, with treatment-emergent adverse events as expected for this class of drugs, including diarrhea (13 patients, 43%), mucositis (10 patients, 33%), and hyperglycemia (8 patients, 27%). No dose-limiting toxicities were observed. Objective responses were seen in 6 of 25 patients with RECIST-measurable disease (ORR 24%). Median time to disease progression was 3.7 months. Twelve of 30 patients (40%) had disease control for 6 months or more. Circulating tumor (ct)DNA studies using next-generation tagged amplicon sequencing identified early indications of treatment response and mechanistically relevant correlates of clinical drug resistance (e.g., mutations in KRAS, ERBB2) in some patients. CONCLUSIONS: Taselisib can be safely combined with tamoxifen at the recommended phase 2 dose of 4 mg given once daily on a continuous schedule. Preliminary evidence of antitumor activity was seen in both PIK3CA mutant and wild-type cancers. The randomized phase 2 part of POSEIDON (testing tamoxifen plus taselisib or placebo) is currently recruiting

Paclitaxel, carboplatin, and trastuzumab in a neo-adjuvant regimen for HER2-positive breast cancer

To evaluate a nonanthracycline-containing regimen consisting of 24 weekly administrations of paclitaxel, carboplatin, and trastuzumab as neo-adjuvant therapy for human epidermal growth factor receptor 2 (HER2)-positive breast cancer. Patients with stage II or III breast cancer, including inflammatory disease, with HER2 overexpression (immunohistochemistry and/or fluorescent in situ hybridization) were treated with 24 weekly administrations of paclitaxel 70 mg/m(2) , carboplatin AUC = 3 mg/mL/minute, and trastuzumab 2 mg/kg (loading dose 4 mg/kg). In cycles 7, 8, 15, 16, 23, and 24, only trastuzumab was given. The primary end point was pathologic complete response (pCR) in both breast and axilla. Of 61 evaluable patients, 61% had stage II disease and 75% were node-positive. The median NRI (Neoadjuvant Response Index, a measure of the degree of downstaging by chemotherapy) of all patients was 0.86. Twenty-seven (44%) had a NRI of 1.0, which corresponds to pCR in breast and lymph nodes. The most commonly reported grade 3/4 toxicities were neutropenia (72%) and thrombocytopenia (36%). Dose reduction was necessary in 51% of the patients. A weekly carboplatin-paclitaxel-trastuzumab neo-adjuvant regimen is highly active in HER2-positive breast cancer with an acceptable toxicity profile. A multicenter phase 2 trial has recently reached its accrual target and will serve as a basis for a subsequent randomized phase 3 study comparing this regimen to a similar regimen preceded by anthracycline

Randomized phase I clinical and pharmacologic study of weekly versus twice-weekly dose-intensive cisplatin and gemcitabine in patients with advanced non-small cell lung cancer

Purpose: To establish the maximum dose intensity of cisplatin plus gemcitabine on a weekly or two-weekly schedule in patients with advanced non-small cell lung cancer (NSCLC). Methods: Patients with NSCLC stage IIIB or IV were randomized to receive weekly or two-weekly courses of gemcitabine on day 1 and cisplatin on day 2. An interpatient dose escalation scheme was used, and pharmacokinetics were determined for both agents in plasma and WBCs. Results: Seventy-three patients were included, 32 on the weekly schedule and 41 on the two-weekly schedule. Fifty patients received all planned courses. Dose-limiting toxicities were leukocytopenia, neutropenia, and trombocytopenia on the weekly schedule and ototoxicity on the two-weekly schedule. Most common nonhematological toxicities consisted of nausea, vomiting, and fatigue. The highest dose intensity of cisplatin could be achieved on the two-weekly schedule, and therefore, further development of the weekly schedule was abandoned. The maximum tolerated dose was established at 1500 mg/m2 gemcitabine in combination with cisplatin 90 mg/m2. More than half (53%) of patients achieved an objective response on the two-weekly schedule, versus 23% in the weekly treatment arm. The pharmacokinetic studies revealed a significant interaction: gemcitabine reduced both GG and AG platinum-DNA intrastrand adducts in WBCs. Conclusion: The combination of gemcitabine (1500 mg/ m2) with cisplatin at a dose intensity of 50 mg/m 2/week is feasible on a two-weekly administration scheme in NSCLC patients

Marking Axillary Lymph Nodes With Radioactive Iodine Seeds for Axillary Staging After Neoadjuvant Systemic Treatment in Breast Cancer Patients The MARI Procedure

Objective: The MARI procedure [marking the axillary lymph node with radioactive iodine (I-125) seeds] is a new minimal invasive method to assess the pathological response of nodal metastases after neoadjuvant systemic treatment (NST) in patients with breast cancer. This method allows axilla-conserving surgery in patients responding well to NST. Methods: Prior to NST, proven tumor-positive axillary lymph nodes were marked with a I-125 seed. This marked lymph node is the so-called MARI-node. After NST, the MARI node was selectively removed using a gamma-detection probe. A complementary axillary lymph node dissection was performed in all patients to assess whether pathological response in the MARI node was indicative for the pathological response in the additional lymph nodes. Results: A tumor-positive axillary lymph node was marked with a I-125 seed in 100 patients. The MARI node was successfully identified in 97 of these 100 patients (identification rate 97%). Two patients did not undergo subsequent axillary lymph node dissection, leaving 95 patients for further analysis. The MARI node contained residual tumor cells in 65 of these 95 patients. In the other 30 patients, the MARI node was free of tumor, but additional positive lymph nodes were found in 5 patients. Thus, the MARI procedure correctly identified 65 of 70 patients with residual axillary tumor activity (false negative rate 5/70 = 7%). Conclusions: This study shows that marking and selectively removing metastatic lymph nodes after neoadjuvant systemic treatment has a high identification rate and a low false negative rate. The tumor response in the marked lymph node may be used to tailor further axillary treatment after NS

Trastuzumab in combination with weekly paclitaxel and carboplatin as neo-adjuvant treatment for HER2-positive breast cancer : The TRAIN-study

Aim To determine the efficacy and safety of an anthracycline-free neo-adjuvant regimen consisting of weekly paclitaxel, carboplatin and trastuzumab in HER2-positive breast cancer. Patients and methods Patients with stage II or III HER2-positive breast cancer received weekly paclitaxel ([P], 70 mg/m2), trastuzumab ([T], 2 mg/kg, loading dose 4 mg/kg) and carboplatin ([C], AUC = 3 mg ml−1 min) for 24 weeks. In weeks 7, 8, 15, 16, 23 and 24, trastuzumab was administered without chemotherapy. The primary end-point was pathologic complete response in the surgical resection specimen, defined as the absence of invasive tumour cells in breast and axilla. Results One hundred and eleven patients were included in the study, and 108 were evaluable for the primary end-point. The pathologic complete response rate was 43% (95% confidence interval [CI]: 33–52). Median follow-up was 52 months, and the 3-year event-free survival was 88% (95% CI: 82–94), and the 3-year overall survival was 92% (95% CI: 88–98). The most common grade 3–4 adverse events were neutropenia (67%) and thrombocytopenia (43%). Less than five percent of patients experienced febrile neutropenia. No symptomatic left ventricular systolic dysfunction was observed during neo-adjuvant treatment. Conclusion An anthracycline-free neo-adjuvant regimen of weekly paclitaxel, trastuzumab and carboplatin is highly effective in HER2-positive breast cancer with manageable toxicity