Clonal Evolutionary Analysis during HER2 Blockade in HER2-Positive Inflammatory Breast Cancer: A Phase II Open-Label Clinical Trial of Afatinib +/- Vinorelbine.

BACKGROUND: Inflammatory breast cancer (IBC) is a rare, aggressive form of breast cancer associated with HER2 amplification, with high risk of metastasis and an estimated median survival of 2.9 y. We performed an open-label, single-arm phase II clinical trial (ClinicalTrials.gov NCT01325428) to investigate the efficacy and safety of afatinib, an irreversible ErbB family inhibitor, alone and in combination with vinorelbine in patients with HER2-positive IBC. This trial included prospectively planned exome analysis before and after afatinib monotherapy. METHODS AND FINDINGS: HER2-positive IBC patients received afatinib 40 mg daily until progression, and thereafter afatinib 40 mg daily and intravenous vinorelbine 25 mg/m2 weekly. The primary endpoint was clinical benefit; secondary endpoints were objective response (OR), duration of OR, and progression-free survival (PFS). Of 26 patients treated with afatinib monotherapy, clinical benefit was achieved in 9 patients (35%), 0 of 7 trastuzumab-treated patients and 9 of 19 trastuzumab-naïve patients. Following disease progression, 10 patients received afatinib plus vinorelbine, and clinical benefit was achieved in 2 of 4 trastuzumab-treated and 0 of 6 trastuzumab-naïve patients. All patients had treatment-related adverse events (AEs). Whole-exome sequencing of tumour biopsies taken before treatment and following disease progression on afatinib monotherapy was performed to assess the mutational landscape of IBC and evolutionary trajectories during therapy. Compared to a cohort of The Cancer Genome Atlas (TCGA) patients with HER2-positive non-IBC, HER2-positive IBC patients had significantly higher mutational and neoantigenic burden, more frequent gain-of-function TP53 mutations and a recurrent 11q13.5 amplification overlapping PAK1. Planned exploratory analysis revealed that trastuzumab-naïve patients with tumours harbouring somatic activation of PI3K/Akt signalling had significantly shorter PFS compared to those without (p = 0.03). High genomic concordance between biopsies taken before and following afatinib resistance was observed with stable clonal structures in non-responding tumours, and evidence of branched evolution in 8 of 9 tumours analysed. Recruitment to the trial was terminated early following the LUX-Breast 1 trial, which showed that afatinib combined with vinorelbine had similar PFS and OR rates to trastuzumab plus vinorelbine but shorter overall survival (OS), and was less tolerable. The main limitations of this study are that the results should be interpreted with caution given the relatively small patient cohort and the potential for tumour sampling bias between pre- and post-treatment tumour biopsies. CONCLUSIONS: Afatinib, with or without vinorelbine, showed activity in trastuzumab-naïve HER2-positive IBC patients in a planned subgroup analysis. HER2-positive IBC is characterized by frequent TP53 gain-of-function mutations and a high mutational burden. The high mutational load associated with HER2-positive IBC suggests a potential role for checkpoint inhibitor therapy in this disease. TRIAL REGISTRATION: ClinicalTrials.gov NCT01325428.

Survival and prognostic factors of stage I-III breast cancer.

OBJECTIVE: To determine the survival duration of stage I-III breast cancer patients, and to determine prognostic factors for overall survival and disease-free survival in stage I to III breast cancer patients treated with surgery and adjuvant therapy. MATERIAL AND METHOD: This retrospective cohort study was conducted by reviewing 166files of stage I-III breast cancer patients treated with surgery and adjuvant therapy in the Oncology Unit, Department of Medicine, Rajavithi Hospital from January 1st 1998 to December 31st 2007. RESULTS: There were 166 patients whose median age was 48 years. The 5-year overall survival rates for stage I, stage II and stage III were 100.0%, 89.0% and 80.8% respectively (p = 0.11). Multivariate analysis showed that pathological lymph node pN2 status was a significant poor prognostic factor for overall survival (HR = 4.32, 95% CI 1.24-15.04; p = 0.022). The one-, three- and five-year disease-free survival (DFS) rates were 96.7%, 81.4% and 76.7% respectively. Multivariate analysis revealed that pathological pN2 (HR = 4.43, 95% CI 1.44-13.57; p = 0.009), pN3 (HR = 5.16, 95% CI 1.54-17.30; p = 0.008) and progesterone receptor status negative (HR = 5.53, 95% CI 1.85-16.59; p = 0.002) were poor prognostic factors for disease-free survival. CONCLUSION: The most important prognostic factor affecting disease-free survival and overall survival of stage I-III breast cancer patients was axillary lymph node metastasis. Progesterone receptor status negative influenced disease relapse. Patients with multiple unfavorable risk factors such as lymph node metastasis and progesterone receptor status negative showed poor DFS, and therefore more aggressive adjuvant chemotherapy is required for these patients.

Clinical and Immunologic Responses to a B-Cell Epitope Vaccine in Patients with HER2/neu-Overexpressing Advanced Gastric Cancer-Results from Phase Ib Trial IMU.ACS.001.

PURPOSE: HER2/neu is overexpressed in up to 30% of gastroesophageal adenocarcinomas (GEA) and linked to poor prognosis. Recombinant mAbs to treat HER2/neu-overexpressing cancers are effective with limitations, including resistance and toxicity. Therefore, we developed a therapeutic B-cell epitope vaccine (IMU-131/HER-Vaxx) consisting of three fused B-cell epitopes from the HER2/neu extracellular domain coupled to CRM197 and adjuvanted with Montanide. This phase Ib study aimed to evaluate the optimal/safe dose leading to immunogenicity and clinical responses (https//clinicaltrials.gov/ct2/show/NCT02795988). PATIENTS AND METHODS: A total of 14 patients with HER2/neu-overexpressing GEA were enrolled, and dose escalation (10, 30, 50 µg) was performed in three cohorts (C). Immunogenicity was evaluated by HER2-specific Abs and cellular responses, clinical responses by CT scans according to RECIST version 1.1. RESULTS: IMU-131 was safe without vaccine-related significant local/systemic reactions or serious adverse events. A total of 11 of 14 patients were evaluable for changes in tumor size and vaccine-specific immune responses. One patient showed complete, 5 partial responses, and 4 stable diseases as their best response. HER2-specific IgG levels were dose dependent. In contrast to patients in C1 and C2, all patients in C3 mounted substantial HER2-specific Ab levels. In addition, cellular vaccine responses, such as Th1-biased cytokine ratios and reduced regulatory T cell numbers, were generated. Progression-free survival was prolonged in C3, correlating with the vaccine-specific humoral and cellular responses. CONCLUSIONS: IMU-131 was well tolerated and safe. The induced HER2-specific Abs and cellular responses were dose dependent and correlated with clinical responses. The highest dose (50 µg) was recommended for further evaluation in a phase II trial, with chemotherapy + IMU-131 or chemotherapy alone, which is currently ongoing.

Prognostic factors for survival in colorectal cancer patients.

OBJECTIVE: To determine the prognostic value for survival of pretreatment characteristics and treatments in stage 1-IV colorectal cancer (CRC) patients. MATERIAL AND METHOD: The present retrospective cohort study was conducted by reviewing 287files of stage I-IV CRC patients. Fifteen clinical variables were investigated through analysis as prognostic factors for survival. RESULTS: The median survival time for CRC patients, colon and rectal cancer patients were 37.2, 43.2, and 29.5 months respectively The 5-year survival rates of CRC patients were 38.6%. 5-year stage-specific survivals for stage I, II, III and IV CRC were 100%, 68%, 44%, and 2% respectively (p < 0.001). Sixty eight percent of CRC patients were in stages III and IV Multivariate analysis revealed age > or =60 years old, WHO performance status 3, stage III and IV disease and poorly differentiated histology as poor prognostic factors for survival, whereas treatment with complete surgical resection and adjuvant chemotherapy was a good prognostic factor for survival in CRC. CONCLUSION: As the majority of patients were in advanced stages with poor prognosis, early stage disease identification and treatment with newer agents would likely improve survival of high-risk CRC patients.

Open-label, phase IIa study of dabrafenib plus trametinib in East Asian patients with advanced BRAF V600-mutant cutaneous melanoma.

PURPOSE: This study (NCT02083354) assessed the efficacy and safety of dabrafenib plus trametinib in East Asian patients with advanced BRAF V600-mutant cutaneous melanoma. METHOD: Overall, 77 patients of East Asian origin (including 61 from Mainland China) with unresectable or metastatic BRAF V600-mutant cutaneous melanoma were enrolled. Prior treatment was allowed except with BRAF/MEK inhibitors. Patients received dabrafenib 150 mg twice daily and trametinib 2 mg once daily. The primary end-point was objective response rate (ORR) using Response Evaluation Criteria in Solid Tumours 1.1. Secondary end-points were duration of response (DOR), progression-free survival (PFS), overall survival (OS), pharmacokinetics and safety. RESULTS: At data cutoff (February 23, 2018; median follow-up, 8.3 months), treatment was ongoing in 36 patients (47%). The median age was 52 years; 32% of patients had elevated lactate dehydrogenase, and 84% had received prior systemic therapy. ORR was 61% (95% confidence interval: 49.2-72.0), with four patients (5%) achieving complete response. Median DOR and PFS were 11.3 and 7.9 months, respectively. Median OS was not reached. The most common adverse event (AE) of any grade was pyrexia (56%). Grade ≥III AEs occurred in 29 patients (38%). The most common grade ≥III AEs were pyrexia (8%) and anaemia (6%). AEs led to permanent discontinuation in five patients (6.5%). Mean Cmax for dabrafenib and trametinib was 3560 and 11.5 ng/mL (day 1) and 2680 and 27.1 ng/mL (day 15), respectively. CONCLUSION: These results support the efficacy and tolerability of dabrafenib in combination with trametinib in East Asian patients with unresectable or metastatic BRAF V600-mutant cutaneous melanoma.

A randomized, double-blind, placebo-controlled study evaluating the efficacy of combination olanzapine, ondansetron and dexamethasone for prevention of chemotherapy-induced nausea and vomiting in patients receiving doxorubicin plus cyclophosphamide.

BACKGROUND: Since most of Thai cancer patients receiving high emetogenic chemotherapy do not have access to neurokinin-1 (NK-1) receptor antagonists or palonosetron as recommended by international guidelines for chemotherapy-induced nausea and vomiting (CINV) prevention. We decided to evaluate the efficacy of olanzapine with the real-life practice antiemetic drugs ondansetron and dexamethasone, in prevention of CINV resulting from doxorubicin plus cyclophosphamide regimen in early-stage breast cancer patients. METHODS: In this randomized, double-blind, placebo-controlled trial, we compared olanzapine with a placebo in combination with ondansetron and dexamethasone in early-stage breast cancer patients receiving doxorubicin 60 mg/m2 plus cyclophosphamide 600 mg/m2. The intervention group received olanzapine 10 mg orally while the control group received a matching placebo daily on day 1 through day 4. All patients received ondansetron 8 mg and dexamethasone 20 mg intravenously 30 minutes before chemotherapy administration and then dexamethasone 10 mg daily orally from day 1 through day 4. The primary endpoint was no nausea rate in the early period. The secondary endpoints were no nausea rate in the delayed and overall periods and a complete response (no vomiting and no use of rescue drug). Outcomes were determined by patients' self-reported daily records of episodes of vomiting or retching, use of rescue therapy and daily levels of nausea based on a visual-analogue scale from the first cycle of chemotherapy. RESULTS: A total of 39 female patients were randomized in a 1:1 ratio to receive olanzapine (20 patients) or a matching placebo (19 patients). A significantly greater proportion of patients reported no nausea in the olanzapine group than in the placebo group in both the early period (0-24 hours after chemotherapy) and the overall period (0-120 hours after chemotherapy). Patients who reported no nausea in the early period accounted for 50% and 10.5% in the olanzapine group and in the placebo group respectively (P=0.008). In the overall period, 30.0% and 0% of patients reported no nausea in the olanzapine and placebo groups respectively (P=0.009). In the early period, there was a significantly different complete response rate between two treatment groups; 75.0% in the olanzapine group and 36.8% in the placebo group (P=0.016). Overall treatment-related adverse events were not significantly different between the two study groups except that somnolence was significantly more common in the olanzapine group than in the placebo group. CONCLUSIONS: Olanzapine 10 mg combined with ondansetron and dexamethasone was more effective than a placebo in preventing CINV resulting from doxorubicin plus cyclophosphamide in early-stage breast cancer patients, especially in the first 24 hours after chemotherapy administration. The short duration of olanzapine was safe and well tolerated.

Prognostic factors for survival in advanced non-small cell lung cancer.

OBJECTIVE: To determine the prognostic value for survival of various pretreatment characteristics and treatments in advanced non-small cell lung cancer (NSCLC) patients. PATIENTS AND METHOD: The retrospective study was conducted by reviewing the 81 files of advanced NSCLC patients treated with chemotherapy at the Oncology Unit, Rajavithi Hospital. Eighteen clinical variables were investigated and analysed as prognostic factors for survival. RESULTS: The first chemotherapy regimens for the 81 patients included: etoposide plus platinum derivatives (41), new drugs (taxanes or gemcitabine) plus platinum derivatives (39) and one other platinum based regimen (1). The overall survival time for all patients was 39.4 weeks with a 95% confidence interval of 30 to 49 weeks. In the multivariate analysis, male gender; bone metastasis and liver metastasis are poor prognostic factors. Receiving palliative surgery and achieving objective response to first regimen chemotherapy are good prognostic factors. Patients who received either old or new drug combinations showed no difference in their survival as determined by univariate or multivariate analyses which could be due to limitations in the present retrospective study. However; this may show that regimens consisting of older, less expensive drug combinations still provide survival advantages in advanced NSCLC and should be considered in limited financial circumstances.