DNA damage repair deficiency as a predictive biomarker for FOLFIRINOX efficacy in metastatic pancreatic cancer.

Patients with pathogenic germline and somatic variants in DNA damage repair (DDR) genes may derive greater benefit with platinum-based chemotherapy in metastatic pancreatic ductal adenocarcinoma (PDAC). This study investigates the role of DDR genes as a predictive biomarker for response to first-line platinum chemotherapy with FOLFIRINOX in metastatic PDAC patients. Demographic, clinical, and pathologic variables were collected for patients with metastatic PDAC who received FOLFIRINOX as frontline treatment and who had germline and somatic genetic testing. Kaplan-Meier analysis of overall survival (OS) and progression free survival (PFS) were correlated to the presence of DDR pathogenic variants. Forty patients with metastatic PDAC met inclusion criteria. Germline genetic testing revealed germline pathogenic variants in DDR genes in 5 patients (12%), and somatic pathogenic variants in DDR genes in 4 patients (10%). Median PFS was significantly longer in patients with any (germline or somatic) pathogenic variant in DDR genes than in those without alterations 18.5 vs. 6.9 months (log-rank P=0.003). When restricted to the presence or absence of germline pathogenic variants in DDR genes, the median PFS was 18.5 vs. 7.4 months (log-rank P=0.005). The median OS for the entire cohort was 11.5 months was not statistically different between the two groups, however there were no deaths in the subgroup with germline pathogenic variants in DDR genes treated with frontline FOLFIRINOX. A subset of patients with metastatic PDAC and germline or somatic pathogenic variants in DDR genes have a statistically superior PFS when treated with the platinum containing regimen FOLFIRINOX. The role of DDR gene alterations as a predictive biomarker for FOLFIRINOX benefit should be further evaluated in prospective trials.

Successful use of Trastuzumab with anthracycline-based chemotherapy followed by trastuzumab maintenance in patients with advanced HER2-positive gastric cancer.

BACKGROUND: There is no standard chemotherapy regimen that is universally accepted for the treatment of advanced gastric cancer. Trastuzumab added to chemotherapy improves survival in patients with metastatic human epidermal growth factor receptor-2 (Her2/neu)-overexpressing gastric cancer. Data are lacking for the combination of trastuzumab with other chemotherapy regimens, apart from the cisplatin/fluorouracil backbone used in the pivotal TOGA trial. PATIENTS AND METHODS: In this retrospective analysis, we included patients with gastric cancer with HER2 overexpression who received trastuzumab in addition to their first-line chemotherapy, with or without trastuzumab maintenance therapy. The end-points were response and tolerance to treatment. RESULTS: We identified seven patients who met the search criteria; six had metastatic disease and one had locally advanced unresectable disease. Four patients received epirubicin/oxaliplatin/capecitabine/trastuzumab, and the others had non-anthracycline-based chemotherapy with trastuzumab. All patients had radiological responses to treatment - one had a complete response and six had partial responses. Among the four patients who received anthracycline-based chemotherapy with trastuzumab, there was a transient decline in cardiac ejection fraction in three, but all resolved without sequelae. All patients received a period of chemotherapy induction followed by trastuzumab monotherapy for maintenance. The median progression-free survival was 14.6 months and median overall survival was 16.4 months. CONCLUSION: Trastuzumab is an important agent for the treatment of HER2-overexpressing gastric cancer. We recorded an acceptable safety and efficacy profile in this small cohort treated with anthracycline-based chemotherapy with trastuzumab followed by trastuzumab maintenance.

Phase II trial of paclitaxel-topotecan-etoposide followed by consolidation chemoradiotherapy for limited-stage small cell lung cancer: CALGB 30002.

PURPOSE: We sought to evaluate the activity and tolerance of the rationally designed sequence of paclitaxel-topotecan-etoposide, a nonplatinum regimen, as induction therapy for limited-stage small-cell lung cancer before combined chemo- and radiotherapy. PATIENTS AND METHODS: Patients with measurable disease, performance status 0 to 2, no prior therapy, and adequate organ function were eligible. Paclitaxel (110 mg/m2, administered intravenously on day 1), topotecan (1.5 mg/m2, administered orally on days 2 to 4), and etoposide (160 mg/m2, administered orally on days 5 to 7 every 21 days), with filgrastim for two cycles, were followed by chest irradiation to 70 Gy (to postinduction tumor volume) concurrent with carboplatin (area under the curve of 5, administered intravenously on day 1) and etoposide (100 mg/m2 on days 1 to 3 every 21 days) without filgrastim for three cycles (five chemotherapy cycles total). We aimed to determine the response rates to induction and overall therapy, overall and failure-free survival, and toxicity. The primary statistical endpoint was to differentiate between complete response rates of 50 and 70% for the overall treatment program. RESULTS: Between June 2001 and January 2003, 65 patients were enrolled, but one never started therapy, and one was ineligible. Patient characteristics included male/female, 27/36; white/black/other/unknown, 58/3/1/1; median age 62 (range, 38-78); performance status 0/1/2, 27/33/3. Induction chemotherapy resulted in six (10%) complete responses and 35 (56%) partial responses. Overall response to chemoradiotherapy included 27 (43%; 95% confidence interval [CI] 30-56%) complete responses and 24 (38%) partial responses. Median progression-free survival is 12 months (95% CI, 9-15 months). Median overall survival is 20 months (95% CI, 16-24 months). Frequent (>20%) grade 3/4 toxicities during all therapy included neutropenia, febrile neutropenia, anemia, thrombocytopenia, fatigue, and dysphagia. One patient died of febrile neutropenia, one died of febrile neutropenia and typhlitis, and one patient who declined transfusion for anemia died of cardiac ischemia. CONCLUSIONS: This treatment regimen has significant activity in limited-stage small-cell lung cancer but did not meet our prospectively defined criteria for further investigation in this setting. The addition of etoposide and the use of a sequenced administration schedule did not seem to improve overall activity beyond our prior experience with a topotecan-paclitaxel doublet.

A phase I study of sequential administration of escalating doses of intravenous paclitaxel, oral topotecan, and fixed-dose oral etoposide in patients with solid tumors.

BACKGROUND: Based on preclinical findings and on the clinical antitumor efficacy of sequential paclitaxel/topotecan and topotecan/etoposide, the authors sought to define the maximum tolerated doses (MTDs) and dose-limiting toxicities (DLTs) associated with a sequential combination of paclitaxel, topotecan, and etoposide in patients with solid tumors. METHODS: The MTDs were determined through standard dose escalation in cohorts of three patients. Patients with refractory solid tumors and performance status < or = 2 were treated with intravenous paclitaxel 50-110 mg/m(2) (Day 1), oral topotecan 0.5-2.0 mg/m(2) (Days 2-4), and oral etoposide 160 mg/m(2) (Days 5-7) during every 21-day cycle. For dose-limiting neutropenia, granulocyte-colony-stimulating factor (G-CSF) was administered on Day 8 in subsequent cohorts. Blood samples were obtained before treatment during Cycle 1 (Days 1, 2, and 5) for topoisomerase I assessment. RESULTS: Twenty-eight patients received a combined total of 129 cycles. The MTDs were paclitaxel 80 mg/m(2), topotecan 1.5 mg/m(2), and etoposide 160 mg/m(2) without G-CSF. In minimally pretreated patients, G-CSF allowed paclitaxel dose escalation to 110 mg/m(2). Three patients (11%) had radiologic partial responses, and 4 patients (14%) had stable disease. Day 2 topoisomerase I levels increased by 2-15 times relative to baseline levels in 7 of 14 patients analyzed (50%). CONCLUSIONS: The novel sequential combination that was evaluated generally was well tolerated and active in patients with refractory solid tumors. Based on hematologic DLTs, the authors recommend further evaluation of paclitaxel 110 mg/m(2), topotecan 1.5 mg/m(2), and etoposide 160 mg/m(2) with G-CSF support in minimally pretreated patients.