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

The characterization of circulating tumor cells (CTCs) holds promises for precision medicine because these cells are an important clinical indicator of treatment efficacy. We established the first and still only nine permanent colon CTC lines from peripheral blood samples of a patient with metastatic colon cancer collected at different time points during treatment and cancer progression. The study objectives were (i) to compare the gene expression profiles of these CTC lines, and (ii) to determine the main features acquired during treatment. The number of upregulated genes was higher in the CTC lines obtained after treatment, indicating that they acquired properties to escape treatment pressure. Among these upregulated genes, some are involved in the mTOR and PI3K/AKT signaling pathways. Moreover, cytidine deaminase expression was significantly increased in the CTC lines obtained after failure of the first- and second-line 5-fluorouracile-based treatments, suggesting that these CTCs can eliminate this specific drug and resist to therapy. Several enzymes involved in xenobiotic metabolism also were upregulated after treatment, suggesting the activation of detoxification mechanisms in response to chemotherapy. Finally, the significant higher expression of aldolase B in four of the six CTC lines obtained after treatment withdrawal and cancer progression indicated that these clones originated from liver metastases. In conclusion, these CTC lines generated at different time points during treatment of metastatic colon cancer in a single patient are characterized by the deregulation of different genes that promote (i) drug resistance, (ii) xenobiotic and energy metabolism, and (iii) stem cell properties and plasticity.

Sorafenib remains one major first-line therapeutic options for advanced hepatocellular carcinoma (aHCC), with modest efficacy. We investigated the addition of gemcitabine and oxaliplatin (GEMOX) to sorafenib in aHCC patients. Our multicentre phase II trial randomised aHCC first-line patients to sorafenib (400 mg BID) or sorafenib-GEMOX every 2 weeks (1000 mg/m² gemcitabine; 100 mg/m² oxaliplatin). Primary endpoint was the 4-month progression-free survival (PFS) rate. Ninety-four patients were randomised (sorafenib-GEMOX: n = 48; sorafenib: n = 46). Median age was 64 years, PS 0 (69%) or 1 (31%), 63% patients had cirrhosis, 29% portal vein thrombosis and 70% extra-hepatic disease. Median duration of sorafenib treatment was 4 months (1–51); median number of GEMOX cycles was 7 (1–16). The 4-month PFS rates were 64% and 61% in the sorafenib-GEMOX and sorafenib arms, respectively; median PFS and OS were 6.2 (95% CI: 3.8–6.8) and 13.5 (7.5–16.2) months, and 4.6 (3.9–6.2) months and 14.8 (12.2–22.2), respectively. The ORR/DCR were 9%/70% and 15%/77% in the sorafenib-GEMOX and sorafenib alone arms, respectively. Main toxicities were (sorafenib-GEMOX/sorafenib) neutropenia (23%/0), thrombocytopenia (33%/0), diarrhoea (18%/9), peripheral neuropathy (5%/0) and hand–foot syndrome (5%/18). Addition of GEMOX had an inpact on ORR and was well-tolerated as frontline systemic therapy. The benefit on PFS seems moderate; no subsequent study was planned.

Idarubicin-eluting beads showed a good safety profile and promising objective response rate and time to progression when used as part of a transarterial chemoembolization regimen for unresectable hepatocellular carcinoma. BackgroundA prior in vitro study showed that idarubicin was the most cytotoxic agent for hepatocellular carcinoma (HCC) cell lines. Idarubicin-loaded beads for transarterial chemoembolization (TACE) were previously evaluated for the appropriate dose in a phase I dose-escalation study.PurposeTo evaluate objective response rate (ORR), safety, and survival after TACE by using idarubicin-loaded beads for unresectable HCC.Materials and MethodsThis prospective single-arm phase II study was conducted between January 2015 and January 2017. Participants with unresectable HCC were included in the trial and underwent TACE with idarubicin-eluting beads. The primary end point was 6-month ORR assessed with independent central review by using modified Response Evaluation Criteria in Solid Tumors. Secondary end points were best ORR during the first 6 months, overall survival, progression-free survival, time to progression, and safety. A two-stage Fleming statistical design was used.ResultsForty-six study participants (me...

Introduction: Stereotactic MR-guided Adaptive RadioTherapy (SMART) is a novel process to treat pancreatic tumors. We present an update of the data from our prospective registry of SMART for pancreatic tumors. Materials and methods: After the establishment of the SMART indication in a multidisciplinary board, we included all patients treated for pancreatic tumors. Primary endpoints were acute and late toxicities. Secondary endpoints were survival outcomes (local control, overall survival, distant metastasis free survival) and dosimetric advantages of adaptive process on targets volumes and OAR. Results: We included seventy consecutive patients in our cohort between October 2019 and April 2022. The prescribed dose was 50 Gy in 5 consecutive fractions. No severe acute SMART related toxicity was noted. Acute and late Grade ≤ 2 gastro intestinal were low. Daily adaptation significantly improved PTV and GTV coverage as well as OAR sparing. With a median follow-up of 10.8 months since SMART completion, the median OS, 6-months OS, and 1-year OS were 20.9 months, 86.7% (95% CI: (75–93%), and 68.6% (95% CI: (53–80%), respectively, from SMART completion. Local control at 6 months, 1 year, and 2 years were, respectively, 96.8 % (95% CI: 88–99%), 86.5 (95% CI: 68–95%), and 80.7% (95% CI: 59–92%). There was no grade > 2 late toxicities. Locally Advanced Pancreatic Cancers (LAPC) and Borderline Resectable Pancreatic Cancers (BRPC) patients (52 patients) had a median OS, 6-months OS, and 1-year OS from SMART completion of 15.2 months, 84.4% (95% CI: (70–92%)), and 60.5% (95% CI: (42–75%)), respectively. The median OS, 1-year OS, and 2-year OS from initiation of induction chemotherapy were 22.3 months, 91% (95% CI: (78–97%)), and 45.8% (95% CI: (27–63%)), respectively. Twenty patients underwent surgical resection (38.7 % of patients with initially LAPC) with negative margins (R0). Conclusion: To our knowledge, this is the largest series of SMART for pancreatic tumors. The treatment was well tolerated with only low-grade toxicities. Long-term OS and LC rates were achieved. SMART achieved high secondary resection rates in LAPC patients.