Relacorilant plus nab-paclitaxel for the treatment of metastatic pancreatic ductal adenocarcinoma: results from the open-label RELIANT study.

BACKGROUND: Modulation of glucocorticoid receptor (GR) activity in tumor cells enhances chemotherapy efficacy. We evaluated the selective GR modulator relacorilant plus nab-paclitaxel in patients with metastatic pancreatic ductal adenocarcinoma (mPDAC) who had received at least 2 prior therapy lines. PATIENTS AND METHODS: In this open-label, single-arm, phase III study, patients received once-daily oral relacorilant (100 mg, titrated to 150 mg in 25 mg increments/cycle) and nab-paclitaxel (80 mg/m2) on days 1, 8, and 15 of 28-day cycles. The primary efficacy endpoint was objective response rate (ORR) by blinded independent central review. Progression-free survival (PFS), overall survival (OS), target gene modulation, and safety were also assessed. RESULTS: Of 43 patients enrolled, 31 were evaluable for ORR (12 did not reach first postbaseline radiographic assessment). An interim analysis to assess whether ORR was ≥10% showed no confirmed responses and the study was discontinued. Two (6.5%) patients attained unconfirmed partial responses and 15 (48.4%) had stable disease. Fourteen of 31 (45.2%) patients had reductions in target lesion size, despite prior nab-paclitaxel exposure in 12 of the 14. Median PFS and OS were 2.4 months (95% CI, 1.4-4.2) and 3.9 months (95% CI, 2.8-4.9), respectively. The most common adverse events were fatigue and nausea. RNA analysis confirmed that relacorilant plus nab-paclitaxel suppressed 8 cortisol target genes of interest. CONCLUSION: Relacorilant plus nab-paclitaxel showed modest antitumor activity in heavily pretreated patients with mPDAC, with no new safety signals. Studies of this combination in other indications with a high unmet medical need are ongoing.

Phase II randomised, double-blind study of mFOLFIRINOX plus ramucirumab versus mFOLFIRINOX plus placebo in advanced pancreatic cancer patients (HCRN GI14-198).

BACKGROUND: Vascular endothelial growth factor receptor (VEGFR)-mediated signalling contributes to andgiogenesis and therapy resistance in pancreatic ductal adenocarcinoma (PDAC). Ramucirumab (RAM) is a VEGFR2 monoclonal antibody. We conducted a randomised phase II trial to compare progression-free survival (PFS) between mFOLFIRINOX with or without RAM in first line therapy of metastatic PDAC. METHODS: This phase II randomised, multi-centre, placebo controlled, double-blinded, trial randomly assigned to recurrent/metastatic PDAC patients to either mFOLFIRINOX/RAM (Arm A) or mFOLFIRINOX/placebo (Arm B). The primary endpoint is PFS at 9 months, and the secondary endpoints include overall survival (OS), response rate and toxicity evaluation. RESULTS: A total of 86 subjects enrolled, 82 eligible (42 in Arm A versus 40 in Arm B). The mean age was comparable (61.7 versus 63.0, respectively). Majority were White (N = 69) and males (N = 43). The median PFS was 5.6 compared to 6.7 months, for Arm A and B, respectively. At 9 months, the PFS rates were 25.1% and 35.0% for Arms A and B, respectively (p = 0.322). The median OS in Arm A was 10.3 compared to 9.7 months for Arm B (p = 0.094). The disease response rate for Arm A was 17.7% compared to Arm B of 22.6%. FOLFIRINOX/RAM combination was well tolerated. CONCLUSIONS: The addition of RAM to FOLFIRINOX did not significantly impact PFS or OS. The combination was well tolerated (Funded by Eli Lilly; ClinicalTrials.gov number, NCT02581215).

Regorafenib plus nivolumab in patients with mismatch repair-proficient/microsatellite stable metastatic colorectal cancer: a single-arm, open-label, multicentre phase 2 study.

Background: Anti-programmed cell death protein 1 antibodies plus multikinase inhibitors have shown encouraging activity in several tumour types, including colorectal cancer. This study assessed regorafenib plus nivolumab in patients with microsatellite stable/mismatch repair-proficient metastatic colorectal cancer. Methods: This single-arm, open-label, multicentre phase 2 study enrolled adults from 13 sites in the USA with previously treated advanced microsatellite stable/mismatch repair-proficient metastatic colorectal cancer. Eligible patients had known extended RAS and BRAF status, progression or intolerance to no more than two (for extended RAS mutant) or three (for extended RAS wild type) lines of systemic chemotherapy and an Eastern Cooperative Oncology Group performance status of 0 or 1. Regorafenib 80 mg/day was administered orally for 3 weeks on/1 week off (increased to 120 mg/day if 80 mg/day was well tolerated) with intravenous nivolumab 480 mg every 4 weeks. Primary endpoint was objective response rate. Secondary endpoints included safety, overall survival, and progression-free survival. Exploratory endpoints included biomarkers associated with antitumour activity. Patients who received at least one dose of study intervention were included in the efficacy and safety analyses. Tumour assessments were carried out every 8 weeks for the first year, and every 12 weeks thereafter until progressive disease/end of the study, and objective response rate was analysed after all patients had met the criteria for primary completion of five post-baseline scans and either 10-months' follow-up or drop out. This trial is registered with ClinicalTrials.gov, number NCT04126733. Findings: Between 14 October 2019 and 14 January 2020, 94 patients were enrolled, 70 received treatment. Five patients had a partial response, yielding an objective response rate of 7% (95% CI 2.4-15.9; p = 0.27). All responders had no liver metastases at baseline. Median overall survival (data immature) and progression-free survival were 11.9 months (95% CI 7.0-not evaluable) and 1.8 months (95% CI 1.8-2.4), respectively. Most patients (97%, 68/70) experienced a treatment-related adverse event; 51% were grade 1 or 2, 40% were grade 3, 3% were grade 4, and 3% were grade 5. The most common (≥20%) events were fatigue (26/70), palmar-plantar erythrodysesthesia syndrome (19/70), maculopapular rash (17/70), increased blood bilirubin (14/70), and decreased appetite (14/70). Higher baseline expression of tumour biomarkers of immune sensitivity correlated with antitumour activity. Interpretation: Further studies are warranted to identify subgroups of patients with clinical characteristics or biomarkers that would benefit most from treatment with regorafenib plus nivolumab. Funding: Bayer/Bristol Myers Squibb.

Neoadjuvant use of sunitinib in locally advanced GIST with intolerance to imatinib.

Gastrointestinal stromal tumors (GIST) arise from precursor cells in the myenteric plexus and comprise the most common mesenchymal tumors of the gastrointestinal tract. Surgical resection is the mainstay of therapy for localized disease. Recurrent, unresectable, and metastatic tumors are associated with a poor prognosis given their resistance to conventional chemotherapy and radiation. Advances in the understanding of molecular pathophysiology of GIST and the use of targeted small-molecule therapies have resulted in dramatic increases in survival. Preliminary data have demonstrated benefits in using imatinib in a neoadjuvant setting; however, there are no studies to date analyzing the use of neoadjuvant sunitinib in primary advanced GIST. Here we present the case of a patient with locally advanced primary GIST who developed severe toxicity on imatinib therapy and was successfully treated with sunitinib in the neoadjuvant setting to achieve complete surgical resection.

Diagnostic and treatment considerations when newly diagnosed breast cancer coincides with pregnancy: a case report and review of literature.

Breast cancer is the most common malignancy associated with pregnancy and is a rare but well-recognized complication. It is hypothesized that as more women continue to delay childbearing, the incidence of breast cancer in pregnancy will increase. Because of the lack of clinical experience with breast cancer in the setting of pregnancy, given its relative infrequency, many patients and physicians believe the diagnosis puts the life of the mother at odds with that of the fetus, but available data suggest that termination of the pregnancy does not improve the outcome for pregnant women with breast cancer. Often diagnosis is delayed because neither patient nor physician suspects malignancy. This report presents a recent case of a young primigravid woman with a newly appreciated breast mass seen at Northwestern University Feinberg School of Medicine as a means of discussing diagnostic considerations, therapeutic options, and supportive care available to the practitioner when managing a pregnant patient with breast cancer.

Thromboembolic and bleeding complications in acute leukemia.

The risk of both thromboembolic and bleeding complications is high in acute leukemia. This double hazard has a significant negative impact on the morbidity and mortality of patients with this disease. The clinical manifestations of both complications show special features specific to the form of acute leukemia. Recognition of these characteristics is important in the diagnosis and management of acute leukemia. In this article, several additional issues are addressed, including the features of bleeding and thrombosis in acute promyelocytic leukemia, the current understanding of the leukostasis syndrome and the iatrogenic complications including catheter-associated thrombosis, and the adverse effects of therapeutic agents used in acute leukemia. As regards the bleeding complications, thrombocytopenia is a major cause. Corrective measures, including recent guidelines on platelet transfusions, are provided.