Purpose: We evaluated the activity of regorafenib, an oral multikinase inhibitor, in advanced gastric adenocarcinoma. Patients and Methods: We conducted an international (Australia and New Zealand, South Korea, and Canada) randomized phase II trial in which patients were randomly assigned at a two-to-one ratio and stratified by lines of prior chemotherapy for advanced disease (one v two) and region. Eligible patients received best supportive care plus regorafenib 160 mg or matching placebo orally on days 1 to 21 of each 28-day cycle until disease progression or prohibitive adverse events occurred. The primary end point was progression-free survival (PFS). Final analysis included data to December 31, 2014. Results: A total of 152 patients were randomly assigned from November 7, 2012, to February 25, 2014, yielding 147 evaluable patients (regorafenib, n = 97; placebo, n = 50). Baseline characteristics were balanced. Median PFS significantly differed between groups (regorafenib, 2.6 months; 95% CI, 1.8 to 3.1 and placebo, 0.9 months; 95% CI, 0.9 to 0.9; hazard ratio [HR], 0.40; 95% CI, 0.28 to 0.59; P < .001). The effect was greater in South Korea than in Australia, New Zealand, and Canada combined (HR, 0.12 v 0.61; interaction P < .001) but consistent across age, neutrophil-to-lymphocyte ratio, primary site, lines of chemotherapy, peritoneal metastasis presence, number of metastatic sites, and plasma vascular endothelial growth factor A. A survival trend in favor of regorafenib was seen (median, 5.8 months; 95% CI, 4.4 to 6.8 v 4.5 months; 95% CI, 3.4 to 5.2; HR, 0.74; P = .147). Twenty-nine patients assigned to placebo received open-label regorafenib after disease progression. Regorafenib toxicity was similar to that previously reported. Conclusion: In this phase II trial, regorafenib was effective in prolonging PFS in refractory advanced gastric adenocarcinoma. Regional differences were found, but regorafenib was effective in both regional groups. A phase III trial is planned.

PURPOSE: Although checkpoint inhibitors have improved first-line treatment for non–small cell lung cancer (NSCLC), a therapeutic need remains for patients whose disease does not respond or who experience disease progression after anti–PD-L1/PD-1 immunotherapy. CONTACT-01 (ClinicalTrials.gov identifier: NCT04471428 ) evaluated atezolizumab plus cabozantinib versus docetaxel in patients with metastatic NSCLC who developed disease progression after concurrent or sequential treatment with anti–PD-L1/PD-1 and platinum-containing chemotherapy. METHODS: This multicenter, open-label, phase III trial randomly assigned patients 1:1 to atezolizumab 1,200 mg intravenously once every 3 weeks (q3w) plus cabozantinib 40 mg orally once daily or docetaxel 75 mg/m² intravenously once every 3 weeks. The primary end point was overall survival (OS). RESULTS: One hundred eighty-six patients were assigned atezolizumab plus cabozantinib, and 180 docetaxel. Minimum OS follow-up was 10.9 months. Median OS was 10.7 months (95% CI, 8.8 to 12.3) with atezolizumab plus cabozantinib and 10.5 months (95% CI, 8.6 to 13.0) with docetaxel (stratified hazard ratio [HR], 0.88 [95% CI, 0.68 to 1.16]; P = .3668). Median progression-free survival was 4.6 months (95% CI, 4.1 to 5.6) and 4.0 months (95% CI, 3.1 to 4.4), respectively (stratified HR, 0.74 [95% CI, 0.59 to 0.92]). Serious adverse events (AEs) occurred in 71 (38.4%) patients receiving atezolizumab plus cabozantinib and 58 (34.7%) receiving docetaxel. Grade 3/4 treatment-related AEs occurred in 73 (39.5%) patients receiving atezolizumab plus cabozantinib and 58 (34.7%) receiving docetaxel. Grade 5 AEs occurred in 14 (7.6%) and 10 (6.0%) patients in the atezolizumab plus cabozantinib and docetaxel arms, respectively (treatment-related in four [2.2%] and one [0.6%], respectively). CONCLUSION: Atezolizumab plus cabozantinib after disease progression following anti–PD-L1/PD-1 immunotherapy and platinum-containing chemotherapy for metastatic NSCLC did not improve OS compared with docetaxel. Safety was consistent with known profiles of these agents.

Bone is the most common site of metastasis from breast cancer. Bone metastases from breast cancer are associated with skeletal-related events (SREs) including pathological fractures, spinal cord compression, surgery and radiotherapy to bone, as well as bone pain and hypercalcemia, leading to impaired mobility and reduced quality of life. Greater understanding of the pathophysiology of bone metastases has led to the discovery and clinical utility of bone-targeted agents such as bisphosphonates and the receptor activator of nuclear factor kappa-B ligand (RANK-L) antibody, denosumab. Both are now a routine part of the treatment of breast cancer bone metastases to reduce SREs. With regards to prevention, there is no evidence that oral bisphosphonates can prevent bone metastases in advanced breast cancer without skeletal involvement. Several phase III clinical trials have evaluated bisphosphonates as adjuvant therapy in early breast cancer to prevent bone metastases. The current published data do not support the routine use of bisphosphonates in unselected patients with early breast cancer for metastasis prevention. However, significant benefit of adjuvant bisphosphonates has been consistently observed in the postmenopausal or ovarian suppression subgroup across multiple clinical trials, which raises the hypothesis that its greatest anti-tumor effect is in a low estrogen microenvironment. An individual patient data meta-analysis will be required to confirm survival benefit in this setting. This review summarizes the key evidence for current clinical practice and future directions.