Pharmacogenetic and clinical risk factors for bevacizumab-related gastrointestinal hemorrhage in prostate cancer patients treated on CALGB 90401 (Alliance).

The objective of this study was to discover clinical and pharmacogenetic factors associated with bevacizumab-related gastrointestinal hemorrhage in Cancer and Leukemia Group B (Alliance) 90401. Patients with metastatic castration-resistant prostate cancer received docetaxel and prednisone ± bevacizumab. Patients were genotyped using Illumina HumanHap610-Quad and assessed using cause-specific risk for association between single nucleotide polymorphisms (SNPs) and gastrointestinal hemorrhage.

FDA Approval Summary: Abemaciclib With Endocrine Therapy for High-Risk Early Breast Cancer.

Purpose: The US Food and Drug Administration approved abemaciclib in combination with endocrine therapy (ET) for the adjuvant treatment of adult patients with hormone receptor-positive, human epidermal growth factor receptor 2-negative, node-positive, early breast cancer (EBC) at high risk of recurrence and a Ki-67 score ≥ 20%.

Patients And Methods: The approval was based on monarchE, a phase III, open-label, 2-cohort, multicenter trial of patients with EBC randomly assigned to receive abemaciclib plus ET (n = 2,808) or ET alone (n = 2,829). Abemaciclib was given at 150 mg orally twice daily for 2 years.

Plasma Protein Biomarkers in Advanced or Metastatic Colorectal Cancer Patients Receiving Chemotherapy With Bevacizumab or Cetuximab: Results from CALGB 80405 (Alliance).

Purpose: CALGB 80405 compared the combination of first-line chemotherapy with cetuximab or bevacizumab in the treatment of advanced or metastatic colorectal cancer (mCRC). Although similar clinical outcomes were observed in the cetuximab-chemotherapy group and the bevacizumab-chemotherapy group, biomarkers could identify patients deriving more benefit from either biologic agent.

Patients And Methods: In this exploratory analysis, the Angiome, a panel of 24 soluble protein biomarkers were measured in baseline plasma samples in CALGB 80405.

Bevacizumab-induced hypertension and proteinuria: a genome-wide study of more than 1000 patients.

Background: Hypertension and proteinuria are common bevacizumab-induced toxicities. No validated biomarkers are available for identifying patients at risk of these toxicities.

Methods: A genome-wide association study (GWAS) meta-analysis was performed in 1039 bevacizumab-treated patients of European ancestry in four clinical trials (CALGB 40502, 40503, 80303, 90401).

A phase I/II study of ixazomib, pomalidomide, and dexamethasone for lenalidomide and proteasome inhibitor refractory multiple myeloma (Alliance A061202).

Preclinical studies have demonstrated activity of the oral proteasome inhibitor (PI) ixazomib (IXA) in bortezomib-resistant multiple myeloma (MM) and synergy with immunomodulatory drugs. We therefore conducted a phase I/II study to establish the safety and preliminary efficacy of IXA with pomalidomide (POM) and dexamethasone (DEX) in lenalidomide (LEN)/PI-refractory MM. Dose escalation established a 4 mg dose of POM and IXA and 20/40 mg dose of DEX as the maximum tolerated dose.

Pharmacogenetic study in gastric cancer patients treated with adjuvant fluorouracil/leucovorin or epirubicin/cisplatin/fluorouracil before and after chemoradiation on CALGB 80101 (Alliance).

There is a lack of pharmacogenetic predictors of outcome in gastric cancer patients. The aim of this study was to assess previously identified candidate genes associated with 5-fluorouracil (5-FU), cisplatin, or epirubicin toxicity or response in a cohort of resected gastric cancer patients treated on CALGB (Alliance) 80101. Gastric or gastroesophageal cancer patients randomized to adjuvant 5-FU/leucovorin or epirubicin/cisplatin/5-FU before and after 5-FU chemoradiation were genotyped for single nucleotide polymorphisms (SNPs) in GSTP1 (rs1695), ERCC1 (rs11615 and rs3212986), XRCC1 (rs25487), UGT2B7 (rs7439366) and the 28 base-pair tandem repeats in TYMS (rs34743033).

FDA Approval Summary: Nivolumab with Ipilimumab and Chemotherapy for Metastatic Non-small Cell Lung Cancer, A Collaborative Project Orbis Review.

On May 26, 2020, the FDA approved nivolumab with ipilimumab and two cycles of platinum-doublet chemotherapy as first-line treatment for patients with metastatic or recurrent non-small cell lung cancer (NSCLC), with no or anaplastic lymphoma kinase () genomic tumor aberrations. The approval was based on results from Study CA2099LA (CheckMate 9LA), an open-label trial in which 719 patients with NSCLC were randomized to receive nivolumab with ipilimumab and two cycles of chemotherapy ( = 361) or four cycles of platinum-doublet chemotherapy ( = 358). Overall survival (OS) was improved for patients who received nivolumab with ipilimumab and chemotherapy, with a median OS of 14.

FDA Approval Summary: Lurbinectedin for the Treatment of Metastatic Small Cell Lung Cancer.

On June 15, 2020, the FDA granted accelerated approval to lurbinectedin for the treatment of adult patients with metastatic small cell lung cancer (SCLC) with disease progression on or after platinum-based chemotherapy. Approval was granted on the basis of the clinically meaningful effects on overall response rate (ORR) and duration of response (DOR), and the safety profile observed in a multicenter, open-label, multicohort clinical trial (PM1183-B-005-14, NCT02454972), referred to as Study B-005, in patients with advanced solid tumors. The trial included a cohort of 105 patients with metastatic SCLC who had disease progression on or after platinum-based chemotherapy.

Genomewide Meta-Analysis Validates a Role for S1PR1 in Microtubule Targeting Agent-Induced Sensory Peripheral Neuropathy.

Microtubule targeting agents (MTAs) are anticancer therapies commonly prescribed for breast cancer and other solid tumors. Sensory peripheral neuropathy (PN) is the major dose-limiting toxicity for MTAs and can limit clinical efficacy. The current pharmacogenomic study aimed to identify genetic variations that explain patient susceptibility and drive mechanisms underlying development of MTA-induced PN.

Differentiation Syndrome with Ivosidenib and Enasidenib Treatment in Patients with Relapsed or Refractory IDH-Mutated AML: A U.S. Food and Drug Administration Systematic Analysis.

Purpose: Differentiation syndrome (DS) is a serious adverse reaction of isocitrate dehydrogenase (IDH) inhibitors ivosidenib and enasidenib in patients with and -mutated acute myeloid leukemia (AML), respectively.

Experimental Design: During FDA review of marketing applications for ivosidenib and enasidenib, data from pivotal trials were queried to identify cases of DS in patients with relapsed or refractory (R/R) AML. One hundred seventy-nine patients with R/R AML received ivosidenib and 214 received enasidenib.

Comparison of iRECIST versus RECIST V.1.1 in patients treated with an anti-PD-1 or PD-L1 antibody: pooled FDA analysis.

Background: Response criteria developed when cytotoxic chemotherapy was the predominant therapeutic modality to treat patients with cancer, do not capture the full spectrum of tumor response patterns observed with anti-PD-1/PD-L1 antibody treatment. iRECIST was developed to capture both typical and atypical response patterns.

Methods: Target, non-target, and new lesion measurements for 7920 patients receiving anti-PD-1/PD-L1 antibody (n=4751) or anti-CTLA-4 antibody (n=613) or undergoing chemotherapy (n=2556) from 14 randomized controlled trials submitted to the U.

A Pharmacogenetic Prediction Model of Progression-Free Survival in Breast Cancer using Genome-Wide Genotyping Data from CALGB 40502 (Alliance).

Genome-wide genotyping data are increasingly available for pharmacogenetic association studies, but application of these data for development of prediction models is limited. Prediction methods, such as elastic net regularization, have recently been applied to genetic studies but only limitedly to pharmacogenetic outcomes. An elastic net was applied to a pharmacogenetic study of progression-free survival (PFS) of 468 patients with advanced breast cancer in a clinical trial of paclitaxel, nab-paclitaxel, and ixabepilone.

The vitamin D receptor gene as a determinant of survival in pancreatic cancer patients: Genomic analysis and experimental validation.

Purpose: Advanced pancreatic cancer is a highly refractory disease almost always associated with survival of little more than a year. New interventions based on novel targets are needed. We aim to identify new genetic determinants of overall survival (OS) in patients after treatment with gemcitabine using genome-wide screens of germline DNA.

Identification of a Genomic Region between and Associated with Risk of Bevacizumab-Induced Hypertension: CALGB 80405 (Alliance).

Bevacizumab is a VEGF-specific angiogenesis inhibitor indicated as an adjunct to chemotherapy for the treatment of multiple cancers. Hypertension is commonly observed during bevacizumab treatment, and high-grade toxicity can limit therapy or lead to cardiovascular complications. The factors that contribute to interindividual variability in blood pressure rise during bevacizumab treatment are not well understood.

Patients with melanoma treated with an anti-PD-1 antibody beyond RECIST progression: a US Food and Drug Administration pooled analysis.

Background: Patients who receive immunotherapeutic drugs might develop an atypical response pattern, wherein they initially meet conventional response criteria for progressive disease but later have decreases in tumour burden. Such responses warrant further investigation into the potential benefits and risks for patients who continue immunotherapy beyond disease progression defined by the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1.

Evaluation of Overall Response Rate and Progression-Free Survival as Potential Surrogate Endpoints for Overall Survival in Immunotherapy Trials.

With the approval of immunotherapies for a variety of indications, methods to assess treatment benefit addressing the response patterns observed are important. We evaluated RECIST criteria-based overall response rate (ORR) and progression-free survival (PFS) as potential surrogate endpoints of overall survival (OS), and explored a modified definition of PFS by altering the threshold percentage determining disease progression to assess the association with survival benefit in immunotherapy trials. Thirteen randomized, multicenter, active-control trials containing immunotherapeutic agents submitted to the FDA were analyzed.

Pharmacogenetic Discovery in CALGB (Alliance) 90401 and Mechanistic Validation of a VAC14 Polymorphism that Increases Risk of Docetaxel-Induced Neuropathy.

Purpose: Discovery of SNPs that predict a patient's risk of docetaxel-induced neuropathy would enable treatment individualization to maximize efficacy and avoid unnecessary toxicity. The objectives of this analysis were to discover SNPs associated with docetaxel-induced neuropathy and mechanistically validate these associations in preclinical models of drug-induced neuropathy.

Experimental Design: A genome-wide association study was conducted in metastatic castrate-resistant prostate cancer patients treated with docetaxel, prednisone and randomized to bevacizumab or placebo on CALGB 90401.

Clinical impact of ABL1 kinase domain mutations and IKZF1 deletion in adults under age 60 with Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL): molecular analysis of CALGB (Alliance) 10001 and 9665.

Recent studies have identified oncogenic lesions in Philadelphia chromosome-positive (Ph+)  acute lymphoblastic leukemia (ALL) and ABL1 kinase mutations that confer resistance to tyrosine kinase inhibitors. We sought to determine the prevalence and clinical impact of these lesions in patients on CALGB 10001, a previously reported Phase II study of imatinib, chemotherapy, and hematopoietic cell transplant in adult Ph + ALL. Of the 58 enrolled, 22 relapsed.

Phase II Study of Allogeneic Transplantation for Older Patients With Acute Myeloid Leukemia in First Complete Remission Using a Reduced-Intensity Conditioning Regimen: Results From Cancer and Leukemia Group B 100103 (Alliance for Clinical Trials in Oncology)/Blood and Marrow Transplant Clinical Trial Network 0502.

Purpose: Long-term survival rates for older patients with newly diagnosed acute myeloid leukemia (AML) are extremely low. Previous observational studies suggest that allogeneic hematopoietic stem-cell transplantation (HSCT) may improve overall survival (OS) because of lower rates of relapse. We sought to prospectively determine the value of HSCT for older patients with AML in first complete remission.

Relationship between obesity and clinical outcome in adults with acute myeloid leukemia: A pooled analysis from four CALGB (alliance) clinical trials.

Obesity has been previously suggested as an adverse prognostic marker in patients with acute leukemia. To evaluate the relationship between obesity and clinical outcome, disease-free survival (DFS) and overall survival (OS), in patients with acute myelogenous leukemia (AML), including acute promyelocytic leukemia (APL), we performed a pooled analysis of four CALGB (Alliance) clinical trials. Our study included 446 patients with APL from CALGB 9710, and 1,648 patients between 18 and 60 years of age with non-APL AML from CALGB 9621, 10503, and 19808.

Long-term outcomes for newly-diagnosed multiple myeloma patients treated with pegylated liposomal doxorubicin and bortezomib: final results of CALGB (Alliance) 10301, a multicentre phase II study.

Long-term outcomes and updated clinical efficacy and safety data were evaluated for newly-diagnosed multiple myeloma patients treated on a phase II study of bortezomib and pegylated liposomal doxorubicin (PegLD). Out of 61 patients, the overall response rate was 57% and the near-complete/complete response rate was 7%. Patients aged ≥65 years old had a higher incidence of treatment-related ≥Grade 3 non-haematological toxicity (80% vs.