Multicenter Phase 1b/2a Clinical Trial of Radioprotectant BIO 300 Oral Suspension for Patients With Non-Small Cell Lung Cancer Receiving Concurrent Chemoradiotherapy.

PURPOSE: Radiation therapy is part of the standard treatment regimen for non-small cell lung cancer (NSCLC). Although radiation therapy is an effective tool to manage NSCLC, it can be associated with significant dose-limiting toxicities. These toxicities can lead to treatment interruption or early termination and worsening clinical outcomes in addition to reductions in patient quality of life. Based on preclinical efficacy for radioprotection of normal tissues, we evaluated the clinical utility of BIO 300 Oral Suspension (BIO 300; synthetic genistein nanosuspension) in patients with NSCLC. METHODS AND MATERIALS: In this multicenter, open-label, single-arm, ascending dose phase 1b/2a study, patients were enrolled with newly diagnosed stage II-IV NSCLC planned for 60 to 70/1.8-2.0 Gy radiation therapy and concurrent weekly paclitaxel/carboplatin. Oral BIO 300 (cohort 1, 500 mg/d; cohort 2, 1000 mg/d; cohort 3, 1500 mg/d) was self-administered once daily starting 2 to 7 days before initiating concurrent chemoradiotherapy and continued until the end of radiation therapy. The primary endpoint was acute dose-limiting toxicities attributable to BIO 300. Secondary outcomes included pharmacokinetics, pharmacodynamics, overall toxicity profile, quality of life, local response rate, and survival. RESULTS: Twenty-one participants were enrolled. No dose-limiting toxicities were reported. BIO 300 dosing did not alter chemotherapy pharmacokinetics. Adverse events were not dose-dependent, and those attributable to BIO 300 (n = 11) were all mild to moderate in severity (grade 1, n = 9; grade 2, n = 2) and predominantly gastrointestinal (n = 7). A dose-dependent decrease in serum transforming growth factor ß1 levels was observed across cohorts. Based on safety analysis, the maximum tolerated dose of BIO 300 was not met. Patient-reported quality of life and weight were largely stable throughout the study period. No patient had progression as their best overall response, and a 65% tumor response rate was achieved (20% complete response rate). CONCLUSIONS: The low toxicity rates, along with the pharmacodynamic results and tumor response rates, support further investigation of BIO 300 as an effective radioprotector.

Comprehensive genomic profiling: Does timing matter?

Purpose: There is variability in utilization of Comprehensive Genomic Profiling (CGP) in most of the metastatic solid tumors (MST). We evaluated the CGP utilization patterns and its impact on outcomes at an academic tertiary center. Patients and Methods: Institutional database was reviewed for CGP data in adult patients with MST between 01/2012 - 04/2020. Patients were categorized based on interval between CGP and metastatic diagnosis; 3 tertiles of distribution (T1-earliest to the diagnosis, T3-furthest), and pre-mets (CGP performed prior to diagnosis of metastasis). Overall survival (OS) was estimated from the time of metastatic diagnosis with left truncation at the time of CGP. Cox regression model was used to estimate the impact of timing of CGP on survival. Results: Among 1,358 patients, 710 were female, 1,109 Caucasian, 186 Afro-Americans, and 36 Hispanic. The common histologies were lung cancer (254; 19%), colorectal cancer (203; 15%), gynecologic cancers (121; 8.9%), and pancreatic cancer (106; 7.8%). Time interval between diagnosis of metastatic disease and CGP was not statistically significantly different based on sex, race and ethnicity after adjusting for histologic diagnoses with 2 exceptions - Hispanics with lung cancer had delayed CGP compared to non-Hispanics (p =0.019) and females with pancreas cancer had delayed CGP compared to males (p =0.025). Lung cancer, gastro-esophageal cancer and gynecologic malignancies had better survival if they had CGP performed during the first tertile after metastatic diagnosis. Conclusion: CGP utilization across cancer types was equitable irrespective of sex, race and ethnicity. Early CGP after metastatic diagnosis might have effect on treatment delivery and clinical outcomes in cancer type with more actionable targets.

Evaluation, Validation, and Implementation of the Idylla System as Rapid Molecular Testing for Precision Medicine.

The Idylla Mutation Test System is an automated, PCR-based mutation testing system. The advantages of this system can greatly impact the delivery of precision medicine. We describe our evaluation, validation, and implementation of this system for routine testing of BRAF, EGFR, KRAS, and NRAS using formalin-fixed, paraffin-embedded cancer samples. All four Idylla test systems showed excellent concordance with reference methods. The analytical sensitivity ranged from 94.66% to 100%, depending on the cartridge, and specificity was 100%. A few discordant results were noted and further investigated: KRAS Q61L was misclassified as Q61H; KRAS Q61R was not identified; there was a false-negative EGFR double mutation (L861Q and G719A); and there was a false-negative EGFR double mutation (T790M and exon 19 deletion). The limit of detection was determined to be 1% or 5% for the variants with available reference material. The turnaround time was shortened by 7 days on average. Idylla testing of a cohort of 25 non-small-cell lung cancer samples with insufficient material for next-generation sequencing testing delivered results for all cases and identified actionable results for eight cases. In addition, patient care would have been changed in four of these cases: targeted therapies were identified in two cases, and repeated biopsies would have been avoided in two cases. The Idylla molecular testing system is an accessible, rapid, robust, and reliable testing option for both routine and challenging formalin-fixed, paraffin-embedded specimens.

Androgen Mediation-and Antiandrogens Mitigation-of the Epidermal Growth Factor Receptor (EGFR) Inhibitor-Induced Rash: Results From a Pilot Randomized Trial and Small Translational Case Series.

BACKGROUND: Although 50% to 90% of patients who receive epidermal growth factor receptor (EGFR) inhibitors develop a rash, options for rash prevention or palliation remain limited. This issue is particularly important from a palliative care standpoint because these agents are prescribed only to patients with incurable cancer. Here, we report (1) gene expression profiling of skin biopsies from patients with an EGFR inhibitor-induced rash and (2) a randomized, placebo-controlled feasibility trial with the antiandrogen, spironolactone. Both investigations were undertaken to begin to explore the hypothesis that androgens mediate EGFR inhibitor-induced rash and that antiandrogens palliate it. METHODS/RESULTS: First, 4 skin biopsies from patients with EGFR inhibitor-induced rash (3 men and 1 woman) were subject to gene expression microarray profiling. A public data set of normal skin gene expression (Gene Expression Omnibus, GSE22998) served as a reference. Sixty percent of commonly interrogated androgen receptor genes (207 of 308 between the 2 data sets) were differentially expressed ( P < .05) in the rash samples. Second, in a 17-patient double-blinded, placebo-controlled trial with topical spironolactone applied to the face, although the primary feasibility end point was not achieved, patients in the spironolactone arm received more doses of EGFR inhibitor, and anecdotal photographic evidence suggested salutatory effects of spironolactone on rash. CONCLUSIONS: Epidermal growth factor receptor inhibitor-induced rash appears to be androgen-mediated; antiandrogen therapy merits further study for rash prevention/palliation.

Brigatinib in Patients With Alectinib-Refractory ALK-Positive NSCLC.

INTRODUCTION: The second-generation anaplastic lymphoma kinase (ALK) inhibitor alectinib recently showed superior efficacy compared to the first-generation ALK inhibitor crizotinib in advanced ALK-rearranged NSCLC, establishing alectinib as the new standard first-line therapy. Brigatinib, another second-generation ALK inhibitor, has shown substantial activity in patients with crizotinib-refractory ALK-positive NSCLC; however, its activity in the alectinib-refractory setting is unknown. METHODS: A multicenter, retrospective study was performed at three institutions. Patients were eligible if they had advanced, alectinib-refractory ALK-positive NSCLC and were treated with brigatinib. Medical records were reviewed to determine clinical outcomes. RESULTS: Twenty-two patients were eligible for this study. Confirmed objective responses to brigatinib were observed in 3 of 18 patients (17%) with measurable disease. Nine patients (50%) had stable disease on brigatinib. The median progression-free survival was 4.4 months (95% confidence interval [CI]: 1.8-5.6 months) with a median duration of treatment of 5.7 months (95% CI: 1.8-6.2 months). Among 9 patients in this study who underwent post-alectinib/pre-brigatinib biopsies, 5 had an ALK I1171X or V1180L resistance mutation; of these, 1 had a confirmed partial response and 3 had stable disease on brigatinib. One patient had an ALK G1202R mutation in a post-alectinib/pre-brigatinib biopsy, and had progressive disease as the best overall response to brigatinib. CONCLUSIONS: Brigatinib has limited clinical activity in alectinib-refractory ALK-positive NSCLC. Additional studies are needed to establish biomarkers of response to brigatinib and to identify effective therapeutic options for alectinib-resistant ALK-positive NSCLC patients.

Liquid Biopsies and Cancer Immunotherapy.

Cancer immunotherapy has recently undergone rapid advances and has become an integral part of the treatment armamentarium in various malignancies. However, tissue-based biomarker development in this arena has been slow, and valid biomarker identification to guide immunotherapeutic management is desperately needed. "Liquid" or blood-based biopsies potentially offer more convenient and efficient means to judge the immune milieu of individual patients and identify who will benefit most from immunotherapy. The following review highlights the current literature regarding the application of liquid biopsies to cancer immunotherapy.

Cinderella in Serum Protein Electrophoresis.

Paraproteinemia is characterised by clonal proliferation of plasma cells. A common laboratory finding in paraproteinemia being a monoclonal peak in serum protein electrophoresis (M band). But there are factors which produce a peak similar to M spike in serum protein electrophoresis and these factors are known as pseudoparaproteins. This case report discusses a rare cause of pseudo M spike in a known case of autoimmune hemolytic anaemia due to administration of drug-Rituximab, a monoclonal antibody by itself.

Advances in Cancer Immunotherapy in Solid Tumors.

Immunotherapy is heralded as one of the most important advances in oncology. Until recently, only limited immunotherapeutic options were available in selected immunogenic cancers like melanoma and renal cell carcinomas. Nowadays, there is an improved understanding that anti-tumor immunity is controlled by a delicate balance in the tumor microenvironment between immune stimulatory and immune inhibitory pathways. Either by blocking the inhibitory pathways or stimulating the activating pathways that regulate cytotoxic lymphocytes, anti-tumor immunity can be enhanced leading to durable anti-tumor responses. Drugs which block the immune regulatory checkpoints namely the PD-1/PDL1 and CTLA 4 pathway have shown tremendous promise in a wide spectrum of solid and hematological malignancies, significantly improving overall survival in newly diagnosed and heavily pretreated patients alike. Hence there is renewed enthusiasm in the field of immune oncology with current research focused on augmenting responses to checkpoint inhibitors by combination therapy as well as studies looking at other immune modulators and adoptive T cell therapy. In this article, we highlight the key clinical advances and concepts in immunotherapy with particular emphasis on checkpoint inhibition as well as the future direction in this field.

Comprehensive Genomic Profiling Identifies a Subset of Crizotinib-Responsive ALK-Rearranged Non-Small Cell Lung Cancer Not Detected by Fluorescence In Situ Hybridization.

INTRODUCTION: For patients with non-small cell lung cancer (NSCLC) to benefit from ALK inhibitors, sensitive and specific detection of ALK genomic rearrangements is needed. ALK break-apart fluorescence in situ hybridization (FISH) is the U.S. Food and Drug Administration approved and standard-of-care diagnostic assay, but identification of ALK rearrangements by other methods reported in NSCLC cases that tested negative for ALK rearrangements by FISH suggests a significant false-negative rate. We report here a large series of NSCLC cases assayed by hybrid-capture-based comprehensive genomic profiling (CGP) in the course of clinical care. MATERIALS AND METHODS: Hybrid-capture-based CGP using next-generation sequencing was performed in the course of clinical care of 1,070 patients with advanced lung cancer. Each tumor sample was evaluated for all classes of genomic alterations, including base-pair substitutions, insertions/deletions, copy number alterations and rearrangements, as well as fusions/rearrangements. RESULTS: A total of 47 patients (4.4%) were found to harbor ALK rearrangements, of whom 41 had an EML4-ALK fusion, and 6 had other fusion partners, including 3 previously unreported rearrangement events: EIF2AK-ALK, PPM1B-ALK, and PRKAR1A-ALK. Of 41 patients harboring ALK rearrangements, 31 had prior FISH testing results available. Of these, 20 were ALK FISH positive, and 11 (35%) were ALK FISH negative. Of the latter 11 patients, 9 received crizotinib based on the CGP results, and 7 achieved a response with median duration of 17 months. CONCLUSION: Comprehensive genomic profiling detected canonical ALK rearrangements and ALK rearrangements with noncanonical fusion partners in a subset of patients with NSCLC with previously negative ALK FISH results. In this series, such patients had durable responses to ALK inhibitors, comparable to historical response rates for ALK FISH-positive cases. IMPLICATIONS FOR PRACTICE: Comprehensive genomic profiling (CGP) that includes hybrid capture and specific baiting of intron 19 of ALK is a highly sensitive, alternative method for identification of drug-sensitive ALK fusions in patients with non-small cell lung cancer (NSCLC) who had previously tested negative using standard ALK fluorescence in situ hybridization (FISH) diagnostic assays. Given the proven benefit of treatment with crizotinib and second-generation ALK inhibitors in patients with ALK fusions, CGP should be considered in patients with NSCLC, including those who have tested negative for other alterations, including negative results using ALK FISH testing.

Alterations in genes other than EGFR/ALK/ROS1 in non-small cell lung cancer: trials and treatment options.

During the last decade, we have seen tremendous progress in the therapy of lung cancer. Discovery of actionable mutations in EGFR and translocations in ALK and ROS1 have identified subsets of patients with excellent tumor response to oral targeted agents with manageable side effects. In this review, we highlight treatment options including corresponding clinical trials for oncogenic alterations affecting the receptor tyrosine kinases MET, FGFR, NTRK, RET, HER2, HER3, and HER4 as well as components of the RAS-RAF-MEK signaling pathway.

Should Vital Signs Be Routinely Obtained Prior to Intravenous Chemotherapy? Results From a 2-Center Study.

BACKGROUND: The American Society of Clinical Oncology and the Oncology Nursing Society have issued guidelines stating that the vital signs of patients should be routinely checked on days that intravenous chemotherapy is administered. This study sought evidence to justify this approach. METHODS: This trial focused on consecutive patients with cancer from 2 institutions and evaluated outcomes during the first cycle of gemcitabine-based chemotherapy. The primary end point of the study was a visit to the ED, hospitalization, or death during the first cycle of chemotherapy. RESULTS: Medical records from 1,158 patients were reviewed, and vital signs were checked in 589 patients on day 1 and in 486 on day 8. A total of 148 patients (12.8%) were evaluated in the emergency department (ED), 145 (12.5%) were hospitalized, and 11 (0.9%) died during their first cycle of chemotherapy. In multivariate analyses, which were adjusted for age, sex, cancer type, role of chemotherapy, number of chemotherapy drugs administered on day 1, and institution, checking vital signs on day 1 was associated with neither higher rates of ED visits nor with increased hospitalization; however, checking vital signs on day 8 was associated with higher rates of ED visits (odds ratio [OR]: 3.71; 95% confidence interval [CI]: 2.18-6.22; P < .0001) and higher rates of hospitalizations (OR: 3.98; 95% CI: 2.34-6.73; P < .0001). CONCLUSION: This study suggests a need for additional, evidence-based data to support the routine checking of vital signs prior to administering cancer chemotherapy.

Maximizing Time with the Patient: the Creative Concept of a Physician Scribe.

The universal implementation of electronic health records has transformed the practice of medicine. However, there is a general perception that electronic health records impede effective communication with patients. Clinicians feel that they paradoxically spend more time doing nonclinical tasks like documentation and writing orders and less time interacting with their patients. This article evaluates the role of medical scribes in augmenting physician workflows and examines if employing a scribe can enhance physician-patient interactions.

Placebo-controlled trial to determine the effectiveness of a urea/lactic acid-based topical keratolytic agent for prevention of capecitabine-induced hand-foot syndrome: North Central Cancer Treatment Group Study N05C5.

PURPOSE: Hand-foot syndrome (HFS) is a dose-limiting toxicity of capecitabine for which no effective preventative treatment has been definitively demonstrated. This trial was conducted on the basis of preliminary data that a urea/lactic acid-based topical keratolytic agent (ULABTKA) may prevent HFS. PATIENTS AND METHODS: A randomized, double-blind phase III trial evaluated 137 patients receiving their first ever cycle of capecitabine at a dose of either 2,000 or 2,500 mg/m(2) per day for 14 days. Patients were randomly assigned to a ULABTKA versus a placebo cream, which was applied to the hands and feet twice per day for 21 days after the start of capecitabine. Patients completed an HFS diary (HFSD) daily. HFS toxicity grade (Common Terminology Criteria for Adverse Events [CTCAE] v3.0) was also collected at baseline and at the end of each cycle. The primary end point was the incidence of moderate/severe HFS symptoms in the first treatment cycle, based on the patient-reported HFSD. RESULTS: The percentage of patients with moderate/severe HFS symptoms was not different between groups, being 13.6% in the ULABTKA arm and 10.2% in the placebo arm (P = .768 by Fisher's exact test). The odds ratio was 1.37 (95% CI, 0.37 to 5.76). Cycle 1 CTCAE skin toxicity was higher in the ULABTKA arm but not significantly so (33% v 27%; P = .82). No significant differences were observed in other toxicities between groups. CONCLUSION: These data do not support the efficacy of a ULABTKA cream for preventing HFS symptoms in patients receiving capecitabine.

Adjuvant chemotherapy for resected stage II and III colon cancer: comparison of two widely used prognostic calculators.

Two Web-based prognostic calculators (Adjuvant! and Numeracy) are widely used to individualize decisions regarding adjuvant therapy among patients with resected stage II and III colon cancer. However, these tools have not been directly compared. Hypothetical scenarios were formulated for the Numeracy calculator based on all potential combinations of age, lymph nodes status, tumor stage, and grade of tumor. These were then applied to three postsurgical therapy choices: observation, 5-fluorouracil (5-FU), or FOLFOX (5-FU, leucovorin, and oxaliplatin chemotherapy) to obtain the predicted 5-year disease-free survival (DFS) and overall survival (OS). Wilcoxon signed rank tests were used to compare the numerical predictions between the Adjuvant! and Numeracy calculators for each combination. A total of 192 hypothetical patient scenarios were obtained. For these patients, DFS and OS predictions from Adjuvant! were statistically significantly different than Numeracy (P <.05), except for four of 144 categories. While the estimated benefit in DFS and OS for 5-FU compared to surgery obtained from Adjuvant! and Numeracy were similar, the benefit in DFS and OS for FOLFOX over 5-FU, obtained from the Adjuvant! tool was slightly lower than that estimated from Numeracy. Among patients with resected stage II and III colon cancer, the DFS and OS estimates obtained from Numeracy and Adjuvant!, regarding the benefit of 5-FU over surgery, are similar, but the benefits of FOLFOX over 5-FU differ. Validation studies are needed to clarify the discrepancy and to assess the accuracy of these tools for predicting actual patient outcomes.

Thromboembolic events with lenalidomide-based therapy for multiple myeloma.

BACKGROUND: The purpose was to evaluate the incidence and risk factors of thromboembolism associated with lenalidomide therapy in newly diagnosed myeloma. METHODS: A pooled analysis was performed of patients with previously untreated multiple myeloma enrolled in clinical trials of lenalidomide-based therapy at the Mayo Clinic, Rochester, Minnesota, and the Italian Myeloma Network, Italy. The incidence of thrombosis, the effect of risk factors such as steroid dose and erythropoietin supplementation, and the effect of prophylaxis were examined. RESULTS: In all, 125 patients enrolled in 3 clinical trials were identified. Patients were stratified based on the concomitant corticosteroid dose. Fifty-two patients were in the high-dose group (dexamethasone 40 mg, 12 days a month); 73 patients were in the low-dose group (prednisone at any dose; or dexamethasone 40 mg, 4 days a month). A total of 110 patients were initiated on thromboprophylaxis; of these, 104 patients (95%) received aspirin. Ten patients (8%) developed deep vein thrombosis, including 4 who were not receiving any thromboprophylaxis at the time of the event. The rate of thromboembolic events was not different between patients who received concomitant erythropoietin therapy and those who did not, 4.8% and 8.6%, respectively (P= .54). A higher number of venous thrombotic episodes occurred in the high-dose corticosteroid group compared with the low-dose corticosteroid therapy group (12% vs 6%), but the difference was not statistically significant (P= .3). CONCLUSIONS: The incidence of deep vein thrombosis is lower than previously reported in the literature. There was a trend to a higher incidence of thrombosis in patients receiving high-dose corticosteroid therapy.