Arkadiusz Z. Dudek

Afatinib for patients with lung adenocarcinoma and epidermal growth factor receptor mutations (LUX-Lung 2): a phase 2 trial

BACKGROUND Afatinib is an irreversible ErbB-family blocker with preclinical activity in non-small-cell lung cancer (NSCLC) with EGFR mutations. We aimed to assess the efficacy of afatinib in patients with lung adenocarcinoma and EGFR mutations. METHODS In this phase 2 study, we enrolled patients from 30 centres in Taiwan and the USA with lung adenocarcinoma (stage IIIb with pleural effusion or stage IV) with EGFR mutations, who had no more than one previous chemotherapy regimen for advanced disease, an Eastern Cooperative Oncology Group performance status of 0-2, and no previous treatment with EGFR tyrosine-kinase inhibitors. We tested two afatinib starting doses: 50 mg daily and subsequently 40 mg daily, introduced to establish whether tolerability could be improved with retention of anti-tumour activity. The primary endpoint was the proportion of patients with a confirmed objective response (complete response or partial response), on the basis of Response Evaluation Criteria in Solid Tumors 1.0 (independent review). This study is registered with ClinicalTrials.gov, number NCT00525148. FINDINGS 129 patients were treated with afatinib, 99 with a starting dose of 50 mg and 30 with a starting dose of 40 mg. 79 (61%) of 129 patients had an objective response (two complete responses, 77 partial responses). 70 (66%) of the 106 patients with the two common activating EGFR mutations (deletion 19 or L858R) had an objective response, as did nine (39%) of 23 patients with less common mutations. Similar proportions of patients had an objective response when analysed by starting dose (18 [60%] of 30 patients at 40 mg vs 61 [62%] of 99 patients at 50 mg). Of the two most common adverse events (diarrhoea and rash or acne), grade 3 events were more common in patients receiving a 50 mg starting dose (22 [22%] of 99 patients for diarrhoea and 28 [28%] of 99 patients for rash or acne) than they were in those receiving a 40 mg starting dose (two [7%] of 30 patients for both diarrhoea and rash or acne); possibly treatment-related serious adverse events were also less common in patients receiving a 40 mg starting dose (two of 30 patients vs 14 of 99 patients). We recorded one possibly drug-related death (interstitial lung disease). INTERPRETATION Afatinib shows activity in the treatment of patients with advanced lung adenocarcinoma with EGFR mutations, especially in patients with deletion 19 or L858R mutations. The efficacy of afatinib 40 mg should be compared with chemotherapy or other EGFR tyrosine-kinase inhibitors in EGFR-mutation-positive NSCLC. FUNDING Boehringer Ingelheim Inc.

Computational Methods in Developing Quantitative Structure-Activity Relationships (QSAR): A Review

Virtual filtering and screening of combinatorial libraries have recently gained attention as methods complementing the high-throughput screening and combinatorial chemistry. These chemoinformatic techniques rely heavily on quantitative structure-activity relationship (QSAR) analysis, a field with established methodology and successful history. In this review, we discuss the computational methods for building QSAR models. We start with outlining their usefulness in high-throughput screening and identifying the general scheme of a QSAR model. Following, we focus on the methodologies in constructing three main components of QSAR model, namely the methods for describing the molecular structure of compounds, for selection of informative descriptors and for activity prediction. We present both the well-established methods as well as techniques recently introduced into the QSAR domain.

Bronchiolitis Obliterans in Chronic Graft-versus-Host Disease: Analysis of Risk Factors and Treatment Outcomes

Bronchiolitis obliterans (BrOb), a late complication of bone marrow transplantation (BMT), is associated with chronic graft-versus-host disease (GVHD) and is frequently fatal. To identify the risk factors associated with BrOb, the factors affecting survival, treatment outcomes, and causes of death of patients with BrOb, we retrospectively analyzed 2859 BMT recipients. No cases of BrOb occurred among 1070 autologous BMT recipients. Among 1789 allogeneic BMT recipients, we identified 47 patients with BrOb. In multivariate analysis, older recipients or donors and acute GVHD were significantly associated with the development of BrOb. Among patients with BrOb, 5-year survival from the time of transplantation was only 10%, versus 40% among allogeneic BMT recipients without BrOb. The clinical course of BrOb had a significant effect on survival: 79% survived 5 years from the time of BrOb diagnosis if BrOb improved versus 13% if there was no improvement after the first-line therapy. Predictors of response included older donors and recipients, a previous diagnosis of chronic GVHD, and diagnosis of BrOb 6 months after transplantation; each of these significantly increased the likelihood of a favorable response to treatment. BrOb had high mortality rate of 55%, and pulmonary failure was the leading cause of death. More effective BrOb therapy is needed, especially for patients with unfavorable presentation.

Sequential therapy with sorafenib and sunitinib in renal cell carcinoma.

Sunitinib and sorafenib are small‐molecule tyrosine kinase inhibitors (TKI) with antitumor activity in advanced renal cell carcinoma. A retrospective study was conducted to assess the response of renal cell carcinoma to sequential treatment with these two agents.

Pericytes and vessel maturation during tumor angiogenesis and metastasis

Despite promising results in preclinical and clinical studies, the therapeutic efficacy of antiangiogenic therapies has been restricted by a narrow focus on inhibiting the growth of endothelial cells. Other cell types in the tumor stroma are also critical to the progression of cancer, including mural cells. Mural cells are vascular support cells that range in phenotype from pericytes to vascular smooth muscle cells. Although the role of pericytes and pericyte‐like cells in the pathophysiology of cancer is still unclear, evidence indicates that aberrations in pericyte–endothelial cell signaling networks could contribute to tumor angiogenesis and metastasis. The purpose of this review is to evaluate critically recent evidence on the role of pericytes in tumor biology and discuss potential therapeutic targets for anticancer intervention. Am. J. Hematol. 85:593–598, 2010.

Irinotecan Plus Gemcitabine Induces Both Radiographic and CA 19-9 Tumor Marker Responses in Patients With Previously Untreated Advanced Pancreatic Cancer

PURPOSE This phase II, multicenter, open-label, single-arm study evaluated the efficacy and safety of irinotecan and gemcitabine as combination chemotherapy for previously untreated patients with unresectable or metastatic pancreatic cancer. PATIENTS AND METHODS Patients received repeated 21-day cycles at starting doses of gemcitabine 1,000 mg/m(2) over 30 minutes followed immediately by irinotecan 100 mg/m(2) over 90 minutes, both given intravenously on days 1 and 8. Patients were evaluated for objective tumor response, changes in the serum tumor marker CA 19-9, time to tumor progression (TTP), survival, and safety. RESULTS Forty-five patients were treated. Eleven patients (24%) had 50% or greater reductions in tumor area. These were confirmed one cycle later in nine patients (response rate, 20%; 95% confidence interval, 8% to 32%). Among 44 patients with baseline CA 19-9 determinations, CA 19-9 decreased during therapy in 22 patients (50%) and was reduced by 50% or more in 13 patients (30%). Median TTP was 2.8 months (range, 0.3 to 10.8 months). There were significant (P <.001) correlations between proportional changes in CA 19-9 and radiographic changes in tumor area with regard to extent of change (r =.67), timing of minimum on-study values (r =.85), and tumor progression (r =.89). Median survival was 5.7 months (range, 0.4 to 19.4+ months), and the 1-year survival rate was 27%. Severe toxicities were uncommon and primarily limited to grade 4 neutropenia (2%), grade 4 vomiting (2%), and grade 3 diarrhea (7%). CONCLUSION Irinotecan/gemcitabine is a new combination that offers encouraging activity in terms of radiographic and CA 19-9 response and notable 1-year survival in pancreatic cancer. The regimen was well tolerated, with minimal grade 3 and 4 toxicities and excellent maintenance of planned dose-intensity.

Bisphosphonate-Related Osteonecrosis of the Jaw: Clinical Features, Risk Factors, Management, and Treatment Outcomes of 26 Patients

PURPOSE To report the clinical features, risk factors, management, and treatment outcomes of nitrogen-containing bisphosphonate (n-BIS)-related osteonecrosis of the jaw (BRONJ). PATIENTS AND METHODS Patients with suspected BRONJ were referred to the School of Dentistry for evaluation and treatment. RESULTS A total of 26 patients (9 men and 17 women, mean age 64 years) were diagnosed with BRONJ. Of the 26 patients, 23 had received n-BIS therapy for cancer and 3 for osteoporosis. BRONJ lesions were noted more frequently in the mandible and in the posterior sextants. Of the 26 patients, 16 had developed BRONJ after dentoalveolar procedures, and 10 had developed it spontaneously. The mean interval to development of BRONJ was shorter in the patients with cancer receiving intravenous n-BIS than in the patients with osteoporosis receiving oral n-BIS (37.1 versus 77.7 months, P = .02). Using the American Association of Oral and Maxillofacial Surgeons staging system, 2 patients were diagnosed with stage I lesions, 19 with stage II, and 5 with stage III lesions. The initial management of BRONJ was nonsurgical, with debridement performed at subsequent visits, if needed. The BRONJ lesions healed completely in 4 patients, healed partially in 8, remained stable in 7, and progressed in 7. The spontaneous lesions responded favorably to BRONJ management compared with lesions that developed after dentoalveolar procedures (P = .01). No significant difference was found in response to BRONJ management between patients who had continued or discontinued n-BIS therapy after the BRONJ diagnosis (P = .54). CONCLUSIONS Long-term n-BIS therapy and recent dental procedures are consistent findings in patients with BRONJ. Spontaneous BRONJ lesions respond favorably to current BRONJ treatment strategies.

Phase II Study of Amrubicin As Second-Line Therapy in Patients With Platinum-Refractory Small-Cell Lung Cancer

PURPOSE Amrubicin is a synthetic anthracycline with potent topoisomerase II inhibition. This phase II study was conducted to confirm safety and activity of amrubicin in the treatment of refractory small-cell lung cancer (SCLC). PATIENTS AND METHODS Patients with refractory SCLC (either with progressive disease as best response or progression within 90 days of first-line therapy) received amrubicin (40 mg/m(2)/d for 3 every 21 days). The primary end point was overall response rate (ORR); secondary end points included progression-free survival (PFS), overall survival (OS), and change in left ventricular ejection fraction (LVEF). RESULTS Seventy-five patients with a median progression-free interval after first-line therapy of 38 days were enrolled; 69 patients received a median of four amrubicin cycles (range, one to 12 cycles). The ORR was 21.3% (95% CI, 12.7% to 32.3%), with one complete response (1.3%) and 15 partial responses (20%). Median PFS and OS were 3.2 months (95% CI, 2.4 to 4.0 months) and 6.0 months (95% CI, 4.8 to 7.1 months), respectively. The ORR in 43 patients who never responded to first-line therapy was 16.3% (95% CI, 6.8% to 30.7%). Most commonly reported grade 3 or 4 adverse events included neutropenia (67%), thrombocytopenia (41%), and anemia (30%), with febrile neutropenia in 12%. There was no decrease in mean LVEF with cumulative amrubicin doses exceeding 750 mg/m(2). CONCLUSION Single-agent amrubicin showed promising activity with a 21.3% ORR and an acceptable safety profile when used as second-line therapy patients with platinum-refractory SCLC. Amrubicin did not induce early cardiotoxicity, but its long-term effects are unknown.

Mechanisms Limiting Distribution of the Threonine-Protein Kinase B-RaF V600E Inhibitor Dabrafenib to the Brain: Implications for the Treatment of Melanoma Brain Metastases

Brain metastases are a common cause of death in stage IV metastatic melanoma. Dabrafenib is a BRAF (gene encoding serine/threonine-protein kinase B-Raf) inhibitor that has been developed to selectively target the valine 600 to glutamic acid substitution (BRAFV600E), which is commonly found in metastatic melanoma. Clinical trials with dabrafenib have shown encouraging results; however, the central nervous system distribution of dabrafenib remains unknown. Thus, the objective of the current study was to evaluate the brain distribution of dabrafenib in mice, and to see whether active efflux by P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) restricts its delivery across the blood-brain barrier (BBB). In vitro accumulation studies conducted in Madin-Darby canine kidney II cells indicate that dabrafenib is an avid substrate for both P-gp and BCRP. Directional flux studies revealed greater transport in the basolateral to apical direction with corrected efflux ratios greater than 2 for both P-gp and Bcrp1 transfected cell lines. In vivo, the ratio of area under the concentration-time curve (AUC)brain to AUCplasma (Kp) of dabrafenib after an i.v. dose (2.5 mg/kg) was 0.023, which increased by 18-fold in Mdr1 a/b−/−Bcrp1−/− mice to 0.42. Dabrafenib plasma exposure was ∼2-fold greater in Mdr1 a/b−/−Bcrp1−/− mice as compared with wild-type with an oral dose (25 mg/kg); however, the brain distribution was increased by ~10-fold with a resulting Kp of 0.25. Further, compared with vemurafenib, another BRAFV600E inhibitor, dabrafenib showed greater brain penetration with a similar dose. In conclusion, the dabrafenib brain distribution is limited in an intact BBB model, and the data presented herein may have clinical implications in the prevention and treatment of melanoma brain metastases.

First in Human Phase I Trial of 852A, a Novel Systemic Toll-like Receptor 7 Agonist, to Activate Innate Immune Responses in Patients with Advanced Cancer

Purpose: Recent advances in the understanding of innate immunity suggest that an orchestrated sequence of events is required to elicit a productive immune response against cancer. We studied the systemic administration of the Toll-like receptor 7 agonist 852A, a small-molecule imidazoquinoline, in patients with advanced cancer. Preclinical studies showed that 852A stimulates plasmacytoid dendritic cells to produce multiple cytokines, such as IFN-α, interleukin-1 receptor antagonist, and IFN-inducible protein-10. Our goal was to define the tolerated dose, pharmacokinetics, pharmacodynamics, and immunologic effects of 852A in humans. Experimental Design: Eligible adult patients with refractory solid organ tumors received i.v. 852A thrice weekly for 2 weeks. Patients who had responses or stable disease were eligible for additional cycles. Results: Twenty-five patients (median age, 55.0 years; 72% male) were enrolled in six cohorts at dose levels of 0.15 to 2.0 mg/m2. Serum drug levels showed dose proportionality and no evidence of drug accumulation. The maximum tolerated dose was 1.2 mg/m2; higher doses were limited by fatigue and constitutional symptoms. Increases in IFN-α, interleukin-1 receptor antagonist, and IFN-inducible protein-10, immunologic activity, and clinical symptoms were observed in all patients receiving dose levels ≥0.6 mg/m2. Significant correlations were found between pharmacodynamic biomarkers and pharmacokinetic variables, and an objective clinical response was seen. Conclusions: 852A was safely administered i.v. at doses up to 1.2 mg/m2 thrice weekly for 2 weeks with transient or reversible adverse effects. This novel Toll-like receptor 7 agonist is biologically active and holds promise for stimulating innate immune responses. Future trials are warranted to assess its therapeutic role in patients with cancer.