A phase 2 trial of consolidation pembrolizumab following concurrent chemoradiation for patients with unresectable stage III non-small cell lung cancer: Hoosier Cancer Research Network LUN 14-179.

BACKGROUND: Five-year overall survival (OS) for patients with unresectable stage III non-small cell lung cancer (NSCLC) is poor. Until recently, a standard of care was concurrent chemoradiation alone. Patients with metastatic NSCLC treated with anti-programmed death 1 antibodies have demonstrated improved OS. This trial evaluated pembrolizumab as consolidation therapy after concurrent chemoradiation in patients with unresectable stage III disease. METHODS: Patients with unresectable stage III NSCLC received concurrent chemoradiation with cisplatin and etoposide, cisplatin and pemetrexed, or carboplatin and paclitaxel and 59.4 to 66.6 Gy of radiation. Patients with nonprogression of disease were enrolled and received pembrolizumab (200 mg intravenously every 3 weeks for up to 12 months). The primary endpoint was the time to metastatic disease or death (TMDD). Secondary endpoints included progression-free survival (PFS) and OS. RESULTS: The median follow-up for 93 patients (92 for efficacy) was 32.2 months (range, 1.2-46.6 months). The median TMDD was 30.7 months (95% confidence interval [CI], 18.7 months to not reached), which was significantly longer than the historical control of 12 months (P < .0001). The median PFS was 18.7 months (95% CI, 12.4-33.8 months), and the median OS was 35.8 months (95% CI, 24.2 months to not reached). The 1-, 2-, and 3-year OS estimates were 81.2%, 62.0%, and 48.5%, respectively. Forty patients (43.5%) completed 12 months of treatment (median number of cycles, 13.5). Symptomatic pneumonitis (grade 2 or higher) was noted in 16 patients (17.2%); these cases included 4 grade 3 events (4.3%), 1 grade 4 event (1.1%), and 1 grade 5 event (1.1%). CONCLUSIONS: Consolidation pembrolizumab after concurrent chemoradiation improves TMDD, PFS, and OS in comparison with historical controls of chemoradiation alone. Rates of grade 3 to 5 pneumonitis were similar to those reported with chemoradiation alone.

Anti-CD22 90Y-epratuzumab tetraxetan combined with anti-CD20 veltuzumab: a phase I study in patients with relapsed/refractory, aggressive non-Hodgkin lymphoma.

A lingering criticism of radioimmunotherapy in non-Hodgkin lymphoma is the use of cold anti-CD20 antibody along with the radiolabeled anti-CD20 antibody. We instead combined radioimmunotherapy with immunotherapy targeting different B-cell antigens. We evaluated the anti-CD22 (90)Y-epratuzumab tetraxetan with the anti-CD20 veltuzumab in patients with aggressive lymphoma in whom at least one prior standard treatment had failed, but who had not undergone stem cell transplantation. Eighteen patients (median age 73 years, median of 3 prior treatments) received 200 mg/m(2) veltuzumab once-weekly for 4 weeks, with (90)Y-epratuzumab tetraxetan at planned doses in weeks 3 and 4, and (111)In-epratuzumab tetraxetan in week 2 for imaging and dosimetry. Veltuzumab effectively lowered levels of B cells in the blood prior to the radioimmunotherapy doses. No significant immunogenicity or change in pharmacokinetics of either agent occurred in combination. (111)In imaging showed tumor targeting with acceptable radiation dosimetry to normal organs. For (90)Y-epratuzumab tetraxetan, transient myelosuppression was dose-limiting with 6 mCi/m(2) (222 MBq/m(2)) × 2 being the maximal tolerated dose. Of 17 assessable patients, nine (53%) had objective responses according to the 2007 revised treatment response criteria, including three (18%) complete responses (2 relapsing after 11 and 13 months, 1 continuing to be clinically disease-free at 19 months), and six (35%) partial responses (1 relapsing after 14 months, 5 at 3 - 7 months). Responses occurred in patients with different lymphoma histologies, treated at different (90)Y dose levels, and with a predicted risk of poor outcome, most importantly including five of the six patients treated with the maximal tolerated dose (2 of whom achieved durable complete responses). In conclusion, the combination of (90)Y-epratuzumab tetraxetan and veltuzumab was well-tolerated with encouraging therapeutic activity in this difficult-to-treat population.

Veliparib and nivolumab in combination with platinum doublet chemotherapy in patients with metastatic or advanced non-small cell lung cancer: A phase 1 dose escalation study.

OBJECTIVES: Both combinations of the PARP inhibitor veliparib plus platinum doublet chemotherapy (CT), and the programmed death receptor-1 (PD-1) inhibitor nivolumab plus CT have demonstrated encouraging efficacy for treatment of non-small cell lung cancer (NSCLC). This phase 1 dose-escalation study (NCT02944396) evaluated the quadruple combination of veliparib with nivolumab and doublet CT in patients with unresectable advanced/metastatic NSCLC. MATERIALS AND METHODS: Patients were enrolled into five dosing cohorts: patients received veliparib 120 mg twice daily (BID) combined with nivolumab 360 mg, carboplatin AUC 6 mg/mL∙min, and paclitaxel 200 mg/m2 (C/PAC) or veliparib 80/120/200/240 mg BID in combination with nivolumab 360 mg, carboplatin AUC 6 mg/mL∙min, and pemetrexed 500 mg/m2 (C/PEM). Primary objective was to identify the recommended phase 2 dose (RP2D) of veliparib + nivolumab + CT. Safety, tolerability, and efficacy of this combination were also assessed. RESULTS: Twenty-five patients were enrolled: 6 patients received veliparib 120 mg BID + nivolumab + C/PAC and 19 received veliparib (80-240 mg BID) + nivolumab + C/PEM. No dose-limiting toxicities were reported, and the RP2Ds were veliparib 120 mg BID + nivolumab + C/PAC, and veliparib 240 mg BID + nivolumab + C/PEM. The most common any-grade adverse events (AEs) were fatigue (56%), nausea (52%), and anemia (48%). Grade 3/4 AEs included anemia (32%) and neutropenia (24%), and the most frequent serious AE was malignant neoplasm progression (12%). Veliparib exhibited approximately dose proportional kinetics in the dose range 80-240 mg BID combined with nivolumab and C/PEM, with no effects on pemetrexed pharmacokinetics. Overall, the confirmed objective response rate was 40%, and best overall response was 64%. CONCLUSION: Veliparib combined with nivolumab and platinum doublet CT was tolerated in patients with advanced/metastatic NSCLC, and no evidence of drug-drug interaction was observed. Although preliminary, this quadruple therapy may have promising antitumor activity.

Phase Ib Study of Tirabrutinib in Combination with Idelalisib or Entospletinib in Previously Treated Chronic Lymphocytic Leukemia.

PURPOSE: Bruton tyrosine kinase (BTK) inhibition alone leads to incomplete responses in chronic lymphocytic leukemia (CLL). Combination therapy may reduce activation of escape pathways and deepen responses. This open-label, phase Ib, sequential dose-escalation and dose-expansion study evaluated the safety, tolerability, pharmacokinetics, and preliminary efficacy of the selective BTK inhibitor tirabrutinib alone, in combination with the PI3K delta (PI3Kδ) inhibitor idelalisib, or with the spleen tyrosine kinase (SYK) inhibitor entospletinib in patients with relapsed/refractory CLL. PATIENTS AND METHODS: Patients received either tirabrutinib monotherapy (80 mg every day) or tirabrutinib 20-150 mg every day in combination with either idelalisib (50 mg twice a day or 100 mg every day) or entospletinib (200 mg or 400 mg every day). RESULTS: Fifty-three patients were included. Systemic tirabrutinib exposure was comparable between monotherapy and combination therapy. No MTD was identified. Across all treatment groups, the most common adverse event was diarrhea (43%, 1 patient grade ≥3); discontinuation due to adverse events was uncommon (13%). Objective response rates were 83%, 93%, and 100%, and complete responses were 7%, 7%, and 10% in patients receiving tirabrutinib, tirabrutinib/idelalisib, and tirabrutinib/entospletinib, respectively. As of February 21, 2019, 46 of 53 patients continue to receive treatment on study. CONCLUSIONS: Tirabrutinib in combination with idelalisib or entospletinib was well tolerated in patients with CLL, establishing an acceptable safety profile for concurrent selective inhibition of BTK with either PI3Kδ or SYK. This small study did not establish a superior efficacy of the combinations over tirabrutinib alone. This trial is registered at www.clinicaltrials.gov (NCT02457598).

Therapy of Small Cell Lung Cancer (SCLC) with a Topoisomerase-I-inhibiting Antibody-Drug Conjugate (ADC) Targeting Trop-2, Sacituzumab Govitecan.

Purpose: We evaluated a Trop-2-targeting antibody conjugated with SN-38 in metastatic small cell lung cancer (mSCLC) patients.Experimental Design: Sacituzumab govitecan was studied in patients with pretreated (median, 2; range, 1-7) mSCLC who received either 8 or 10 mg/kg i.v. on days 1 and 8 of 21-day cycles. The primary endpoints were safety and objective response rate (ORR); duration of response, progression-free survival (PFS), and overall survival (OS) were secondary endpoints.Results: Sixty percent of patients showed tumor shrinkage from baseline CTs. On an intention-to-treat basis (N = 50), the ORR was 14% (17% for the 10-mg/kg group); the median response duration, 5.7 months; the clinical benefit rate (CBR ≥4 months), 34%; median PFS, 3.7 months; and median OS, 7.5 months. There was a suggested improvement in PR, CBR, and PFS with sacituzumab govitecan in second-line patients who were sensitive to first-line therapy, but no difference between first-line chemosensitive versus chemoresistant patients in the overall population. There was a statistically significant higher OS in those patients who received prior topotecan versus no topotecan therapy in a small subgroup. Grade ≥3 adverse events included neutropenia (34%), fatigue (13%), diarrhea (9%), and anemia (6%). Trop-2 tumor staining was not required for patient selection. No antibodies to the drug conjugate or its components were detected on serial blood collections.Conclusions: Sacituzumab govitecan appears to have a safe and effective therapeutic profile in heavily pretreated mSCLC patients, including those who are chemosensitive or chemoresistant to first-line chemotherapy. Additional studies as a monotherapy or combination therapy are warranted. Clin Cancer Res; 23(19); 5711-9. ©2017 AACR.

Cytogenetic remission with imatinib therapy in hypereosinophilic syndrome with trisomy 8 and resolution of severe cardiac dysfunction.

We report a 50-year-old patient with idiopathic hypereosinophilic syndrome with trisomy 8 who experienced a complete and durable hematological and cytogenetic remission with low-dose imatinib therapy. He also had a significant reversal of cardiac dysfunction with a reduction in cardiac hypertrophy, resolution of pericardial effusion and mitral and tricuspid regurgitation. He remained in remission 3 years after therapy.

Overexpression of nucleolin in chronic lymphocytic leukemia cells induces stabilization of bcl2 mRNA.

B-cell chronic lymphocytic leukemia (CLL) is characterized by the accumulation of clonal B cells that are resistant to apoptosis as a result of bcl2 oncogene overexpression. Studies were done to determine the mechanism for the up-regulation of bcl-2 protein observed in CD19+ CLL cells compared with CD19+ B cells from healthy volunteers. The 11-fold higher level of bcl-2 protein in CLL cells was positively correlated with a 26-fold elevation in the cytosolic level of nucleolin, a bcl2 mRNA-stabilizing protein. Measurements of the bcl2 heterogeneous nuclear/bcl2 mRNA (hnRNA)/mRNA ratios and the rates of bcl2 mRNA decay in cell extracts indicated that the 3-fold higher steady-state level of bcl2 mRNA in CLL cells was the result of increased bcl2 mRNA stability. Nucleolin was present throughout the nucleus and cytoplasm of CLL cells, whereas in normal B cells nucleolin was only detected in the nucleus. The addition of recombinant human nucleolin to extracts of normal B cells markedly slowed the rate of bcl2 mRNA decay. SiRNA knockdown of nucleolin in MCF-7 cells resulted in decreased levels of bcl2mRNA and protein but no change in beta-actin. These results indicate that bcl-2 overexpression in CLL cells is related to stabilization of bcl2 mRNA by nucleolin.