Phase I Study of 2- or 3-Week Dosing of Telisotuzumab Vedotin, an Antibody-Drug Conjugate Targeting c-Met, Monotherapy in Patients with Advanced Non-Small Cell Lung Carcinoma.

PURPOSE: Telisotuzumab vedotin (Teliso-V) is an anti-c-Met-directed antibody-drug conjugate. Here, we present safety and efficacy data from a phase I/Ib study of Teliso-V monotherapy evaluated in once every 2 weeks/once every 3 weeks schedules in patients with non-small cell lung cancer (NSCLC). PATIENTS AND METHODS: During dose escalation, patients received Teliso-V monotherapy intravenously once every 3 weeks (0.15-3.3 mg/kg) or once every 2 weeks (1.6-2.2 mg/kg). The dose-expansion phase enrolled patients with NSCLC and c-Met H-score ≥150 (c-Met+) or MET amplification/exon 14 skipping mutations. Safety, pharmacokinetics, and efficacy were assessed. Herein, the analysis of patients receiving ≥1.6 mg/kg once every 2 weeks or ≥2.4 mg/kg once every 3 weeks Teliso-V is reported. RESULTS: Fifty-two patients with NSCLC were enrolled and received ≥1.6 mg/kg Teliso-V once every 2 weeks (n = 28) or ≥2.4 mg/kg Teliso-V once every 3 weeks (n = 24). The most common adverse events were fatigue (54%), peripheral neuropathy (42%), and nausea (38%). No dose-limiting toxicities were observed for Teliso-V once every 2 weeks and once every 3 weeks up to 2.2 and 2.7 mg/kg, respectively. The recommended phase II dose was established at 1.9 mg/kg once every 2 weeks and 2.7 mg/kg once every 3 weeks on the basis of overall safety and pharmacokinetics. Forty of 52 patients were c-Met+ (33 nonsquamous, 6 squamous, 1 mixed histology) and were included in the efficacy-evaluable population. Of those, 9 (23%) had objective responses with median duration of response of 8.7 months; median progression-free survival was 5.2 months. CONCLUSIONS: Teliso-V monotherapy was tolerated and showed antitumor activity in c-Met+ NSCLC. On the basis of overall safety, pharmacokinetics, and efficacy outcomes, 1.9 mg/kg Teliso-V once every 2 weeks and 2.7 mg/kg once every 3 weeks schedules were selected for further clinical development.

Veliparib in Combination with Carboplatin and Etoposide in Patients with Treatment-Naïve Extensive-Stage Small Cell Lung Cancer: A Phase 2 Randomized Study.

PURPOSE: This study investigated the efficacy and safety of oral PARP inhibitor veliparib, plus carboplatin and etoposide in patients with treatment-naïve, extensive-stage small cell lung cancer (ED-SCLC). PATIENTS AND METHODS: Patients were randomized 1:1:1 to veliparib [240 mg twice daily (BID) for 14 days] plus chemotherapy followed by veliparib maintenance (400 mg BID; veliparib throughout), veliparib plus chemotherapy followed by placebo (veliparib combination only), or placebo plus chemotherapy followed by placebo (control). Patients received 4-6 cycles of combination therapy, then maintenance until unacceptable toxicity/progression. The primary endpoint was progression-free survival (PFS) with veliparib throughout versus control. RESULTS: Overall (N = 181), PFS was improved with veliparib throughout versus control [hazard ratio (HR), 0.67; 80% confidence interval (CI), 0.50-0.88; P = 0.059]; median PFS was 5.8 and 5.6 months, respectively. There was a trend toward improved PFS with veliparib throughout versus control in SLFN11-positive patients (HR, 0.6; 80% CI, 0.36-0.97). Median overall survival (OS) was 10.1 versus 12.4 months in the veliparib throughout and control arms, respectively (HR, 1.43; 80% CI, 1.09-1.88). Grade 3/4 adverse events were experienced by 82%, 88%, and 68% of patients in the veliparib throughout, veliparib combination-only and control arms, most commonly hematologic. CONCLUSIONS: Veliparib plus platinum chemotherapy followed by veliparib maintenance demonstrated improved PFS as first-line treatment for ED-SCLC with an acceptable safety profile, but there was no corresponding benefit in OS. Further investigation is warranted to define the role of biomarkers in this setting.

Impact of Emergent Circulating Tumor DNA RAS Mutation in Panitumumab-Treated Chemoresistant Metastatic Colorectal Cancer.

Purpose: The accumulation of emergent RAS mutations during anti-EGFR therapy is of interest as a mechanism for acquired resistance to anti-EGFR treatment. Plasma analysis of circulating tumor (ct) DNA is a minimally invasive and highly sensitive method to determine RAS mutational status.Experimental Design: This biomarker analysis of the global phase III ASPECCT study used next-generation sequencing to detect expanded RAS ctDNA mutations in panitumumab-treated patients. Plasma samples collected at baseline and posttreatment were analyzed categorically for the presence of RAS mutations by the PlasmaSelect-R 64-gene panel at 0.1% sensitivity.Results: Among panitumumab-treated patients with evaluable plasma samples at baseline (n = 238), 188 (79%) were wild-type (WT) RAS, and 50 (21%) were mutant RAS Of the 188 patients with baseline ctDNA WT RAS status, 164 had evaluable posttreatment results with a 32% rate of emergent RAS mutations. The median overall survival for WT and RAS mutant status by ctDNA at baseline was 13.7 (95% confidence interval, 11.5-15.4) and 7.9 months (6.4-9.6), respectively (P < 0.0001). Clinical outcomes were not significantly different between patients with and without emergent ctDNA RAS mutations.Conclusions: Although patients with baseline ctDNA RAS mutations had worse outcomes than patients who were WT RAS before initiating treatment, emergent ctDNA RAS mutations were not associated with less favorable patient outcomes in panitumumab-treated patients. Further research is needed to determine a clinically relevant threshold for baseline and emergent ctDNA RAS mutations. Clin Cancer Res; 24(22); 5602-9. ©2018 AACR.

Regional variation and challenges in estimating the incidence of giant cell tumor of bone.

BACKGROUND: Estimating the incidence of giant cell tumor of bone is challenging because few population-based cancer registries record benign bone tumors. We compared two approaches, the indirect (relative index) estimation approach used in The Burden of Musculoskeletal Diseases in the United States (BMUS) and a direct incidence rate approach (from registries that record giant cell tumor), to estimate giant cell tumor incidence in France, Germany, Italy, Spain, the U.K., Sweden, Australia, Canada, Japan, and the U.S. METHODS: Giant cell tumor of bone incidence was calculated with use of the BMUS relative index of giant cell tumor to osteosarcoma in three scenarios (low, base case, and high) from case series. We compared the BMUS approach with the latest data from tumor registries in Australia (1972 to 1996), Japan (2006 to 2008), and Sweden (1993 to 2011) that record giant cell tumors. United Nations population estimates were used to project results to 2013. RESULTS: The low scenario in the BMUS approach reflects data from Unni and Inwards; the incidence of giant cell tumor of bone is 0.34 relative to osteosarcoma. As the incidence of osteosarcoma is 31.4% of the total incidence of bone and joint cancers, the incidence of giant cell tumor is 0.11 times that of all bone and joint cancers. The base scenario reflects the series by Mirra et al., with a giant cell tumor incidence of 0.47 relative to osteosarcoma (0.15 to all bone and joint cancers). The high scenario reflects the series by Ward, with an incidence of 0.84 relative to osteosarcoma (0.26 to all bone and joint cancers). Differences among the three series reflect referral to a national center of excellence compared with referral to a local oncology practice. Registry data indicated a giant cell tumor incidence rate per million per year of 1.33 in Australia, 1.03 in Japan, and 1.11 in Sweden in 2013. The estimated incidence rate per million in the ten countries in 2013 ranged from 1.03 (Japan) to 1.17 (Canada) with use of the registry-based approach and from 0.73 (Japan) for the low scenario) to 2.20 (Germany) for the base case with use of the BMUS approach. CONCLUSIONS: Giant cell tumor of bone affects approximately one person per million per year in the ten countries studied. Estimates derived with use of age-specific incidences from tumor registries were typically within the range of the low and base case BMUS scenarios. We recommend the registry-derived method for estimating the incidence of giant cell tumor.