Phase Ib study of telisotuzumab vedotin in combination with erlotinib in patients with c-Met protein-expressing non-small-cell lung cancer

PURPOSE: Overexpression of c-Met protein and epidermal growth factor receptor ( PATIENTS AND METHODS: This study evaluated Teliso-V (2.7 mg/kg once every 21 days) plus erlotinib (150 mg once daily) in adult patients (age ≥ 18 years) with c-Met+ NSCLC. Later enrollment required presence of an RESULTS: As of January 2020, 42 patients were enrolled (N = 36 efficacy-evaluable). Neuropathies were the most common any-grade adverse events reported, with 24 of 42 patients (57%) experiencing at least one event. The pharmacokinetic profile of Teliso-V plus erlotinib was similar to Teliso-V monotherapy. Median PFS for all efficacy-evaluable patients was 5.9 months (95% CI, 2.8 to not reached). ORR for CONCLUSION: Teliso-V plus erlotinib showed encouraging antitumor activity and acceptable toxicity in EGFR TKI-pretreated patients wit

A phase 1b study of telisotuzumab vedotin in combination with nivolumab in patients with NSCLC

INTRODUCTION: Telisotuzumab vedotin (Teliso-V) is an anti-c-Met-directed antibody-drug conjugate that has exhibited antitumor activity as monotherapy in NSCLC. Its potential activity combined with programmed cell death protein-1 inhibitors has not been previously evaluated. METHODS: In a phase 1b study (NCT02099058), adult patients (≥18 y) with advanced NSCLC received combination therapy with Teliso-V (1.6, 1.9, or 2.2 mg/kg, every 2 wk) plus nivolumab (3 mg/kg, 240 mg, or per locally approved label). The primary objective was to assess safety and tolerability; secondary objectives included the evaluation of antitumor activity. RESULTS: As of January 2020, a total of 37 patients received treatment with Teliso-V (safety population) in combination with nivolumab; 27 patients (efficacy population) were c-Met immunohistochemistry-positive. Programmed death-ligand 1 (PD-L1) status was evaluated in the efficacy population (PD-L1-positive [PD-L1+]: n = 15; PD-L1-negative [PD-L1-]: n = 9; PD-L1-unknown: n = 3). The median age was 67 years and 74% (20 of 27) of patients were naive to immune checkpoint inhibitors. The most common any-grade treatment-related adverse events were fatigue (27%) and peripheral sensory neuropathy (19%). The pharmacokinetic profile of Teliso-V plus nivolumab was similar to Teliso-V monotherapy. The objective response rate was 7.4%, with two patients (PD-L1+, c-Met immunohistochemistry H-score 190, n = 1; PD-L1-, c-Met H-score 290, n = 1) having a confirmed partial response. Overall median progression-free survival was 7.2 months (PD-L1+: 7.2 mo; PD-L1-: 4.5 mo; PD-L1-unknown: not reached). CONCLUSIONS: Combination therapy with Teliso-V plus nivolumab was well tolerated in patients with c-Met+ NSCLC with limited antitumor activity

Risk-stratified patients with resectable soft tissue sarcoma benefit from epirubicin-based adjuvant chemotherapy

As adjuvant chemotherapy (AC) for soft tissue sarcomas is controversial, we performed a retrospective analysis of patients seen at Washington University in St. Louis to evaluate whether it benefited our patient population. Patients were risk-assessed using the Memorial Sloan Kettering Predictive Nomogram (MSKPN). We defined high-risk patients by a MSKPN 4-year postoperative probability of sarcoma-specific death of ≥0.3 and investigated if they benefited from AC. Retrospective review was performed on patients seen between 15 February 1996 and 6 February 2010. A propensity score method in the logistic regression framework was used to model the likelihood of receiving AC. To make causal inference on the effect of AC on survival outcomes, a propensity score inverse probability of treatment weighting approach was applied to survival analysis. Overall, 135 high-grade patients were assessed, 33 were treated with Ifosfamide/Epirubicin (I/Epi) and 102 were non AC patients. The stratified MSKPN risk was not significantly associated with any survival endpoint in the whole cohort, but trended for overall survival (OS) when evaluated against non AC patients. After adjustment for MSKPN risk and other variables, patients not receiving chemotherapy had significantly worse OS, recurrent free survival, and disease-specific survival (DSS) with adjusted hazard ratios of 4.18 (95% CI: 2.22–7.90), 8.96 (95% CI: 3.85–20.83), and 5.42 (95% CI: 2.09–14.06), respectively. In retrospective analyses, risk-stratified patients with soft tissue sarcoma benefited from I/Epi-based AC. Randomized I/Epi versus I/Doxorubicin clinical trials may determine the optimal adjuvant treatment

A phase 1 study evaluating rovalpituzumab tesirine in frontline treatment of patients with extensive-stage SCLC

INTRODUCTION: Rovalpituzumab tesirine (Rova-T) is an antibody-drug conjugate targeting DLL3, a Notch pathway ligand highly expressed on SCLC cells. Rova-T was evaluated alone or in combination with platinum-based chemotherapy (cisplatin or carboplatin combined with etoposide [CE]) in frontline treatment of extensive-stage SCLC. METHODS: One cycle of CE pre-enrollment was permitted (later mandated). The following four cohorts were enrolled: Rova-T monotherapy (0.3 mg/kg, every 6 [q6] wk × 2; cohort 1; n = 4); Rova-T induction (0.3 mg/kg, q6 wk × 2) followed by CE every 21 days (q21) × 4 (cohort 2; n = 5); Rova-T (0.1 or 0.2 mg/kg, q6 wk × 2) overlapping with CE q21 × 4 (cohort 3; n = 14); and Rova-T maintenance (0.3 mg/kg, q6 wk × 2) after CE q21 × 4 (cohort 4; n = 3). RESULTS: A total of 26 patients were dosed (cohort 3: 14; cohorts 1, 2, and 4 combined: 12). Median age was 66 years, and 73% had Eastern Cooperative Oncology Group performance status of 1. In cohort 3, seven patients (50%) had confirmed objective responses, with a median progression-free survival of 5.2 months and median overall survival of 10.3 months. Compared with cohorts 1, 2, and 4 combined, cohort 3 had lower frequency of some Rova-T-related adverse events of special interest, such as pleural effusion (0 versus 33%), pericardial effusion (0 versus 17%), ascites (0 versus 8%), peripheral edema (36% versus 42%), generalized edema (0 versus 8%), pneumonia (7% versus 25%), and hypoalbuminemia (0 versus 17%). CONCLUSIONS: Lower Rova-T doses may be associated with lower incidence of some Rova-T-related adverse events of special interest. Rova-T 0.2 mg/kg plus CE (cohort 3) was tolerable; however, there was no clear efficacy benefit of adding Rova-T to CE

Factors associated with incomplete resection for large, locally invasive non-small cell lung cancer

BACKGROUND: Large, node-negative but locally invasive non-small cell lung cancer (NSCLC) is associated with increased perioperative risk but improved survival if a complete resection is obtained. Factors associated with positive margins in this population are not well-studied. METHODS: We performed a retrospective cohort study using National Cancer Database (NCDB) for adult patients with \u3e5 cm, clinically node-negative NSCLC with evidence of invasion of nearby structures [2006-2015]. Patients were classified as having major structure involvement (azygous vein, pulmonary artery/vein, vena cava, carina/trachea, esophagus, recurrent laryngeal/vagus nerve, heart, aorta, vertebrae) or chest wall invasion (rib pleura, chest wall, diaphragm). Our primary outcome was to evaluate factors associated with incomplete resection (microscopic: R1, macroscopic: R2). Kaplan-Meier analysis and cox multivariable regression models were used to evaluate overall survival (OS), 90-day mortality, and factors associated with positive margins. RESULTS: Among 2,368 patients identified, the median follow-up was 33.8 months [interquartile range (IQR), 12.6-66.5 months]. Most patients were white (86.9%) with squamous cell histology (47.3%). Major structures were involved in 26.4% of patients and chest wall invasion was seen in 73.6%. Four hundred and seventy-eight patients (20.2%) had an incomplete resection. Multivariable analysis revealed that black race [hazard ratio (HR) 1.568, 95% confidence interval (CI): 1.109-2.218] and major structure involvement (HR 1.412, 95% CI: 1.091-1.827) was associated with increased risk of incomplete resection and surgery at an academic hospitals (HR 0.773, 95% CI: 0.607-0.984), adenocarcinoma histology (HR 0.672, 95% CI: 0.514-0.878), and neoadjuvant chemotherapy (HR 0.431, 95% CI: 0.316-0.587) were associated with decreased risk of incomplete resection. The 5-year OS was 43.7% in the entire cohort and 28.8% in patients with positive margins and 47.5% in patients with an R0 resection. Positive margin was also associated with a significantly higher 90-day mortality rate (9.9% versus 6.7%). CONCLUSIONS: For patients with large, node-negative NSCLC invading nearby structures, R0 resection portends better survival. Treatment at academic centers, adenocarcinoma histology, and receipt of neoadjuvant chemotherapy are associated with R0 resection in this high-risk cohort

A Phase 1b Study of Telisotuzumab Vedotin in Combination With Nivolumab in Patients With NSCLC

Introduction: Telisotuzumab vedotin (Teliso-V) is an anti-c-Met-directed antibody-drug conjugate that has exhibited antitumor activity as monotherapy in NSCLC. Its potential activity combined with programmed cell death protein-1 inhibitors has not been previously evaluated. Methods: In a phase 1b study (NCT02099058), adult patients (≥18 y) with advanced NSCLC received combination therapy with Teliso-V (1.6, 1.9, or 2.2 mg/kg, every 2 wk) plus nivolumab (3 mg/kg, 240 mg, or per locally approved label). The primary objective was to assess safety and tolerability; secondary objectives included the evaluation of antitumor activity. Results: As of January 2020, a total of 37 patients received treatment with Teliso-V (safety population) in combination with nivolumab; 27 patients (efficacy population) were c-Met immunohistochemistry-positive. Programmed death-ligand 1 (PD-L1) status was evaluated in the efficacy population (PD-L1-positive [PD-L1+]: n = 15; PD-L1-negative [PD-L1-]: n = 9; PD-L1-unknown: n = 3). The median age was 67 years and 74% (20 of 27) of patients were naive to immune checkpoint inhibitors. The most common any-grade treatment-related adverse events were fatigue (27%) and peripheral sensory neuropathy (19%). The pharmacokinetic profile of Teliso-V plus nivolumab was similar to Teliso-V monotherapy. The objective response rate was 7.4%, with two patients (PD-L1+, c-Met immunohistochemistry H-score 190, n = 1; PD-L1-, c-Met H-score 290, n = 1) having a confirmed partial response. Overall median progression-free survival was 7.2 months (PD-L1+: 7.2 mo; PD-L1-: 4.5 mo; PD-L1-unknown: not reached). Conclusions: Combination therapy with Teliso-V plus nivolumab was well tolerated in patients with c-Met+ NSCLC with limited antitumor activity

Nab-paclitaxel plus durvalumab in patients with previously treated advanced stage non-small cell lung cancer (ABOUND.2L+)

Background: The standard therapy for advanced stage non-small cell lung cancer (NSCLC) with no actionable gene alterations is a platinum-based chemotherapy doublet and immune checkpoint blocker (ICB), either concurrently or sequentially, followed by docetaxel at the time of tumor progression. However, more effective treatments are needed. We evaluated the nab-paclitaxel and durvalumab combination in patients with previously treated advanced stage NSCLC.Methods: Patients with advanced stage NSCLC previously treated with one line of platinum-based doublet with or without an ICB and no activating EGFR mutations or ALK translocations received nab-paclitaxel 100 mg/m(2) (days 1 and 8) plus durvalumab 1,125 mg (day 15) every 21 days. The primary endpoint was progression-free survival (PFS). Key secondary endpoints included overall survival (OS) and safety.Results: Between February 2016 and December 2016, 79 patients were enrolled. The median age was 63 years. Most patients were males (68.4%), had non-squamous histology (69.6%), and had no prior ICB treatment (88.6%). The median PFS was 4.5 months; median OS was 10.1 months. A post hoc analysis of survival by prior ICB treatment revealed a median PFS and OS of 4.4 and 9.9 months, respectively, in ICB-naive patients and 6.9 months and not estimable, respectively, in patients previously treated with ICB. The most common treatment-emergent adverse events were asthenia (46.2%) and diarrhea (34.6%); four treatment-related deaths (5.1%) occurred.Conclusions: The nab-paclitaxel and durvalumab combination is feasible and demonstrated antitumor activity without new safety signals. Additional studies using taxanes and ICB in patients with previously treated NSCLC are warranted.EudraCT number: 2014-001105-41Pathogenesis and treatment of chronic pulmonary disease

Strengths and Weaknesses of Immunotherapy for Advanced Non-Small-Cell Lung Cancer: A Meta-Analysis of 12 Randomized Controlled Trials

Background: Lung cancer is one of the leading causes of cancer death worldwide. Non-small-cell lung cancer (NSCLC) accounts for approximately 85 % of all lung cancers. Immunotherapy has yielded no consistent benefit to date for those patients. Assessing the objective efficacy and safety of immunotherapy for advanced NSCLC patients will help to instruct the future development of immunotherapeutic drugs. Methodology and Principal Findings: We performed a meta-analysis of 12 randomized controlled trials including 3134 patients (1570 patients in the immunotherapy group and 1564 patients in the control group) with histologically confirmed stage IIIA, IIIB, or IV NSCLC. The analysis was executed with efficacy end points regarding overall survival (OS), progressionfre