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Rovalpituzumab tesirine (Rova-T), an antibody-drug conjugate directed against Delta-like protein 3 (DLL3), is under development for patients with small cell lung cancer (SCLC). DLL3 is expressed on the majority of SCLC samples. Because SCLC is rarely biopsied in the course of disease, data regarding DLL3 expression in relapses is not available. The aim of this study was to investigate the expression of DLL3 in chemorelapsed (but untreated with Rova-T) SCLC samples and compare the results with chemonaive counterparts. Two evaluation methods to assess DLL3 expression were explored. Additionally, we assessed if DLL3 expression of chemorelapsed and/or chemonaive samples has prognostic impact and if it correlates with other clinicopathological data. The study included 30 paired SCLC samples, which were stained with an anti DLL3 antibody. DLL3 expression was assessed using tumor proportion score (TPS) and H-score and was categorized as DLL3 low (TPS < 50%, H-score ≤ 150) and DLL3 high (TPS ≥ 50%, H-score > 150). Expression data were correlated with clinicopathological characteristics. Kaplan–Meier curves were used to illustrate overall survival (OS) depending on DLL3 expression in chemonaive and chemorelapsed samples, respectively, and depending on dynamics of expression during course of therapy. DLL3 was expressed in 86.6% chemonaive and 80% chemorelapsed SCLC samples without significant differences between the two groups. However, the extent of expression varied in a substantial proportion of pairs (36.6% with TPS, 43.3% with H-score), defined as a shift from low to high or high to low expression. TPS and H-score provided comparable results. There were no profound correlations with clinicopathological data. Survival analysis revealed a trend toward a more favorable OS in DLL low-expressing chemonaive SCLC (p = 0.57) and, in turn, in DLL3 high-expressing chemorelapsed SCLC (p = 0.42) as well as in SCLC demonstrating a shift from low to high expression (p = 0.56) without being statistically significant. This is the first study to investigate DLL3 expression in a large cohort of rare paired chemonaive-chemorelapsed SCLC specimens. Comparative analysis revealed that DLL3 expression was not stable during the course of therapy, suggesting therapy-based alterations. Unlike in chemonaive samples, a high DLL3 expression in chemorelapsed samples indicated a trend for a more favorable prognosis. Our results highlight the importance to investigate DLL3 in latest chemorelapsed SCLC tumor tissue.

Background: AT-101 (A), a small molecule oral inhibitor of the Bcl-2 family, has activity alone and in combination with docetaxel (Taxotere) and prednisone (DP) in metastatic castration-resistant prostate cancer (mCRPC). A randomized, double-blind, placebo-controlled phase II trial compared DP combined with either AT-101 (A) or placebo in chemonaive mCRPC.Patients and methods: Men with progressive mCRPC despite androgen deprivation were eligible and randomized 1 : 1. Patients received docetaxel (75 mg/m2 day 1) and prednisone 5 mg orally twice daily every 21 days with either AT-101 (40 mg) or placebo twice daily orally on days 1–3. The primary end point was overall survival (OS).Results: Two hundred and twenty-one patients were randomly assigned. Median OS for AT-101 plus docetaxel–prednisone (ADP) and placebo–DP was 18.1 versus 17.8 months [hazard ratio (HR) 1.07, 95% confidence interval 0.72–1.55, P = 0.63]. Secondary end points were also not statistically different. Grade 3/4 toxic effects for ADP versus placebo–DP were cardiac events (5% versus 2%), lymphopenia (23% versus 16%), neutropenia (47% versus 40%), ileus (2% versus 0%) and pulmonary embolism (6% versus 2%). In a subgroup of high-risk mCRPC (n = 34), outcomes appeared to favor ADP (median OS 19 versus 14 months).Conclusions: AT-101 was tolerable but did not extend OS when combined with DP in mCRPC; a potential benefit was observed in high-risk patients. [ABSTRACT FROM PUBLISHER]

Abstract: Purpose: This multicenter, randomized, open-label, phase II study (JO19907) compared the efficacy and safety of first-line carboplatin-paclitaxel (CP) alone with bevacizumab-CP in Japanese patients with advanced non-squamous non-small-cell lung cancer (NSCLC). Methods: Chemonaïve patients with stage IIIB, IV or recurrent non-squamous NSCLC were eligible for participation. Patients were randomly assigned in a 2:1 ratio to receive bevacizumab-CP or CP alone. Chemotherapy was repeated for up to 6 cycles or until disease progression or unacceptable toxicity. Bevacizumab recipients who completed ≥3 cycles of chemotherapy could continue bevacizumab as monotherapy until disease progression or unacceptable toxicity. The primary endpoint was progression-free survival (PFS). Results: After confirming the tolerability of bevacizumab-CP in a small number of patients, 180 patients were recruited, of whom 121 were assigned to bevacizumab-CP and 59 to CP alone. Hazard ratio (HR) for PFS was 0.61 with bevacizumab-CP versus CP alone (p =0.0090; median 6.9 versus 5.9 months). Objective response rate was significantly higher with bevacizumab-CP than with CP alone (60.7% versus 31.0%; p =0.0013). Median overall survival was >22 months in both treatment groups (HR 0.99; p =0.9526). No new safety signals were detected. Conclusion: Study JO19907 met its primary endpoint, demonstrating that the addition of bevacizumab to first-line CP significantly improves PFS in Japanese patients with advanced non-squamous NSCLC. This prolonged PFS by bevacizumab did not translate into OS benefit with the extremely longer underlying survival compared to historical data. No new safety signals were identified in this population. (Japan Pharmaceutical Information Center [JAPIC] registration number: CTI-060338). [Copyright &y& Elsevier]

Background: Both bevacizumab and erlotinib have clinical activity in non-small-cell lung cancer (NSCLC). Preclinical data suggest synergistic activity.Patients and methods: Chemonaive patients with stage IIIb or IV non-squamous NSCLC were treated with bevacizumab 15 mg/kg every 3 weeks and erlotinib 150 mg daily until progression. Primary end point was non-progression rate (NPR) at 6 weeks. Tumor response was measured with computed tomography, 2-[fluorine-18]fluoro-2-deoxy-D-glucose (FDG–PET) and dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI). KRAS and EGFR mutations were assessed in tumor samples.Results: Forty-seven patients were included. Median follow-up was 15.2 months. NPR at 6 weeks was 75%. Median progression-free survival (PFS) was 3.8 [95% confidence interval (CI) 2.3–5.4] months and median overall survival (OS) was 6.9 (95% CI 5.5–8.4) months. Toxicity was mainly mild. The presence of KRAS (n = 10) or EGFR mutations (n = 5) did not influence outcome. After 3 weeks of treatment, >20% decrease in standard uptake value as measured with positron emission tomography predicted for longer PFS (9.7 versus 2.8 months; P = 0.01) and >40% decrease in Ktrans as assessed by DCE-MRI did not predict for longer PFS.Conclusions: First-line treatment with bevacizumab and erlotinib in stage IIIb/IV NSCLC resulted in an NPR of 75%. OS was however disappointing. Early response evaluation with FDG–PET is the best predictive test for PFS. [ABSTRACT FROM AUTHOR]

Background: Preclinically, protein kinase C and AKT activation can be inhibited by enzastaurin and reduce tumor growth of colorectal cancer cells. In asymptomatic patients with metastatic colorectal cancer (mCRC), enzastaurin activity was evaluated by measuring the 6-month progression-free survival (PFS) rate in a window study design. [ABSTRACT FROM PUBLISHER]

Abstract: Introduction: This phase II study assessed the efficacy and safety of oral vinorelbine given weekly in combination with carboplatin (CBDCA) AUC 5 once every 3 weeks for four cycles in chemonaive patients with advanced non-small cell lung carcinoma (NSCLC), followed by consolidation therapy with single-agent oral vinorelbine in non-progressive patients. Methods: Chemonaive advanced NSCLC patients received four cycles of combination therapy with CBDCA AUC 5 day 1 and oral vinorelbine, 60mg/m2 on days 1, 8 and 15 (cycle 1), dose increased to 80mg/m2 (cycles 2–4) in absence of grades 3–4 neutropenia (NCI-CTCv2). Consolidation therapy with oral vinorelbine was continued (cycle 5) at same dosage; if dose was decreased during combination therapy, it was given at 60mg/m2, then increased at 80mg/m2 (cycle 6) in absence of grades 3–4 neutropenia until PD, toxicity or patient''s refusal. Results: A total of 57 patients were registered and 56 patients were treated (ITT population), median age was 61 years (37–71). Objective response evaluated by RECIST was 17.9% (95% confidence interval, CI [8.9–30.4]) and disease control (CR, PR, NC) 73.2% (95% CI [59.7–84.2]), median progression-free survival 4.3 months (95% CI [3.1–5.1]) with median overall survival 9.7 months (95% CI [7.7–11.9]) and 1-year survival 37.1% (95% CI [24.4, 49.9]). Grades 3–4 neutropenia occurred in 67.9% of patients during combination and 20% during consolidation; febrile neutropenia occurred in 4 patients (7.1%) during combination therapy. Non-hematological toxicities occurred primarily during combination (grade 3 nausea and grade 3 vomiting in 7.1% of patients). Conclusions: The combination of oral vinorelbine given weekly in 3-week cycles in combination with carboplatin followed by consolidation therapy with oral vinorelbine as a single-agent was able to achieve efficacy results in line with other doublets including carboplatin in terms of response as well as survival. This regimen reported a good profile of tolerability in the treatment of advanced NSCLC, allowing that this combination can be easily proposed for the palliative care of NSCLC patients where the advantages of carboplatin over cisplatin are still appreciated. [Copyright &y& Elsevier]

Summary: Pemetrexed is an antitumor agent traditionally used as monotherapy for the second-line treatment of patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) as well as in combination with cisplatin for the treatment of chemonaïve patients with unresectable malignant pleural mesothelioma. Recently, pemetrexed has been approved in combination with cisplatin for the first-line treatment of patients with locally advanced or metastatic NSCLC other than predominantly squamous cell histology. Studies that support the development of this indication are detailed in this review. We performed a PubMed/Medline database search to identify relevant literature from 1998 until August 2008. Bibliographies from identified references were searched, as well as were abstracts from the most relevant congresses in lung cancer area (American Society of Clinical Oncology Congress, World Conferences of Lung Cancer). We detailed pemetrexed studies in the first-line setting of NSCLC treatment, in monotherapy, in combination with platinum and also, with other agents. Data regarding efficacy differences related to different histologic types were also analyzed. [Copyright &y& Elsevier]

Summary: Chemotherapy (CT) is recommended in numerous clinical guidelines for advanced non-small cell lung cancer (NSCLC) and offers improved survival over best supportive care. However, many patients with advanced NSCLC never receive CT because of advanced age, poor performance status, comorbidities, or patient refusal. The epidermal growth factor receptor tyrosine kinase inhibitor gefitinib has shown antitumor activity and a favorable toxicity profile in pretreated patients with recurrent advanced NSCLC and was made available in a worldwide Expanded Access Program (EAP) to >37,000 patients who did not respond to standard treatment or were ineligible for or refused CT. A retrospective chart review of 1671 consecutive patients enrolled at 11 sites in the US arm of the EAP identified 198 patients with advanced NSCLC who had not received previous CT. All patients were treated with gefitinib 250mg/d until treatment failure or toxicity occurred. Patients were treated for a mean of 4.7 months. The most common adverse events were diarrhea (31.3%) and rash (31.3%). Complete and partial response rates were 0.7 and 5.6%, respectively, and 40.6% had stable disease. Median survival was 6 months, and estimated 1-year survival was 29.7%. The majority of patients did not receive subsequent CT. [Copyright &y& Elsevier]

Docetaxel and Gemcitabine are active agents in non-small cell lung carcinoma (NSCLC). They have different mechanism of action, minimal overlapping toxicity, and are easily administered on an outpatient basis. This phase II study evaluated Docetaxel administered with Gemcitabine on days 1 and 8 in a 3-week cycle, to determine its efficacy, while attempting to lower the regimen’s toxicity, especially myelosuppression which can occur when Docetaxel is administered at full dose on day 1 only. Forty-three chemonaive patients, 40 evaluable, were entered in this trial between May 2001 and March 2002. Thirty-seven patients had stage IV and three patients had stage III B NSCLC, median age 58 (ages 32–78), median performance status (PS) 1 (range 0–2). They were treated with Docetaxel 36 mg/m2 and Gemcitabine 1000 mg/m2 intravenously on days 1 and 8 in a 3-week cycle. No growth factors were administered. Of 40 evaluable patients, 4 achieved partial response (10%), 25 stable disease (62.5%) and 11 progressive disease (27.5%). Median time-to-disease progression was 15 weeks. Median survival was 7.75 months. One year survival was 32.5% (13 patients). Hematologic toxicity was minimal, non-hematologic toxicity was easily treatable. Docetaxel, when given with Gemcitabine on days 1 and 8 every 3 weeks, is less myelotoxic, yet still an effective treatment for metastatic NSCLC. [Copyright &y& Elsevier]

: ObjectiveThis phase II study was performed to evaluate the activity and toxicity of gemcitabine plus cisplatin as first-line treatment of advanced epithelial ovarian cancer.: MethodsChemonaive patients with histologically or cytologically confirmed FIGO stage III or IV epithelial ovarian carcinoma were enrolled. Patients received cisplatin 75 mg/m2 on Day 1 and gemcitabine 1250 mg/m2 on Days 1 (after cisplatin) and 8 of a 21-day cycle.: ResultsOf the 42 female patients (median age 60 years) enrolled, 81% had a Zubrod performance status of 0 or 1. Among the 37 response-evaluable patients, there were 5 (13.5%) pathological complete responses (CRs), 16 (43.2%) pathological partial responses (PRs), and 3 (8.1%) clinical PRs, for an overall response rate of 64.9% (95% CI: 47.4–79.8%) and a pathological response rate of 56.8%. Per an intent-to-treat analysis, the overall response rate was 57.1% (95% CI: 41.0–72.3%). After a median follow-up time of 15.8 months, the median survival was 24.0 months and median progression-free survival was 13.4 months. Grade 3/4 neutropenia and thrombocytopenia occurred in 69.0 and 33.3% of patients, respectively, with no febrile neutropenia or hemorrhage. Grade 3/4 nausea and vomiting occurred in 35.7% and grade 3 alopecia in 21.4% of the patients. One patient died due to a toxicity-related death (dyspnea).: ConclusionsGemcitabine plus cisplatin is active and feasible as first-line treatment of advanced epithelial ovarian cancer. Further clinical trials adding gemcitabine to first-line treatment seem warranted. [Copyright &y& Elsevier]

Rovalpituzumab tesirine (Rova-T), an antibody-drug conjugate directed against Delta-like protein 3 (DLL3), is under development for patients with small cell lung cancer (SCLC). DLL3 is expressed on the majority of SCLC samples. Because SCLC is rarely biopsied in the course of disease, data regarding DLL3 expression in relapses is not available. The aim of this study was to investigate the expression of DLL3 in chemorelapsed (but untreated with Rova-T) SCLC samples and compare the results with chemonaive counterparts. Two evaluation methods to assess DLL3 expression were explored. Additionally, we assessed if DLL3 expression of chemorelapsed and/or chemonaive samples has prognostic impact and if it correlates with other clinicopathological data. The study included 30 paired SCLC samples, which were stained with an anti DLL3 antibody. DLL3 expression was assessed using tumor proportion score (TPS) and H-score and was categorized as DLL3 low (TPS < 50%, H-score ≤ 150) and DLL3 high (TPS ≥ 50%, H-score > 150). Expression data were correlated with clinicopathological characteristics. Kaplan-Meier curves were used to illustrate overall survival (OS) depending on DLL3 expression in chemonaive and chemorelapsed samples, respectively, and depending on dynamics of expression during course of therapy. DLL3 was expressed in 86.6% chemonaive and 80% chemorelapsed SCLC samples without significant differences between the two groups. However, the extent of expression varied in a substantial proportion of pairs (36.6% with TPS, 43.3% with H-score), defined as a shift from low to high or high to low expression. TPS and H-score provided comparable results. There were no profound correlations with clinicopathological data. Survival analysis revealed a trend toward a more favorable OS in DLL low-expressing chemonaive SCLC ( p = 0.57) and, in turn, in DLL3 high-expressing chemorelapsed SCLC ( p = 0.42) as well as in SCLC demonstrating a shift from low to high expression ( p = 0.56) without being statistically significant. This is the first study to investigate DLL3 expression in a large cohort of rare paired chemonaive-chemorelapsed SCLC specimens. Comparative analysis revealed that DLL3 expression was not stable during the course of therapy, suggesting therapy-based alterations. Unlike in chemonaive samples, a high DLL3 expression in chemorelapsed samples indicated a trend for a more favorable prognosis. Our results highlight the importance to investigate DLL3 in latest chemorelapsed SCLC tumor tissue., Competing Interests: SP is a consultant of Ventana, Roche, Novartis, Astellar, Astrazeneca, Bristol-Myers Squibb, Merck Serono and MSD. JK is a consultant of Roche, Novartis, BMS and MSD. BM received an honorary from AbbVie for a one-time consulting activity. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Kuempers, Jagomast, Krupar, Paulsen, Heidel, Ribbat-Idel, Idel, Märkl, Anlauf, Berezowska, Tiemann, Bösmüller, Fend, Kalsdorf, Bohnet, Dreyer, Sailer, Kirfel and Perner.)