BackgroundBlocking programmed cell death protein 1 (PD-1) has become a standard cancer immunotherapy, increasingly used in kidney, liver, or heart transplant recipients who develop skin cancer or hepatocellular carcinoma, despite the increased risk of graft failure or rejection. The mechanism of action of PD-1 blockade relies on stimulating CD8+ T cell activity, but its impact on humoral immunity in general and on alloimmunization in particular remains uncertain.ObjectiveThe aim of this study was to investigate the impact on anti-PD-1 treatment on alloimmunization.MethodsThe effect of anti-PD-1 treatment on the generation of anti-HLA (Human Leucocyte Antigen) antibodies was investigated in 72 patients with non-small cell lung cancer vaccinated with an allogeneic plasmacytoid dendritic cell line (PDC*line; six weekly injections), with or without pembrolizumab administered every three weeks. The kinetics and functionality of the anti-HLA generated were analyzed.ResultsThe results show that 51.4% of the patients developed anti-HLA antibodies, primarily dependent on the vaccine dose. In 60% of cases, the antibody response appeared after the sixth injection, peaked after one month, and then gradually declined over two years. Anti-HLA class II antibodies appeared earlier than class I antibodies. Functional assays demonstrated complement-dependent cytotoxicity against allogeneic B lymphocytes and PDC*line cells in the serum of some patients, with no difference related to treatment. PD-1 blockade did not alter the magnitude, kinetics, or cytotoxic potential of the vaccine-induced humoral response. ConclusionThese results indicate that, during allogeneic human vaccination, PD-1 signaling exerts a limited effect on antibody production and effector function, suggesting a more complex regulatory role in humoral immunity than previously thought.

Pemetrexed is a cornerstone in chemo(immunotherapy) of non‐small cell lung cancer and mesothelioma; however, it is contraindicated in patients with renal impairment due to severe toxicity concerns. Therefore, a large proportion of patients is withheld from effective chemo(immunotherapy). We performed an intra‐patient 3 + 3 dose escalation renal impairment study (eGFR < 45 mL/min). The pemetrexed dose was calculated based on renal function to reach a target AUC, and patients received oral folinic acid prophylaxis 45 mg four times daily on Days 2–15 of each cycle. Endpoints included safety (incidence of hematological and non‐hematological toxicity, treatment delays) and pharmacokinetics in line with regulatory guidance for renal impairment trials. Six patients with an estimated glomerular filtration rate (eGFR) between 26 and 41 mL/min were included. All patients were successfully escalated to the full dose. Adverse event patterns and pharmacokinetics were comparable to those in patients with normal renal function. Grade I/II anemia occurred in five patients (already present at baseline). One occurrence of grade IV neutropenia was observed, which resolved without intervention. Moreover, in three patients, a 1‐week treatment delay occurred. Treatment resulted in a response in four patients ( n = 1 complete response, n = 2 partial response, n = 1 stable disease). Pemetrexed can be safely administered in patients with impaired renal function when the dose is calculated based on renal function and folinic acid prophylaxis is administered, thereby enabling an effective treatment modality for patients that, thus far, could not be treated.

Abstract We have developed an innovative cancer vaccine for the treatment of advanced NSCLC patients in combination with checkpoint inhibitors. This PDC*lung01 product based on an irradiated plasmacytoid dendritic cell line loaded with HLA-A*02:01 restricted peptides (NY-ESO-1, MAGE-A3, MAGE-A4, Multi-MAGE-A, MUC1, Survivin and Melan-A) is able to prime and expand peptide-specific CD8+ T cells in vitro and in vivo, and is synergistic with anti-Programmed Death (PD)-1 (Plumas et al, 2022; Hannani et al, 2023, NCT03970746). In study PDC-LUNG-101 with EudraCT number 2018-002382-19, PDC*lung01 is injected intravenously and subcutaneously for 6 times at two dose levels, 14 million, or 140 million cells in stage II/IIIA (cohort A1 & A2, monotherapy) or stage IV with TPS≥50% (cohort B1 & B2; in combination with pembrolizumab) patients. We report here the analysis of immune response of 3 cohorts (A1, A2, B1) of patients and the first 19 patients out of 42 (cohort B2) treated with high dose of PDC*lung01 in combination with Pembrolizumab at baseline and 3 timepoints post injection. Several circulating immune parameters have been evaluated at different times before and after vaccination using different assays we have developed: leukocyte count and determination of circulation peptide specific CD8+ T cells by flow cytometry using multimer tools without prior in vitro culture. The assay made on purified CD8+ T-cells allowed us to define a limit of quantification (LOQ) to accurately assess the fold changes of the cell expansion. In addition, tumor microenvironment (TME) was analyzed by multiplex fluorescence immunochemistry. The data of 42 patients for who an immune response has been evaluated (cohorts A and B) will be presented. No major changes in circulating main lymphocyte frequencies (B cells, NK cells, CD4+, CD8+, or Treg T cells) were observed during treatment. In addition, no major cell activation (CD25+, CD54, or DR+) was noted. In contrast, in a significant number of patients, PDC*lung01 induced circulating peptide-specific CD8+ T cell expansion in all 4 cohorts at different levels and time points against at least one out of seven peptides used. The percentages of patients for who an expansion of antigen-specific T-cell were observed were 50%, 64%, 66.7% and 68.4% in A1, A2, B1 and B2 cohorts respectively. The intensity of the immune response was proportional to the dose of PDC*lung01 and to the combination with pembrolizumab. When possible, total and peptide-specific CD8+ T cells were sorted for analysis of TCR repertoire, illustrating the modelling and dynamics of the immune response. The TME features will also be illustrated. To conclude, treatment with PDC*lung01 induces an anti-tumor immune response in a significant number of patients which appears to be enhanced by the combination with pembrolizumab. Citation Format: Joel Plumas, Anne Sibille, Ingel Demedts, Elvire Pons-Tostivint, Charlotte Van de Kerkhove, Sofie Derijcke, Willemijn Theelen, Bonne Biesma, Frank Borm, Els Wauters, Mike Collodoro, Kays Al Badawy, Camille Duchayne, Channa Debruyne, Beatrice Devos, Benoit Colinet, Denis Moro-Sibilot, Maurice Perol, Eva-Lotte Buchmeier, Marcin Skrzypski, Kristof Cuppens, Johan Vansteenkiste. PDC*lung01: An innovative therapeutic cancer vaccine induces specific immune responses in combination with anti- PD-1 treatment in patients with non-small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1182.

Abstract Background PDC*lung01 (IMP) is a therapeutic cancer vaccine based on an irradiated plasmacytoid dendritic cell line loaded with HLA-A*02:01-restricted peptides (NY-ESO-1, MAGE-A3, MAGE-A4, Multi-MAGE-A, MUC1, Survivin and Melan-A), able to prime and expand peptide-specific CD8+ T cells in vitro and in vivo, and is synergistic with anti-PD-1. Methods In this phase I/II study, HLA-A*02 positive NSCLC pts were enrolled in 4 cohorts: resected stage II/IIIA in adjuvant setting treated with low dose (A1) or high dose (A2) of IMP following SOC; or untreated stage IV NSCLC with measurable disease, PD-L1≥50% and no targetable driver mutation, treated with low dose (B1) or high dose (B2) of IMP in combination to pembrolizumab 200mg q3w, continuously. IMP was simultaneously administered by SC and IV route weekly for 6 consecutive doses. Objective response rate (ORR) and progression-free survival (PFS) were assessed in cohort B2. We report herein preliminary efficacy results of the first 21 pts analysed when the 19th evaluable patient reached the 9-months PFS and the safety of 38 pts. Results Out of 21, 19 pts receiving at least 5 doses of IMP and having 1 post-baseline radiological evaluation were evaluated. The median follow-up was 12.5 months. The best objective response (BOR) included 12 PR (63.2%) and 7 SD (36.8%) with ORR of 63.2% (80% CI 45.9% - 78.2%) and a disease control rate (DCR) of 94.7%. The 9mPFS according to the Kaplan-Meier estimate was 52.1% (80% CI 36.5% - 65.56%). The mPFS was 10.9 months. The median duration of response was 9.49 months. An antigen-specific CD8+ T-cell response was induced against the lung antigens of the IMP in 68.4% of pts. Immune responses with remarkable expanded anti-tumor CD8+ T-cells were observed both in PR and SD. More immune response results will be available in the final analysis of the 45 pts of cohort B2. Treatment-related AEs (TRAEs) were mostly Grade 1-2. Only 1 severe TRAE occurred, a Grade 4 allergic infusion-related reaction, leading to IMP discontinuation. Thirteen pts experienced a serious AE, of which 3 were considered causally related to the IMP. Conclusions The BOR, ORR, DCR, PFS, duration of response and safety of PDC*lung01 in combination with anti-PD-1 showed encouraging signals suggesting that this combination may provide a clinical meaningful tumour response in stage IV NSCLC population with a mild safety profile. Interestingly, the immune response observed confirms the mechanism of action of the IMP in relation to clinical activity. Citation Format: Willemijn Theelen, Maurice Perol, Kristof Cuppens, Ingel Demedts, Frank Borm, Bonne Biesma, Els Wauters, Benoit Colinet, Eva-Lotte Buchmeier, Friederike Althoff, Elvire Pons-Tostivint, Charlotte Van de Kerkhove, Denis Moro-Sibilot, Anne Sibille, Sofie Derijcke, Marcin Skrzypski, Joel Plumas, Beatrice De Vos, Channa Debruyne, Frederique Cantero, Stefanie Adriaenssens, Florence Renard, Johan Vansteenkiste. Preliminary clinical results of a therapeutic cancer vaccine PDC*lung01 in combination with anti-PD-1 in patients (pts) with stage IV NSCLC [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT021.

PurposeCisplatin plus gemcitabine is a standard regimen for first-line treatment of advanced non–small-cell lung cancer (NSCLC). Phase II studies of pemetrexed plus platinum compounds have also shown activity in this setting.Patients and MethodsThis noninferiority, phase III, randomized study compared the overall survival between treatment arms using a fixed margin method (hazard ratio [HR] < 1.176) in 1,725 chemotherapy-naive patients with stage IIIB or IV NSCLC and an Eastern Cooperative Oncology Group performance status of 0 to 1. Patients received cisplatin 75 mg/m2on day 1 and gemcitabine 1,250 mg/m2on days 1 and 8 (n = 863) or cisplatin 75 mg/m2and pemetrexed 500 mg/m2on day 1 (n = 862) every 3 weeks for up to six cycles.ResultsOverall survival for cisplatin/pemetrexed was noninferior to cisplatin/gemcitabine (median survival, 10.3 v 10.3 months, respectively; HR = 0.94; 95% CI, 0.84 to 1.05). Overall survival was statistically superior for cisplatin/pemetrexed versus cisplatin/gemcitabine in patients with adenocarcinoma (n = 847; 12.6 v 10.9 months, respectively) and large-cell carcinoma histology (n = 153; 10.4 v 6.7 months, respectively). In contrast, in patients with squamous cell histology, there was a significant improvement in survival with cisplatin/gemcitabine versus cisplatin/pemetrexed (n = 473; 10.8 v 9.4 months, respectively). For cisplatin/pemetrexed, rates of grade 3 or 4 neutropenia, anemia, and thrombocytopenia (P ≤ .001); febrile neutropenia (P = .002); and alopecia (P < .001) were significantly lower, whereas grade 3 or 4 nausea (P = .004) was more common.ConclusionIn advanced NSCLC, cisplatin/pemetrexed provides similar efficacy with better tolerability and more convenient administration than cisplatin/gemcitabine. This is the first prospective phase III study in NSCLC to show survival differences based on histologic type.

Pemetrexed is a chemotherapeutic drug in the treatment of non-small cell lung cancer and mesothelioma. Optimized dosing of pemetrexed based on renal function instead of body surface area (BSA) is hypothesized to reduce pharmacokinetic variability in systemic exposure and could therefore improve treatment outcomes. The aim of this study is to compare optimized dosing to standard BSA-based dosing. A multicenter randomized (1:1) controlled trial was performed to assess superiority of optimized dosing versus BSA-based dosing in patients who were eligible for pemetrexed-based chemotherapy. The individual exposure to pemetrexed in terms of area under the concentration–time curve (AUC) was determined. The fraction of patients attaining to a predefined typical target AUC (164 mg × h/L ± 25

Patients with advanced non-squamous non-small cell lung cancers without oncogenic drivers have poor treatment outcomes. Overall, no survival benefit was observed in patients (N = 595) receiving veliparib plus chemotherapy versus chemotherapy alone. However, in the LP52+ population (n = 80), patients receiving veliparib plus chemotherapy trended toward improved survival. The LP52 signature may help predict patients more likely to benefit from veliparib. Background: This open-label Phase III trial (NCT02264990) evaluated the PARP inhibitor, veliparib, combined with carboplatin/paclitaxel versus chemotherapy alone for first-line treatment of patients with advanced non-squamous non-small cell lung cancers (NSCLC). A 52-gene expression classifier (LP52) previously shown to identify patients more likely to respond to veliparib was evaluated as a planned correlative analysis. Materials and Methods: Adult current or former smokers with advanced non-squamous NSCLC were randomized 1:1 to veliparib (120 mg daily for 7 days/cycle) with carboplatin and paclitaxel or to investigators' choice of platinum doublet chemotherapy (up to 6, 21-day cycles), with optional pemetrexed maintenance. Prospective analysis of the LP52 signature was conducted using a clinical Oiagen/HTG assay. The primary endpoint was overall survival (OS) in LP52+ patients. Results: Overall, 595 patients received veliparib + carboplatin/paclitaxel (n = 298) or chemotherapy alone (n = 297); 13% (n = 40) in each arm were LP52+. The primary endpoint was not met; median OS was 11.2 months with veliparib + carboplatin/paclitaxel versus 9.2 months with chemotherapy alone in the LP52+ subgroup (hazard ratio [HR] 0.644, 95% confidence interval [CI]: 0.396-1.048; P = .113). In the overall population, median OS was 12.1 months in both arms (HR 0.986, 95% CI: 0.827-1.176; P = .846). No new safety signals were observed. Conclusion: In patients with non-squamous NSCLC, there was no significant improvement in OS with veliparib + carboplatin/paclitaxel versus chemotherapy alone, although a trend toward improved OS in the LP52+ population suggests this subgroup may benefit from veliparib. Statistical power was limited due to the small sample size. (C) 2022 The Authors. Published by Elsevier Inc.

PDC*lung01 (IMP) is a therapeutic cancer vaccine consisting of an irradiated plasmacytoid dendritic cell line loaded with HLA-A*02:01 restricted peptides (NY-ESO-1, MAGE-A3, MAGE-A4, Multi-MAGE-A, MUC1, Survivin and Melan-A) and able to prime and expand peptide-specific CD8+ T cells in vitro and in vivo, and is synergistic with anti-PD-1. HLA-A*02 positive NSCLC patients are enrolled in 4 cohorts: resected stage II/IIIA in adjuvant setting treated with low dose (A1) or high dose (A2) of IMP as single agent following standard of care; or stage IV NSCLC with measurable disease, PD-L1 tumour proportion score ≥50% and no targetable driver mutation, treated with low dose (B1) or high dose (B2) of IMP in combination to pembrolizumab. The IMP is administered by subcutaneous and intravenous route weekly for 6 consecutive doses. Safety, tolerability and immune response are assessed and in addition clinical activity for B cohorts. We report here on the first 3 cohorts that have been completed. Of the 25 patients (6 in A1, 12 in A2 and 7 in B1) that started treatment, 22 received at least 5 doses and were evaluable. Treatment-related AEs were all Grade 1-2 and 1 Grade 3 with no dose-limiting toxicity (DLT) observed. Six patients experienced a serious adverse event (SAE), but none was considered related to the IMP. An antigen-specific CD8+ T-cell response was induced against the lung antigens of the IMP in 33%, 45% and 67% of evaluable patients in respectively A1, A2 and B1 cohort. The best objective response in 6 evaluable patients of the B1 cohort, according to RECIST criteria included 4 partial responses, 1 stable disease and 1 progressive disease with an objective response rate (ORR) of 66.7% (80% CI 33.3% - 90.7%). PDC*lung01 treatment was feasible with an acceptable safety profile and was found to be biologically active to trigger an antitumor immune response in a significant number of patients. Interestingly, a very promising ORR was observed in combination with pembrolizumab in first line setting in stage IV patients. Updated results will be presented.

BACKGROUND:Gemcitabine is a frequently used chemotherapeutic agent but its effects on the immune system are incompletely understood. Recently, the randomized NVALT19-trial revealed that maintenance gemcitabine after first-line chemotherapy significantly prolonged progression-free survival (PFS) compared to best supportive care (BSC) in malignant mesothelioma. Whether these effects are paralleled by changes in circulating immune cell subsets is currently unknown. These analyses could offer improved mechanistic insights into the effects of gemcitabine on the host and guide development of effective combination therapies in mesothelioma. METHODS:We stained peripheral blood mononuclear cells (PBMCs) and myeloid-derived suppressor cells (MDSCs) at baseline and 3 weeks following start of gemcitabine or BSC treatment in a subgroup of mesothelioma patients included in the NVALT19-trial. In total, 24 paired samples including both MDSCs and PBMCs were included. We performed multicolour flow-cytometry to assess co-inhibitory and-stimulatory receptor- and cytokine expression and matched these parameters with PFS and OS. FINDINGS:Gemcitabine treatment was significantly associated with an increased NK-cell- and decreased T-regulatory cell proliferation whereas the opposite occurred in control patients. Furthermore, myeloid-derived suppressor cells (MDSCs) frequencies were lower in gemcitabine-treated patients and this correlated with increased T-cell proliferation following treatment. Whereas gemcitabine variably altered co-inhibitory receptor expression, co-stimulatory molecules including ICOS, CD28 and HLA-DR were uniformly increased across CD4+ T-helper, CD8+ T- and NK-cells. Although preliminary in nature, the increase in NK-cell proliferation and PD-1 expression in T cells following gemcitabine treatment was associated with improved PFS and OS. INTERPRETATION:Gemcitabine treatment was associated with widespread effects on circulating immune cells of mesothelioma patients with responding patients displaying increased NK-cell and PD-1 + T-cell proliferation. These exploratory data provide a platform for future on treatment-biomarker development and novel combination treatment strategies.

We previously showed in a retrospective multi-center analysis in pts with KRAS mutated NSCLC that outcome with first-line platinum-based chemotherapy was improved with taxane-based combinations compared to other regimens (Mellema, Lung Cancer 2015; 90:245). Therefore, we initiated NVALT22, a multi-center open-label randomized phase III study comparing cis-pem and CPB in pts with advanced KRAS mutated NSCLC. Here we present the progression free survival (PFS) as assessed by local investigator.

Pemetrexed is an important component of first line treatment in patients with non-squamous non-small cell lung cancer. However, a limitation is the contraindication in patients with renal impairment due to hematological toxicity. Currently, it is unknown how to safely dose pemetrexed in these patients. The aim of our study was to elucidate the relationship between pemetrexed exposure and toxicity to support the development of a safe dosing regimen in patients with renal impairment. A population pharmacokinetic/pharmacodynamic analysis was performed based on phase II study results in three patients with renal dysfunction, supplemented with data from 106 patients in early clinical studies. Findings were externally validated with data of different pemetrexed dosing regimens. Alternative dosing regimens were evaluated using the developed model. We found that pemetrexed toxicity was driven by the time above a toxicity threshold concentration. The threshold for vitamin-supplemented patients was 0.110 mg/mL (95% CI: 0.092-0.146 mg/mL). It was observed that in patients with renal impairment (estimated glomerular filtration rate [eGFR]: <45 mL/min) the approved dose of 500 mg/m(2) would yield a high probability of severe neutropenia in the range of 51.0% to 92.6%. A pemetrexed dose of 20 mg for patients (eGFR: 20 mL/min) is shown to be neutropenic-equivalent to the approved dose in patients with adequate renal function (eGFR: 90 mL/min), but would result in an approximately 13-fold lower area under the concentration-time curve. The pemetrexed exposure-toxicity relationship is explained by a toxicity threshold and substantially different from previously thought. Without prophylaxis for toxicity, it is unlikely that a therapeutic dose can be safely administered to patients with renal impairment.

Pemetrexed is a cytotoxic drug for first‐line treatment of lung cancer. It is often combined with other anticancer drugs such as cisplatin or carboplatin. In clinical practice, hyperhydration regimens are applied to overcome cisplatin‐related nephrotoxicity. As pemetrexed is almost completely eliminated from the body by the kidneys, hyperhydration can result in augmented clearance. Furthermore, administration of large quantities of fluid may increase the volume of distribution of pemetrexed. Pharmacokinetics and, thus, efficacy and toxicity may be influenced by hyperhydration. This has not yet been properly studied. We performed a population pharmacokinetic analysis to assess hyperhydration as a covariate for pemetrexed clearance and for volume of distribution A relevant change was defined as >25% increase in clearance or volume of distribution. In our extensive dataset of 133 individuals, we found that hyperhydration did not significantly or relevantly explain variability in pemetrexed clearance (unchanged, P = .196) or volume of distribution (+7% change, P = .002), despite a power of >99% to detect a relevant change. Therefore, dose adjustments of pemetrexed are not required during hyperhydration with cisplatin.

BackgroundAlmost all patients with malignant mesothelioma eventually have disease progression after first-line therapy. Previous studies have investigated maintenance therapy, but none has shown a great effect. We aimed to assess the efficacy and safety of switch-maintenance gemcitabine in patients with malignant mesothelioma without disease progression after first-line chemotherapy.MethodsWe did a randomised, open-label, phase 2 trial in 18 hospitals in the Netherlands (NVALT19). We recruited patients aged older than 18 years with unresectable malignant mesothelioma with no evidence of disease progression after at least four cycles of first-line chemotherapy (with platinum and pemetrexed), who had a WHO performance status of 0–2, adequate organ function, and measurable or evaluable disease. Exclusion criteria were active uncontrolled infection or severe cardiac dysfunction, serious disabling conditions, symptomatic CNS metastases, radiotherapy within 2 weeks before enrolment, and concomitant use of any other drugs under investigation. Patients were randomly assigned (1:1), using the minimisation method, to maintenance intravenous gemcitabine (1250 mg/m2 on days 1 and 8, in cycles of 21 days) plus supportive care, or to best supportive care alone, until disease progression, unacceptable toxicity, serious intercurrent illness, patient request for discontinuation, or need for any other anticancer agent, except for palliative radiotherapy. A CT scan of the thorax or abdomen (or both) and pulmonary function tests were done at baseline and repeated every 6 weeks. The primary outcome was progression-free survival in the intention-to-treat population. Safety was analysed in all participants who received one or more doses of the study drug or had at least one visit for supportive care. Recruitment is now closed; treatment and follow-up are ongoing. This study is registered with the Netherlands Trial Registry, NTR4132/NL3847.FindingsBetween March 20, 2014, and Feb 27, 2019, 130 patients were enrolled and randomly assigned to gemcitabine plus supportive care (65 patients [50%]) or supportive care alone (65 patients [50%]). No patients were lost to follow-up; median follow-up was 36·5 months (95% CI 34·2 to not reached), and one patient in the supportive care group withdrew consent. Progression-free survival was significantly longer in the gemcitabine group (median 6·2 months [95% CI 4·6–8·7]) than in the supportive care group (3·2 months [2·8–4·1]; hazard ratio [HR] 0·48 [95% CI 0·33–0·71]; p=0·0002). The benefit was confirmed by masked independent central review (HR 0·49 [0·33–0·72]; p=0·0002). Grade 3–4 adverse events occurred in 33 (52%) of 64 patients in the gemcitabine group and in ten (16%) of 62 patients in the supportive care group. The most frequent adverse events were anaemia, neutropenia, fatigue or asthenia, pain, and infection in the gemcitabine group, and pain, infection, and cough or dyspnoea in the supportive care group. One patient (2%) in the gemcitabine group died, due to a treatment-related infection.InterpretationSwitch-maintenance gemcitabine, after first-line chemotherapy, significantly prolonged progression-free survival compared with best supportive care alone, among patients with malignant mesothelioma. This study confirms the activity of gemcitabine in treating malignant mesothelioma.FundingDutch Cancer Society (Koningin Wilhelmina Fonds voor de Nederlandse Kankerbestrijding) and Stichting NVALT studies.

Introduction: Approximately 80% of non-small cell lung cancer (NSCLC) patients with bone metastases have cancer induced bone pain (CIBP). Methods: The NVALT-9 was an open-label, single arm, phase II, multicenter study. Main inclusion criterion: bone metastasized NSCLC patients with uncontrolled CIBP [brief pain inventory [BPI] ≥ 5 over last 7 days]. Patients were treated with six milligram ibandronate intravenously (day 1-3) once a day. Main exclusion criteria: active secondary malignancy, systemic anti-tumor treatment and radiotherapy ≤4 weeks before study start, previous bisphosphonate treatment. Statistics: Simon's Optimal two-stage design with a 90% power to declare the treatment active if the pain response rate is ≥ 80% and 95% confidence to declare the treatment inactive if the pain response rate is ≤ 60%. If pain response is observed in ≤ 12 of the first 19 patients further enrollment will be stopped. Primary endpoint: bone pain response, defined as 25% decrease in worst pain score (PSc) over a 3-day period (day 5-7) compared to baseline PSc with maximum of 25% increase in mean analgesic consumption during the same period. Secondary endpoints: BPI score, quality of life, toxicity and World Health Organization Performance Score. Results: Of the 19 enrolled patients in the first stage, 18 were evaluable for response. All completed ibandronate treatment according to protocol. In 4 (22.2%), a bone pain response was observed. According to the stopping rule, further enrollment was halted. Discussion: Ibandronate loading doses lead to insufficient pain relief in NSCLC patients with CIBP.

The diagnostic landscape of non-small cell lung cancer (NSCLC) is changing rapidly with the availability of novel treatments. Despite high-level healthcare in the Netherlands, not all patients with NSCLC are tested with the currently relevant predictive tumor markers that are necessary for optimal decision-making for today's available targeted or immunotherapy. An expert workshop on the molecular diagnosis of NSCLC involving pulmonary oncologists, clinical chemists, pathologists, and clinical scientists in molecular pathology was held in the Netherlands on December 10, 2018. The aims of the workshop were to facilitate cross-disciplinary discussions regarding standards of practice, and address recent developments and associated challenges that impact future practice. This paper presents a summary of the discussions and consensus opinions of the workshop participants on the initial challenges of harmonization of the detection and clinical use of predictive markers of NSCLC. A key theme identified was the need for broader and active participation of all stakeholders involved in molecular diagnostic services for NSCLC, including healthcare professionals across all disciplines, the hospitals and clinics involved in service delivery, healthcare insurers, and industry groups involved in diagnostic and treatment innovations. Such collaboration is essential to integrate different technologies into molecular diagnostics practice, to increase nationwide patient access to novel technologies, and to ensure consensus-preferred biomarkers are tested.

Objectives: Expression of the Notch-family ligand delta-like protein 3 (DLL3), a potential therapeutic target in small cell lung cancer (SCLC), has not been assessed in the real-world setting. To identify the real-world utility of DLL3 as an SCLC therapeutic target, we performed the largest retrospective international noninterventional study to date to evaluate DLL3 prevalence in SCLC patients. Materials and Methods: DLL3 expression was assessed using immunohistochemistry in archived histological and cytological specimens (independent and paired) and correlated to patient demographics, clinical disease characteristics, and survival. The primary endpoint was the proportion of patients with DLL3 expression in >= 25 % of tumor cells. DLL3 expression concordance was assessed in paired specimens. Results: Independent tumor specimens were collected from 1073 patients. The mean age at biopsy was 66 years (SD, 10); 682 (64 %) patients were male. Paired specimens were collected from 36 patients. The mean age at biopsy was 62 years (SD, 11); 16 (44 %) patients were male. Most patients had ECOG performance status of 0-1, were smokers/ex-smokers, and received >= 1 prior therapy. Positive DLL3 expression (defined as >= 25 % of tumor cells) was identified in 895/1050 (85 %) patients with 1 specimen and evaluable DLL3 expression; 719/1050 (68 %) patients had high DLL3 expression (defined as >= 75 % of tumor cells). DLL3 expression concordance was 88 % between paired specimens (n = 17; Cohen's kappa P value, .9412). There was no significant difference in median overall survival from SCLC diagnosis for evaluable patients with nonmissing data based on DLL3 expression (negative DLL3 expression [n = 139], 9.5 months; positive DLL3 expression [n = 747], 9.5 months; all evaluable patients [n = 893, 9.5 months). Conclusion: These real-world epidemiologic findings indicate that DLL3 is robustly expressed across SCLC disease stages and remains stable despite treatment, consistent with available clinical trial data. There was no prognostic role for DLL3 observed in this study for overall survival.