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Anti-CD38 monoclonal antibodies have consistently shown increased efficacy when added to standard of care for patients with multiple myeloma. We aimed to assess the efficacy of isatuximab in addition to lenalidomide, bortezomib, and dexamethasone in patients with newly diagnosed transplantation-eligible multiple myeloma.This open-label, multicentre, randomised, active-controlled, phase 3 trial was done at 67 academic and oncology practice centres in Germany. This study is ongoing and divided into two parts; herein, we report results from part 1. Eligible patients were aged 18-70 years; had a confirmed diagnosis of untreated multiple myeloma requiring systemic treatment and a WHO performance status of 0-2; and were eligible for induction therapy, high-dose melphalan and autologous haematopoietic stem-cell transplantation, and maintenance treatment. Patients were randomly assigned (1:1) to receive three 42-day cycles of induction therapy either with isatuximab plus lenalidomide, bortezomib, and dexamethasone (isatuximab group) or lenalidomide, bortezomib, and dexamethasone alone (control group) using a web-based system and permuted blocks. Patients in both groups received lenalidomide (25 mg orally on days 1-14 and 22-35), bortezomib (1·3 mg/mBetween Oct 23, 2018, and Sep 22, 2020, 660 patients were included in the ITT analysis (331 in the isatuximab group and 329 in the control group). 654 (99%) patients were White, two were African, one was Arabic, and three were Asian. 250 (38%) were women and 410 (62%) were men. The median age was 59 years (IQR 54-64). MRD negativity after induction therapy was reached in 166 (50%) patients in the isatuximab group versus 117 (36%) in the control group (OR 1·82 [95% CI 1·33-2·48]; p=0·00017). Median follow-up time from start to end of induction therapy was 125 days (IQR 125-131) versus 125 days (125-132). At least one grade 3 or 4 adverse event occurred in 208 (63%) of 330 patients versus 199 (61%) of 328 patients. Neutropenia of grade 3 or 4 occurred in 77 (23%) versus 23 (7%) patients and infections of grade 3 or 4 occurred in 40 (12%) versus 32 (10%) patients. Among 12 deaths during induction therapy, one death due to septic shock in the isatuximab group and four deaths (one cardiac decompensation, one hepatic and renal failure, one cardiac arrest, and one drug-induced enteritis) in the control group were considered treatment-related.Addition of isatuximab to lenalidomide, bortezomib, and dexamethasone for induction therapy improved rates of MRD negativity with no new safety signals in patients with newly diagnosed transplantation-eligible multiple myeloma.Sanofi and Bristol Myers Squibb (Celgene).

Therapeutic decisions in lung cancer critically depend on the determination of histologic types and oncogene mutations. Therefore, tumor samples are subjected to standard histologic and immunohistochemical analyses and examined for relevant mutations using comprehensive molecular diagnostics. In this study, an alternative diagnostic approach for automatic and label-free detection of mutations in lung adenocarcinoma tissue using quantum cascade laser-based infrared imaging is presented. For this purpose, a five-step supervised classification algorithm was developed, which was not only able to detect tissue types and tumor lesions, but also the tumor type and mutation status of adenocarcinomas. Tumor detection was verified on a data set of 214 patient samples with a specificity of 97% and a sensitivity of 95%. Furthermore, histology typing was verified on samples from 203 of the 214 patients with a specificity of 97% and a sensitivity of 94% for adenocarcinoma. The most frequently occurring mutations in adenocarcinoma (KRAS, EGFR, and TP53) were differentiated by this technique. Detection of mutations was verified in 60 patient samples from the data set with a sensitivity and specificity of 95% for each mutation. This demonstrates that quantum cascade laser infrared imaging can be used to analyze morphologic differences as well as molecular changes. Therefore, this single, one-step measurement provides comprehensive diagnostics of lung cancer histology types and most frequent mutations.

Background: High-risk (HR) multiple myeloma (MM) has an impaired prognostic outcome. Addition of anti-CD38 monoclonal antibodies to standard-of-care regimens improved response rates and depth of response. Here, we report a prespecified interim analysis (IA) following induction therapy with the quadruplet regimen isatuximab, carfilzomib, lenalidomide and dexamethasone (Isa-KRd) in newly diagnosed (ND) HR MM patients (pts) in the phase II multicentric GMMG-CONCEPT trial (NCT03104842). Methods: 153 pts with HR NDMM were enrolled into the trial, the IA reports on the first 50 pts evaluable for IA. Pts receive Isa-KRd in induction, consolidation and Isa-KR maintenance. Transplant eligible pts undergo high-dose therapy. This IA reports on overall response rates (ORR) during induction. Findings: 50 pts were included in the IA population for ORR. HR MM was defined by del17p in 52%, t(4;14) in 38%, t(14;16) in 12% and > 3 copies 1q21 in 42% and ISS stage 2/3 disease. 46/50 pts completed induction treatment. ORR was 100%, with 5 pts (10·0%) showing partial response (PR), 22 (44·0%; including 4 in arm B) very good partial response (VGPR) and 23 (46·0%) complete response (CR). Hematologic grade 3/4 treatment-emergent adverse events (≥ 10%) were neutropenia (34·0%), leukopenia (26·0%) and thrombocytopenia (14·0%). Main non-hematologic toxicities grade 3/4 were hypertension (12·0%) and infection (8·0%). Interpretation: We report for the first time on a trial investigating Isa-KRd quadruplet treatment in solely HR NDMM. Isa-KRd induction induces rapid and deep responses. The overall safety profile is consistent with previous reports. Trial Registration: The trial is registered at clinicaltrials.gov (NCT03104842). Funding Statement: Study drug and financial support by Amgen, Celgene-BMS and Sanofi. Declaration of Interests: Dr. Leypoldt reports grants and non-financial support from Celgene-BMS, grants and non-financial support from Sanofi, grants and non-financial support from Amgen, during the conduct of the study; non-financial support from GSK, non-financial support from Abbvie, outside the submitted work; Dr. Asemissen has nothing to disclose. Dr. Besemer has nothing to disclose. Dr. Hanel reports personal fees from Celgene, personal fees from Novartis, personal fees from Takeda, personal fees from Amgen, during the conduct of the study; Dr. Blau has nothing to disclose. Dr. Gorner has nothing to disclose. Dr. Ko has nothing to disclose. Dr. Reinhardt reports personal fees from Abbvie, grants from Gilead, personal fees from Merck, other from CDL Therapeutics GmbH, outside the submitted work; Dr. Staib reports grants, personal fees, non-financial support and other from Abbvie, grants, personal fees, non-financial support and other from Amgen, grants, personal fees, non-financial support and other from Celgene, grants, personal fees, non-financial support and other from Janssen-Cilag, grants, personal fees, non-financial support and other from Novartis, grants, personal fees, non-financial support and other from Gilead, grants, personal fees, non-financial support and other from Pfizer, grants, personal fees, non-financial support and other from Roche, outside the submitted work; Dr. Mann has nothing to disclose. Dr. Lutz has nothing to disclose. Dr. Munder reports personal fees and non-financial support from Janssen, personal fees and non-financial support from Amgen, grants from Incyte, personal fees and non-financial support from BMS, personal fees from Abbvie, personal fees from Sanofi, personal fees from GSK, personal fees from Takeda, outside the submitted work; Dr. Graeven reports personal fees from Amgen, personal fees and non-financial support from Boehringer Ingelheim, personal fees from Daichi Sankyo, personal fees from Servier, personal fees from Celgene, personal fees from Astra Zeneca, personal fees from Johnson Johnson, non-financial support from Merck, personal fees from MSD, personal fees from BMS, during the conduct of the study; Dr. Peceny reports grants and personal fees from Sanofi Genzyme, grants from Novartis, grants from DRK Blutspendedienst NSTOB, grants from Boehringer Ingelheim Pharma GmbH & Co KG, grants from Celgene, outside the submitted work; Dr. Salwender reports personal fees from Bristol-Myers Squibb/Celgene, personal fees from Janssen Cilag, personal fees from Glaxo Smith Kline, personal fees from Oncopeptides, personal fees from Takeda, personal fees from Sanofi, personal fees from AbbVie, personal fees from Amgen, outside the submitted work; Dr. Jauch has nothing to disclose. Dr. Zago has nothing to disclose. Axel Benner has nothing to disclose. Dr. Tichy has nothing to disclose. Dr. Bokemeyer reports personal fees from Sanofi Aventis, personal fees from Merck KgA, personal fees from Bristol-Myers Squibb, personal fees from Merck Sharp & Dohme, personal fees from Lilly Imclone, personal fees from Bayer Healthcare, personal fees from GSO Contract research, personal fees from AOK-Rheinland-Hamburg, personal fees from Novartis, outside the submitted work; Dr. Goldschmidt reports grants, personal fees, non-financial support and other from Amgen, grants, personal fees, non-financial support and other from BMS, grants, personal fees, non-financial support and other from Celgene, grants, personal fees, and other from Chugai, grants, personal fees, non-financial support and other from Janssen, grants, personal fees, non-financial support and other from Sanofi, other from Incyte, other from Molecular Partners, other from Merck Sharp and Dohme (MSD), other from Mundipharma, grants, personal fees, non-financial support and other from Takeda, personal fees and other from Novartis, personal fees from Adaptive Biotechnology, personal fees from GlaxoSmithKline (GSK), outside the submitted work. Dr. Weisel reports grants from AMGEN, grants from Celgene, grants from Sanofi, during the conduct of the study; grants, personal fees and non-financial support from Amgen, personal fees and non-financial support from BMS, grants, personal fees and non-financial support from Celgene, personal fees from Adaptive Biotech, grants, personal fees and non-financial support from Janssen, personal fees and non-financial support from GSK, personal fees from Karyopharm, grants, personal fees and non-financial support from Sanofi, personal fees and non-financial support from Takeda, personal fees from Oncopeptides, personal fees from Roche, outside the submitted work. Ethics Approval Statement: All patients provided written informed consent. The trial was approved by the competent authorities and the Tuebingen University Ethics Committee.

BACKGROUND Variable chemotherapy exposure may cause toxicity or lack of efficacy. This study was initiated to validate pharmacokinetically (PK)-guided paclitaxel dosing in patients with advanced non-small-cell lung cancer (NSCLC) to avoid supra- or subtherapeutic exposure. PATIENTS AND METHODS Patients with newly diagnosed, advanced NSCLC were randomly assigned to receive up to 6 cycles of 3-weekly carboplatin AUC 6 or cisplatin 80 mg/m(2) either with standard paclitaxel at 200 mg/m(2) (arm A) or PK-guided dosing of paclitaxel (arm B). In arm B, initial paclitaxel dose was adjusted to body surface area, age, sex, and subsequent doses were guided by neutropenia and previous-cycle paclitaxel exposure [time above a plasma concentration of 0.05 µM (Tc>0.05)] determined from a single blood sample on day 2. The primary end point was grade 4 neutropenia; secondary end points included neuropathy, radiological response, progression-free survival (PFS) and overall survival (OS). RESULTS Among 365 patients randomly assigned, grade 4 neutropenia was similar in both arms (19% versus 16%; P = 0.10). Neuropathy grade ≥2 (38% versus 23%, P < 0.001) and grade ≥3 (9% versus 2%, P < 0.001) was significantly lower in arm B, independent of the platinum drug used. The median final paclitaxel dose was significantly lower in arm B (199 versus 150 mg/m(2), P < 0.001). Response rate was similar in arms A and B (31% versus 27%, P = 0.405), as was adjusted median PFS [5.5 versus 4.9 months, hazard ratio (HR) 1.16, 95% confidence interval (CI) 0.91-1.49, P = 0.228] and OS (10.1 versus 9.5 months, HR 1.05, 95% CI 0.81-1.37, P = 0.682). CONCLUSION PK-guided dosing of paclitaxel does not improve severe neutropenia, but reduces paclitaxel-associated neuropathy and thereby improves the benefit-risk profile in patients with advanced NSCLC. CLINICAL TRIAL INFORMATION NCT01326767 (https://clinicaltrials.gov/ct2/show/NCT01326767).

Purpose: Outcomes in patients with brain metastases undergoing whole-brain radiotherapy (WBRT) are hardly encouraging, and an improvement in results is therefore needed. One possible approach is the addition of chemotherapeutics. However the data presented thus far are also disappointing. A promising substance in this setting could become topotecan, which is known to cross the blood–brain barrier and additionally offers radiosensitizing effects. Therefore we performed a phase I/II trial to evaluate the feasibility of a concurrent radiochemotherapy regimen. Methods and Materials: From January 1999 to July 2001, a total of 75 patients (10 in phase I and 65 in phase II) were included. The WBRT was applied with a fraction size of 2 Gy/day for a total of 40 Gy. Topotecan was administered as a 30-min infusion with 0.2 to 0.5 mg/m 2 /day for 5 days over 4 weeks within 2 h to radiation therapy. Results: Because of the higher toxic rates seen in patients receiving 0.5 mg/m 2 /day, the recommended dosage for phase II was 0.4 mg/m 2 /day. In this group Grade 3/4 hematologic and nonhematologic side effects occurred in 19% and 21% of the patients, respectively. The overall response rate was 72% with an overall survival of 17 weeks and 30 weeks among the responders. Conclusions: Based on the moderate toxicity profile presented here we recommend to perform a phase III trial to confirm the promising phase I/II data.