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Background: Programmed cell death protein 1 (PD-1) antibody treatment is standard of care for melanoma and non-small-cell lung cancer (NSCLC). Accurately predicting which patients will benefit is currently not possible. Tumor uptake and biodistribution of the PD-1 antibody might play a role. Therefore, we carried out a positron emission tomography (PET) imaging study with zirconium-89 ( 89Zr)-labeled pembrolizumab before PD-1 antibody treatment. Patients and methods: Patients with advanced or metastatic melanoma or NSCLC received 37 MBq (1 mCi) 89Zr-pembrolizumab (∼2.5 mg antibody) intravenously plus 2.5 or 7.5 mg unlabeled pembrolizumab. After that, up to three PET scans were carried out on days 2, 4, and 7. Next, PD-1 antibody treatment was initiated. 89Zr-pembrolizumab tumor uptake was calculated as maximum standardized uptake value (SUV max) and expressed as geometric mean. Normal organ uptake was calculated as SUV mean and expressed as a mean. Tumor response was assessed according to (i)RECIST v1.1. Results: Eighteen patients, 11 with melanoma and 7 with NSCLC, were included. The optimal dose was 5 mg pembrolizumab, and the optimal time point for PET scanning was day 7. The tumor SUV max did not differ between melanoma and NSCLC (4.9 and 6.5, P = 0.49). Tumor 89Zr-pembrolizumab uptake correlated with tumor response (P trend = 0.014) and progression-free (P = 0.0025) and overall survival (P = 0.026). 89Zr-pembrolizumab uptake at 5 mg was highest in the spleen with a mean SUV mean of 5.8 (standard deviation ±1.8). There was also 89Zr-pembrolizumab uptake in Waldeyer's ring, in normal lymph nodes, and at sites of inflammation. Conclusion: 89Zr-pembrolizumab uptake in tumor lesions correlated with treatment response and patient survival. 89Zr-pembrolizumab also showed uptake in lymphoid tissues and at sites of inflammation.

BACKGROUND: Systemic relapses remain a major problem in locally advanced rectal cancer. Using short-course radiotherapy followed by chemotherapy and delayed surgery, the Rectal cancer And Preoperative Induction therapy followed by Dedicated Operation (RAPIDO) trial aimed to reduce distant metastases without compromising locoregional control. METHODS: In this multicentre, open-label, randomised, controlled, phase 3 trial, participants were recruited from 54 centres in the Netherlands, Sweden, Spain, Slovenia, Denmark, Norway, and the USA. Patients were eligible if they were aged 18 years or older, with an Eastern Cooperative Oncology Group (ECOG) performance status of 0-1, had a biopsy-proven, newly diagnosed, primary, locally advanced rectal adenocarcinoma, which was classified as high risk on pelvic MRI (with at least one of the following criteria: clinical tumour [cT] stage cT4a or cT4b, extramural vascular invasion, clinical nodal [cN] stage cN2, involved mesorectal fascia, or enlarged lateral lymph nodes), were mentally and physically fit for chemotherapy, and could be assessed for staging within 5 weeks before randomisation. Eligible participants were randomly assigned (1:1), using a management system with a randomly varying block design (each block size randomly chosen to contain two to four allocations), stratified by centre, ECOG performance status, cT stage, and cN stage, to either the experimental or standard of care group. All investigators remained masked for the primary endpoint until a prespecified number of events was reached. Patients allocated to the experimental treatment group received short-course radiotherapy (5?*?5 Gy over a maximum of 8 days) followed by six cycles of CAPOX chemotherapy (capecitabine 1000 mg/m2 orally twice daily on days 1-14, oxaliplatin 130 mg/m2 intravenously on day 1, and a chemotherapy-free interval between days 15-21) or nine cycles of FOLFOX4 (oxaliplatin 85 mg/m2 intravenously on day 1, leucovorin [folinic acid] 200 mg/m2 intravenously on days 1 and 2, followed by bolus fluorouracil 400 mg/m2 intravenously and fluorouracil 600 mg/m2 intravenously for 22 h on days 1 and 2, and a chemotherapy-free interval between days 3-14) followed by total mesorectal excision. Choice of CAPOX or FOLFOX4 was per physician discretion or hospital policy. Patients allocated to the standard of care group received 28 daily fractions of 1·8 Gy up to 50·4 Gy or 25 fractions of 2·0 Gy up to 50·0 Gy (per physician discretion or hospital policy), with concomitant twice-daily oral capecitabine 825 mg/m2 followed by total mesorectal excision and, if stipulated by hospital policy, adjuvant chemotherapy with eight cycles of CAPOX or 12 cycles of FOLFOX4. The primary endpoint was 3-year disease-related treatment failure, defined as the first occurrence of locoregional failure, distant metastasis, new primary colorectal tumour, or treatment-related death, assessed in the intention-to-treat population. Safety was assessed by intention to treat. This study is registered with the EudraCT, 2010-023957-12, and ClinicalTrials.gov, NCT01558921, and is now complete. FINDINGS: Between June 21, 2011, and June 2, 2016, 920 patients were enrolled and randomly assigned to a treatment, of whom 912 were eligible (462 in the experimental group; 450 in the standard of care group). Median follow-up was 4·6 years (IQR 3·5-5·5). At 3 years after randomisation, the cumulative probability of disease-related treatment failure was 23·7% (95% CI 19·8-27·6) in the experimental group versus 30·4% (26·1-34·6) in the standard of care group (hazard ratio 0·75, 95% CI 0·60-0·95; p=0·019). The most common grade 3 or higher adverse event during preoperative therapy in both groups was diarrhoea (81 [18%] of 460 patients in the experimental group and 41 [9%] of 441 in the standard of care group) and neurological toxicity during adjuvant chemotherapy in the standard of care group (16 [9%] of 187 patients). Serious adverse events occurred in 177 (38%) of 460 participants in the experimental group and, in the standard of care group, in 87 (34%) of 254 patients without adjuvant chemotherapy and in 64 (34%) of 187 with adjuvant chemotherapy. Treatment-related deaths occurred in four participants in the experimental group (one cardiac arrest, one pulmonary embolism, two infectious complications) and in four participants in the standard of care group (one pulmonary embolism, one neutropenic sepsis, one aspiration, one suicide due to severe depression). INTERPRETATION: The observed decreased probability of disease-related treatment failure in the experimental group is probably indicative of the increased efficacy of preoperative chemotherapy as opposed to adjuvant chemotherapy in this setting. Therefore, the experimental treatment can be considered as a new standard of care in high-risk locally advanced rectal cancer. FUNDING: Dutch Cancer Foundation, Swedish Cancer Society, Spanish Ministry of Economy and Competitiveness, and Spanish Clinical Research Network.

Bispecific antibodies (bsAbs) are antibodies that bind two distinct epitopes to cancer.. For use in oncology, one bsAb has been approved and 57 bsAbs are in clinical trials, none of which has reached phase 3. These bsAbs show great variability in design and mechanism of action. The various designs are often linked to the mechanisms of actions. The majority of bsAbs engage immune cells to destroy tumor cells. However, some bsAbs are also used to deliver payloads to tumors or to block tumor signaling pathways. This review provides insight into the choice of construct for bsAbs, summarizes the clinical development of bsAbs in oncology and identifies subsequent challenges. (C) 2019 The Authors. Published by Elsevier Inc.

Background Large-scale genetic tumor profiling can identify increasing numbers of potentially actionable molecular variants for which approved anti-cancer drugs are available. In daily practice, however, when patients with such variants are treated with drugs outside of their approved label, successes and failures are not systematically collected or shared. Methods We initiated the Drug Rediscovery Protocol (DRUP), an innovative and adaptive precision oncology trial aimed at identifying signals of activity in cohorts of patients with defined tumor types and molecular variants, treated with anti-cancer drugs outside their approved label. Eligible patients have exhausted (or declined) standard therapies and have malignancies with potentially actionable variants for which no approved anti-cancer drugs are available. Results Here, we show an overall clinical benefit rate (defined as complete or partial response, or stable disease ≥16 weeks) of 34% in the first 215 treated patients. This comprised 136 patients who received targeted therapies, and 79 patients who received immunotherapy. Overall median clinical benefit duration was nine months (95% CI 8 – 11 months), including 26 patients with ongoing clinical benefit at data cutoff. The potential of DRUP was illustrated by the identification of a successful cohort of patients with microsatellite instable tumors receiving nivolumab, and a cohort of colorectal cancer patients with relatively low mutational load with limited clinical benefit from immunotherapy. Conclusions The DRUP hereby facilitates defined use of approved drugs beyond their label in (rare) cancer subgroups, identifies early signals of activity in these subgroups, accelerates clinical translation of new insights, and creates a publicly available knowledge-base for future decision making. Legal entity responsible for the study Netherlands Cancer Institute. Funding Hartwig Medical Foundation, Dutch Cancer Society, Barcode for Life, Roche, Novartis, MSD, GSK, Pfizer, AstraZeneca, BMS. Disclosure E.E. Voest: Research grant / Funding (self), Legally responsible for all contracts: All pharma. C. van Herpen: Advisory / Consultancy: Bayer; Advisory / Consultancy, Research grant / Funding (self): Bristol-Myers Squibb; Advisory / Consultancy, Research grant / Funding (self): Ipsen; Advisory / Consultancy, Research grant / Funding (self): MSD; Advisory / Consultancy: Regeneron; Research grant / Funding (self): AstraZeneca; Research grant / Funding (self): Merck; Research grant / Funding (self): Novartis; Research grant / Funding (self): Sanofi. M. Chalabi: Honoraria (institution), Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Netherlands Cancer Institute. E.F. Smit: Honoraria (institution), Research grant / Funding (institution): AstraZeneca; Honoraria (institution), Research grant / Funding (institution): Bristol-Myers Squibb; Honoraria (institution): Bayer; Honoraria (institution), Advisory / Consultancy: Eli Lilly; Honoraria (institution), Research grant / Funding (institution): MSD; Honoraria (institution), Research grant / Funding (institution): Merck; Honoraria (institution): Novartis ; Honoraria (institution): Pfizer; Honoraria (institution): Takeda; Honoraria (institution): Regeneron; Honoraria (institution), Research grant / Funding (institution): Roche Genentech; Honoraria (institution): Seattle Genetics. N. Mehra: Honoraria (institution), Advisory / Consultancy, Research grant / Funding (institution): Bristol-Myers Squibb; Advisory / Consultancy: Bayer; Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Roche; Advisory / Consultancy, Travel / Accommodation / Expenses: MSD; Advisory / Consultancy, Research grant / Funding (institution): Janssen-Cilag; Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Astellas; Advisory / Consultancy, Research grant / Funding (institution): Sanofi. E. Cuppen: Honoraria (institution), Advisory / Consultancy: Illumina; Honoraria (self), Advisory / Consultancy: InteRNA Technologies; Full / Part-time employment, Officer / Board of Directors: Hartwig Medical Foundation. H.M.W. Verheul: Honoraria (institution), Advisory / Consultancy: Glycostem; Honoraria (institution), Advisory / Consultancy: Lava Therapeutics. H. Gelderblom: Research grant / Funding (institution): Five Prime; Research grant / Funding (institution): Novartis; Research grant / Funding (institution): Deciphera; Research grant / Funding (institution): Eli Lilly; Research grant / Funding (institution): Roche; Research grant / Funding (institution): Eisai; Research grant / Funding (institution): Debio; Research grant / Funding (institution): Boehringer Ingelheim; Research grant / Funding (institution): Pfizer; Research grant / Funding (institution): Amgen; Research grant / Funding (institution): Teva. All other authors have declared no conflicts of interest.

Most solid tumors express the cyclooxygenase-2 (COX-2) protein, a target of NSAIDs. COX-2 overexpression in tumorsis considered a predictor of more advanced stage disease and of worse prognosis in a number of studies investigating solid malignancies. Therefore, NSAIDs are evaluated as anti-cancer drugs. NSAIDs inhibit proliferation, invasiveness of tumors, and angiogenesis and overcome apoptosis resistance in a COX-2 dependent and independent manner. This review will focus on the rationale behind NSAIDs, including selective COX-2 inhibitors, in combination with conventional chemotherapeutic drugs or novel molecular targeted drugs. Studies investigating anti-cancer effects of NSAIDs on cell lines and xenograft models have shown modulation of the Akt, NF-kappa B, tyrosine kinase and the death receptor-mediated apoptosis pathways. COX-2 expression in tumors is not yet used as biomarker in the clinic. Despite the increased risk on cardiovascular toxicity induced by selective COX-2 inhibitors, several ongoing clinical trials are still investigating the therapeutic benefits of NSAIDs in oncology. The anti-tumor effects in these trials balanced with the side effects data will define the precise role of selective COX-2 inhibitors in the treatment of cancer patients. (c) 2006 Elsevier Ireland Ltd. All rights reserved.