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Background The prognosis of malignant primary high-grade brain tumors, predominantly glioblastomas, is poor despite intensive multimodality treatment options. In more than 50% of patients with glioblastomas, potentially targetable mutations are present, including rearrangements, altered splicing, and/or focal amplifications of epidermal growth factor receptor (EGFR) by signaling through the RAF/RAS pathway. We studied whether treatment with the clinically available anti-EGFR monoclonal antibody panitumumab provides clinical benefit for patients with RAF/RAS-wild-type (wt) glioblastomas in the Drug Rediscovery Protocol (DRUP). Methods Patients with progression of treatment refractory RAF/RASwt glioblastoma were included for treatment with panitumumab in DRUP when measurable according to RANO criteria. The primary endpoints of this study are clinical benefit (CB: defined as confirmed objective response [OR] or stable disease [SD] ≥ 16 weeks) and safety. Patients were enrolled using a Simon-like 2-stage model, with 8 patients in stage 1 and up to 24 patients in stage 2 if at least 1 in 8 patients had CB in stage 1. Results Between 03-2018 and 02-2022, 24 evaluable patients were treated. CB was observed in 5 patients (21%), including 2 patients with partial response (8.3%) and 3 patients with SD ≥ 16 weeks (12.5%). After median follow-up of 15 months, median progression-free survival and overall survival were 1.7 months (95% CI 1.6-2.1 months) and 4.5 months (95% CI 2.9-8.6 months), respectively. No unexpected toxicities were observed. Conclusions Panitumumab treatment provides limited CB in patients with recurrent RAF/RASwt glioblastoma precluding further development of this therapeutic strategy. New treatment options are needed for patients with recurrent glioblastomas. This study focused on whether treatment with the clinically available anti-EGFR monoclonal antibody panitumumab provides clinical benefit for patients with RAF/RAS -wild-type glioblastomas in the Drug Rediscovery Protocol.

Combined BRAF-MEK inhibitor therapy is the standard of care for BRAFV600-mutant advanced melanoma. We investigated encorafenib, a BRAF inhibitor with unique target-binding properties, alone or in combination with the MEK inhibitor binimetinib, versus vemurafenib in patients with advanced BRAFV600-mutant melanoma. COLUMBUS was conducted as a two-part, randomised, open-label phase 3 study at 162 hospitals in 28 countries. Eligible patients were aged 18 years or older and had histologically confirmed locally advanced (American Joint Committee on Cancer [AJCC] stage IIIB, IIIC, or IV), unresectable or metastatic cutaneous melanoma, or unknown primary melanoma; a BRAFV600E or BRAFV600K mutation; an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1; and were treatment naive or had progressed on or after previous first-line immunotherapy. In part 1 of the study, patients were randomly assigned (1:1:1) via interactive response technology to receive either oral encorafenib 450 mg once daily plus oral binimetinib 45 mg twice daily (encorafenib plus binimetinib group), oral encorafenib 300 mg once daily (encorafenib group), or oral vemurafenib 960 mg twice daily (vemurafenib group). The primary endpoint was progression-free survival by blinded independent central review for encorafenib plus binimetinib versus vemurafenib. Efficacy analyses were by intention-to-treat. Safety was analysed in patients who received at least one dose of study drug and one postbaseline safety assessment. The results of part 2 will be published separately. This study is registered with ClinicalTrials.gov, number NCT01909453, and EudraCT, number 2013-001176-38. Between Dec 30, 2013, and April 10, 2015, 577 of 1345 screened patients were randomly assigned to either the encorafenib plus binimetinib group (n=192), the encorafenib group (n=194), or the vemurafenib group (n=191). With a median follow-up of 16·6 months (95% CI 14·8–16·9), median progression-free survival was 14·9 months (95% CI 11·0–18·5) in the encorafenib plus binimetinib group and 7·3 months (5·6–8·2) in the vemurafenib group (hazard ratio [HR] 0·54, 95% CI 0·41–0·71; two-sided p<0·0001). The most common grade 3–4 adverse events seen in more than 5% of patients in the encorafenib plus binimetinib group were increased γ-glutamyltransferase (18 [9%] of 192 patients), increased creatine phosphokinase (13 [7%]), and hypertension (11 [6%]); in the encorafenib group they were palmoplantar erythrodysaesthesia syndrome (26 [14%] of 192 patients), myalgia (19 [10%]), and arthralgia (18 [9%]); and in the vemurafenib group it was arthralgia (11 [6%] of 186 patients). There were no treatment-related deaths except for one death in the combination group, which was considered possibly related to treatment by the investigator. Encorafenib plus binimetinib and encorafenib monotherapy showed favourable efficacy compared with vemurafenib. Overall, encorafenib plus binimetinib appears to have an improved tolerability profile compared with encorafenib or vemurafenib. Encorafenib plus binimetinib could represent a new treatment option for patients with BRAF-mutant melanoma. Array BioPharma, Novartis.

Encorafenib plus binimetinib and encorafenib alone improved progression-free survival compared with vemurafenib in patients with BRAFV600-mutant melanoma in the COLUMBUS trial. Here, we report the results of the secondary endpoint of overall survival. COLUMBUS was a two-part, randomised, open-label, phase 3 study done at 162 hospitals in 28 countries. Eligible patients were aged at least 18 years with histologically confirmed, locally advanced, unresectable, or metastatic cutaneous melanoma, or unknown primary melanoma, BRAFV600E or BRAFV600K mutation, an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, and were treatment naive or had progressed on or after first-line immunotherapy. In part 1 of the study, patients were randomly assigned (1:1:1) by use of interactive response technology to receive oral encorafenib 450 mg once daily plus oral binimetinib 45 mg twice daily (encorafenib plus binimetinib group), oral encorafenib 300 mg once daily (encorafenib group), or oral vemurafenib 960 mg twice daily (vemurafenib group). Randomisation was stratified by the American Joint Committee on Cancer stage, ECOG performance status, and BRAF mutation status. The primary outcome of the trial, progression-free survival with encorafenib plus binimetinib versus vemurafenib, was reported previously. Here we present the prespecified interim overall survival analysis. Efficacy analyses were by intent to treat. Safety was analysed in patients who received at least one dose of study drug. Part 2 of the study was initiated at the request of the US Food and Drug Administration to better understand the contribution of binimetinib to the combination therapy by comparing encorafenib 300 mg once daily plus binimetinib 45 mg twice daily with encorafenib 300 mg once daily alone. Results of part 2 will be published separately. This trial is ongoing and is registered with ClinicalTrials.gov, number NCT01909453, and EudraCT, number 2013-001176-38. Between Dec 30, 2013, and April 10, 2015, 577 of 1345 screened patients were randomly assigned to receive encorafenib plus binimetinib (n=192), encorafenib (n=194), or vemurafenib (n=191). Median follow-up for overall survival was 36·8 months (95% CI 35·9–37·5). Median overall survival was 33·6 months (95% CI 24·4–39·2) with encorafenib plus binimetinib and 16·9 months (14·0–24·5) with vemurafenib (hazard ratio 0·61 [95% CI 0·47–0·79]; two-sided p<0·0001). The most common grade 3 or 4 adverse events did not change substantially from the first report; those seen in more than 5% of patients treated with encorafenib plus binimetinib were increased γ-glutamyltransferase (18 [9%] of 192 patients), increased blood creatine phosphokinase (14 [7%]), and hypertension (12 [6%]); those seen with encorafenib alone were palmar-plantar erythrodysaesthesia syndrome (26 [14%] of 192 patients), myalgia (19 [10%]), and arthralgia (18 [9%]); and with vemurafenib the most common grade 3 or 4 adverse event was arthralgia (11 [6%] of 186 patients). One death in the combination treatment group was considered by the investigator to be possibly related to treatment. The combination of encorafenib plus binimetinib provided clinically meaningful efficacy with good tolerability as shown by improvements in both progression-free survival and overall survival compared with vemurafenib. These data suggest that the combination of encorafenib plus binimetinib is likely to become an important therapeutic option in patients with BRAFV600-mutant melanoma. Array BioPharma, Novartis.

The PREOPANC-2 trial aimed to evaluate whether neoadjuvant FOLFIRINOX improved overall survival compared with neoadjuvant gemcitabine-based chemoradiotherapy followed by adjuvant gemcitabine in patients with resectable or borderline resectable pancreatic ductal adenocarcinoma (PDAC). In this investigator-initiated, open-label, nationwide, phase 3 randomised trial, patients aged 18 years or older with resectable or borderline resectable PDAC and a WHO performance status of 0 or 1 were enrolled across 19 Dutch centres. Patients in the FOLFIRINOX (FFX) group received FOLFIRINOX (85 mg/m2 intravenous oxaliplatin, 180 mg/m2 intravenous irinotecan, 400 mg/m2 intravenous leucovorin, followed by a 400 mg/m2 intravenous fluorouracil bolus and then continuous infusion at 2400 mg/m2 intravenously over 46 h every 14 days for eight cycles) followed by surgery without adjuvant treatment. Patients in the chemoradiotherapy (CRT) group received three cycles of neoadjuvant gemcitabine (1000 mg/m2 intravenously on days 1, 8, and 15 of each 28-day cycle and on days 1 and 8 only for cycles one and three) combined with hypofractionated radiotherapy (36 Gy in 15 fractions) during the second cycle only, followed by surgery and four cycles of adjuvant gemcitabine. Randomisation (1:1) was done using a minimisation technique and stratified by resectability status (resectable vs borderline resectable disease) and centre. The primary endpoint was overall survival in the modified intention-to-treat population, after excluding ineligible patients. Data on race and ethnicity were not collected. This trial is registered with EudraCT (2017-002036-17) and is complete. From June 5, 2018, to Jan 28, 2021, 375 patients were randomly assigned to the FFX group (n=188) or the CRT group (n=187). Six patients (three per group) were excluded due to ineligibility (n=4) or immediate withdrawal of informed consent after randomisation (n=2). 208 (56%) of 369 patients were male and 161 (44%) were female. After a median follow-up of 42·3 months (IQR 35·7–48·7), median overall survival was 21·9 months (95% CI 17·7–27·0) in the FFX group versus 21·3 months (16·8–25·5) in the CRT group (HR 0·88 [95% CI 0·69–1·13], p=0·32). The most common grade 3–4 adverse events were neutropenia (43 [25%] of 175 in the FFX group vs 38 [22%] of 176 in the CRT group), diarrhoea (41 [23%] vs two [1%]), and leukopenia (14 [8%] vs 26 [15%]). Serious adverse events occurred in 85 (49%) patients in the FFX group compared with 75 (43%) in the CRT group (p=0·26). Adverse events of grades 3 or worse occurred in 117 (67%) patients in the FFX group versus 106 (60%) patients in the CRT group (p=0·20). Treatment-related deaths occurred in two (1%) patients in the FFX group (multi-organ failure and intestinal mucositis) and one (1%) patient in the CRT group (upper gastrointestinal haemorrhage). This randomised trial did not show a difference in overall survival between neoadjuvant FOLFIRINOX and neoadjuvant gemcitabine-based chemoradiotherapy in patients with resectable or borderline resectable PDAC. Both neoadjuvant treatment regimens may be considered in these patients. Dutch Cancer Society and ZonMw.

The advent of immune checkpoint inhibitors has reinvigorated the field of immuno-oncology. These monoclonal antibody-based therapies allow the immune system to recognize and eliminate malignant cells. This has resulted in improved survival of patients across several tumor types. However, not all patients respond to immunotherapy therefore predictive biomarkers are important. There are only a few Food and Drug Administration-approved biomarkers to select patients for immunotherapy. These biomarkers do not consider the heterogeneity of tumor characteristics across lesions within a patient. New molecular imaging tracers allow for whole-body visualization with positron emission tomography (PET) of tumor and immune cell characteristics, and drug distribution, which might guide treatment decision making. Here, we summarize recent developments in molecular imaging of immune checkpoint molecules, such as PD-L1, PD-1, CTLA-4, and LAG-3. We discuss several molecular imaging approaches of immune cell subsets and briefly summarize the role of FDG-PET for evaluating cancer immunotherapy. The main focus is on developments in clinical molecular imaging studies, next to preclinical studies of interest given their potential translation to the clinic.

Background Anti-PD-1 antibodies and BRAF/MEK inhibitors are the two main groups of systemic therapy in the treatment of BRAF V600 -mutant advanced melanoma. Until now, data are inconclusive on which therapy to use as first-line treatment. The aim of this study was to use propensity score matching to compare first-line anti-PD-1 monotherapy vs. BRAF/MEK inhibitors in advanced BRAF V600 -mutant melanoma patients. Methods We selected patients diagnosed between 2014 and 2017 with advanced melanoma and a known BRAF V600 -mutation treated with first-line BRAF/MEK inhibitors or anti-PD-1 antibodies, registered in the Dutch Melanoma Treatment Registry. Patients were matched based on their propensity scores using the nearest neighbour and the optimal matching method. Results Between 2014 and 2017, a total of 330 and 254 advanced melanoma patients received BRAF/MEK inhibitors and anti-PD-1 monotherapy as first-line systemic therapy. In the matched cohort, patients receiving anti-PD-1 antibodies as a first-line treatment had a higher median and 2-year overall survival compared to patients treated with first-line BRAF/MEK inhibitors, 42.3 months (95% CI: 37.3-NE) vs. 19.8 months (95% CI: 16.7–24.3) and 65.4% (95% CI: 58.1–73.6) vs. 41.7% (95% CI: 34.2–51.0). Conclusions Our data suggest that in the matched BRAF V600 -mutant advanced melanoma patients, anti-PD-1 monotherapy is the preferred first-line treatment in patients with relatively favourable patient and tumour characteristics.

Immune checkpoint blockade has become standard treatment for many types of cancer. Such therapy is indicated most often in patients with advanced or metastatic disease but has been increasingly used as adjuvant therapy in those with early-stage disease. Adverse events include immune-related organ inflammation resembling autoimmune diseases. We describe a case of severe immune-related gastroenterocolitis in a 4-month-old infant who presented with intractable diarrhea and failure to thrive after in utero exposure to pembrolizumab. Known causes of the symptoms were ruled out, and the diagnosis of pembrolizumab-induced immune-related gastroenterocolitis was supported by the results of histopathological assays, immunophenotyping, and analysis of the level of antibodies against programmed cell death protein 1 (PD-1). The infant’s condition was successfully treated with prednisolone and infliximab. After a pregnant woman with melanoma received pembrolizumab therapy, severe autoimmune enteritis developed in her healthy newborn infant. The condition was treated with prednisolone and infliximab.

BackgroundNeoadjuvant treatment consisting of five cycles of carboplatin and paclitaxel with concurrent radiotherapy (41.4 Gy), followed by esophagectomy, is the standard treatment for resectable esophageal cancer in The Netherlands. It remains unclear whether intensification of neoadjuvant therapy leads to better outcomes. This study analyzed the outcomes of intensified chemoradiotherapy.MethodsWe included patients who were deemed eligible for esophagectomy between January 2008 and December 2014. Neoadjuvant therapy consisted of six cycles of carboplatin (area under the curve = 2 mg/mL/min) and paclitaxel (50 mg/m2 of body surface area) and concurrent radiotherapy (50.4 Gy administered in 28 fractions of 1.8 Gy each, 5 days per week), followed by esophagectomy.ResultsOf the 176 patients included in this study, 73% underwent a resection. At a median follow-up of 29.3 months for the total cohort, median disease-free survival (DFS) was 22.5 months. DFS at 3 and 5 years was 42% and 36%, respectively, while the overall survival (OS) rates were 47% and 38%, respectively. In addition, the 5-year DFS and OS rates of our resection group were 44% and 48%, respectively. In 102 patients (58%), grade 3 or higher adverse events were observed, mainly hematological. The postoperative mortality rate within 30 days was 4%, and pathological complete response was achieved in 35% of patients.ConclusionsIntensification of neoadjuvant chemoradiotherapy for patients with potentially resectable esophageal cancer is well tolerated, yielding high pathological complete response rates, but adverse events occurred frequently, and survival compared with conventional neoadjuvant chemoradiotherapy seems similar. Therefore, intensification of neoadjuvant chemoradiotherapy should not be routinely used.