COLUMBUS 7-year update: A randomized, open-label, phase III trial of encorafenib plus binimetinib versus vemurafenib or encorafenib in patients with BRAF V600E/K-mutant melanoma.

BACKGROUND: Treatment with encorafenib plus binimetinib and encorafenib monotherapy is associated with improved progression-free survival (PFS) and overall survival (OS) compared with vemurafenib in patients with BRAF V600E/K-mutant metastatic melanoma. We report results from the 7-year analysis of COLUMBUS part 1 (NCT01909453) at 99.7 months (median duration between randomization and data cutoff). METHODS: 577 patients with locally advanced unresectable or metastatic BRAF V600E/K-mutant melanoma who were treatment-naive or progressed after first-line immunotherapy were randomized 1:1:1 to encorafenib 450 mg once daily (QD) plus binimetinib 45 mg twice daily (BID) (n = 192), vemurafenib 960 mg BID (n = 191), or encorafenib monotherapy 300 mg QD (n = 194). No prior BRAF/MEK inhibitor was allowed. RESULTS: Seven-year PFS and OS rates (95 % CI) were 21.2 % (14.7-28.4 %) and 27.4 % (21.2-33.9%) in the encorafenib plus binimetinib arm and 6.4 % (2.1-14.0 %) and 18.2 % (12.8-24.3 %) in the vemurafenib arm, respectively. Median melanoma-specific survival (95 % CI) was 36.8 months (27.7-51.5 months) in the encorafenib plus binimetinib arm and 19.3 months (14.8-25.9 months) in the vemurafenib arm. Thirty-four long-term responders (complete/partial response ongoing at 7 years) were identified across arms. CONCLUSIONS: This is the longest follow-up from a phase III trial of BRAF/MEK inhibitor combination in BRAF V600E/K-mutant metastatic melanoma. Safety results were consistent with the known tolerability profile of encorafenib plus binimetinib. Results support the long-term efficacy and known safety of encorafenib plus binimetinib in this population and provide new insights on long-term responders. Interactive data visualization is available at the COLUMBUS dashboard (https://clinical-trials.dimensions.ai/columbus7/).

Multi-omic analysis identifies hypoalbuminemia as independent biomarker of poor outcome upon PD-1 blockade in metastatic melanoma.

We evaluated the prognostic value of hypoalbuminemia in context of various biomarkers at baseline, including clinical, genomic, transcriptomic, and blood-based markers, in patients with metastatic melanoma treated with anti-PD-1 monotherapy or anti-PD-1/anti-CTLA-4 combination therapy (n = 178). An independent validation cohort (n = 79) was used to validate the performance of hypoalbuminemia compared to serum LDH (lactate dehydrogenase) levels. Pre-treatment hypoalbuminemia emerged as the strongest predictor of poor outcome for both OS (HR = 4.01, 95% CI 2.10-7.67, Cox P = 2.63e-05) and PFS (HR = 3.72, 95% CI 2.06-6.73, Cox P = 1.38e-05) in univariate analysis. In multivariate analysis, the association of hypoalbuminemia with PFS was independent of serum LDH, IFN-γ signature expression, TMB, age, ECOG PS, treatment line, treatment type (combination or monotherapy), brain and liver metastasis (HR = 2.76, 95% CI 1.24-6.13, Cox P = 0.0131). Our validation cohort confirmed the prognostic power of hypoalbuminemia for OS (HR = 1.98, 95% CI 1.16-3.38; Cox P = 0.0127) and was complementary to serum LDH in analyses for both OS (LDH-adjusted HR = 2.12, 95% CI 1.2-3.72, Cox P = 0.00925) and PFS (LDH-adjusted HR = 1.91, 95% CI 1.08-3.38, Cox P = 0.0261). In conclusion, pretreatment hypoalbuminemia was a powerful predictor of outcome in ICI in melanoma and showed remarkable complementarity to previously established biomarkers, including high LDH.

The Assessment of Burden of ColoRectal Cancer (ABCRC)-tool; a validity and reliability study.

INTRODUCTION: Follow-up care after treatment for colorectal cancer (CRC) is increasingly focused on health-related quality of life (HRQoL) and functional outcomes. The Assessment of Burden of ColoRectal Cancer (ABCRC)-tool is developed to measure these outcomes and support patient-oriented care. The tool comprises items assessing burden of disease and lifestyle parameters. It consists of a generic module combined with one of the three CRC specific modules. The objective of this study is to assess the construct validity and reliability of the items of the ABCRC-tool. METHODS: Patients who were receiving follow-up care after surgical CRC treatment were invited to complete the ABCRC-tool together with other validated patient-reported outcome measures (PROMs). Construct validity was assessed by testing expected correlations between items of the ABCRC-tool and domains of other PROMs and by examining predefined hypotheses regarding differences in subgroups of patients. Patients completed the ABCRC-tool twice, with 8 days apart, to evaluate its reliability. RESULTS: In total, 177 patients participated (64% male) with a mean age of 67 years (range 33-88). The colon, rectum and stoma module were completed by subsequently 89, 53 and 35 patients. Most items correlated as expected with anticipated domains of the EORTC QLQ-C30 or EORTC QLQ-CR29 (all p-values <0.05). Furthermore, the ABCRC-tool could discriminate between subgroups of patients. The intraclass correlation coefficient (ICC) was good (>0.70) for most items, indicating good reliability. CONCLUSION: The ABCRC-tool is a valid and reliable instrument that is ready for use in a clinical setting to support personalized follow-up care after CRC treatment.

Implementation of Best Practices in Pancreatic Cancer Care in the Netherlands: A Stepped-Wedge Randomized Clinical Trial.

Importance: Implementation of new cancer treatment strategies as recommended by evidence-based guidelines is often slow and suboptimal. Objective: To improve the implementation of guideline-based best practices in the Netherlands in pancreatic cancer care and assess the impact on survival. Design, setting, and participants: This multicenter, stepped-wedge cluster randomized trial compared enhanced implementation of best practices with usual care in consecutive patients with all stages of pancreatic cancer. It took place from May 22, 2018 through July 9, 2020. Data were analyzed from April 1, 2022, through February 1, 2023. It included all patients in the Netherlands with pathologically or clinically diagnosed pancreatic ductal adenocarcinoma. This study reports 1-year follow-up (or shorter in case of deceased patients). Intervention: The 5 best practices included optimal use of perioperative chemotherapy, palliative chemotherapy, pancreatic enzyme replacement therapy (PERT), referral to a dietician, and use of metal stents in patients with biliary obstruction. A 6-week implementation period was completed, in a randomized order, in all 17 Dutch networks for pancreatic cancer care. Main Outcomes and Measures: The primary outcome was 1-year survival. Secondary outcomes included adherence to best practices and quality of life (European Organisation for Research and Treatment of Cancer [EORTC] global health score). Results: Overall, 5887 patients with pancreatic cancer (median age, 72.0 [IQR, 64.0-79.0] years; 50% female) were enrolled, 2641 before and 2939 after implementation of best practices (307 during wash-in period). One-year survival was 24% vs 23% (hazard ratio, 0.98, 95% CI, 0.88-1.08). There was no difference in the use of neoadjuvant chemotherapy (11% vs 11%), adjuvant chemotherapy (48% vs 51%), and referral to a dietician (59% vs 63%), while the use of palliative chemotherapy (24% vs 30%; odds ratio [OR], 1.38; 95% CI, 1.10-1.74), PERT (34% vs 45%; OR, 1.64; 95% CI, 1.28-2.11), and metal biliary stents increased (74% vs 83%; OR, 1.78; 95% CI, 1.13-2.80). The EORTC global health score did not improve (area under the curve, 43.9 vs 42.8; median difference, -1.09, 95% CI, -3.05 to 0.94). Conclusions and Relevance: In this randomized clinical trial, implementation of 5 best practices in pancreatic cancer care did not improve 1-year survival and quality of life. The finding that most patients received no tumor-directed treatment paired with the poor survival highlights the need for more personalized treatment options. Trial Registration: ClinicalTrials.gov Identifier: NCT03513705.

Improving survival in advanced melanoma patients: a trend analysis from 2013 to 2021.

Background: The prognosis of advanced melanoma patients has significantly improved over the years. We aimed to evaluate the survival per year of diagnosis. Methods: All systemically treated patients diagnosed with advanced melanoma from 2013 to 2021 were included from the Dutch Melanoma Treatment Registry. Baseline characteristics and overall survival (OS) were compared between the different years of diagnosis. A multivariable Cox proportional hazards model was used to estimate the association between year of diagnosis and OS. Findings: For this cohort study, we included 6260 systemically treated advanced melanoma patients. At baseline, there was an increase over the years in age, the percentage of patients with an ECOG PS ≥ 2, with brain metastases, and a synchronous diagnosis of primary and unresectable melanoma. Median OS increased from 11.2 months (95% CI 10.0-12.4) for patients diagnosed in 2013 to 32.0 months (95% CI 26.6-36.7) for patients diagnosed in 2019. Median OS was remarkably lower for patients diagnosed in 2020 (26.6 months; 95% CI 23.9-35.1) and 2021 (24.0 months; 95% CI 20.4-NR). Patients diagnosed in 2020 and 2021 had a higher hazard of death compared to patients diagnosed in 2019, although this was not significant. The multivariable Cox regression showed a lower hazard of death for the years of diagnosis after 2013. In contrast, patients diagnosed in 2020 and 2021 had a higher hazard of death compared to patients diagnosed in 2019. Interpretation: After a continuous survival improvement for advanced melanoma patients between 2013 and 2019, outcomes of patients diagnosed in 2020 and 2021 seem poorer. This trend of decreased survival remained after correcting for known prognostic factors and previous neoadjuvant or adjuvant treatment, suggesting that it is explained by unmeasured factors, which-considering the timing-could be COVID-19-related. Funding: For the Dutch Melanoma Treatment Registry (DMTR), the Dutch Institute for Clinical Auditing foundation received a start-up grant from governmental organization The Netherlands Organization for Health Research and Development (ZonMW, project number 836002002). The DMTR is structurally funded by Bristol-Myers Squibb, Merck Sharpe & Dohme, Novartis, and Roche Pharma. Roche Pharma stopped funding in 2019, and Pierre Fabre started funding the DMTR in 2019. For this work, no funding was granted.

Adjuvant dendritic cell therapy in stage IIIB/C melanoma: the MIND-DC randomized phase III trial.

Autologous natural dendritic cells (nDCs) treatment can induce tumor-specific immune responses and clinical responses in cancer patients. In this phase III clinical trial (NCT02993315), 148 patients with resected stage IIIB/C melanoma were randomized to adjuvant treatment with nDCs (n = 99) or placebo (n = 49). Active treatment consisted of intranodally injected autologous CD1c+ conventional and plasmacytoid DCs loaded with tumor antigens. The primary endpoint was the 2-year recurrence-free survival (RFS) rate, whereas the secondary endpoints included median RFS, 2-year and median overall survival, adverse event profile, and immunological response The 2-year RFS rate was 36.8% in the nDC treatment group and 46.9% in the control group (p = 0.31). Median RFS was 12.7 months vs 19.9 months, respectively (hazard ratio 1.25; 90% CI: 0.88-1.79; p = 0.29). Median overall survival was not reached in both treatment groups (hazard ratio 1.32; 90% CI: 0.73-2.38; p = 0.44). Grade 3-4 study-related adverse events occurred in 5% and 6% of patients. Functional antigen-specific T cell responses could be detected in 67.1% of patients tested in the nDC treatment group vs 3.8% of patients tested in the control group (p < 0.001). In conclusion, while adjuvant nDC treatment in stage IIIB/C melanoma patients generated specific immune responses and was well tolerated, no benefit in RFS was observed.

A prediction model for response to immune checkpoint inhibition in advanced melanoma.

Predicting who will benefit from treatment with immune checkpoint inhibition (ICI) in patients with advanced melanoma is challenging. We developed a multivariable prediction model for response to ICI, using routinely available clinical data including primary melanoma characteristics. We used a population-based cohort of 3525 patients with advanced cutaneous melanoma treated with anti-PD-1-based therapy. Our prediction model for predicting response within 6 months after ICI initiation was internally validated with bootstrap resampling. Performance evaluation included calibration, discrimination and internal-external cross-validation. Included patients received anti-PD-1 monotherapy (n = 2366) or ipilimumab plus nivolumab (n = 1159) in any treatment line. The model included serum lactate dehydrogenase, World Health Organization performance score, type and line of ICI, disease stage and time to first distant recurrence-all at start of ICI-, and location and type of primary melanoma, the presence of satellites and/or in-transit metastases at primary diagnosis and sex. The over-optimism adjusted area under the receiver operating characteristic was 0.66 (95% CI: 0.64-0.66). The range of predicted response probabilities was 7%-81%. Based on these probabilities, patients were categorized into quartiles. Compared to the lowest response quartile, patients in the highest quartile had a significantly longer median progression-free survival (20.0 vs 2.8 months; P < .001) and median overall survival (62.0 vs 8.0 months; P < .001). Our prediction model, based on routinely available clinical variables and primary melanoma characteristics, predicts response to ICI in patients with advanced melanoma and discriminates well between treated patients with a very good and very poor prognosis.

Efficacy and Safety of Panitumumab in Patients With RAF/RAS-Wild-Type Glioblastoma: Results From the Drug Rediscovery Protocol.

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.

The Predictive Value of FDG PET/CT for Determining Progression-Free Survival in Advanced Stage III-IV BRAF -Mutated Melanoma Patients Treated With Targeted Therapy-What Can Be Learned From Progression?

PURPOSE: The aims of this study were to investigate whether (early) PERCIST response monitoring with 18 F-FDG PET/CT is predictive for progression-free survival (PFS) in unresectable stage III or IV melanoma patients treated with BRAF/MEK inhibitor (MEKi) and to define dissemination patterns at progression with a lesion-based evaluation in direct comparison to baseline to improve our understanding of 18 F-FDG PET/CT during BRAF/MEKi. PATIENTS AND METHODS: This prospective multicenter single-arm study included 70 patients with unresectable stage III/IV BRAF -mutated melanoma who underwent contrast-enhanced CT and 18 F-FDG PET/CT at baseline and 2 and 7 weeks during treatment with vemurafenib plus cobimetinib and at progression if possible. Tumor response assessment was done with RECIST1.1 and PERCIST. Follow-up PET/CT scans were visually compared with baseline to assess dissemination patterns. RESULTS: Using RECIST1.1, PFS was not significantly different between the response groups ( P = 0.26). At 2 weeks, PERCIST median PFS was 15.7 months for patients with complete metabolic response (CMR) versus 8.3 months for non-CMR ( P = 0.035). The hazards ratio (HR) for progression/death in non-CMR versus CMR was 1.99 (95% confidence interval [CI], 1.03-3.84; P = 0.040) and 1.77 (95% CI, 0.91-3.43; P = 0.0935) when adjusting for lactate dehydrogenase (LDH). At 7 weeks, median PFS for PERCIST CMR was 16.7 months versus 8.5 months for non-CMR ( P = 0.0003). The HR for progression/death in the non-CMR group was significantly increased (HR, 2.94; 95% CI, 1.60-5.40; P = 0.0005), even when adjusting for LDH (HR, 2.65; 95% CI, 1.43-4.91; P = 0.0020). At week 7, 18 F-FDG PET/CT was false-positive in all 4 (6%) patients with new FDG-avid lesions but CMR of known metastases. When 18 F-FDG PET/CT was performed at progressive disease, 18/22 (82%) patients had progression of known metastases with or without new 18 F-FDG-avid lesions. CONCLUSIONS: This study shows that PERCIST response assessment at week 7 is predictive for PFS, regardless of LDH. At 2 weeks, patients with CMR have longer PFS than patients with non-CMR, but different PET parameters should be investigated to further evaluate the added value of early 18 F-FDG PET/CT. Disease progression on PET/CT is predominated by progression of known metastases, and new 18 F-FDG-avid lesions during BRAF/MEKi are not automatically a sign of recurrent disease.

Timing of Initiation of Palliative Chemotherapy in Asymptomatic Patients with Metastatic Pancreatic Cancer: An International Expert Survey and Case-Vignette Study.

Background: The use of imaging, in general, and during follow-up after resection of pancreatic cancer, is increasing. Consequently, the number of asymptomatic patients diagnosed with metastatic pancreatic cancer (mPDAC) is increasing. In these patients, palliative systemic therapy is the only tumor-directed treatment option; hence, it is often immediately initiated. However, delaying therapy in asymptomatic palliative patients may preserve quality of life and avoid therapy-related toxicity, but the impact on survival is unknown. This study aimed to gain insight into the current perspectives and clinical decision=making of experts regarding the timing of treatment initiation of patients with asymptomatic mPDAC. Methods: An online survey (13 questions, 9 case-vignettes) was sent to all first and last authors of published clinical trials on mPDAC over the past 10 years and medical oncologists of the Dutch Pancreatic Cancer Group. Inter-rater variability was determined using the Kappa Light test. Differences in the preferred timing of treatment initiation among countries, continents, and years of experience were analyzed using Fisher's exact test. Results: Overall, 78 of 291 (27%) medical oncologists from 15 countries responded (62% from Europe, 23% from North America, and 15% from Asia-Pacific). The majority of respondents (63%) preferred the immediate initiation of chemotherapy following diagnosis. In 3/9 case-vignettes, delayed treatment was favored in specific clinical contexts (i.e., patient with only one small lung metastasis, significant comorbidities, and higher age). A significant degree of inter-rater variability was present within 7/9 case-vignettes. The recommended timing of treatment initiation differed between continents for 2/9 case-vignettes (22%), in 7/9 (77.9%) comparing the Netherlands with other countries, and based on years of experience for 5/9 (56%). Conclusions: Although the response rate was limited, in asymptomatic patients with mPDAC, immediate treatment is most often preferred. Delaying treatment until symptoms occur is considered in patients with limited metastatic disease, more comorbidities, and higher age.

[Nationwide multidisciplinary developments in pancreatic cancer care in the Netherlands]. / Ontwikkelingen in de zorg voor patiënten met pancreascarcinoom.

In the past years several developments have occurred in the care for patients with pancreatic cancer in the Netherlands. New palliative chemotherapy strategies using FOLFRINOX or gemcitabine/nab-paclitaxel were introduced for patients with advanced disease. Due to centralization of pancreatic surgery, introduction of neoadjuvant therapy, and the implementation of standardized postoperative care more patients became enable for resection, postoperative mortality decreased, and survival improved. Within the randomized PREOPANC trial of the Dutch Pancreatic Cancer Group (DPCG), neoadjuvant therapy using chemoradiation for (borderline) resectable pancreatic cancer improved five-year survival from 7% to 21%. Furthermore, due to nationwide training programs, the use of minimally invasive surgery has increased. Regardless of these developments, the survival of patients with pancreatic cancer is still low and 61% of Dutch patients with pancreatic cancer patients do not receive any tumor targeted therapy. The DPCG is active to improve quality of care through auditing, research, guideline development, and education.

Severe Immune-Related Enteritis after In Utero Exposure to Pembrolizumab.

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.

Health-Related Quality of Life in Patients With Metastatic Colorectal Cancer Undergoing Systemic Therapy With or Without Maximal Tumor Debulking.

BACKGROUND: Maintaining a sufficient health-related quality of life (HRQoL) is important in the palliative treatment of patients with metastatic colorectal cancer (mCRC). The ORCHESTRA trial (ClinicalTrials.gov identifier: NCT01792934) is designed to prospectively evaluate overall survival benefit and impact on HRQoL of tumor debulking when added to first-line palliative systemic therapy in patients with multiorgan mCRC. In the present study, we report the HRQoL associated with this combination treatment compared with standard systemic therapy. METHODS: Patients included in the ORCHESTRA trial with clinical benefit after 3 or 4 cycles of first-line palliative systemic therapy with fluoropyrimidines and oxaliplatin with or without bevacizumab were randomly assigned to maximal tumor debulking followed by systemic therapy versus systemic therapy alone. Patients completed the EORTC Quality of Life Questionnaire-Core 30 and the Multidimensional Fatigue Inventory questionnaire at prespecified time points during treatment. Between-group differences in HRQoL over time were evaluated with linear mixed model analyses. A pattern mixture approach was applied to correct for missing questionnaires due to progressive disease. RESULTS: A total of 300 patients were randomized to the intervention arm (n=148) or the standard arm (n=152). No statistically significant or clinically relevant differences in HRQoL and fatigue were observed when tumor debulking was added to systemic therapy. In patients of both study arms, HRQoL after 1 year of treatment was not significantly different from HRQoL at the time of randomization. Patients in the intervention arm experienced serious adverse events (SAEs) twice as often as patients in the standard arm (P≤.001). CONCLUSIONS: Maximal tumor debulking in combination with palliative systemic therapy in patients with multiorgan mCRC was significantly associated with more SAEs resulting from local therapy but no difference in HRQoL compared with palliative systemic therapy alone. There is a remarkable lack of association between the occurrence of SAEs and impact on HRQoL.

Contribution of MEK Inhibition to BRAF/MEK Inhibitor Combination Treatment of BRAF-Mutant Melanoma: Part 2 of the Randomized, Open-Label, Phase III COLUMBUS Trial.

PURPOSE: In COLUMBUS part 1, patients with advanced BRAFV600-mutant melanoma were randomly assigned 1:1:1 to encorafenib 450 mg once daily plus binimetinib 45 mg twice a day (COMBO450), vemurafenib 960 mg twice a day, or encorafenib 300 mg once daily (ENCO300). As previously reported, COMBO450 improved progression-free survival (PFS) versus vemurafenib (part 1 primary end point) and ENCO300 (part 1 key secondary end point; not statistically significant). Part 2, requested by the US Food and Drug Administration, evaluated the contribution of binimetinib by maintaining the same encorafenib dosage in the combination (encorafenib 300 mg once daily plus binimetinib 45 mg twice daily [COMBO300]) and ENCO300 arms. METHODS: In part 2, patients were randomly assigned 3:1 to COMBO300 or ENCO300. ENCO300 (parts 1 and 2) data were combined, per protocol, for PFS analysis (key secondary end point) by a blinded independent review committee (BIRC). Other analyses included overall response rate (ORR), overall survival, and safety. RESULTS: Two hundred fifty-eight patients received COMBO300, and 86 received ENCO300. Per protocol, ENCO300 arms (parts 1 and 2 combined) were also evaluated (n = 280). The median follow-up for ENCO300 was 40.8 months (part 1) and 57.1 months (part 2). The median PFS (95% CI) was 12.9 months (10.9 to 14.9) for COMBO300 versus 9.2 months (7.4 to 11.1) for ENCO300 (parts 1 and 2) and 7.4 months (5.6 to 9.2) for ENCO300 (part 2). The hazard ratio (95% CI) for COMBO300 was 0.74 (0.60 to 0.92; two-sided P = .003) versus ENCO300 (parts 1 and 2). The ORR by BIRC (95% CI) was 68% (62 to 74) and 51% (45 to 57) for COMBO300 and ENCO300 (parts 1 and 2), respectively. COMBO300 had greater relative dose intensity and fewer grade 3/4 adverse events than ENCO300. CONCLUSION: COMBO300 improved PFS, ORR, and tolerability compared with ENCO300, confirming the contribution of binimetinib to efficacy and safety.

IMPemBra: a phase 2 study comparing pembrolizumab with intermittent/short-term dual MAPK pathway inhibition plus pembrolizumab in patients with melanoma harboring the BRAFV600 mutation.

BACKGROUND: Continuous combination of MAPK pathway inhibition (MAPKi) and anti-programmed death-(ligand) 1 (PD-(L)1) showed high response rates, but only limited improvement in progression-free survival (PFS) at the cost of a high frequency of treatment-related adverse events (TRAE) in patients with BRAFV600-mutated melanoma. Short-term MAPKi induces T-cell infiltration in patients and is synergistic with anti-programmed death-1 (PD-1) in a preclinical melanoma mouse model. The aim of this phase 2b trial was to identify an optimal regimen of short-term MAPKi with dabrafenib plus trametinib in combination with pembrolizumab. METHODS: Patients with treatment-naïve BRAFV600E/K-mutant advanced melanoma started pembrolizumab 200 mg every 3 weeks. In week 6, patients were randomized to continue pembrolizumab only (cohort 1), or to receive, in addition, intermittent dabrafenib 150 mg two times per day plus trametinib 2 mg one time per day for two cycles of 1 week (cohort 2), two cycles of 2 weeks (cohort 3), or continuously for 6 weeks (cohort 4). All cohorts continued pembrolizumab for up to 2 years. Primary endpoints were safety and treatment-adherence. Secondary endpoints were objective response rate (ORR) at week 6, 12, 18 and PFS. RESULTS: Between June 2016 and August 2018, 33 patients with advanced melanoma have been included and 32 were randomized. Grade 3-4 TRAE were observed in 12%, 12%, 50%, and 63% of patients in cohort 1, 2, 3, and 4, respectively. All planned targeted therapy was given in 88%, 63%, and 38% of patients in cohort 2, 3, and 4. ORR at week 6, 12, and 18 were 38%, 63%, and 63% in cohort 1; 25%, 63%, and 75% in cohort 2; 25%, 50%, and 75% in cohort 3; and 0%, 63%, and 50% in cohort 4. After a median follow-up of 43.5 months, median PFS was 10.6 months for pembrolizumab monotherapy and not reached for patients treated with pembrolizumab and intermittent dabrafenib and trametinib (p=0.17). The 2-year and 3-year landmark PFS were both 25% for cohort 1, both 63% for cohort 2, 50% and 38% for cohort 3 and 75% and 60% for cohort 4. CONCLUSIONS: The combination of pembrolizumab plus intermittent dabrafenib and trametinib seems more feasible and tolerable than continuous triple therapy. The efficacy is promising and appears to be favorable over pembrolizumab monotherapy. TRIAL REGISTRATION NUMBER: NCT02625337.

First-line systemic treatment strategies in patients with initially unresectable colorectal cancer liver metastases (CAIRO5): an open-label, multicentre, randomised, controlled, phase 3 study from the Dutch Colorectal Cancer Group.

BACKGROUND: Patients with initially unresectable colorectal cancer liver metastases might qualify for local treatment with curative intent after reducing the tumour size by induction systemic treatment. We aimed to compare the currently most active induction regimens. METHODS: In this open-label, multicentre, randomised, phase 3 study (CAIRO5), patients aged 18 years or older with histologically confirmed colorectal cancer, known RAS/BRAFV600E mutation status, WHO performance status of 0-1, and initially unresectable colorectal cancer liver metastases were enrolled at 46 Dutch and one Belgian secondary and tertiary centres. Resectability or unresectability of colorectal cancer liver metastases was assessed centrally by an expert panel of liver surgeons and radiologists, at baseline and every 2 months thereafter by predefined criteria. Randomisation was done centrally with the minimisation technique via a masked web-based allocation procedure. Patients with right-sided primary tumour site or RAS or BRAFV600E mutated tumours were randomly assigned (1:1) to receive FOLFOX or FOLFIRI plus bevacizumab (group A) or FOLFOXIRI plus bevacizumab (group B). Patients with left-sided and RAS and BRAFV600E wild-type tumours were randomly assigned (1:1) to receive FOLFOX or FOLFIRI plus bevacizumab (group C) or FOLFOX or FOLFIRI plus panitumumab (group D), every 14 days for up to 12 cycles. Patients were stratified by resectability of colorectal cancer liver metastases, serum lactate dehydrogenase concentration, choice of irinotecan versus oxaliplatin, and BRAFV600E mutation status (for groups A and B). Bevacizumab was administered intravenously at 5 mg/kg. Panitumumab was administered intravenously at 6 mg/kg. FOLFIRI consisted of intravenous infusion of irinotecan at 180 mg/m2 with folinic acid at 400 mg/m2, followed by bolus fluorouracil at 400 mg/m2 intravenously, followed by continuous infusion of fluorouracil at 2400 mg/m2. FOLFOX consisted of oxaliplatin at 85 mg/m2 intravenously together with the same schedule of folinic acid and fluorouracil as in FOLFIRI. FOLFOXIRI consisted of irinotecan at 165 mg/m2 intravenously, followed by intravenous infusion of oxaliplatin at 85 mg/m2 with folinic acid at 400 mg/m2, followed by continuous infusion of fluorouracil at 3200 mg/m2. Patients and investigators were not masked to treatment allocation. The primary outcome was progression-free survival, analysed on a modified intention-to-treat basis, excluding patients who withdrew consent before starting study treatment or violated major entry criteria (no metastatic colorectal cancer, or previous liver surgery for colorectal cancer liver metastases). The study is registered with ClinicalTrials.gov, NCT02162563, and accrual is complete. FINDINGS: Between Nov 13, 2014, and Jan 31, 2022, 530 patients (327 [62%] male and 203 [38%] female; median age 62 years [IQR 54-69]) were randomly assigned: 148 (28%) patients to group A, 146 (28%) patients to group B, 118 (22%) patients to group C, and 118 (22%) patients to group D. Groups C and D were prematurely closed for futility. 521 patients were included in the modified intention-to-treat population (147 in group A, 144 in group B, 114 in group C, and 116 in group D). The median follow-up at the time of this analysis was 51·1 months (95% CI 47·7-53·1) in groups A and B and 49·9 months (44·5-52·5) in in groups C and D. Median progression-free survival was 9·0 months (95% CI 7·7-10·5) in group A versus 10·6 months (9·9-12·1) in group B (stratified hazard ratio [HR] 0·76 [95% CI 0·60-0·98]; p=0·032), and 10·8 months (95% CI 9·9-12·6) in group C versus 10·4 months (9·8-13·0) in group D (stratified HR 1·11 [95% CI 0·84-1·48]; p=0·46). The most frequent grade 3-4 events in groups A and B were neutropenia (19 [13%] patients in group A vs 57 [40%] in group B; p<0·0001), hypertension (21 [14%] vs 20 [14%]; p=1·00), and diarrhoea (five [3%] vs 28 [19%]; p<0·0001), and in groups C and D were neutropenia (29 [25%] vs 24 [21%]; p=0·44), skin toxicity (one [1%] vs 29 [25%]; p<0·0001), hypertension (20 [18%] vs eight [7%]; p=0·016), and diarrhoea (five [4%] vs 18 [16%]; p=0·0072). Serious adverse events occurred in 46 (31%) patients in group A, 75 (52%) patients in group B, 41 (36%) patients in group C, and 49 (42%) patients in group D. Seven treatment-related deaths were reported in group B (two due to multiorgan failure, and one each due to sepsis, pneumonia, portal vein thrombosis, septic shock and liver failure, and sudden death), one in group C (multiorgan failure), and three in group D (cardiac arrest, pulmonary embolism, and abdominal sepsis). INTERPRETATION: In patients with initially unresectable colorectal cancer liver metastases, FOLFOXIRI-bevacizumab was the preferred treatment in patients with a right-sided or RAS or BRAFV600E mutated primary tumour. In patients with a left-sided and RAS and BRAFV600E wild-type tumour, the addition of panitumumab to FOLFOX or FOLFIRI showed no clinical benefit over bevacizumab, but was associated with more toxicity. FUNDING: Roche and Amgen.

A Survival Tree of Advanced Melanoma Patients with Brain Metastases Treated with Immune Checkpoint Inhibitors.

The efficacy of immune checkpoint inhibitors (ICIs) in patients with advanced melanoma that develop brain metastases (BM) remains unpredictable. In this study, we aimed to identify prognostic factors in patients with melanoma BM who are treated with ICIs. Data from advanced melanoma patients with BM treated with ICIs in any line between 2013 and 2020 were obtained from the Dutch Melanoma Treatment Registry. Patients were included from the time of the treatment of BM with ICIs. Survival tree analysis was performed with clinicopathological parameters as potential classifiers and overall survival (OS) as the response variable. In total, 1278 patients were included. Most patients were treated with ipilimumab-nivolumab combination therapy (45%). The survival tree analysis resulted in 31 subgroups. The median OS ranged from 2.7 months to 35.7 months. The strongest clinical parameter associated with survival in advanced melanoma patients with BM was the serum lactate dehydrogenase (LDH) level. Patients with elevated LDH levels and symptomatic BM had the worst prognosis. The clinicopathological classifiers identified in this study can contribute to optimizing clinical studies and can aid doctors in giving an indication of the patients' survival based on their baseline and disease characteristics.

Real-world Outcomes of Ipilimumab Plus Nivolumab Combination Therapy in a Nation-wide Cohort of Advanced Melanoma Patients in the Netherlands.

In phase III trials, ipilimumab plus nivolumab combination therapy is highly efficacious for advanced melanoma, despite many treatment-related grades 3-4 adverse events. Here, we report real-world safety and survival outcomes of ipilimumab plus nivolumab for advanced melanoma. Patients with advanced melanoma who received first-line ipilimumab plus nivolumab between January 1, 2015 and June 30, 2021 were selected from the Dutch Melanoma Treatment Registry. We evaluated response status at 3, 6, 12, 18, and 24 months. OS and PFS were estimated with the Kaplan-Meier method. Separate analyses were performed for patients with or without brain metastases and for patients who met the inclusion criteria of the Checkmate-067 trial. In total, 709 patients received first-line ipilimumab plus nivolumab. Three hundred sixty (50.7%) patients experienced grade 3-4 adverse events, with 211 of the (58.6%) patients requiring hospital admission. The median treatment duration was 42 days (IQR = 31-139). At 24 months, disease control was achieved in 37% of patients. Median PFS since the start of treatment was 6.6 months (95% CI: 5.3-8.7), and median OS was 28.7 months (95% CI: 20.7-42.2). CheckMate-067 trial-like patients had a 4-year OS of 50% (95% CI: 43-59). Among patients with no asymptomatic or symptomatic brain metastases, the 4-year OS probabilities were 48% (95% CI: 41-55), 45% (95% CI: 35-57), and 32% (95% CI: 23-46). Ipilimumab plus nivolumab can achieve long-term survival in advanced melanoma patients in a real-world setting, including patients not represented in the CheckMate-067 trial. However, the proportion of patients with disease control in the real world is lower compared with clinical trials.

Possible Value of Faecal Immunochemical Test (FIT) When Added in Symptomatic Patients Referred for Colonoscopy: A Systematic Review.

If Colorectal cancer (CRC) is detected and treated early, the survival rate is high. This is one of the reasons that population-based screening programs for the early detection of CRC using the faecal immunochemical test (FIT) started worldwide. These programs compete with regular colonoscopy programs and increase the waiting time for symptomatic patients. However, the literature has shown that the correlation between intestinal complaints and the gain of colonoscopy is poor. The aim of this study is to assess the diagnostic utility of symptoms for the yield (CRC) of colonoscopy and to compare this with the diagnostic utility of FIT when offered to symptomatic patients. METHODS: We performed a systematic review search for CRC as an outcome of colonoscopy in referred symptomatic patients and separately for CRC as an outcome in symptomatic patients with a positive FIT. We searched systematically for clinical trials or observational studies in databases, followed by hand-searching of reference lists. We used random Meta-Disc to evaluate the diagnostic performance, using the exploration of heterogeneity with a variety of test statistics and by computing the pooled estimates. RESULTS: We included 35 studies, with almost 5 million symptomatic patients. In addition, we included nine prospective studies with a positive FIT in symptomatic patients, with more than 5000 patients. Significant heterogeneity was found for every symptom and the outcome of colonoscopy in the effect size of sensitivity, specificity, positive likelihood ratio, negative likelihood ratio and diagnostic odds ratio. In a random effect model, the pooled sensitivity of colonoscopy in symptomatic patients was very low (25%). However, the pooled sensitivity in symptomatic patients with a positive FIT was 83% and the pooled specificity 77%. A total of 75 symptomatic patients (1.4%) had a false-negative FIT. CONCLUSION: Adding FIT in symptomatic patients seems useful for predicting CRC as an outcome of colonoscopy. FIT seems a potential tool for an improved triage of colonoscopy in symptomatic patients.