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BACKGROUND: To determine whether the addition of durvalumab (anti-PD-L1) and oleclumab (anti-CD73) to standard-of-care treatment (FOLFOX and bevacizumab) enhances the anti-tumour effect in patients with metastatic colorectal cancer (mCRC). METHODS: COLUMBIA-1 (NCT04068610) was a Phase Ib (feasibility; Part 1)/Phase II (randomised; Part 2) trial in patients with treatment-naïve microsatellite stable mCRC. Patients in Part 2 were randomised to receive standard-of-care (control arm) or standard-of-care plus durvalumab and oleclumab (experimental arm). Primary objectives included safety and efficacy. RESULTS: Seven patients were enrolled in Part 1 and 52 in Part 2 (n = 26 in each arm). Grade ≥3 treatment-emergent adverse events (TEAE) occurred in 80.8% and 65.4% of patients in the control and experimental arms of Part 2, respectively, with 26.9% and 46.3% experiencing serious TEAEs. The confirmed objective response rate (ORR) was numerically higher in the experimental arm compared with the control arm (61.5% [95% confidence interval (CI), 40.6-79.8] vs 46.2% [95% CI, 26.6-66.6]) but did not meet the statistically significant threshold in either arm. CONCLUSION: The safety profile of FOLFOX and bevacizumab in combination with durvalumab and oleclumab was manageable; however, the efficacy results do not warrant further development of this combination in patients with microsatellite stable mCRC. REGISTRATION: NCT04068610.

Background: Enco + cetux (doublet) has been approved in the US, EU, and Japan for the treatment of BRAF V600E-mutant mCRC after progression on 1-2 prior regimens. In the BEACON CRC study (NCT02928224), median OS (95% CI) with the doublet was 9.3 months (8.0-11.3) vs 5.9 months (5.1-7.1) with cetux + irinotecan or FOLFIRI (control) in patients (pts) with BRAF V600E-mutant mCRC (HR 0.61 [95% CI: 0.5-0.8]). This post hoc analysis investigates OS by prior therapies to the doublet treatment in pts with BRAF V600E-mutant mCRC from the BEACON CRC study. Methods : OS of pts treated with the doublet or control were compared according to prior treatment with bevacizumab, oxaliplatin or FOLFOXIRI and duration of prior anticancer therapy (ACT). Results : Sixty-four per cent and 55% of pts in the doublet and control arm respectively received prior bevacizumab. Of pts who had one prior therapy, 95% and 88% received prior oxaliplatin and 20% and 14% received prior FOLFOXIRI, respectively. In the doublet arm, pts who had bevacizumab < 4 months before start of study treatment had a median OS of 8.3 months (95% CI: 6.2-11.2); those who had bevacizumab >=4 months prior had a median OS of 10.7 (95% CI: 7.5-17.7). Within each treatment arm, OS was similar regardless of prior treatment with oxaliplatin or FOLFOXIRI. The duration of prior ACT was similar across study arms, ranging from 5.6 to 5.8 months for the first line of ACT. Conclusions : In the BEACON CRC study, pts treated with the doublet for BRAF V600E-mutant mCRC demonstrated similar OS regardless of prior therapies or duration of prior therapy use. This exploratory post hoc analysis provides data that reflect the prior treatment landscape clinicians may face when deciding subsequent treatment regimens for pts with BRAF V600E-mutant mCRC.

Background: In the BEACON study, encorafenib + binimetinib + cetuximab (enco/bini/cetux; triplet) and enco + cetux (doublet) improved OS and ORR vs standard of care in previously treated BRAF V600E-mutant mCRC pts. Molecular profiling of tumours from this study was performed to identify molecular correlates of outcome. Methods : Baseline tumour samples were analysed by whole-exome sequencing (WES) and whole transcriptome sequencing (WTS). BRAF-mutant (BM) and consensus molecular subtypes (CMS) were determined and pathway activities evaluated with gene set variation analysis. Tumour response was evaluated for each subtype. Additional association and interaction analyses between molecular features and outcomes by treatments are ongoing and will be presented. Results : Baseline tumour samples were analysed by WES and/or WTS for 79.2% of pts. Of the 460 pts analysed by WTS (73.7% in the triplet arm, 66.4% in the doublet arm, 67.4% in the control arm), 84.6% were classified as CMS1 or CMS4. Overall 32.2% of pts were classified as BM1 and the majority (84.5%) of these were CMS4. Many of those classified as BM2 (67.8%) were CMS1 (64.7%). In the BM1 and CMS4 tumours, expression of inflammatory response and epithelial mesenchymal transition genes were elevated, and expression of cell cycle genes was reduced. Response rate in pts with CMS4 and/or BM1 tumors was higher in the triplet arm (CMS4: 33.3% [95% CI: 21.7-46.7]; BM1: 33.3% [95% CI: 21.4-47.1]) vs the doublet arm (CMS4: 19.2% [95% CI: 9.6-32.5]; BM1: 14.9% [95% CI: 6.2-28.3]). Conclusions : Molecular characteristics and biological properties observed in BRAF V600E-mutant mCRC suggest a subset of pts with specific molecular features may derive greater clinical benefit from triplet vs doublet therapy. These findings support further investigating the biological landscape in BRAF-mutant mCRC to enable potential hypotheses for pt selection to improve clinical outcome in future studies.

BACKGROUND: In the BEACON CRC study (NCT02928224), encorafenib plus cetuximab with binimetinib {9.3 versus 5.9 months; hazard ratio (HR) [95% confidence interval (CI)]: 0.60 [0.47-0.75]} or without binimetinib [9.3 versus 5.9 months; HR (95% CI): 0.61 (0.48-0.77)] significantly improved overall survival (OS) compared with the previous standard of care (control) in patients with BRAF V600E metastatic colorectal cancer (mCRC). Quality of life (QoL) was a secondary endpoint, assessed using validated instruments. PATIENTS AND METHODS: BEACON CRC was a randomized, open-label, phase III study comparing encorafenib plus cetuximab with or without binimetinib and the investigator's choice of irinotecan plus cetuximab or FOLFIRI plus cetuximab (chemotherapy control) in patients with previously treated BRAF V600E mCRC. Patient-reported QoL assessments included the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC) and Functional Assessment of Cancer Therapy-Colorectal (FACT-C). The primary outcome for these tools was time to definitive 10% deterioration. RESULTS: Encorafenib plus cetuximab, both with and without binimetinib, was associated with longer median times to definitive 10% deterioration versus the control group in the EORTC Global Health Status scale [HR (95% CI): 0.65 (0.52-0.80) versus 0.61 (0.49-0.75), respectively] and the FACT-C functional well-being subscale [HR (95% CI): 0.62 (0.50-0.76) versus 0.58 (0.47-0.72), respectively]. Consistent results were observed across all subscales of the EORTC and FACT-C instruments. QoL was generally maintained during treatment for the global EORTC and FACT-C scales. CONCLUSIONS: In addition to improving OS, encorafenib plus cetuximab with or without binimetinib delays QoL decline in previously treated patients with BRAF V600E-mutant mCRC.

Single-cell RNA sequencing studies have suggested that total mRNA content correlates with tumor phenotypes. Technical and analytical challenges, however, have so far impeded at-scale pan-cancer examination of total mRNA content. Here we present a method to quantify tumor-specific total mRNA expression (TmS) from bulk sequencing data, taking into account tumor transcript proportion, purity and ploidy, which are estimated through transcriptomic/genomic deconvolution. We estimate and validate TmS in 6,590 patient tumors across 15 cancer types, identifying significant inter-tumor variability. Across cancers, high TmS is associated with increased risk of disease progression and death. TmS is influenced by cancer-specific patterns of gene alteration and intra-tumor genetic heterogeneity as well as by pan-cancer trends in metabolic dysregulation. Taken together, our results indicate that measuring cell-type-specific total mRNA expression in tumor cells predicts tumor phenotypes and clinical outcomes.

Background: BEACONCRC is a randomized, phase 3 study which evaluated the triplet of encorafenib (ENCO) + binimetinib (BINI) + cetuximab (CETUX) and the doublet of ENCO + CETUX vs. investigator's choice of irinotecan + CETUX or FOLFIRI + CETUX in patients (pts) with BRAFV600E metastatic colorectal cancer (mCRC) whose disease had progressed after 1-2 prior regimens in the metastatic setting. Primary endpoints were overall survival (OS) and objective response rate (ORR; by blinded central review) for triplet vs control. In a previous interim analysis, triplet and doublet improvedOS andORRversus standard of care. Here we report on an updated analysis. Method(s): Updated analysis includes 6 months of additional follow-up and response data for all randomized pts. The study is ongoing. Result(s): Patients received triplet (n = 224), doublet (n = 220), or control (n = 221). Median OS was 9.3 months (95% confidence interval [CI]:8.2, 10.8) for triplet and 5.9 months (95% CI:5.1-7.1) for control (hazard ratio [HR] (95% CI): 0.60 (0.47-0.75)). Median OS for doublet was 9.3 months (95% CI: 8.0-11.3) (HR vs control: 0.61 (0.48- 0.77). Confirmed ORR was 26.8% (95% CI: 21.1%-33.1%) for triplet, 19.5% (95% CI: 14.5%-25.4%) for doublet, and 1.8% (95% CI: 0.5%- 4.6%) for control. Retrospective subgroup analyses suggested some pts may benefit more from triplet than doublet therapy (Table). Both triplet and doublet showedimprovedOS compared to control in all subgroups. Adverse events were consistent with prior analysis, with grade >=3 adverse events in 65.8%, 57.4%, and 64.2% for triplet, doublet and control, respectively. Conclusion(s): The updated analysis of the BEACON CRC study confirmed that encorafenib + cetuximab with or without binimetinib improved OS and ORR in previously treated pts with BRAF V600E mCRC compared with standard chemotherapy.

BRAF V600E mutations are identified in <=15% of metastatic colorectal cancer (mCRC) patients and confer a poor prognosis. In patient's refractory to initial therapy, ORR to standard chemotherapy and biologic combinations are generally <10%, with median PFS and OS of ~2 and 4-6 months, respectively. The BEACON CRC Study (NCT02928224) was a multicentre, randomized, open-label, 3-arm, phase 3 study evaluating ENCO + CETUX +/- BINI (triplet or doublet combination) versus investigator's choice of Irinotecan or FOLFIRI + CETUX (control) in patients with BRAF V600E-mutant mCRC who had failed one or two prior regimens in the metastatic setting. Primary endpoints were OS and ORR (blinded central review) for the triplet versus control arm; secondary endpoints included OS for the doublet versus control arm, as well as PFS, duration of response and safety. A total of 665 patients were randomly assigned to receive: triplet combination (n= 224), doublet combination (n= 220) or control regimen (n= 221). Median OS was 9.0 months (95% CI, 8.0-11.4) for the triplet versus 5.4 months (95% CI, 4.8-6.6) for control regimens (HR: 0.52; 95% CI, 0.39-0.70; P < .0001). ConfirmedORR(blinded central review) was 26% (95% CI, 18-35%) for the triplet versus 2% (95% CI, <1% to 7%) for control (P < .0001). Median OS for the doublet was 8.4months (95% CI, 7.5-11.0) (HR vs control, 0.60; 95% CI, 0.45-0.79; P = .0003). Adverse events (AEs) were consistent with prior trials with each combination. AEs >=grade 3 occurred in 58%, 50% and 61% of patients in the triplet, doublet and control arms, respectively. ENCO + BINI + CETUX improved OS and ORR in patients with BRAF V600E-mutant mCRC compared with current standard of care chemotherapy and had a safety profile consistent with the known safety profile of each agent. This targeted therapy regimen should be a new standard of care for this patient population.

Colorectal cancer is the second leading cause of cancer deaths worldwide, with a 5-year relative survival of 14% in patients with metastatic colorectal cancer (mCRC). Patients with BRAF V600E mutations, which occur in ∼10%-15% of patients with mCRC, have a poorer prognosis compared with those with wild-type BRAF tumours. The combination of the BRAF inhibitor encorafenib with the epidermal growth factor receptor inhibitor cetuximab currently represents the only chemotherapy-free targeted therapy approved in the USA and Europe for previously treated patients with BRAF V600E-mutated mCRC. As a class, BRAF inhibitors are associated with dermatologic, gastrointestinal, and renal events, as well as pyrexia and secondary skin malignancies. Adverse event (AE) profiles of specific BRAF inhibitors vary, however, and are affected by the specific agents given in combination. In patients with mCRC, commonly reported AEs of cetuximab monotherapy include infusion reactions and dermatologic toxicities. Data from the phase III BEACON CRC study indicate that the combination of encorafenib with cetuximab has a distinct safety profile. Here we review the most frequently reported AEs that occurred with this combination in BEACON CRC and best practices for managing and mitigating AEs that require more than standard supportive care.