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We previously reported a 35-gene expression classifier identifying four clear-cell renal cell carcinoma groups (ccrcc1 to ccrcc4) with different tumour microenvironments and sensitivities to sunitinib in metastatic clear-cell renal cell carcinoma. Efficacy profiles might differ with nivolumab and nivolumab–ipilimumab. We therefore aimed to evaluate treatment efficacy and tolerability of nivolumab, nivolumab–ipilimumab, and VEGFR-tyrosine kinase inhibitors (VEGFR-TKIs) in patients according to tumour molecular groups. This biomarker-driven, open-label, non-comparative, randomised, phase 2 trial included patients from 15 university hospitals or expert cancer centres in France. Eligible patients were aged 18 years or older, had an Eastern Cooperative Oncology Group performance status of 0–2, and had previously untreated metastatic clear-cell renal cell carcinoma. Patients were randomly assigned (1:1) using permuted blocks of varying sizes to receive either nivolumab or nivolumab–ipilimumab (ccrcc1 and ccrcc4 groups), or either a VEGFR-TKI or nivolumab–ipilimumab (ccrcc2 and ccrcc3 groups). Patients assigned to nivolumab–ipilimumab received intravenous nivolumab 3 mg/kg plus ipilimumab 1 mg/kg every 3 weeks for four doses followed by intravenous nivolumab 240 mg every 2 weeks. Patients assigned to nivolumab received intravenous nivolumab 240 mg every 2 weeks. Patients assigned to VEGFR-TKIs received oral sunitinib (50 mg/day for 4 weeks every 6 weeks) or oral pazopanib (800 mg daily continuously). The primary endpoint was the objective response rate by investigator assessment per Response Evaluation Criteria in Solid Tumors version 1.1. The primary endpoint and safety were assessed in the population who received at least one dose of study drug. This trial is registered with ClinicalTrials.gov, NCT02960906, and with the EU Clinical Trials Register, EudraCT 2016-003099-28, and is closed to enrolment. Between June 28, 2017, and July 18, 2019, 303 patients were screened for eligibility, 202 of whom were randomly assigned to treatment (61 to nivolumab, 101 to nivolumab–ipilimumab, 40 to a VEGFR-TKI). In the nivolumab group, two patients were excluded due to a serious adverse event before the first study dose and one patient was excluded from analyses due to incorrect diagnosis. Median follow-up was 18·0 months (IQR 17·6–18·4). In the ccrcc1 group, objective responses were seen in 12 (29%; 95% CI 16–45) of 42 patients with nivolumab and 16 (39%; 24–55) of 41 patients with nivolumab–ipilimumab (odds ratio [OR] 0·63 [95% CI 0·25–1·56]). In the ccrcc4 group, objective responses were seen in seven (44%; 95% CI 20–70) of 16 patients with nivolumab and nine (50% 26–74) of 18 patients with nivolumab–ipilimumab (OR 0·78 [95% CI 0·20–3·01]). In the ccrcc2 group, objective responses were seen in 18 (50%; 95% CI 33–67) of 36 patients with a VEGFR-TKI and 19 (51%; 34–68) of 37 patients with nivolumab–ipilimumab (OR 0·95 [95% CI 0·38–2·37]). In the ccrcc3 group, no objective responses were seen in the four patients who received a VEGFR-TKI, and in one (20%; 95% CI 1–72) of five patients who received nivolumab–ipilimumab. The most common treatment-related grade 3–4 adverse events were hepatic failure and lipase increase (two [3%] of 58 for both) with nivolumab, lipase increase and hepatobiliary disorders (six [6%] of 101 for both) with nivolumab–ipilimumab, and hypertension (six [15%] of 40) with a VEGFR-TKI. Serious treatment-related adverse events occurred in two (3%) patients in the nivolumab group, 38 (38%) in the nivolumab–ipilimumab group, and ten (25%) patients in the VEGFR-TKI group. Three deaths were treatment-related: one due to fulminant hepatitis with nivolumab–ipilimumab, one death from heart failure with sunitinib, and one due to thrombotic microangiopathy with sunitinib. We demonstrate the feasibility and positive effect of a prospective patient selection based on tumour molecular phenotype to choose the most efficacious treatment between nivolumab with or without ipilimumab and a VEGFR-TKI in the first-line treatment of metastatic clear-cell renal cell carcinoma. Bristol Myers Squibb, ARTIC.

Aims To investigate the efficacy and safety of a single intracameral bevacizumab injection to improve the outcome of trabeculectomy. Methods A 12-month, prospective, randomised, double-masked, placebo-controlled trial. Patients with medically uncontrolled open-angle glaucoma scheduled for a primary trabeculectomy were recruited and randomised to receive 50 µL of either bevacizumab (1.25 mg) or placebo (balanced salt solution) peroperatively. Absolute success was defined as intraocular pressure (IOP) ≤18 mm Hg and >5 mm Hg with at least 30% reduction from baseline and no loss of light perception. Success through the use of additional medical and/or surgical IOP-lowering treatments was defined as qualified success. Results 138 patients completed a 12-month follow-up, 69 of whom were in the bevacizumab treated group. IOP at 1 year postoperatively was significantly lower than baseline (placebo: 25.6±9.9 mm Hg vs 11.5±3.9 mm Hg, p<0.01; bevacizumab: 24.8±8.1 mm Hg vs 11.9±3.8 mm Hg, p<0.01), with no difference between treatment groups (p=0.69). However, absolute success was higher in the bevacizumab group (71% vs 51%, p=0.02), with the need for IOP-lowering interventions (needlings) being lower in this group (12% vs 33%, p=0.003). Complication rates were low and comparable between groups. Conclusions Peroperative administration of intracameral bevacizumab significantly reduces the need for additional interventions during the follow-up of patients undergoing trabeculectomy.

Regorafenib has proven activity in patients with pretreated gastrointestinal stromal tumours and colorectal and hepatocellular carcinoma. We designed REGOBONE to assess the efficacy and safety of regorafenib for patients with progressive metastatic osteosarcoma and other bone sarcomas. This trial comprised four parallel independent cohorts: osteosarcoma, Ewing sarcoma, chondrosarcoma, and chordoma. In this Article, we report the results of the osteosarcoma cohort. In this non-comparative, double-blind, placebo-controlled, phase 2 trial, patients aged 10 years or older with histologically confirmed osteosarcoma whose disease had progressed after treatment with one to two previous lines of chemotherapy for metastatic disease and an Eastern Cooperative Oncology Group performance status of 0 or 1 were enrolled. Patients were randomly assigned (2:1) to receive either oral regorafenib (160 mg/day, for 21 of 28 days) or matching placebo. Patients in both groups also received best supportive care. Randomisation was done using a web-based system and was stratified (permuted block) by age at inclusion (<18 vs ≥18 years old). Investigators and patients were masked to treatment allocation. Patients in the placebo group, after centrally confirmed progressive disease, could cross over to receive regorafenib. The primary endpoint was the proportion of patients without disease progression at 8 weeks. Analyses were done by modified intention to treat (ie, patients without any major entry criteria violation who initiated masked study drug treatment were included). All participants who received at least one dose of study drug were included in the safety analyses. This study is registered with ClinicalTrials.gov, number NCT02389244, and the results presented here are the final analysis of the osteosarcoma cohort (others cohorts are ongoing). Between Oct 10, 2014, and April 4, 2017, 43 adult patients were enrolled from 13 French comprehensive cancer centres. All patients received at least one dose of assigned treatment and were evaluable for safety; five patients were excluded for major protocol violations (two in the placebo group and three in the regorafenib group), leaving 38 patients who were evaluable for efficacy (12 in the placebo group and 26 in the regorafenib group). 17 of 26 patients (65%; one-sided 95% CI 47%) in the regorafenib group were non-progressive at 8 weeks compared with no patients in the placebo group. Ten patients in the placebo group crossed over to receive open-label regorafenib after centrally confirmed disease progression. 13 treatment-related serious adverse events occurred in seven (24%) of 29 patients in the regorafenib group versus none of 14 patients in the placebo group. The most common grade 3 or worse treatment-related adverse events during the double-blind period of treatment included hypertension (in seven [24%] of 29 patients in the regorafenib group vs none in the placebo group), hand–foot skin reaction (three [10%] vs none), fatigue (three [10%] vs one [3%]), hypophosphataemia (three [10%] vs none), and chest pain (three [10%] vs none). No treatment-related deaths occurred. Regorafenib demonstrated clinically meaningful antitumour activity in adult patients with recurrent, progressive, metastatic osteosarcoma after failure of conventional chemotherapy, with a positive effect on delaying disease progression. Regorafenib should be further evaluated in the setting of advanced disease as well as potentially earlier in the disease course for patients at high risk of relapse. Regorafenib might have an important therapeutic role as an agent complementary to standard cytotoxic chemotherapy in the therapeutic armamentarium against osteosarcoma. Bayer HealthCare.

Glioblastoma is a highly vascularised tumour and there are few treatment options after disease recurrence. Regorafenib is an oral multikinase inhibitor of angiogenic, stromal, and oncogenic receptor tyrosine kinases. We aimed to assess the efficacy and safety of regorafenib in the treatment of recurrent glioblastoma. REGOMA is a randomised, multicentre, open-label phase 2 trial done in ten centres in Italy. Eligible patients (aged ≥18 years) with histologically confirmed glioblastoma, Eastern Cooperative Oncology Group performance status 0 or 1, and documented disease progression after surgery followed by radiotherapy and temozolomide chemoradiotherapy were randomly assigned (1:1) by a web-based system, stratified by centre and surgery at recurrence (yes vs no), to receive regorafenib 160 mg once daily for the first 3 weeks of each 4-week cycle or lomustine 110 mg/m2 once every 6 weeks until disease progression, death, unacceptable toxicity, or consent withdrawal. The primary endpoint was overall survival in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, NCT02926222, and is currently in follow-up. Between Nov 27, 2015, and Feb 23, 2017, 124 patients were screened and 119 eligible patients were randomly assigned to receive regorafenib (n=59) or lomustine (n=60). Median follow-up was 15·4 months (IQR 13·8–18·1). At the analysis cutoff date, 99 (83%) of 119 patients had died: 42 (71%) of 59 in the regorafenib group and 57 (95%) of 60 in the lomustine group. Overall survival was significantly improved in the regorafenib group compared with the lomustine group, with a median overall survival of 7·4 months (95% CI 5·8–12·0) in the regorafenib group and 5·6 months (4·7–7·3) in the lomustine group (hazard ratio 0·50, 95% CI 0·33–0·75; log-rank p=0·0009). Grade 3–4 treatment-related adverse events occurred in 33 (56%) of 59 patients treated with regorafenib and 24 (40%) of 60 with lomustine. The most frequent grade 3 or 4 adverse events related to regorafenib were hand–foot skin reaction, increased lipase, and blood bilirubin increased (in six [10%] of 59 patients each). In the lomustine group, the most common grade 3 or 4 adverse events were decreased platelet count (eight [13%] of 60 patients), decreased lymphocyte count (eight [13%]), and neutropenia (seven [12%]). No death was considered by the investigators to be drug related. REGOMA showed an encouraging overall survival benefit of regorafenib in recurrent glioblastoma. This drug might be a new potential treatment for these patients and should be investigated in an adequately powered phase 3 study. Veneto Institute of Oncology and Bayer Italy.

Faricimab is a bispecific antibody that acts through dual inhibition of both angiopoietin-2 and vascular endothelial growth factor A. We report primary results of two phase 3 trials evaluating intravitreal faricimab with extension up to every 16 weeks for neovascular age-related macular degeneration (nAMD). TENAYA and LUCERNE were randomised, double-masked, non-inferiority trials across 271 sites worldwide. Treatment-naive patients with nAMD aged 50 years or older were randomly assigned (1:1) to intravitreal faricimab 6·0 mg up to every 16 weeks, based on protocol-defined disease activity assessments at weeks 20 and 24, or aflibercept 2·0 mg every 8 weeks. Randomisation was performed through an interactive voice or web-based response system using a stratified permuted block randomisation method. Patients, investigators, those assessing outcomes, and the funder were masked to group assignments. The primary endpoint was mean change in best-corrected visual acuity (BCVA) from baseline averaged over weeks 40, 44, and 48 (prespecified non-inferiority margin of four letters), in the intention-to-treat population. Safety analyses included patients who received at least one dose of study treatment. These trials are registered with ClinicalTrials.gov (TENAYA NCT03823287 and LUCERNE NCT03823300). Across the two trials, 1329 patients were randomly assigned between Feb 19 and Nov 19, 2019 (TENAYA n=334 faricimab and n=337 aflibercept), and between March 11 and Nov 1, 2019 (LUCERNE n=331 faricimab and n=327 aflibercept). BCVA change from baseline with faricimab was non-inferior to aflibercept in both TENAYA (adjusted mean change 5·8 letters [95% CI 4·6 to 7·1] and 5·1 letters [3·9 to 6·4]; treatment difference 0·7 letters [−1·1 to 2·5]) and LUCERNE (6·6 letters [5·3 to 7·8] and 6·6 letters [5·3 to 7·8]; treatment difference 0·0 letters [–1·7 to 1·8]). Rates of ocular adverse events were comparable between faricimab and aflibercept (TENAYA n=121 [36·3%] vs n=128 [38·1%], and LUCERNE n=133 [40·2%] vs n=118 [36·2%]). Visual benefits with faricimab given at up to 16-week intervals demonstrates its potential to meaningfully extend the time between treatments with sustained efficacy, thereby reducing treatment burden in patients with nAMD. F Hoffmann-La Roche.

To reduce treatment burden and optimise patient outcomes in diabetic macular oedema, we present 1-year results from two phase 3 trials of faricimab, a novel angiopoietin-2 and vascular endothelial growth factor-A bispecific antibody. YOSEMITE and RHINE were randomised, double-masked, non-inferiority trials across 353 sites worldwide. Adults with vision loss due to centre-involving diabetic macular oedema were randomly assigned (1:1:1) to intravitreal faricimab 6·0 mg every 8 weeks, faricimab 6·0 mg per personalised treatment interval (PTI), or aflibercept 2·0 mg every 8 weeks up to week 100. PTI dosing intervals were extended, maintained, or reduced (every 4 weeks up to every 16 weeks) based on disease activity at active dosing visits. The primary endpoint was mean change in best-corrected visual acuity at 1 year, averaged over weeks 48, 52, and 56. Efficacy analyses included the intention-to-treat population (non-inferiority margin 4 Early Treatment Diabetic Retinopathy Study [ETDRS] letters); safety analyses included patients with at least one dose of study treatment. These trials are registered with ClinicalTrials.gov (YOSEMITE NCT03622580 and RHINE NCT03622593). 3247 patients were screened for eligibility in YOSEMITE (n=1532) and RHINE (n=1715). After exclusions, 940 patients were enrolled into YOSEMITE between Sept 5, 2018, and Sept 19, 2019, and 951 patients were enrolled into RHINE between Oct 9, 2018, and Sept 20, 2019. These 1891 patients were randomly assigned to faricimab every 8 weeks (YOSEMITE n=315, RHINE n=317), faricimab PTI (n=313, n=319), or aflibercept every 8 weeks (n=312, n=315). Non-inferiority for the primary endpoint was achieved with faricimab every 8 weeks (adjusted mean vs aflibercept every 8 weeks in YOSEMITE 10·7 ETDRS letters [97·52% CI 9·4 to 12·0] vs 10·9 ETDRS letters [9·6 to 12·2], difference −0·2 ETDRS letters [−2·0 to 1·6]; RHINE 11·8 ETDRS letters [10·6 to 13·0] vs 10·3 ETDRS letters [9·1 to 11·4] letters, difference 1·5 ETDRS letters [−0·1 to 3·2]) and faricimab PTI (YOSEMITE 11·6 ETDRS letters [10·3 to 12·9], difference 0·7 ETDRS letters [−1·1 to 2·5]; RHINE 10·8 ETDRS letters [9·6 to 11·9], difference 0·5 ETDRS letters [−1·1 to 2·1]). Incidence of ocular adverse events was comparable between faricimab every 8 weeks (YOSEMITE n=98 [31%], RHINE n=137 [43%]), faricimab PTI (n=106 [34%], n=119 [37%]), and aflibercept every 8 weeks (n=102 [33%], n=113 [36%]). Robust vision gains and anatomical improvements with faricimab were achieved with adjustable dosing up to every 16 weeks, demonstrating the potential for faricimab to extend the durability of treatment for patients with diabetic macular oedema. F Hoffmann-La Roche.

A number of agents are now approved for the treatment of renal cancer. A comparison of two agents, pazopanib and sunitinib, showed similar levels of antitumor activity but distinct side-effect profiles. Symptoms affecting quality of life were somewhat worse with sunitinib. Renal-cell carcinoma is the most common kidney cancer. 1 Up to 30% of patients have metastases at the time of the initial diagnosis. 2 Systemic treatment for patients who have metastatic renal-cell carcinoma with a clear-cell histologic component has shifted from cytokines to drugs targeting angiogenesis. Sunitinib, pazopanib, and five other agents have been approved by the Food and Drug Administration for the treatment of clear-cell, metastatic renal-cell carcinoma. 3 , 4 Among the tyrosine kinase inhibitors, pazopanib and sunitinib are first-line treatment options. Sunitinib has been compared with interferon alfa in patients who had not previously received systemic therapy for renal-cell carcinoma, 5 whereas . . .

Despite increasing worldwide use of anti-vascular endothelial growth factor agents for treatment of retinopathy of prematurity (ROP), there are few data on their ocular efficacy, the appropriate drug and dose, the need for retreatment, and the possibility of long-term systemic effects. We evaluated the efficacy and safety of intravitreal ranibizumab compared with laser therapy in treatment of ROP. This randomised, open-label, superiority multicentre, three-arm, parallel group trial was done in 87 neonatal and ophthalmic centres in 26 countries. We screened infants with birthweight less than 1500 g who met criteria for treatment for retinopathy, and randomised patients equally (1:1:1) to receive a single bilateral intravitreal dose of ranibizumab 0·2 mg or ranibizumab 0·1 mg, or laser therapy. Individuals were stratified by disease zone and geographical region using computer interactive response technology. The primary outcome was survival with no active retinopathy, no unfavourable structural outcomes, or need for a different treatment modality at or before 24 weeks (two-sided α=0·05 for superiority of ranibizumab 0·2 mg against laser therapy). Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, NCT02375971. Between Dec 31, 2015, and June 29, 2017, 225 participants (ranibizumab 0·2 mg n=74, ranibizumab 0·1 mg n=77, laser therapy n=74) were randomly assigned. Seven were withdrawn before treatment (n=1, n=1, n=5, respectively) and 17 did not complete follow-up to 24 weeks, including four deaths in each group. 214 infants were assessed for the primary outcome (n=70, n=76, n=68, respectively). Treatment success occurred in 56 (80%) of 70 infants receiving ranibizumab 0·2 mg compared with 57 (75%) of 76 infants receiving ranibizumab 0·1 mg and 45 (66%) of 68 infants after laser therapy. Using a hierarchical testing strategy, compared with laser therapy the odds ratio (OR) of treatment success following ranibizumab 0·2 mg was 2·19 (95% Cl 0·99–4·82, p=0·051), and following ranibizumab 0·1 mg was 1·57 (95% Cl 0·76–3·26); for ranibizumab 0·2 mg compared with 0·1 mg the OR was 1·35 (95% Cl 0·61–2·98). One infant had an unfavourable structural outcome following ranibizumab 0·2 mg, compared with five following ranibizumab 0·1 mg and seven after laser therapy. Death, serious and non-serious systemic adverse events, and ocular adverse events were evenly distributed between the three groups. In the treatment of ROP, ranibizumab 0·2 mg might be superior to laser therapy, with fewer unfavourable ocular outcomes than laser therapy and with an acceptable 24-week safety profile. Novartis.

The treatment of advanced renal cell carcinoma has been revolutionised by targeted therapy with drugs that block angiogenesis. So far, no phase 3 randomised trials comparing the effectiveness of one targeted agent against another have been reported. We did a randomised phase 3 study comparing axitinib, a potent and selective second-generation inhibitor of vascular endothelial growth factor (VEGF) receptors, with sorafenib, an approved VEGF receptor inhibitor, as second-line therapy in patients with metastatic renal cell cancer. We included patients coming from 175 sites (hospitals and outpatient clinics) in 22 countries aged 18 years or older with confirmed renal clear-cell carcinoma who progressed despite first-line therapy containing sunitinib, bevacizumab plus interferon-alfa, temsirolimus, or cytokines. Patients were stratified according to Eastern Cooperative Oncology Group performance status and type of previous treatment and then randomly assigned (1:1) to either axitinib (5 mg twice daily) or sorafenib (400 mg twice daily). Axitinib dose increases to 7 mg and then to 10 mg, twice daily, were allowed for those patients without hypertension or adverse reactions above grade 2. Participants were not masked to study treatment. The primary endpoint was progression-free survival (PFS) and was assessed by a masked, independent radiology review and analysed by intention to treat. This trial was registered on ClinicalTrials.gov, number NCT00678392. A total of 723 patients were enrolled and randomly assigned to receive axitinib (n=361) or sorafenib (n=362). The median PFS was 6·7 months with axitinib compared to 4·7 months with sorafenib (hazard ratio 0·665; 95% CI 0·544–0·812; one-sided p<0·0001). Treatment was discontinued because of toxic effects in 14 (4%) of 359 patients treated with axitinib and 29 (8%) of 355 patients treated with sorafenib. The most common adverse events were diarrhoea, hypertension, and fatigue in the axitinib arm, and diarrhoea, palmar-plantar erythrodysaesthesia, and alopecia in the sorafenib arm. Axitinib resulted in significantly longer PFS compared with sorafenib. Axitinib is a treatment option for second-line therapy of advanced renal cell carcinoma. Pfizer Inc.

In the TRIBE study, FOLFOXIRI (fluorouracil, leucovorin, oxaliplatin, and irinotecan) plus bevacizumab significantly improved progression-free survival of patients with metastatic colorectal cancer compared with FOLFIRI (fluorouracil, leucovorin, and irinotecan) plus bevacizumab. In this updated analysis, we aimed to provide mature results for overall survival—a secondary endpoint—and report treatment efficacy in RAS and BRAF molecular subgroups. TRIBE was an open-label, multicentre, phase 3 randomised study of patients (aged 18–70 years with Eastern Cooperative Oncology Group [ECOG] performance status of 2 or less and aged 71–75 years with an ECOG performance status of 0) with unresectable metastatic colorectal cancer who were recruited from 34 Italian oncology units. Patients were randomly assigned (1:1) via a web-based procedure to receive FOLFIRI plus bevacizumab or FOLFOXIRI plus bevacizumab. Bevacizumab was given as a 5 mg/kg intravenous dose. FOLFIRI consisted of a 180 mg/m2 intravenous infusion of irinotecan for 60 min followed by a 200 mg/m2 intravenous infusion of leucovorin for 120 min, a 400 mg/m2 intravenous bolus of fluorouracil, and a 2400 mg/m2 continuous infusion of fluorouracil for 46 h. FOLFOXIRI consisted of a 165 mg/m2 intravenous infusion of irinotecan for 60 min, followed by an 85 mg/m2 intravenous infusion of oxaliplatin given concurrently with 200 mg/m2 leucovorin for 120 min, followed by a 3200 mg/m2 continuous infusion of fluorouracil for 48 h. Tissue samples for RAS and BRAF mutational status analyses were centrally collected. In this updated analysis, we assessed the secondary endpoint of overall survival in the main cohort and treatment efficacy in RAS and BRAF molecular subgroups. All analyses were by intention to treat. TRIBE was concluded on Nov 30, 2014. The trial is registered with ClinicalTrials.gov, number NCT00719797. Between July 17, 2008, and May 31, 2011, 508 patients were randomly assigned. At a median follow-up of 48·1 months (IQR 41·7–55·6), median overall survival was 29·8 months (95% CI 26·0–34·3) in the FOLFOXIRI plus bevacizumab group compared with 25·8 months (22·5–29·1) in the FOLFIRI plus bevacizumab group (hazard ratio [HR] 0·80, 95% CI 0·65–0·98; p=0·03). Median overall survival was 37·1 months (95% CI 29·7–42·7) in the RAS and BRAF wild-type subgroup compared with 25·6 months (22·4–28·6) in the RAS-mutation-positive subgroup (HR 1·49, 95% CI 1·11–1·99) and 13·4 months (8·2–24·1) in the BRAF-mutation-positive subgroup (HR 2·79, 95% CI 1·75–4·46; likelihood-ratio test p<0·0001). Treatment effect was not significantly different across molecular subgroups (pinteraction=0·52). FOLFOXIRI plus bevacizumab is a feasible treatment option for those patients who meet the inclusion criteria of the present study, irrespective of baseline clinical characteristics and RAS or BRAF mutational status. GONO (Gruppo Oncologico del Nord Ovest) Cooperative Group and ARCO Foundation.