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Colorectal cancers with BRAF mutations have an aggressive natural history and are often resistant to therapy. A treatment regimen that combined BRAF inhibition, MET inhibition, and blocking of EGFR signaling resulted in a response rate of 26% and a median overall survival of 9 months.

The recent advent of immunomodulatory therapies into the clinic has demanded the identification of innovative predictive biomarkers to identify patients most likely to respond to immunotherapy and support the design of tailored clinical trials. Current molecular testing for selection of patients with gastrointestinal or pulmonary carcinomas relies on the prevalence of PD-L1 expression in tumor as well as immune cells by immunohistochemistry and/or on the evaluation of the microsatellite status. Tumor Mutational Burden (TMB) has emerged as a promising novel biomarker in this setting to further aid in patient selection. This has been facilitated by the increasing implementation of molecular pathology laboratories with comprehensive next generation sequencing (NGS) technologies. However, the significant overall costs and expertise required for the interpretation of NGS data has limited TMB evaluation in routine diagnostics, so far. This review focuses on the current use of TMB analysis in the clinical setting in the context of immune checkpoint inhibitor therapies.

DESTINY-CRC01 (NCT03384940) was a multicenter, open-label, phase 2 trial assessing the efficacy and safety of trastuzumab deruxtecan (T-DXd) in patients with HER2-expressing metastatic colorectal cancer (mCRC) that progressed after ≥2 prior regimens; results of the primary analysis are published. Patients received T-DXd 6.4 mg/kg every 3 weeks and were assigned to either: cohort A (HER2-positive, immunohistochemistry [IHC] 3+ or IHC 2+/in situ hybridization [ISH]+), cohort B (IHC 2+/ISH−), or cohort C (IHC 1+). Primary endpoint was objective response rate (ORR) by independent central review in cohort A. Secondary endpoints included ORR (cohorts B and C), duration of response, disease control rate, progression-free survival, overall survival, pharmacokinetics, and safety of T-DXd. 86 patients were enrolled (53 in cohort A, 15 in cohort B, and 18 in cohort C). Results of the primary analysis are published, reporting an ORR of 45.3% in cohort A. Here, we report the final results. No responses occurred in cohorts B or C. Median progression-free survival, overall survival, and duration of response were 6.9, 15.5, and 7.0 months, respectively. Overall serum exposure (cycle 1) of T-DXd, total anti-HER2 antibody, and DXd were similar regardless of HER2 status. Most common grade ≥3 treatment-emergent adverse events were decreased neutrophil count and anemia. Adjudicated drug-related interstitial lung disease/pneumonitis occurred in 8 patients (9.3%). These findings support the continued exploration of T-DXd in HER2-positive mCRC. HER2 amplification in metastatic colorectal cancer (mCRC) identifies a group of patients with poorer prognosis. Here, the authors report the results of a phase II clinical trial assessing the clinical response and safety of trastuzumab deruxtecan as a third-line treatment in patients with mCRC with different HER2 expression levels

In patients with metastatic colon cancer, fluorouracil, oxaliplatin, and irinotecan plus bevacizumab, as compared with fluorouracil and irinotecan plus bevacizumab, improved progression-free and overall survival, with an increase in some side effects.

Background Immune-inflammatory biomarkers (IIBs) showed a prognostic relevance in patients with metastatic CRC (mCRC). We aimed at evaluating the prognostic power of a new comprehensive biomarker, the Pan-Immune-Inflammation Value (PIV), in patients with mCRC receiving first-line therapy. Methods In the present pooled-analysis, we included patients enrolled in the Valentino and TRIBE trials. PIV was calculated as: (neutrophil count × platelet count × monocyte count)/lymphocyte count. A cut-off was determined using the maximally selected rank statistics method. Generalised boosted regression (GBR), the Kaplan–Meier method and Cox hazards regression models were used for survival analyses. Results A total of 438 patients were included. Overall, 208 patients (47%) had a low-baseline PIV and 230 (53%) had a high-baseline PIV. Patients with high PIV experienced a worse PFS (HR, 1.66; 95% CI, 1.36–2.03, P  < 0.001) and worse OS (HR, 2.01; 95% CI, 1.57–2.57; P  < 0.001) compared to patients with low PIV. PIV outperformed the other IIBs in the GBR model and in the multivariable models. Conclusion PIV is a strong predictor of survival outcomes with better performance than other well-known IIBs in patients with mCRC treated with first-line therapy. PIV should be prospectively validated to better stratify mCRC patients undergoing first-line therapy.

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.

HER2 amplification has been identified in 2–3% of patients with colorectal cancer, although there are currently no approved HER2-targeted therapies for colorectal cancer. We aimed to study the antitumour activity and safety of trastuzumab deruxtecan (an antibody–drug conjugate of humanised anti-HER2 antibody with topoisomerase I inhibitor payloads) in patients with HER2-expressing metastatic colorectal cancer. DESTINY-CRC01 is an open-label, phase 2 study that recruited patients from 25 clinics and hospitals in Italy, Japan, Spain, the UK, and the USA. Eligible patients had centrally confirmed HER2-expressing metastatic colorectal cancer that had progressed on two or more previous regimens (HER2-targeted therapies other than trastuzumab deruxtecan permitted), were aged 18 years or older (≥20 years in Japan), had an Eastern Cooperative Oncology Group score of 0 or 1, and had RAS and BRAFV600E wild-type tumours. Patients were enrolled into one of three cohorts by HER2 expression level: cohort A (HER2-positive, immunohistochemistry [IHC] 3+ or IHC2+ and in-situ hybridisation [ISH]-positive), cohort B (IHC2+ and ISH-negative), or cohort C (IHC1+). Patients received 6·4 mg/kg trastuzumab deruxtecan intravenously every 3 weeks until disease progression, unacceptable adverse events, withdrawal of consent, or death. The primary endpoint was confirmed objective response rate in cohort A by independent central review which was assessed in the full analysis set and safety was assessed in the safety analysis set. Both the full analysis set and the safety analysis set included all patients who received one or more doses of trastuzumab deruxtecan. This ongoing trial is registered with ClinicalTrials.gov, number NCT03384940. Between Feb 23, 2018, and July 3, 2019, 78 patients were enrolled in the study (53 in cohort A, seven in cohort B, and 18 in cohort C), all of whom received at least one dose of study drug. For the 53 (68%) patients with HER2-positive tumours (cohort A), a confirmed objective response was reported in 24 (45·3%, 95% CI 31·6–59·6) patients after a median follow-up of 27·1 weeks (IQR 19·3–40·1). Grade 3 or worse treatment-emergent adverse events that occurred in at least 10% of all participants were decreased neutrophil count (17 [22%] of 78) and anaemia (11 [14%]). Five patients (6%) had adjudicated interstitial lung disease or pneumonitis (two grade 2; one grade 3; two grade 5, the only treatment-related deaths). Trastuzumab deruxtecan showed promising and durable activity in HER2-positive metastatic colorectal cancer refractory to standard treatment, with a safety profile consistent with that reported in previous trastuzumab deruxtecan trials. Interstitial lung disease and pneumonitis are important risks requiring careful monitoring and prompt intervention. Daiichi Sankyo.

Response to first-line therapy is a primary determinant of outcome in patients with metastatic colorectal cancer (mCRC). In the past decade, the development of antiangiogenic and anti-EGFR biologic agents, doublet and triplet chemotherapy regimens, and combinations of these treatment modalities has created not only new first-line treatment options, but also new challenges for the management of this disease. In this Perspectives, these advances and the confusion surrounding their implications are discussed. The authors attempt to address some of the challenges in clinical decision-making and propose an algorithm for personalized allocation of first-line treatments in patients with mCRC. The response to first-line therapy is a primary determinant of outcome in patients with metastatic colorectal cancer (mCRC), for three main reasons: effective upfront therapy provides a unique opportunity to cure some patients; can be crucial in delaying disease progression and achieving symptom relief; and can improve patient eligibility for, and the effectiveness of, further treatments. In the past decade, decision-making regarding the choice of first-line therapy for mCRC has been complicated by the availability of many different options without a definitive consensus on a specific standard of care (despite major advances in categorizing predictive molecular disease subtypes). Most of the efforts of the scientific community have been directed at establishing the best biologic agent to be combined with a chemotherapy doublet, although a different branch of research has produced new data that underscore the importance of defining the optimal chemotherapy backbone. Herein, we review the key clinical trials completed in the past 10 years that have investigated and compared the use of chemotherapy doublets, triplets, and monotherapies, with or without molecularly targeted biologic agents, in the first-line treatment of patients with mCRC. Our examination of the literature led us to propose a new patient-oriented algorithm to guide clinicians' decisions on the best choice of upfront therapy for mCRC.

The role of aberrant hepatocyte growth factor receptor (c-MET, also known as tyrosine-protein kinase MET)/hepatocyte growth factor (HGF) signaling in cancer progression and invasion has been extensively studied. c-MET inhibitors have shown promising pre-clinical and early phase clinical trial anti-tumor activity in several tumor types, although results of most phase III trials with these agents have been negative. To date, two small molecule c-MET inhibitors, cabozantinib and crizotinib, have been approved by regulatory authorities for the treatment of selected cancer types, but several novel c-MET inhibitors (either monoclonal antibodies or small molecule c-MET tyrosine kinase inhibitors) and treatment combinations are currently under study in different settings. Here we provide an overview of the mechanism of action and rationale of c-MET inhibition in cancer, the efficacy of approved agents, and novel promising c-MET-inhibitors and novel targeted combination strategies under development in different cancer types, with a focus on the safety profile and tolerability of these compounds.

We sought to develop criteria for ERBB2 -positivity ( HER2 ) in colorectal cancer to ensure accurate identification of ERBB2 -amplified metastatic colorectal cancer patients suitable for enrolment in a phase II trial of ERBB2-targeted therapy (HERACLES trial). A two-step approach was used. In step 1, a consensus panel of pathologists adapted existing protocols for use in colorectal cancer to test ERBB2 expression and amplification. Collegial revision of an archival test cohort of colorectal cancer samples led to specific recommendations for adapting current breast and gastric cancer criteria for scoring ERBB2 in colorectal cancer. In step 2, from September 2012 to January 2015, colorectal-specific ERBB2 testing protocols and ERBB2 scoring criteria were used to centrally screen for ERBB2 -positive KRAS wild-type colorectal cancer patients to be enrolled in the HERACLES trial (clinical validation cohort). In both archival test ( N =256) and clinical validation ( N =830) cohorts, a clinically sizeable 5% fraction of KRAS wild-type colorectal cancer patients was found to be ERBB2 -positive according to the colorectal cancer-specific ERBB2 scoring criteria. ERBB2 -positive tumors showed ERBB2 immunostaining consisting of intense membranous ERBB2 protein expression, corresponding to homogenous ERBB2 amplification, in >50% of cells. None of the immunohistochemistry 0 or 1+ cases was amplified. Concordance between SISH and FISH was 100%. In conclusion, we propose specific criteria for defining ERBB2 -positivity in colorectal cancer (HERACLES Diagnostic Criteria). In a phase II trial of trastuzumab and lapatinib in a cetuximab-resistant population, HERACLES Diagnostic Criteria shaped the selection of patients and defined ERBB2 as a predictive marker for response to ERBB2-targeted therapy in metastatic colorectal cancer.