Challenges and Therapeutic Opportunities in the dMMR/MSI-H Colorectal Cancer Landscape.

About 5 to 15% of all colorectal cancers harbor mismatch repair deficient/microsatellite instability-high status (dMMR/MSI-H) that associates with high tumor mutation burden and increased immunogenicity. As a result, and in contrast to other colorectal cancer phenotypes, a significant subset of dMMR/MSI-H cancer patients strongly benefit from immunotherapy. Yet, a large proportion of these tumors remain unresponsive to any immuno-modulating treatment. For this reason, current efforts are focused on the characterization of resistance mechanisms and the identification of predictive biomarkers to guide therapeutic decision-making. Here, we provide an overview on the new advances related to the diagnosis and definition of dMMR/MSI-H status and focus on the distinct clinical, functional, and molecular cues that associate with dMMR/MSI-H colorectal cancer. We review the development of novel predictive factors of response or resistance to immunotherapy and their potential application in the clinical setting. Finally, we discuss current and emerging strategies applied to the treatment of localized and metastatic dMMR/MSI-H colorectal tumors in the neoadjuvant and adjuvant setting.

First-Line Biological Agents Plus Chemotherapy in Older Patients with Metastatic Colorectal Cancer: A Retrospective Pooled Analysis.

BACKGROUND: Biologicals, in combination with chemotherapy, are recommended as first-line treatment of metastatic colorectal cancer (mCRC); however, evidence guiding the appropriate management of older patients with mCRC is limited. OBJECTIVE: This study was undertaken to compare the efficacy and safety outcomes in older versus younger patients with mCRC who received first-line biological therapy. METHODS: This retrospective analysis used pooled data from five trials undertaken by the Spanish Cooperative Group for the Treatment of Digestive Tumours. All were studies of adults with advanced CRC who received first-line treatment with chemotherapy plus bevacizumab, cetuximab or panitumumab, stratified by age (≥ 65 vs. < 65 years). Endpoints included progression-free survival (PFS), overall survival (OS), overall response rate (ORR) and safety. RESULTS: In total, 999 patients from five studies were included in the analysis: 480 (48%) were aged ≥ 65 years, and 519 (52%) were aged < 65 years. Median PFS did not differ significantly between patients aged ≥ 65 and < 65 years (9.9 vs. 9.4 months; hazard ratio [HR] 1.01; 95% confidence interval [CI] 0.88-1.17). Median OS was significantly shorter in older than in younger patients (21.3 vs. 25.0 months; HR 1.21; 95% CI 1.04-1.41). There was no significant difference between older and younger patients in ORR (59 vs. 62%). Patients aged ≥ 65 years experienced significantly more treatment-related grade 3 or higher adverse events (61.67%) than did patients aged < 65 years (45.86%). CONCLUSIONS: Biologicals plus chemotherapy is an effective first-line treatment option for selected patients aged ≥ 65 years with mCRC and has a manageable safety profile and efficacy comparable to that observed in younger patients.

Gemcitabine-erlotinib versus gemcitabine-erlotinib-capecitabine in the first-line treatment of patients with metastatic pancreatic cancer: Efficacy and safety results of a phase IIb randomised study from the Spanish TTD Collaborative Group.

BACKGROUND: Gemcitabine and erlotinib have shown a survival benefit in the first-line setting in metastatic pancreatic cancer (mPC). The aim of this study was to assess whether combining capecitabine (C) with gemcitabine + erlotinib (GE) was safe and effective versus GE in patients with mPC. PATIENTS AND METHODS: Previously untreated mPC patients were randomised to receive G (1000 mg/m2, days 1, 8, 15) + E (100 mg/day, days 1-28) + C (1660 mg/m2, days 1-21) or GE, q4 weeks, until progression or unacceptable toxicity. Primary end-point: progression-free survival (PFS); secondary end-points: overall survival (OS), response rate, relationship of rash with PFS/OS and safety. RESULTS: 120 patients were randomised, median age 63 years, ECOG status 0/1/2 33%/58%/8%; median follow-up 16.5 months. Median PFS in the gemcitabine-erlotinib-capecitabine (GEC) and GE arms was 4.3 and 3.8 months, respectively (hazard ratio [HR]: 0.88, 95% confidence interval [CI]: 0.58-1.31; p = 0.52). Median OS in the GEC and GE arms was 6.8 and 7.7 months, respectively (HR: 1.09, 95% CI: 0.72-1.63; p = 0.69). Grade 3/4 neutropenia (GEC 43% versus GE 15%; p = 0.0008) and mucositis (GEC 9% versus GE 0%; p = 0.03) were the only statistically significant differences in grade 3/4 adverse events. PFS and OS were significantly longer in patients with rash (grade ≥1) versus no rash (grade = 0): PFS 5.5 versus 2.0 months (HR = 0.39, 95% CI: 0.26-0.6; p < 0.0001) and OS: 9.5 versus 4.0 months (HR = 0.51, 95% CI: 0.33-0.77; p = 0.0014). CONCLUSION: PFS with GEC was not significantly different to that with GE in patients with mPC. Skin rash strongly predicted erlotinib efficacy. The study was registered with ClinicalTrials.gov: NCT01303029.

Sorafenib and bevacizumab combination targeted therapy in advanced neuroendocrine tumour: a phase II study of Spanish Neuroendocrine Tumour Group (GETNE0801).

BACKGROUND: Sorafenib and bevacizumab as single agents have shown efficacy and acceptable toxicity in NETs phase II trials. Sorafenib and bevacizumab combination has shown manageable toxicity in phase I trials in solid tumours. The purpose of this study was to evaluate the safety and efficacy of the combination of sorafenib and bevacizumab in patients with advanced neuroendocrine tumours. METHODS: Open-label, uncontrolled, multicenter, phase II clinical trial. ELIGIBILITY CRITERIA: age ≥18 years, histologically confirmed measurable advanced NETs; 1 prior chemotherapy allowed; ECOG-PS 0-2. Patients were treated during 6 months and followed up for an additional 6 months. TREATMENT: sorafenib 200mg bid (days 1-5 of each week) and bevacizumab 5mg/kg once every 2 weeks (day 1, week 1). Tumour response was performed according to RECIST (v1.0) every 2 months during the treatment period. Adverse events were graded according to CTCAE (v3.0). FINDINGS: 44 Patients enrolled, 59.1% men, median age 60 years (range 32-76). 70.5% carcinoid tumours, 29.5% pancreatic tumour. Baseline target lesions mainly in the liver (86.4%). Global PFSR was 90.9% (91.7% carcinoid tumours and 88.9% pancreatic tumours). Median PFS was 12.4 months, median TTP was 14.5 months, ORR was 9.4% and DCR was 95.1%. Most common grade 3-4 toxicities: asthenia (11.4%) and hand-foot skin reaction (15.9%). INTERPRETATION: Sorafenib and bevacizumab combination showed clinical benefit but unfavourable safety results compared with drugs in monotherapy. Further development of this combination is not warranted and a sequential approach is recommended instead.