Durvalumab plus tremelimumab for the treatment of advanced neuroendocrine neoplasms of gastroenteropancreatic and lung origin.

Single immune checkpoint blockade in advanced neuroendocrine neoplasms (NENs) shows limited efficacy; dual checkpoint blockade may improve treatment activity. Dune (NCT03095274) is a non-randomized controlled multicohort phase II clinical trial evaluating durvalumab plus tremelimumab activity and safety in advanced NENs. This study included 123 patients presenting between 2017 and 2019 with typical/atypical lung carcinoids (Cohort 1), G1/2 gastrointestinal (Cohort 2), G1/2 pancreatic (Cohort 3) and G3 gastroenteropancreatic (GEP) (Cohort 4) NENs; who progressed to standard therapies. Patients received 1500 mg durvalumab and 75 mg tremelimumab for up to 13 and 4 cycles (every 4 weeks), respectively. The primary objective was the 9-month clinical benefit rate (CBR) for cohorts 1-3 and 9-month overall survival (OS) rate for Cohort 4. Secondary endpoints included objective response rate, duration of response, progression-free survival according to irRECIST, overall survival, and safety. Correlation of PD-L1 expression with efficacy was exploratory. The 9-month CBR was 25.9%/35.5%/25% for Cohorts 1, 2, and 3 respectively. The 9-month OS rate for Cohort 4 was 36.1%, surpassing the futility threshold. Benefit in Cohort 4 was observed regardless of differentiation and Ki67 levels. PD-L1 combined scores did not correlate with treatment activity. Safety profile was consistent with that of prior studies. In conclusion, durvalumab plus tremelimumab is safe in NENs and shows modest survival benefit in G3 GEP-NENs; with one-third of these patients experiencing a prolonged OS.

Association of Circulating Tumor Cells and Tumor Molecular Profile With Clinical Outcomes in Patients With Previously Untreated Metastatic Colorectal Cancer: A Pooled Analysis of the Phase III VISNÚ-1 and Phase II VISNÚ-2 Randomized Trials.

BACKGROUND: The bCTC count is a well-established prognostic biomarker in mCRC, as well as in other tumor types. The aim of this analysis was to evaluate the prognostic/predictive role of the bCTC count (≥3 vs. <3) in previously untreated mCRC. PATIENTS AND METHODS: The study involved 589 untreated mCRC patients included in the intention-to-treat population of 2 randomized clinical trials (phase III VISNU-1 [NCT01640405] and phase II VISNU-2 [NCT01640444] studies). RESULTS: Of the 589 patients, 349 (59.2%) had bCTC≥3 and 240 (40.7%) had bCTC<3. Multivariate analysis showed that the bCTC count is an independent prognostic factor for overall survival (OS) (HR 0.59, 95% CI 0.48-0.72; P = 0.000) and potential for progression-free survival (PFS) (P = 0.0549). Median OS was 32.9 and 19.5 months in patients with bCTC<3 and bCTC≥3 (P <0.001), respectively. This effect was also observed comparing OS in RASwt patients from both studies. Other prognostic factors were: ECOG-PS, primary tumor site, number of metastatic sites and surgery of the primary tumor. Median OS was lower for patients treated with anti-VEGF versus anti-EGFR (22.3 vs. 33.3 months, P <0.0001) while there were no significant differences in PFS according to the targeted treatment received. CONCLUSION: This post-hoc analysis of 2 randomized studies confirms the poor prognosis of patients with bCTC≥3 but this is not associated with other adverse independent prognostic factors such as RAS/BRAF mutations.

Influence of BRAF and PIK3CA mutations on the efficacy of FOLFIRI plus bevacizumab or cetuximab as first-line therapy in patients with RAS wild-type metastatic colorectal carcinoma and <3 baseline circulating tumour cells: the randomised phase II VISNÚ-2 study.

BACKGROUND: We explored the influence of BRAF and PIK3CA mutational status on the efficacy of bevacizumab or cetuximab plus 5-fluorouracil/leucovorin and irinotecan (FOLFIRI) as first-line therapy in patients with RAS wild-type metastatic colorectal cancer (mCRC). PATIENTS AND METHODS: VISNÚ-2 was a multicentre, randomised, phase II study. Patients with RAS wild-type mCRC and <3 circulating tumour cells/7.5 ml blood were stratified by BRAF/PIK3CA status (wild-type versus mutated) and number of affected organs (1 versus >1), and allocated to bevacizumab (5 mg/kg every 2 weeks) or cetuximab (400 mg/m2 then 250 mg/m2 weekly) plus FOLFIRI [irinotecan 180 mg/m2, leucovorin 400 mg/m2, 5-fluorouracil 400 mg/m2 (bolus) then 2400 mg/m2 (46-h continuous infusion) every 2 weeks]. The primary endpoint was progression-free survival (PFS). All analyses were exploratory. RESULTS: Two hundred and forty patients with BRAF/PIK3CA wild-type (n = 196) or BRAF- and/or PIK3CA-mutated tumours (n = 44) were enrolled. Median PFS was 12.7 and 8.8 months in patients with BRAF/PIK3CA wild-type and BRAF/PIK3CA-mutated tumours, respectively [hazard ratio (HR) = 1.22; 95% confidence interval (CI) 0.80-1.85; P = 0.3602]. In the BRAF- and/or PIK3CA-mutated cohort, median PFS was 2.8, 8.8 and 15.0 months in patients with BRAF/PI3KCA-mutated (n = 8), BRAF-mutated/PI3KCA wild-type (n = 16) and BRAF wild-type/PI3KCA-mutated (n = 20) tumours, respectively (P = 0.0002). PFS was similar with bevacizumab plus FOLFIRI versus cetuximab plus FOLFIRI in BRAF/PIK3CA wild-type (HR = 0.99; 95% CI 0.67-1.45; P = 0.9486) and BRAF/PIK3CA-mutated tumours (HR = 1.11; 95% CI 0.53-2.35; P = 0.7820). The most common grade 3/4 treatment-related adverse events were neutropenia, diarrhoea and asthenia in both treatment groups. CONCLUSIONS: BRAF/PIK3CA status influences outcomes in patients with RAS wild-type mCRC but does not appear to assist with the selection of first-line targeted therapy.

Biliary tract cancers: SEOM clinical guidelines.

Biliary tract cancer (BTC) is an uncommon and highly fatal malignancy. It is composed of three main different entities; Gall bladder carcinoma (GBC), intrahepatic cholangiocarcinoma (iCC) and extrahepatic cholangiocarcinoma (eCC) sharing different genetic, risk factors and clinical presentation. Multidetector-row computed tomography (MDCT) and magnetic resonance cholangio-pancreatography (MRCP) are the more important diagnostic techniques. Surgery is the only potentially curative therapy but disease recurrence is frequent. Treatment with chemotherapy, radiotherapy or both has not demonstrated survival benefit in the adjuvant setting. Cisplatin plus gemcitabine constitutes the gold standard in metastatic disease. New ongoing studies mainly in the adjuvant and neoadjuvant setting along with molecular research will hopefully help to improve survival and quality of life of this disease.