Lurbinectedin in patients with pretreated neuroendocrine tumours: Results from a phase II basket study.

BACKGROUND: Patients with neuroendocrine tumours (NETs) need alternative therapies after failure of first-line therapy. PATIENTS AND METHODS: This phase II trial evaluated lurbinectedin, a selective inhibitor of oncogenic transcription, at 3.2 mg/m2 as a 1-h intravenous infusion every 3 weeks in 32 NETs patients treated in the second- or third-line setting. The primary efficacy endpoint was overall response rate (ORR) according to RECIST v1.1 assessed by the investigators. Secondary endpoints included duration of response (DoR), progression-free survival (PFS), overall survival (OS) and safety. RESULTS: Two of 31 evaluable patients had confirmed partial responses (ORR = 6.5%; 95%CI, 0.8-21.4%). Median DoR was 4.7 months (95% CI, 4.0-5.4 months), median PFS was 1.4 months (95% CI, 1.2-3.0 months) and median OS was 7.4 months (95% CI, 3.4-16.2 months). Lurbinectedin showed an acceptable, predictable and manageable safety profile. The most common grade 3/4 toxicity was neutropenia (40.6%; grade 4, 12.4%; febrile neutropenia, 3.1%). CONCLUSIONS: Considering the exploratory aim of this trial that evaluated a heterogeneous population of NETs patients, and the signs of antitumour activity observed (two confirmed partial responses and seven long disease stabilisations), further development of lurbinectedin is warranted in a more selected NETs population. TRIAL REGISTRATION NUMBER: Sponsor Study Code: PM1183-B-005-14. EudraCT number: 2014-003773-42. CLINICALTRIALS: gov reference: NCT02454972.

Early Clinical Experience with Trifluridine/Tipiracil for Refractory Metastatic Colorectal Cancer: The ROS Study.

Trifluridine/tipiracil is currently approved for metastatic colorectal cancer (mCRC) refractory to available therapies. However, there is no consensus on factors that predict treatment outcomes in daily practice. We assessed the early clinical experience with trifluridine/tipiracil in Spain and potential survival markers. This was a retrospective cohort study of mCRC patients who participated in the trifluridine/tipiracil early clinical experience programme in Spain. The primary outcome was overall survival (OS). Associations between OS and patient characteristics were assessed using multivariate Cox regression analyses. A total of 379 patients were included in the study. Trifluridine/tipiracil was administered for a median of 3.0 cycles and discontinued mainly due to disease progression (79.2%). The median OS was 7.9 months, with a 12-month OS rate of 30.5%. Cox analyses revealed that the following variables independently enhanced OS: ≤2 metastatic sites, no liver metastasis, alkaline phosphatase < 300 IU, trifluridine/tipiracil dose reductions, and neutrophil/lymphocyte ratio < 5. Grade ≥ 3 toxicities were reported in 141 (37.2%) patients, including mainly afebrile neutropaenia (23.2%), anaemia (12.1%), and thrombocytopaenia (5.3%). This study supports the real-life efficacy and safety of trifluridine/tipiracil for refractory mCRC and identifies tumour burden, liver metastasis, alkaline phosphatase, dose reductions, and neutrophil/lymphocyte ratio as survival markers.

Association of the Lung Immune Prognostic Index with Immunotherapy Outcomes in Mismatch Repair Deficient Tumors.

Background: MSI-H/dMMR is considered the first predictive marker of efficacy for immune checkpoint inhibitors (ICIs). However, around 39% of cases are refractory and additional biomarkers are needed. We explored the prognostic value of pretreatment LIPI in MSI-H/dMMR patients treated with ICIs, including identification of fast-progressors. Methods: A multicenter retrospective study of patients with metastatic MSI-H/dMMR tumors treated with ICIs between April 2014 and May 2019 was performed. LIPI was calculated based on dNLR > 3 and LDH > upper limit of normal. LIPI groups were good (zero factors), intermediate (one factor) and poor (two factors). The primary endpoint was overall survival (OS), including the fast-progressor rate (OS < 3 months). Results: A total of 151 patients were analyzed, mainly female (59%), with median age 64 years, performance status (PS) 0 (42%), and sporadic dMMR status (68%). ICIs were administered as first or second-line for 59%. The most frequent tumor types were gastrointestinal (66%) and gynecologic (22%). LIPI groups were good (47%), intermediate (43%), and poor (10%). The median follow-up was 32 months. One-year OS rates were 81.0%, 67.1%, and 21.4% for good, intermediate, and poor-risk groups (p < 0.0001). After adjustment for tumor site, metastatic sites and PS, LIPI remained independently associated with OS (HR, poor-LIPI: 3.50, 95%CI: 1.46-8.40, p = 0.02. Overall, the fast-progressor rate was 16.0%, and 35.7% with poor-LIPI vs. 7.5% in the good-LIPI group (p = 0.02). Conclusions: LIPI identifies dMMR patients who do not benefit from ICI treatment, particularly fast-progressors. LIPI should be included as a stratification factor for future trials.

Experiencia inicial del tratamiento de la carcinomatosis peritoneal irresecable con PIPAC / Initial Single-center Experience of PIPAC in Patients With Unresectable Peritoneal Metastasis

Introducción: La carcinomatosis peritoneal se asocia a un mal pronóstico y las opciones terapéuticas son limitadas. El desarrollo de la quimioterapia intraperitoneal presurizada en aerosol (PIPAC) ofrece una alternativa de tratamiento paliativo para estos pacientes con una baja tasa de morbimortalidad. Nuestro objetivo es evaluar la implantación y la experiencia inicial de PIPAC para el tratamiento de la carcinomatosis peritoneal irresecable en nuestro centro. Material y métodos: Realizamos un estudio prospectivo incluyendo todos los pacientes a los que se les realizó PIPAC entre enero de 2019 y febrero de 2020 en nuestro hospital. Se recogieron: el origen del tumor primario, el volumen de ascitis, la extensión de la carcinomatosis peritoneal, el régimen de quimioterapia aplicada, el tiempo quirúrgico, las complicaciones postoperatorias, la estancia hospitalaria y la mortalidad. Resultados: Analizamos 9 PIPAC realizadas en 5pacientes con carcinomatosis peritoneal de origen gástrico, ovárico y neoplasia mucinosa apendicular. La tasa de acceso a la cavidad peritoneal fue del 100%. El PCI medio fue 27,6 (24-35). El tiempo quirúrgico medio fue de 93min (70-125). En nuestra serie solo hubo una complicación Clavien-DindoII (1/9 procedimientos). La estancia hospitalaria media fue de 2días (1-4). La mortalidad fue del 0%. Conclusión: La implantación de PIPAC en nuestro centro se ha llevado a cabo con seguridad, pudiendo afirmar que es una técnica reproducible y con una baja tasa de morbimortalidad en nuestra experiencia inicial. (AU)

Introduction: Peritoneal carcinomatosis remains a condition with poor prognosis and limited therapeutic options. Pressurized Intrapertioneal Aerosol Chemotherapy (PIPAC) has been developed as a new tool for delivering intraperitoneal chemotherapy with low morbidity. The aim of this study was to evaluate the initial experience of PIPAC in patients with peritoneal carcinomatosis at our hospital. Methods: A prospective study between January 2019 and February 2020 was carried at a tertiary public hospital. Primary tumor, ascites volume, PCI, chemotherapy regimen, operative time, morbidity, length of hospital stay and mortality were recorded for analysis. Results: We analyzed 9 PIPAC procedures performed in 5patients. Median PCI was 27.6 (24-35). Median surgical time was 93minutes (70-125). Only one adverse event occurred out of 9 procedures (Clavien-DindoII). Median length of hospital stay was 2days (1-4). Mortality was 0%. Conclusion: PIPAC seems to be a feasible and safe procedure to treat peritoneal carcinomatosis, with low morbidity and short hospital stay. (AU)

Initial Single-center Experience of PIPAC in Patients With Unresectable Peritoneal Metastasis. / Experiencia inicial del tratamiento de la carcinomatosis peritoneal irresecable con PIPAC.

INTRODUCTION: Peritoneal carcinomatosis remains a condition with poor prognosis and limited therapeutic options. Pressurized Intrapertioneal Aerosol Chemotherapy (PIPAC) has been developed as a new tool for delivering intraperitoneal chemotherapy with low morbidity. The aim of this study was to evaluate the initial experience of PIPAC in patients with peritoneal carcinomatosis at our hospital. METHODS: A prospective study between January 2019 and February 2020 was carried at a tertiary public hospital. Primary tumor, ascites volume, PCI, chemotherapy regimen, operative time, morbidity, length of hospital stay and mortality were recorded for analysis. RESULTS: We analyzed 9 PIPAC procedures performed in 5patients. Median PCI was 27.6 (24-35). Median surgical time was 93minutes (70-125). Only one adverse event occurred out of 9 procedures (Clavien-DindoII). Median length of hospital stay was 2days (1-4). Mortality was 0%. CONCLUSION: PIPAC seems to be a feasible and safe procedure to treat peritoneal carcinomatosis, with low morbidity and short hospital stay.

The subgroups of the phase III RECOURSE trial of trifluridine/tipiracil (TAS-102) versus placebo with best supportive care in patients with metastatic colorectal cancer.

BACKGROUND: In the phase III RECOURSE trial, trifluridine/tipiracil (TAS-102) extended overall survival (OS) and progression-free survival (PFS) with an acceptable toxicity profile in patients with metastatic colorectal cancer refractory or intolerant to standard therapies. The present analysis investigated the efficacy and safety of trifluridine/tipiracil in RECOURSE subgroups. METHODS: Primary and key secondary end-points were evaluated using a Cox proportional hazards model in prespecified subgroups, including geographical subregion (United States of America [USA], European Union [EU], Japan), age (<65 years, ≥65 years) and v-Ki-ras2 Kirsten rat sarcoma 2 viral oncogene homologue (KRAS) status (wild type, mutant). Safety and tolerability were reported with descriptive statistics. RESULTS: Eight-hundred patients were enrolled: USA, n = 99; EU, n = 403; Japan, n = 266. Patients aged ≥65 years and those with mutant KRAS tumours comprised 44% and 51% of all patients in the subregions, respectively. Final OS analysis (including 89% of events, compared with 72% in the initial analysis) confirmed the survival benefit associated with trifluridine/tipiracil, with a hazard ratio (HR) of 0.69 (95% confidence interval [CI] 0.59-0.81; P = 0.0001). Median OS in the three regions was 6.5-7.8 months in the trifluridine/tipiracil arm and 4.3-6.7 months in the placebo arm (USA: HR 0.56; 95% CI 0.34-0.94; P = 0.0277; EU: HR 0.62; 95% CI 0.48-0.80; P = 0.0002; Japan: HR 0.75; 95% CI 0.57-1.00; P = 0.0470). Median PFS was 2.0-2.8 months for trifluridine/tipiracil and 1.7-1.8 months for placebo; HRs favoured trifluridine/tipiracil in all regions. Similar clinical benefits of trifluridine/tipiracil were observed in elderly patients and in those with mutant KRAS tumours. There were no marked differences among subregions in terms of safety and tolerability. CONCLUSIONS: Trifluridine/tipiracil was effective in all subgroups, regardless of age, geographical origin or KRAS status. This trial is registered with ClinicalTrials.gov: NCT01607957.

First-line panitumumab plus FOLFOX4 or FOLFIRI in colorectal cancer with multiple or unresectable liver metastases: A randomised, phase II trial (PLANET-TTD).

BACKGROUND: In first-line wild-type (WT)-Kirsten rat sarcoma viral oncogene homologue (KRAS) metastatic colorectal cancer (mCRC), panitumumab (Pmab) improves outcomes when added to FOLFOX [folinic acid, 5-fluorouracil, and oxaliplatin] or FOLFIRI [folinic acid, 5-fluorouracil, and irinotecan]. However no trial has directly compared these combinations. METHODS: Multicentre, open-label study in untreated patients ≥ 18 years with (WT)-KRAS mCRC and multiple or unresectable liver-limited disease (LLD) randomised to either Pmab-FOLFOX4 or Pmab-FOLFIRI. The primary end-point was objective response rate (ORR). Secondary end-points included liver metastases resection rate (R0 + R1), progression-free survival (PFS), overall survival (OS), adverse events and perioperative safety. Exploratory end-points were: response by RAS status, early tumour shrinkage (ETS) and depth of response (DpR) in WT-RAS patients. RESULTS: Data on 77 patients were analysed (38 Pmab-FOLFOX4; 39 Pmab-FOLFIRI; WT-RAS: 27/26, respectively). ORR was 74% with Pmab-FOLFOX4 and 67% with Pmab-FOLFIRI (WT-RAS: 78%/73%). Out of the above, 45% and 59% underwent surgical resection, respectively (WT-RAS: 37%/69%). The R0-R1 resection rate was 34%/46% (WT-RAS:26%/54%). Median PFS was 13/14 months (hazard ratio [HR] Pmab-FOLFIRI versus Pmab-FOLFOX4: 0.9; 95% confidence interval: [0.6-1.5]; WT-RAS:13/15; HR: 0.7 [0.4-1.3]). Median OS was 37/41 months (HR:1.0 [0.6-1.8]; WT-RAS: 39/49; HR:0.9 [0.4-1.9]). In WT-RAS patients with confirmed response, median DpR was 71%/66%, and 65%/77% of patients showed ETS ≥ 30%/ ≥ 20% at week 8, without significant differences between arms; these patients had longer median PFS and OS and higher resectability rates. Surgery was associated with longer survival. Perioperative and overall safety were similar, except for higher grade 3/4 neutropenia (40%/10%; p = 0.003) and neuropathy (13%/0%; p = 0.025) in the Pmab-FOLFOX4 arm. CONCLUSIONS: In patients with WT-KRAS mCRC and LLD, both first-line Pmab-FOLFOX4 and Pmab-FOLFIRI resulted in high ORR and ETS, allowing potentially curative resection. No significant differences in efficacy were observed between the two regimens. (clinicaltrials.gov:NCT00885885).