Irinotecan

The following chemotherapies were used in these studies: 5-fluorouracil (5-FU), bleomycin, cisplatin, cyclophosphamide (CY), docetaxel, doxorubicin, etoposide phosphate, gemcitabine, irinotecan, vinorelbine and were obtained from the pharmacy department at Sir Charles Gardiner Hospital, Perth, Australia. Further details are available in Additional file 1: Table S1. All mice were dosed intraperitoneally (i.p) using a 29G insulin syringe. Chemotherapy was prepared and diluted under sterile conditions in either phosphate buffered saline (PBS) or 0.9% sodium chloride as per manufacturer’s instructions. Where possible, chemotherapy was made to a dilution whereby a 20 g mouse would receive a 100 μl i.p injection.

Data were used from the phase III CAIRO study of the DCCG (Koopman et al, 2006 (link), 2007a (link)). In this study patients were randomised between sequential and combination treatment with capecitabine, irinotecan and oxaliplatin. Stratification parameters included WHO performance status, serum lactate dehydrogenase (LDH), prior adjuvant therapy, predominant localisation of metastases and participation institution. Assessment of tumour response was scheduled every three cycles (9 weeks) according to RECIST criteria (Therasse et al, 2000 (link)). Follow-up after completion of treatment was performed every 3 months until death. The primary endpoint was overall survival.
Patients were divided into synchronous and metachronous disease, with synchronous disease defined as distant metastases occurring within, and metachronous disease beyond 6 months of the primary diagnosis of CRC. For two reasons only patients in whom a resection of the primary tumour had been performed were included in the analysis. First, tissue of the primary tumour was required for histopathological review. Second, the arguments for non-resection may greatly vary from patients with an asymptomatic primary and excellent performance status to patients with a symptomatic primary with extensive metastases and poor performance status in whom a delay in systemic treatment is not warranted. These arguments are often not recorded in the patients’ files.

Simmiparib was synthesized at the Shanghai Institute of Materia Medica, Chinese Academy of Sciences. Olaparib, G007‐LK, VE‐821, chloroquine, losmapimod, RBN‐2397, cisplatin, and LY3214996 were purchased from MedChemExpress (NJ, USA). Talazoparib, veliparib, irinotecan, and rucaparib were purchased from Selleck Chemicals (Shanghai, China). All drugs were dissolved in DMSO and stored at −20°C.

Patients with RAS and BRAF wt mCRC, treated with R or T versus anti-EGFR-based treatment in third-line, were retrospectively included in the study. Patients were enrolled by four Italian Medical Oncology Units (Comprehensive Cancer Center, Fondazione Policlinico Universitario Agostino Gemelli-IRCCS, Università Cattolica del Sacro Cuore, Rome; Ospedale Fatebenefratelli Isola Tiberina - Gemelli Isola, Rome; Department of Medical Oncology, Campus Bio-Medico University, Rome; Ospedale F. Spaziani - ASL Frosinone)
Patients had to have received two prior regimens of standard chemotherapy (oxaliplatin, irinotecan, fluoropyrimidine) for metastatic disease. Previous treatments could include bevacizumab. Patients who received cetuximab and/or panitumumab in first- or second-line were excluded from the anti-EGFR group; on the contrary, they could be enrolled in the R/T group. Prior therapy with R or T was not allowed.
The R-sided tumor was defined as cancer from the cecum to the transverse colon, L-sided tumor was defined as cancer from the splenic flexure to the rectum. For each patient we collected the following available variables: baseline ECOG performance status (PS), gender, age, synchronous vs metachronous disease, previous anticancer treatments, and number of metastatic sites (single vs multiple).

This was a single-center, single-arm, phase II trial. Patients were enrolled from May 2019 to May 2021 at Tianjin Medical University Cancer Institute and Hospital in this study. The key inclusion criteria were:
age of ≥ 18 years;
Eastern Cooperative Oncology Group (ECOG) performance status of 0–2;
histologically confirmed metastatic or recurrent gastric or gastroesophageal junction (GEJ) adenocarcinoma;
previous first-line use of platinum combined with fluorouracil or disease progression within 6 months after withdrawal of adjuvant chemotherapy with platinum and fluorouracil-based regimen, or failure of second-line irinotecan or paclitaxel;
measurable lesions according to the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1;
adequate organ and bone marrow function (hemoglobin: ≥90 g/L, neutrophils: ≥1.5 × 10⁹/L, platelets: ≥100 × 10⁹/L, bilirubin: ≤1.5 × upper limit of normal [ULN], alanine aminotransferase [ALT] and aspartate aminotransferase [AST]: ≤2.5 × ULN [if liver metastasis is present, then ALT and AST ≤ 5 × ULN], endogenous creatinine clearance rate: ≥50 mL/min [Cockcroft–Gault formula], routine urinalysis: normal results or urine protein less than (++) or 24-hour protein urine of < 1.0 g, and normal blood coagulation with no active bleeding or thrombosis [international normalized ratio of ≤ 1.5 and activated partial thromboplastin time of ≤ 1.5 × ULN]);
estimated survival time of ≥ 3 months.
The key exclusion criteria included:
previous use of PD-1/PD-L1 inhibitor or other anti-angiogenesis targeted drug;
hypertension that could not be reduced to normal range by antihypertensive drugs;
clearly gastrointestinal bleeding tendency, including locally active ulcer lesions, fecal occult blood (++), or a history of melena and hematemesis within 1 month;
serious cardiovascular and cerebrovascular diseases;
immune system diseases requiring treatment;
inability to swallow or intestinal obstruction;
contraindication or allergy to the study drugs;
concomitant diseases that seriously endanger the safety of the patient or affect the completion of the study.
The study was approved by the independent ethics committees of Tianjin Medical University Cancer Institute and Hospital and was performed in accordance with the Declaration of Helsinki. All enrolled patients provided written informed consent. This trial was registered with ClinicalTrials.gov, number NCT05025033.