e15573 Background: Treatment of non-resectable metastatic colorectal cancer (mCRC) involves chemotherapy based on 5-fluorouracil, oxaliplatin and irinotecan and monoclonal antibodies targeting VEGF or EGFR. Rechallenge with oxaliplatin and irinotecan bi fractionation (FOLFIRI3) have previously shown efficacy in chemorefractory patients but desynchronized triplet chemotherapy was never tested. The aim of this study was to evaluate the safety and efficacy of a new regimen so-called: FOLFIRINOX-3 bevacizumab in chemorefractory mCRC. Methods: A phase I study to test bFOLFIRINOX 3 regimen was designed using Standard “3 + 3” design for dose escalation. Patients enrolled, >18years and ECOG 0 or 1, have a pathologically confirmed mCRC and experienced treatment failure after standard chemotherapy that include 5-fluorouracil, oxaliplatin and irinotecan. Absence of residual neuropathy and previous grade 3 irinotecan related toxicity was manditory. Regimen tested consisted of bevacizumab (5mg/kg) plus simplified FOLFOX4 (folinic acid (400mg/m2), 5-fluorouracil (400mg/m2 bolus followed by 2400mg/m2 for 46h), oxaliplatin (85mg/m2) and irinotecan (administered before and after infusional 5-fluorouracil). Three irinotecan levels were planned at 60, 70 and 90 mg/m² (day 1 and day 3). Dose limiting toxicities (DLT) were identified during the first 2 cycles. Primary endpoint was assessment of maximum tolerable dose trough evaluation of acute toxicities (CTCAE v4.03). Secondary endpoints included objective response (RECIST 1.1), progression free survival, overall survival and late toxicity. Results: Thirteen patients received experimental treatment on this study. The RP2D was irinotecan 70mg/m² day 1 and day 3. Two patients experienced DLTs (G3 diarhea ) at dose level 90mg/m² and one DLT occured (G3 diarrhea) at 70mg/m² level. The most common drug-related adverse events (all grades) were fatigue (92.3%), diarrhea (76.9%), nausea (61.5%), peripheral neuropathy (61.5%), thrombopenia (46.1%) and anemia (15.3%). Among 11 response-evaluable patients, we noticed 4 partial responses, 7 stable disease and no progression as best response. Conclusions: The combination of bFOLFIRINOX-3 at the RP2D of 70mg/m² day 1 and day 3. was well tolerated and feseably. The regimen resulted in high response rate in chemorefractory metastatic colorectal cancer. Phase II is ongoing. Clinical trial information: NCT03795311.

CPS+EG scoring system properly defined prognosis subgroups of early breast cancer (eBC) patients (pts) treated with neoadjuvant chemotherapy (NACT) with a higher CPS+EG associated with worse outcomes. It remains unknown if CPS+EG similarly stratify prognostic in HER2-low and HER2-zero eBC patients after NACT. This pluricenter french retrospective study included eBC pts treated with NACT from 2 cohorts, a monocenter local database at CGFL, Dijon and a pluricenter clinical trial PRIMUNEO (NCT01513408). Molecular features were determined on core biopsies. Threshold for HR positivity was ≥10%. HER2-low/zero status was defined by immunohistochemistry (IHC) HER2 staining. CPS+EG score was calculated for all pts with available data. 608 patients with HER2-negative eBC that have received NACT were included. Median age at diagnosis was 51.0 y-o. Nearly all pts (98.2%) received >3 NACT cycles. In the overall population, 288 pts (47.4%) were HER2-low. More pts were HR+ than TNBC with 367 (60.3%) and 241 pts (39.7%), respectively. The majority of pts harboring HR+ disease were HER2-low (61.0%) contrary to TNBC eBC pts (26.5%). In the HER2-low and HER2-zero population, CPS+EG was able to well categorized pts within prognosis subgroups (log-rank p <0.0001).Table: 255PCPS+EG HER2-low (n =288)CPS+EG HER2-zero (n =320)Score5-year DFS rate (%) (95% CI)5-year DFS rate (%) (95% CI)0100 (100-100)100 (100-100)192.9 (82.14-97.28)86.11 (74.1-92.81)271.95 (60.8-80.43)86.8 (77.89-92.3)369.78 (58.09-78.8)72.5 (61.18-81.01)448.03 (29.17-64.63)55.48 (40.12-68.39)538.1 (8.92-68.02)30.77 (9.5-55.43) Open table in a new tab In HR+/HER2-negative pts, CPS+EG still properly separated pts within prognosis subgroups between HER2-low and HER2-zero pts (log-rank p =0.0012 and p <0.0001, respectively). In TNBC population, CPS+EG appears to be less accurate. Within HR+ and TNBC molecular subtypes, there was no difference in 5-year DFS between HER2-low and HER2-zero pts harboring a similar CPS+EG score. In this study, we show that the CPS+EG scoring system retains its interest for the prognostic stratification of pts treated with NACT for HER2-low and HER2-zero eBC. While it seems especially true for HR+ disease, CPS+EG appears to be less effective for TNBC in isolating different outcomes.

Currently, there are no reliable biomarkers to predict the effectiveness of FOLFIRINOX/FOLFOX regimens. Predictive tests that assist clinicians in choosing the most appropriate first-line chemotherapy regimen are needed. In 2022, we developed a blood-based RNA signature, the GemciTest, which predicts the response to gemcitabine-based first-line treatment in patients with PDAC. The objective of this study was to evaluate the effectiveness of a complementary blood-based RNA signature (F/FX) to predict the response to FOLFIRINOX/FOLFOX regimens in advanced pancreatic adenocarcinoma. Clinical validation was conducted through a discovery and a validation phase on 164 previously untreated advanced PDAC patients (at baseline) (mean age of 68.7 years; 37-88) who received either a gemcitabine- or fluoropyrimidine-based regimen (Id.: NCT03599154 and NCT02818829). The F/FX test measures the expression levels of ten genes using real-time PCR process (MCEMP1, S100A12, MMP9, RACK1, DSC2, LYN, LPP, ARL4C, ALDOA and AC007877.1). Among FOLFIRINOX/FOLFOX treated patients (n=90), those with a positive F/FX (31.1%) had a significantly longer progression-free survival (PFS) (14.3 vs. 3.5 months; HR=0.21 (95% confidence interval CI: 0.12–0.35); p=5.56e-09) and median overall survival (OS) (23 vs. 7.7 months; HR=0.22 (95% CI: 0.13–0.36); p=3.16e-09). The Pearson correlation coefficient between OS and PFS was 0.73 (95% CI: 0.62-0.81; p=2,2E-16). On the contrary, gem-based treated patients (n=74) showed no significant difference in PFS (11.3 vs. 5.8 months; HR=0.68 (95% CI: 0.24–1.91); p=0.48) and OS (13.6 vs. 7.3 months; HR=0.7 (95% CI: 0.25–1.95); p=0.5) between the patients with a positive F/FX versus the patients with a negative F/FX. The F/FX demonstrates the potential of a blood-based RNA signature as a minimally-invasive alternative to improve patient survival and implement personalized therapy in PDAC for patients treated with a FOLFIRINOX/FOLFOX regimen as first-line treatment. While these data show promise, they should be confirmed in a prospective trial, distinguishing patients with non resectable locally advanced and those with metastatic tumors.

BACKGROUND:BI 836880 is a humanized bispecific nanobody® that inhibits vascular endothelial growth factor and angiopoietin-2. Here, we report results from two phase I, nonrandomized, dose-escalation studies (NCT02674152 and NCT02689505; funded by Boehringer Ingelheim) evaluating BI 836880 in patients with confirmed locally advanced or metastatic solid tumors, refractory to standard therapy, or for which standard therapy was ineffective. PATIENTS AND METHODS:Patients aged ≥18 years, with an Eastern Cooperative Oncology Group performance status of 0-2 and adequate organ function received escalating intravenous doses of BI 836880 once every 3 weeks (Q3W; Study 1336.1) or once weekly (QW; Study 1336.6). Primary objectives were maximum tolerated dose (MTD) and recommended phase II dose of BI 836880, based on dose-limiting toxicities (DLTs) during the first cycle. RESULTS:Patients received one of five dosages of 40-1000 mg Q3W (29 patients) or 40-240 mg QW (24 patients). One DLT occurred with Q3W treatment [Grade (G) 3 pulmonary embolism (1000 mg)]. Five DLTs occurred in four patients treated QW [G2 proteinuria (120 mg); G3 hypertension (180 mg); G3 proteinuria and G3 hypertension (240 mg); and G4 respiratory distress (240 mg)]. All patients experienced adverse events, most commonly hypertension with Q3W treatment (89.7%; G3 41.4%), and asthenia with QW treatment (62.5%). Two patients treated Q3W (both 1000 mg) and three patients treated QW (120 mg, 2 patients; 180 mg, 1 patient) experienced partial response. CONCLUSIONS:The MTD of BI 836880 was 720 mg Q3W and 180 mg QW. BI 836880 was generally manageable and demonstrated preliminary efficacy. CLINICAL TRIAL REGISTRATION:ClinicalTrials.govNCT02674152; https://clinicaltrials.gov/ct2/show/NCT02674152 and NCT02689505; https://clinicaltrials.gov/ct2/show/NCT02689505.

Granulocyte colony-stimulating factors (G-CSF) are commonly given to limit chemotherapy-induced neutropenia. However, for weekly chemotherapy such as eribulin, their administration schedules remain empirical. This pharmacokinetic/pharmacodynamic (PK/PD) study was conducted to establish the effect of different G-CSF regimens on neutropenia’s incidence for patients treated by eribulin, to propose an optimal G-CSF dosing schedule. A semi-physiological population PK/PD neutropoiesis model was developed from absolute neutrophil counts (ANC) obtained in 87 cancer patients receiving eribulin for two cyccles. The structural model considered ANC dynamics, neutropenic effect of eribulin and the stimulating effect of G-CSF on neutrophils. Final model parameters were used to calculate the incidence of neutropenia following different G-CSF dosing schedules for 1’000 virtual subjects. The final model successfully described the ANC time-course for all patients. Simulations showed that a single G-CSF administration 48h after each eribulin injection reduced the risk of severe neutropenia from 29.7% to 5.2%. G-CSF administration after the 2nd eribulin injection was responsible for similar incidence of neutropenia compared to absence of administration. The PK/PD model well described our population's ANC data. Simulations showed a single G-CSF administration 48 hours after the end of each chemotherapy seems to be the optimal schedule to reduce eribulin-induced neutropenia.

Granulocyte colony-stimulating factors (G-CSF) are commonly given to limit chemotherapy-induced neutropenia. However, for weekly chemotherapy such as eribulin, their administration schedules remain empirical. A pharmacokinetic/pharmacodynamic (PK/PD) study was conducted to establish the effect of different G-CSF regimens on neutropenia’s incidence for patients treated by eribulin, to propose an optimal G-CSF dosing schedule. Additionally, in a real-life setting, the best G-CSF dosing schedule was compared, in a small subset of patients, to the most frequently used.

MEN1611 (MEN) is an oral PI3K inhibitor active on the p110α mut and WT, β and γ isoforms, while sparing the δ. Antitumor activity of MEN combined with other agents in patient-derived xenografts and BC cell lines with different PIK3CA mutations, provides a strong rationale for clinical testing. B-PRECISE-01 is an ongoing phase Ib study in patients (pts) with HER2+/PIK3CAmut a/m BC treated with at least 2 anti-HER2 therapies. A 3+3 design combined 3 dose levels of MEN BID and T weekly IV. HR+ postmenopausal pts also received F. Primary objectives are to determine safety and recommended phase II dose (RP2D). Dose-limiting toxicities (DLTs) were assessed during cycle 1. Secondary objectives included assessment of preliminary clinical activity, pharmacokinetics and pharmacodynamics. Here we present mature data from dose escalation cohorts. As of Oct. 2019, 12 female pts were treated: 9 MEN+T+F and 3 MEN+T. Median age: 59 years (range 39-77). Median prior metastatic regimens: 5.5 (4-12). No DLTs were observed at any dose cohort. 48 mg was selected as RP2D. Most common grade (G)1/2 treatment-related adverse events (TRAEs) were diarrhoea (n=9), anemia (n=6), nausea (n=4), asthenia (n=4), decreased appetite (n=4), hyperglycemia (n=4), and mucosal inflammation (n=3). G3/4 TRAEs were not dose-dependent and occurred in 4 pts such as hyperglycemia (n=3), pneumonitis (n=1), decreased appetite (n=1), mucosal inflammation (n=1), and AST/ALT increase (n=1). Dose was reduced in one pt at 48 mg. No deaths from toxicity occurred. There were no overt differences in the safety profile of MEN+T+F vs. MEN+T. 5 pts (42%) had partial response, 5 stable disease, 4 disease control >8 months (mo) and 2 were on treatment >11 mo. MEN exposure tends to increase with increasing doses. Tmax was reached after 0.5-8 h following administration and the terminal half-life was ∼3.5 h. Tolerability of MEN+T±F is acceptable; most TRAEs were reversible and manageable by supportive care. Promising antitumor activity in heavily pretreated pts, together with prolonged disease control, provide the rationale for cohort expansion at RP2D in pts with HER2+/PIK3CA mut a/m BC.

PurposeThe Time to First Metastatic Recurrence (TFMR) could be considered as an indirect reflection of the tumour growth kinetics which plays an important role in cancer. Molecular subtypes such as expression of estrogen receptor are known predictive factors of TFMR. The CinéBreast study aimed to identify predictive factors of the time to TFMR.MethodsThe French Epidemiological Strategy and Medical Economics (ESME) Metastatic Breast Cancer (MBC) Database (NCT03275311) was used, which contains data from a cohort of metastatic breast cancer patients from 2008 to 2016 using retrospective data collection. It is a national multi-centre database. The impact of TFMR on overall survival (OS) since first metastasis was also evaluated.ResultsAmong 16 702 patients recorded in the ESME MBC database, 10 595 had an initially localised breast cancer with hormone receptor (HR) and HER2 status available, with a metastatic recurrence. Median follow up was 56 months. Median TFMR was 59 months (<24: 20%, 24–60: 31%, 60–120: 25%, >120: 24%). HER2+ and TNBC were respectively 4 times and 12 times (p < 0.0001) more likely to have a recurrence within 2 years when compared to the luminal subgroup. Short TFMR and HR-/HER2-subtype significantly correlated with a poor OS in multivariate analysis.Some patients with MBC (20% in HER2+, 10% in ER+/HER2-and <5% in the ER-/HER2-) were long-term survivors in all 3 subgroups.ConclusionsIn this large-scale real-life data study, patients with a TNBC metastatic recurrence had a shorter TFMR. Short TFMR significantly correlated with worse overall survival.

Background Pathologic complete response (pCR) is a surrogate marker of a better relapse-free (RFS) and overall survival (OS), particularly in HER2 overexpressing and triple-negative breast cancer (TNBC) subtypes. Our aim is to assess the impact of HER2 expression level on pCR, in patients with luminal or TNBC treated with neoadjuvant chemotherapy (NAC). Methods We conducted a retrospective analysis in luminal and TN non-metastatic breast cancer patients, addressed to cancer center Georges Francois Leclerc in Dijon for NAC. Hormone receptor and HER2 expression were centrally assessed according to CAP/ASCO criteria. The pathologic response was dichotomized in pCR and non-pCR and evaluated according to Chevalier classification. Results Between 2007 and 2018, 761 patients (pts) were recorded, of which 263 (34.5%) had TNBC and 498 (65.5%) luminal-HER2 negative BC. Among TNBC, 189 pts (70.8%), 54 pts (20.2%) and 24 pts (8.9%) had respectively score 0, 1 and 2, and negative FISH. In luminal tumors these results were respectively 246 (49.3%), 181 (36.3%) and 21 (4.2%). Median age, size of primary tumour and lymph node involvement were similar in both subpopulations. Regarding NAC, 20.9% received only taxanes, 22.1% only anthracyclines and 55.1% both agents. The combination was more often recommended in TNBC 74.2% vs 59.3% (p = 0.03). pCR rate in the primary tumour and lymph nodes was 29% (157 pts) in the whole cohort. This rate varied according to HER2 expression (0, 1+, 2+) from respectively 48.6% (51pts), 36.4% (8pts) and 28.6% (4pts) (p = 0.256) in TNBC and from 8.5% (7pts), 5.3% (5pts) and 4.1% (2pts) (p = 0.532) among luminal tumors. Both OS and RFS were associated with a good Chevalier pathologic response (p Conclusions No correlation between pCR and the level of HER 2 expression was found neither in luminal nor in TNBC patients. In TNBC patients, differences in terms of pCR were noticed between the 3 HER expression groups. The predictive role of HER2 expression should be further explored in early localized TNBC in a larger population. Editorial acknowledgement Isabel Gregoire, medical writer, Department of Biostatistics Georges Francois Leclerc Cancer Center, Dijon, France. Legal entity responsible for the study The authors. Funding Has not received any funding. Disclosure All authors have declared no conflicts of interest.

Introduction: Several options have been evaluated as second-line treatments in metastatic gastroesophageal adenocarcinomas (MGA) after failure of first-line 5FU and cisplatin-based chemotherapy: docetaxel, paclitaxel, and irinotecan as monotherapies or paclitaxel combined with ramucirumab. Regorafenib monotherapy showed promising efficacy data in the second or third line MGA (INTEGRATE trial; Pavlakis N et al, J Clin Oncol. 2016). Methods: This phase 2 multicenter randomized study (NCT03722108) is designed to evaluate the efficacy of regorafenib combined with irinotecan vs irinotecan alone as second-line treatment in MGA patients with 1:1 randomization and stratification by prior use of PD1/PD-L1 inhibitors and location of tumour. Main eligibility criteria are patients ≥ 18 years old with histologically proven gastroesophageal adenocarcinomas (gastric location or gastroesophageal junction Siewert II and III), asymptomatic primary tumour, metastatic disease, having progressed after a fluoropyrimidine and platinum-based chemotherapy, performance status ECOG 0-1, adequate hematologic, hepatic, renal and other vital functions. The tumour has to be measurable (RECIST 1.1) and the patient has to give informed consent. Treatment regimens are as follows: Arm A: irinotecan 180 mg/m 2 IV on D1 and D15, regorafenib 160 mg/day on D2-D8 and D16-D22, D1=D28; Arm B: irinotecan 180 mg/m 2 IV infusion on D1 and D15, D1=D28. Treatment is administered until disease progression or unacceptable toxicity. The primary endpoint is OS. Secondary endpoints include PFS, DCR, ORR, safety, and quality of life. The sample size calculation is based on an assumption of a gain of 4 months in median OS from 6 to 10 months (HR = 0.60), power 80%, two-sided alpha risk 5%. A safety interim analysis is planned after 38 patients are enrolled in the experimental arm with predefined stopping rules based on the G3-4 diarrhoea rate and an efficacy interim analysis planned after 40 OS events. At the present time, 1 patient among the 154 planned patients has been enrolled.

Background: 5-Fluorouracil plus irinotecan or oxaliplatin with target therapy are standard 1st line therapy for metastatic colorectal cancer (mCRC). 5-Fluorouracil plus oxaliplatin are known to present immunogenic properties. Durvalumab (D) is a human monoclonal antibody (mAb) that blocks programmed cell death ligand 1 (PD-L1) binding to its receptor (PD-1). Tremelimumab (T) is a mAb directed against the cytotoxic T-lymphocyte-associated protein 4 (CTLA-4). This study is designed to evaluate whether the addition of PD-L1 and CTLA-4 inhibition to FOLFOX increases treatment efficacy. Methods: After a phase I with 9 patients, this phase II study (ClinicalTrials.gov NCT03202758) will assess the efficacy and safety of FOLFOX/D/T association in patients (pts) with good performance status pts (ECOG < 2) with untreated, RAS mutational status mCRC. Prior adjuvant therapy is allowed provided recurrence is > 6 months post-completion. Assuming no safety concerns the study will go on to include 39 additional pts. Pts will receive folinic acid/5-fluorouracil (400mg/m2 as bolus followed by 2400mg/m2 as a 46h infusion)/Oxaliplatin (85mg/m2) q14 days with D (750 mg) D1 q 14 days and T (75 mg) D1q 28 days. After 6 cycles of FOLFOX only, D/T will continue until disease progression, death, intolerable toxicity, or patient/investigator decision to stop. Primary endpoint is safety and efficacy according to PFS; secondary endpoints include overall response rate and quality of life. Results: 9 patients were enrolled in the phase I. Grade 3-4 treatment-related adverse events occurred in 3 of 9 patients. The most common treatment-related grade 3-4 adverse events were neutropenia and diarrhea. No patients discontinued due to a drug-related adverse event. First clinical outcomes have shown 4 patients with partial response, 3 patients with stable disease and 2 patients with progression disease. Ancillary analysis were performed. Conclusions: FOLFOX/D/T was tolerable with manageable toxicity. Preliminary results have shown encouraging clinical outcome. The results of this phase I study have led to phase II study which are ongoing. Clinical trial identification: NCT03202758. Legal entity responsible for the study: Nicolas Isambert. Funding: AstraZeneca. Disclosure: All authors have declared no conflicts of interest.