Ramucirumab with cisplatin and fluoropyrimidine as first-line therapy in patients with metastatic gastric or junctional adenocarcinoma (RAINFALL): a double-blind, randomised, placebo-controlled, phase 3 trial

BACKGROUND: VEGF and VEGF receptor 2 (VEGFR-2)-mediated signalling and angiogenesis can contribute to the pathogenesis and progression of gastric cancer. We aimed to assess whether the addition of ramucirumab, a VEGFR-2 antagonist monoclonal antibody, to first-line chemotherapy improves outcomes in patients with metastatic gastric or gastro-oesophageal junction adenocarcinoma. METHODS: For this double-blind, randomised, placebo-controlled, phase 3 trial done at 126 centres in 20 countries, we recruited patients aged 18 years or older with metastatic, HER2-negative gastric or gastro-oesophageal junction adenocarcinoma, an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, and adequate organ function. Eligible patients were randomly assigned (1:1) with an interactive web response system to receive cisplatin (80 mg/m2, on the first day) plus capecitabine (1000 mg/m2, twice daily for 14 days), every 21 days, and either ramucirumab (8 mg/kg) or placebo on days 1 and 8, every 21 days. 5-Fluorouracil (800 mg/m2 intravenous infusion on days 1-5) was permitted in patients unable to take capecitabine. The primary endpoint was investigator-assessed progression-free survival, analysed by intention to treat in the first 508 patients. We did a sensitivity analysis of the primary endpoint, including a central review of CT scans. Overall survival was a key secondary endpoint. This study is registered with ClinicalTrials.gov, number NCT02314117. FINDINGS: Between Jan 28, 2015, and Sept 16, 2016, 645 patients were randomly assigned to receive ramucirumab plus fluoropyrimidine and cisplatin (n=326) or placebo plus fluoropyrimidine and cisplatin (n=319). Investigator-assessed progression-free survival was significantly longer in the ramucirumab group than the placebo group (hazard ratio [HR] 0·753, 95% CI 0·607-0·935, p=0·0106; median progression-free survival 5·7 months [5·5-6·5] vs 5·4 months [4·5-5·7]). A sensitivity analysis based on central independent review of the radiological images did not corroborate the investigator-assessed difference in progression-free survival (HR 0·961, 95% CI 0·768-1·203, p=0·74). There was no difference in overall survival between groups (0·962, 0·801-1·156, p=0·6757; median overall survival 11·2 months [9·9-11·9] in the ramucirumab group vs 10·7 months [9·5-11·9] in the placebo group). The most common grade 3-4 adverse events were neutropenia (85 [26%] of 323 patients in the ramucirumab group vs 85 [27%] of 315 in the placebo group), anaemia (39 [12%] vs 44 [14%]), and hypertension (32 [10%] vs 5 [2%]). The incidence of any-grade serious adverse events was 160 (50%) of 323 patients in the ramucirumab group and 149 (47%) of 315 patients in the placebo group. The most common serious adverse events were vomiting (14 [4%] in the ramucirumab group vs 21 [7%] in the placebo group) and diarrhoea (11 [3%] vs 19 [6%]). There were seven deaths in each group, either during study treatment or within 30 days of discontinuing study treatment, which were the result of treatment-related adverse events. In the ramucirumab group, these adverse events were acute kidney injury, cardiac arrest, gastric haemorrhage, peritonitis, pneumothorax, septic shock, and sudden death (n=1 of each). In the placebo group, these adverse events were cerebrovascular accident (n=1), multiple organ dysfunction syndrome (n=2), pulmonary embolism (n=2), sepsis (n=1), and small intestine perforation (n=1). INTERPRETATION: Although the primary analysis for progression-free survival was statistically significant, this outcome was not confirmed in a sensitivity analysis of progression-free survival by central independent review, and did not improve overall survival. Therefore, the addition of ramucirumab to cisplatin plus fluoropyrimidine chemotherapy is not recommended as first-line treatment for this patient population. FUNDING: Eli Lilly and Company.status: publishe

Lenvatinib plus pembrolizumab versus lenvatinib plus placebo for advanced hepatocellular carcinoma (LEAP-002): a randomised, double-blind, phase 3 trial

Summary Background Systemic therapies have improved the management of hepatocellular carcinoma, but there is still a need to further enhance overall survival in first-line advanced stages. This study aimed to evaluate the addition of pembrolizumab to lenvatinib versus lenvatinib plus placebo in the first-line setting for unresectable hepatocellular carcinoma. Methods In this global, randomised, double-blind, phase 3 study (LEAP-002), patients aged 18 years or older with unresectable hepatocellular carcinoma, Child Pugh class A liver disease, an Eastern Cooperative Oncology Group performance status of 0 or 1, and no previous systemic treatment were enrolled at 172 global sites. Patients were randomly assigned (1:1) with a central interactive voice-response system (block size of 4) to receive lenvatinib (bodyweight <60 kg, 8 mg/day; bodyweight ≥60 kg, 12 mg/day) plus pembrolizumab (200 mg every 3 weeks) or lenvatinib plus placebo. Randomisation was stratified by geographical region, macrovascular portal vein invasion or extrahepatic spread or both, α-fetoprotein concentration, and Eastern Cooperative Oncology Group performance status. Dual primary endpoints were overall survival (superiority threshold at final overall survival analysis, one-sided p=0·019; final analysis to occur after 532 events) and progression-free survival (superiority threshold one-sided p=0·002; final analysis to occur after 571 events) in the intention-to-treat population. Results from the final analysis are reported. This study is registered with ClinicalTrials.gov, NCT03713593, and is active but not recruiting. Findings Between Jan 17, 2019, and April 28, 2020, of 1309 patients assessed, 794 were randomly assigned to lenvatinib plus pembrolizumab (n=395) or lenvatinib plus placebo (n=399). Median age was 66·0 years (IQR 57·0–72·0), 644 (81%) of 794 were male, 150 (19%) were female, 345 (43%) were Asian, 345 (43%) were White, 22 (3%) were multiple races, 21 (3%) were American Indian or Alaska Native, 21 (3%) were Native Hawaiian or other Pacific Islander, 13 (2%) were Black or African American, and 46 (6%) did not have available race data. Median follow up as of data cutoff for the final analysis (June 21, 2022) was 32·1 months (IQR 29·4–35·3). Median overall survival was 21·2 months (95% CI 19·0–23·6; 252 [64%] of 395 died) with lenvatinib plus pembrolizumab versus 19·0 months (17·2–21·7; 282 [71%] of 399 died) with lenvatinib plus placebo (hazard ratio [HR] 0·84; 95% CI 0·71–1·00; stratified log-rank p=0·023). As of data cutoff for the progression-free survival final analysis (April 5, 2021), median progression-free survival was 8·2 months (95% CI 6·4–8·4; 270 events occurred [42 deaths; 228 progressions]) with lenvatinib plus pembrolizumab versus 8·0 months (6·3–8·2; 301 events occurred [36 deaths; 265 progressions]) with lenvatinib plus placebo (HR 0·87; 95% CI 0·73–1·02; stratified log-rank p=0·047). The most common treatment-related grade 3–4 adverse events were hypertension (69 [17%] of 395 patients in the lenvatinib plus pembrolizumab group vs 68 [17%] of 395 patients) in the lenvatinib plus placebo group), increased aspartate aminotransferase (27 [7%] vs 17 [4%]), and diarrhoea (25 [6%] vs 15 [4%]). Treatment-related deaths occurred in four (1%) patients in the lenvatinib plus pembrolizumab group (due to gastrointestinal haemorrhage and hepatorenal syndrome [n=1 each] and hepatic encephalopathy [n=2]) and in three (1%) patients in the lenvatinib plus placebo group (due to gastrointestinal haemorrhage, hepatorenal syndrome, and cerebrovascular accident [n=1 each]). Interpretation In earlier studies, the addition of pembrolizumab to lenvatinib as first-line therapy for advanced hepatocellular carcinoma has shown promising clinical activity; however, lenvatinib plus pembrolizumab did not meet prespecified significance for improved overall survival and progression-free survival versus lenvatinib plus placebo. Our findings do not support a change in clinical practice. Funding Eisai US, and Merck Sharp & Dohme, a subsidiary of Merck

Probing the nature of the χc1(3872)\chi_{c1}(3872) state using radiative decays

International audienceThe radiative decays $\chi_{c1}(3872)\rightarrow\psi(2S)\gamma$ and $\chi_{c1}(3872)\rightarrow J/\psi\gamma$ are used to probe the~nature of the~$\chi_{c1}(3872)$ state using proton-proton collision data collected with the LHCb detector, corresponding to an~integrated luminosity of~9fb$^{-1}$. Using the~$B^+\rightarrow \chi_{c1}(3872)K^+$decay, the $\chi_{c1}(3872)\rightarrow \psi(2S)\gamma$ process is observed for the first time and the ratio of its partial width to that of the $\chi_{c1}(3872)\rightarrow J/\psi\gamma$ decay is measured to be $$\frac{\Gamma_{\chi_{c1}(3872)\rightarrow \psi(2S)\gamma}} {\Gamma_{\chi_{c1}(3872)\rightarrow J/\psi\gamma}} = 1.67 \pm 0.21 \pm 0.12 \pm0.04 ,$$ where the first uncertainty is statistical, the second systematic and the third is due to the uncertainties on the branching fractions of the $\psi(2S)$ and $J/\psi$ mesons. The measured ratio makes the interpretation of the $\chi_{c1}(3872)$ state as a~pure $D^0\bar{D}^{*0}+\bar{D}^0D^{*0}$ molecule questionable and strongly indicates a sizeable compact charmonium or tetraquark component within the $\chi_{c1}(3872)$ state

Amplitude analysis of B+→ψ(2S)K+π+π−B^+ \to \psi(2S) K^+ \pi^+ \pi^- decays

International audienceThe first full amplitude analysis of $B^+ \to \psi(2S) K^+ \pi^+ \pi^-$ decays is performed using proton-proton collision data corresponding to an integrated luminosity of $9\,\text{fb}^{-1}$ recorded with the LHCb detector. The rich $K^+ \pi^+ \pi^-$ spectrum is studied and the branching fractions of the resonant substructure associated with the prominent $K_1(1270)^+$ contribution are measured. The data cannot be described by conventional strange and charmonium resonances only. An amplitude model with 53 components is developed comprising 11 hidden-charm exotic hadrons. New production mechanisms for charged charmonium-like states are observed. Significant resonant activity with spin-parity $J^P = 1^+$ in the $\psi(2S) \pi^+$ system is confirmed and a multi-pole structure is demonstrated. The spectral decomposition of the $\psi(2S) \pi^+ \pi^-$ invariant-mass structure, dominated by $X^0 \to \psi(2S) \rho(770)^0$ decays, broadly resembles the $J/\psi \phi$ spectrum observed in $B^+ \to J/\psi \phi K^+$ decays. Exotic $\psi(2S) K^+ \pi^-$ resonances are observed for the first time

Tracking of charged particles with nanosecond lifetimes at LHCb

International audienceA method is presented to reconstruct charged particles with lifetimes between 10 ps and 10 ns, which considers a combination of their decay products and the partial tracks created by the initial charged particle. Using the $\Xi^-$ baryon as a benchmark, the method is demonstrated with simulated events and proton-proton collision data at $\sqrt{s}=13$ TeV, corresponding to an integrated luminosity of 2.0 fb${}^{-1}$ collected with the LHCb detector in 2018. Significant improvements in the angular resolution and the signal purity are obtained. The method is implemented as part of the LHCb Run 3 event trigger in a set of requirements to select detached hyperons. This is the first demonstration of the applicability of this approach at the LHC, and the first to show its scaling with instantaneous luminosity

Transverse polarisation measurement of Λ\Lambda hyperons in ppNe collisions at sNN\sqrt{s_{NN}}=68.4 GeV with the LHCb detector

A measurement of the transverse polarization of the $\Lambda$ and $\bar{\Lambda}$hyperons in $p$Ne fixed-target collisions at $\sqrt{s_{NN}}$=68.4 GeV is presented using data collected by the LHCb detector. The polarization is studied using the decay $\Lambda \rightarrow p \pi^-$ together with its charge conjugated process, the integrated values measured are $$P_{\Lambda} = 0.029 \pm 0.019 \, (\rm{stat}) \pm 0.012 \, (\rm{syst}) \, ,$$ $$P_{\bar{\Lambda}} = 0.003 \pm 0.023 \, (\rm{stat}) \pm 0.014 \,(\rm{syst}) \,$$ Furthermore, the results are shown as a function of the Feynman $x$ variable, transverse momentum, pseudorapidity and rapidity of the hyperons, and are compared with previous measurements.A measurement of the transverse polarization of the $\Lambda$ and $\bar{\Lambda}$ hyperons in $p$Ne fixed-target collisions at $\sqrt{s_{NN}}$ = 68.4 GeV is presented using data collected by the LHCb detector. The polarization is studied using the decay $\Lambda \rightarrow p \pi^-$ together with its charge conjugated process, the integrated values measured are $$P_{\Lambda} = 0.029 \pm 0.019 \, (\rm{stat}) \pm 0.012 \, (\rm{syst}) \, ,$$ $$P_{\bar{\Lambda}} = 0.003 \pm 0.023 \, (\rm{stat}) \pm 0.014 \,(\rm{syst}) \,.$$ Furthermore, the results are shown as a function of the Feynman~$x$~variable, transverse momentum, pseudorapidity and rapidity of the hyperons, and are compared with previous measurements

Amplitude analysis and branching fraction measurement of B+→D∗−Ds+π+B^{+}\to D^{*-}D^{+}_{s}\pi^{+} decays

International audienceThe decays of the $B^{+}$ meson to the final state $D^{*-}D^{+}_{s}\pi^{+}$ are studied in proton-proton collision data collected with the LHCb detector at centre-of-mass energies of 7, 8, and 13 TeV, corresponding to a total integrated luminosity of 9 fb$^{-1}$. The ratio of branching fractions of the $B^{+}\to D^{*-}D^{+}_{s}\pi^{+}$ and $B^{0}\to D^{*-}D^{+}_{s}$ decays is measured to be $0.173\pm 0.006\pm 0.010$, where the first uncertainty is statistical and the second is systematic. Using partially reconstructed $D^{*+}_{s}\to D^{+}_{s}\gamma$ and $D^{+}_{s}\pi^{0}$ decays, the ratio of branching fractions between the $B^{+}\to D^{*-}D^{*+}_{s}\pi^{+}$ and $B^{+}\to D^{*-}D^{+}_{s}\pi^{+}$ decays is determined as $1.31\pm 0.07\pm 0.14$. An amplitude analysis of the $B^{+}\to D^{*-}D^{+}_{s}\pi^{+}$ decay is performed for the first time, revealing dominant contributions from known excited charm resonances decaying to the $D^{*-}\pi^{+}$ final state. No significant evidence of exotic contributions in the $D^{+}_{s}\pi^{+}$ or $D^{*-}D^{+}_{s}$ channels is found. The fit fraction of the scalar state $T_{c\bar{s} 0}^{\ast}(2900)^{++}$ observed in the $B^{+}\to D^{-}D^{+}_{s}\pi^{+}$ decay is determined to be less than 2.3% at a 90% confidence level

Search for the lepton-flavor violating decay Bs0→ϕμ±τ∓B^0_s\to\phi\mu^\pm\tau^\mp

International audienceA search for the lepton-flavor violating decays $B^0_s\to\phi\mu^\pm\tau^\mp$ is presented, using a sample of proton-proton collisions at center-of-mass energies of 7, 8, and 13 TeV, collected with the LHCb detector and corresponding to a total integrated luminosity of $9\,\text{fb}^{-1}$. The $\tau$ leptons are selected using decays with three charged pions. No significant excess is observed, and an upper limit on the branching fraction is determined to be ${\cal B}( B^0_s\to\phi\mu^\pm\tau^\mp) < 1.0\times 10^{-5}$ at 90% confidence level