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Background: The combination of atezolizumab-bevacizumab has been proven to be superior to sorafenib for the treatment of unresectable hepatocellular carcinoma not amenable to locoregional treatments, be-coming the standard of care of systemic therapy.Aim: This study aimed at assessing real-world feasibility of atezolizumab-bevacizumab in patients treated with tyrosine-kinase inhibitors.Methods: Among 1447 patients treated with tyrosine-kinase inhibitors from January 2010 to December 2020, we assessed the percentage of those potentially eligible to atezolizumab-bevacizumab (according to IMbrave-150 trial criteria), and the overall survival of eligible and non-eligible patients.Results: 422 (29%) patients were qualified for atezolizumab-bevacizumab therapy. The main exclusion causes were Child-Pugh class and Performance Status. Adopting the more permissive inclusion criteria of SHARP trial, 535 patients became eligible. The median overall survival of tyrosine-kinase inhibitors patients was 14.9 months, longer in eligible patients than in their counterpart due to better baseline liver function and oncological features.Conclusion: Real-world data indicate that less than one-third of hepatocellular carcinoma patients treated with tyrosine-kinase inhibitors are potentially eligible to atezolizumab-bevacizumab according to the reg-istration trial criteria. These patients have a longer survival than the non-eligible ones. If the selection criteria of atezolizumab-bevacizumab trial are maintained in clinical practice, tyrosine-kinase inhibitors will remain the most used systemic therapy for hepatocellular carcinoma patients.(c) 2022 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.

Background: Plasma AR status has been identified as a potential biomarker of response in metastatic castration-resistant prostate cancer (mCRPC) patients receiving docetaxel or AR-targeted therapies. However, the relevance of plasma AR in the overall management of CRPC patients receiving different docetaxel doses is unknown. Patients and methods: This was a multi-institution study of associations between baseline plasma AR copy number status, assessed by droplet digital PCR, and outcome in 325 mCRPC patients receiving docetaxel at standard or adapted regimen at the discretion of the treating physician. Upon analysis, patients were assigned randomly to either a training (n = 217) or validation (n = 108) cohort. Results: In the training cohort, AR-gained patients treated with adapted docetaxel regimen had a significantly worse median progression-free survival (PFS) (3.8 vs 6.3 months, hazard ratio [HR] 2.58, 95% confidence interval [CI] 1.34–4.95, p < 0.0001), median overall survival (10.8 vs 20.6 months, HR 1.98, 95% CI 1.09–3.62, p = 0.0064) and PSA response (PSA > −50%: odds ratio 4.88 95%CI 1.55–14.32, p = 0.013) as compared to plasma AR normal patients. These findings were all confirmed in the validation cohort. However, in patients treated with standard docetaxel regimen, these differences were not seen. The interaction between AR CN status and dose reduction of docetaxel was considered as independent factor for PFS in both the training and validation cohort (HR 2.84, 95% CI 1.41–5.73, p = 0.003, and HR 4.79, 95% CI 1.79–12.82, p = 0.002). Conclusion: Despite the retrospective non-randomised design of this study, our hypothesis-generating findings could suggest plasma AR as a potential biomarker for optimal docetaxel timing and dose in mCRPC patients. Prospective trials are warranted.

Background The combination of trifluridine-tipiracil and bevacizumab was compared with trifluridine-tipiracil monotherapy in a randomized, open-label, phase II trial, resulting in a statistically significant and clinically relevant improvement in progression-free survival (PFS), with tolerable toxicity in patients with refractory metastatic colorectal cancer (mCRC); however, evidence supporting the role of this combination in a real-world setting is limited. Objective The aim of our work was to provide further evidence on the activity and safety of this combination in a real-world series of Western mCRC patients refractory or intolerant to previous therapies. Patient and Methods We conducted a retrospective, observational study of patients with mCRC refractory or intolerant to standard therapies. Patients were treated with trifluridine-tipiracil and bevacizumab. Previous therapy with fluoropyrimidines, irinotecan, oxaliplatin, bevacizumab, aflibercept, regorafenib, and cetuximab or panitumumab (only RAS wild-type) was allowed, as was previous participation in clinical trials. Clinicopathological characteristics, overall response rate (ORR), disease control rate (DCR), overall survival (OS), PFS, and safety data were retrospectively collected and analyzed. Results We recorded 31 patients treated between 1 December 2017 and 30 June 2022. Median age was 69 years (range 38-82 years), 39% were male, 100% had an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0-1, tumor location was left-sided in 77% of cases, 54% had synchronous presentation, 35% were RAS mutant, 3% were BRAF mutant, and 71% underwent primary tumor resection; 64% of patients had liver metastases, 55% had lung metastases, and 23% had peritoneal carcinomatosis. The median number of previous treatment lines was 2 (range 0-5), and 84% of patients received at least one previous anti-angiogenic agent. The ORR and DCR were 3% and 71%, respectively. With a median follow-up of 8 months (range 2-39), median PFS was 6 months (95% confidence interval [CI] 3.1-8.9 months) and median OS was 14 months (95% CI 10.1-17.8 months). Adverse events of any grade were reported in 58% of patients. The most common grade 3-4 toxicities were neutropenia (19%) and anemia (6%); 35% of patients required either dose delays or dose reductions due to toxicity. Granulocyte colony-stimulating factor (G-CSF) prophylaxis was administered either on first or subsequent cycles of treatment in 35% of patients. No treatment-related deaths occurred. Sixty percent of the patients who discontinued treatment eventually received one or more lines of subsequent therapy. Conclusions Our series provides further evidence on the activity and safety of the combination of trifluridine-tipiracil and bevacizumab in a real-world series of Western refractory mCRC patients.

We assessed the concordance between immunohistochemistry (IHC) and gene expression profiling (GEP) for determining diffuse large B-cell lymphoma (DLBCL) cell of origin (COO) in the phase III PHOENIX trial of rituximab plus cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP) with or without ibrutinib. Among 910 of 1114 screened patients with non-germinal centre B cell-like (non-GCB) DLBCL by IHC, the concordance with GEP for non-GCB calls was 82·7%, with 691 (75·9%) identified as activated B cell-like (ABC), and 62 (6·8%) as unclassified. Among 746 of 837 enrolled patients with verified non-GCB DLBCL by IHC, the concordance with GEP was 82·8%, with 567 (76·0%) identified as ABC and 51 (6·8%) unclassified; survival outcomes were similar regardless of COO or treatment, whereas among patients with ABC DLBCL aged

Summary Background PD-1 blockade via pembrolizumab monotherapy has shown antitumour activity and toxicity in patients with relapsed or refractory classical Hodgkin lymphoma. Here, we present interim analyses from the KEYNOTE-204 study evaluating pembrolizumab versus brentuximab vedotin for relapsed or refractory classical Hodgkin lymphoma. Methods In this randomised, open-label, phase 3 study, patients aged 18 years or older with relapsed or refractory classical Hodgkin lymphoma with measurable disease and an Eastern Cooperative Oncology Group performance status of 0 or 1 who were ineligible for or had relapsed after autologous haematopoietic stem-cell transplantation (HSCT) were enrolled at 78 hospitals and cancer centres in 20 countries and territories. Patients were randomly assigned (1:1) with an interactive voice response system to pembrolizumab 200 mg intravenously every 3 weeks or brentuximab vedotin 1·8 mg/kg intravenously every 3 weeks. Randomisation was stratified by previous autologous HSCT and status after front-line therapy. Results from the second interim analysis are presented here, with a database cutoff of Jan 16, 2020. The dual primary endpoints assessed in the intention-to-treat population were progression-free survival as assessed by blinded independent central review, and overall survival (not analysed at this interim analysis). Safety was assessed in all patients who received at least one dose of the study drug. This study is registered with ClinicalTrials.gov, NCT02684292. Recruitment for this trial is closed. Findings Between July 8, 2016, and July 13, 2018, 151 patients were randomly assigned to pembrolizumab and 153 to brentuximab vedotin. After a median time from randomisation to data cutoff of 25·7 months (IQR 23·4–33·0), median progression-free survival was 13·2 months (95% CI 10·9–19·4) for pembrolizumab versus 8·3 months (5·7–8·8) for brentuximab vedotin (hazard ratio 0·65 [95% CI 0·48–0·88]; p=0·0027). The most common grade 3–5 treatment-related adverse events were pneumonitis (six [4%] of 148 patients in the pembrolizumab group vs one [1%] of 152 patients in the brentuximab vedotin group), neutropenia (three [2%] vs 11 [7%]), decreased neutrophil count (one [1%] vs seven [5%]), and peripheral neuropathy (one [1%] vs five [3%]). Serious treatment-related adverse events occurred in 24 (16%) of 148 patients receiving pembrolizumab and 16 (11%) of 152 patients receiving brentuximab vedotin. One treatment-related death due to pneumonia occurred in the pembrolizumab group. Interpretation Pembrolizumab showed statistically significant and clinically meaningful improvement in progression-free survival compared with brentuximab vedotin, with safety consistent with previous reports. These data support pembrolizumab as the preferred treatment option for patients with relapsed or refractory classical Hodgkin lymphoma who have relapsed post-autologous HSCT or are ineligible for autologous HSCT. Funding Merck Sharp & Dohme Corp (a subsidiary of Merck & Co, Inc, Kenilworth, NJ, USA). Translation For the Portuguese translation of the Article see Supplementary Materials section.

PURPOSE Melphalan flufenamide (melflufen) is a first-in-class peptide-drug conjugate that targets aminopeptidases and rapidly and selectively releases alkylating agents into tumor cells. The phase II HORIZON trial evaluated the efficacy of melflufen plus dexamethasone in relapsed and refractory multiple myeloma (RRMM), a population with an important unmet medical need. PATIENTS AND METHODS Patients with RRMM refractory to pomalidomide and/or an anti-CD38 monoclonal antibody received melflufen 40 mg intravenously on day 1 of each 28-day cycle plus once weekly oral dexamethasone at a dose of 40 mg (20 mg in patients older than 75 years). The primary end point was overall response rate (partial response or better) assessed by the investigator and confirmed by independent review. Secondary end points included duration of response, progression-free survival, overall survival, and safety. The primary analysis is complete with long-term follow-up ongoing. RESULTS Of 157 patients (median age 65 years; median five prior lines of therapy) enrolled and treated, 119 patients (76%) had triple-class–refractory disease, 55 (35%) had extramedullary disease, and 92 (59%) were refractory to previous alkylator therapy. The overall response rate was 29% in the all-treated population, with 26% in the triple-class–refractory population. In the all-treated population, median duration of response was 5.5 months, median progression-free survival was 4.2 months, and median overall survival was 11.6 months at a median follow-up of 14 months. Grade ≥ 3 treatment-emergent adverse events occurred in 96% of patients, most commonly neutropenia (79%), thrombocytopenia (76%), and anemia (43%). Pneumonia (10%) was the most common grade 3/4 nonhematologic event. Thrombocytopenia and bleeding (both grade 3/4 but fully reversible) occurred concomitantly in four patients. GI events, reported in 97 patients (62%), were predominantly grade 1/2 (93%); none were grade 4. CONCLUSION Melflufen plus dexamethasone showed clinically meaningful efficacy and a manageable safety profile in patients with heavily pretreated RRMM, including those with triple-class–refractory and extramedullary disease.

Background The phase III SANDPIPER study assessed taselisib (GDC-0032), a potent, selective PI3K inhibitor, plus fulvestrant in estrogen receptor-positive, HER2-negative, PIK3CA-mutant locally advanced or metastatic breast cancer. Patients and methods Postmenopausal women with disease recurrence/progression during/after an aromatase inhibitor were randomized 2 : 1 to receive taselisib (4 mg; taselisib arm) or placebo (placebo arm) plus fulvestrant (500 mg). Stratification factors were visceral disease, endocrine sensitivity, and geographic region. Patients with PIK3CA-mutant tumors (central cobas® PIK3CA Mutation Test) were randomized separately from those without detectable mutations. The primary endpoint was investigator-assessed progression-free survival (INV-PFS) in patients with PIK3CA-mutant tumors. Secondary endpoints included objective response rate, overall survival, clinical benefit rate, duration of objective response, PFS by blinded independent central review (BICR-PFS), safety, and time to deterioration in health-related quality of life. Results The PIK3CA-mutant intention-to-treat population comprised 516 patients (placebo arm: n = 176; taselisib arm: n = 340). INV-PFS was significantly improved in the taselisib {7.4 months [95% confidence interval (CI), 7.26-9.07]} versus placebo arm (5.4 months [95% CI, 3.68-7.29]) (stratified hazard ratio [HR] 0.70; 95% CI, 0.56-0.89; P = 0.0037) and confirmed by BICR-PFS (HR 0.66). Secondary endpoints, including objective response rate, clinical benefit rate, and duration of objective response, showed consistent improvements in the taselisib arm. Safety was assessed in all randomized patients who received at least one dose of taselisib/placebo or fulvestrant regardless of PIK3CA-mutation status (n = 629). Serious adverse events were lower in the placebo versus taselisib arm (8.9% versus 32.0%). There were more discontinuations (placebo arm: 2.3%; taselisib arm: 16.8%) and dose reductions (placebo arm: 2.3%; taselisib arm: 36.5%) in the taselisib arm. Conclusion SANDPIPER met its primary endpoint; however, the combination of taselisib plus fulvestrant has no clinical utility given its safety profile and modest clinical benefit.

Aim: Comparison of first-line FOLFIRINOX (FFN) and nab-paclitaxel plus gemcitabine (NabGem) in patients with metastatic pancreatic ductal adenocarcinoma. Patients & methods: The authors analyzed data from 160 patients with metastatic pancreatic adenocarcinoma receiving first-line FFN (n=43) or NabGem (n=117). Results: FFN and NabGem were similar in median progression-free survival (24.43 vs 26.28weeks; hazard ratio [HR]: 0.88) and medial overall survival (47.43 vs 42.86weeks; HR: 0.90). Of the 43 patients receiving FFN, 26 (60.4%) were treated with second-line NabGem; 14/117 (12.0%) patients receiving NabGem received second-line FFN (p&nbsp

A unique collaboration of multidisciplinary experts from the European Dermatology Forum (EDF), the European Association of Dermato-Oncology (EADO), and the European Organization of Research and Treatment of Cancer (EORTC) was formed to make recommendations on cutaneous melanoma diagnosis and treatment, based on the systematic literature reviews and the experts' experience. Cutaneous melanomas are excised with one to 2-cm safety margins. Sentinel lymph node dissection shall be performed as a staging procedure in patients with tumor thickness ≥1.0mm or ≥0.8mm with additional histological risk factors, although there is as yet no clear survival benefit for this approach. Therapeutic decisions in stage III/IV patients should be primarily made by an interdisciplinary oncology team ("tumor board"). Adjuvant therapies can be proposed in stage III/completely resected stage IV patients and are primarily anti-PD-1, independent of mutational status, or alternatively dabrafenib plus trametinib for BRAF mutant patients. In distant metastases (stage IV), either resected or not, systemic treatment is always indicated. For first-line treatment particularly in BRAF wild-type patients, immunotherapy with PD-1 antibodies alone or in combination with CTLA-4 antibodies shall be considered. In stage IV melanoma with a BRAF-V600E/K mutation, first-line therapy with BRAF/MEK inhibitors can be offered as an alternative to immunotherapy. In patients with primary resistance to immunotherapy and harboring a BRAF-V600E/K mutation, this therapy shall be offered as second-line therapy. Systemic therapy in stage III/IV melanoma is a rapidly changing landscape, and it is likely that these recommendations may change in the near future.

Summary Background The triplet FOLFOXIRI (fluorouracil, leucovorin, oxaliplatin, and irinotecan) plus bevacizumab showed improved outcomes for patients with metastatic colorectal cancer, compared with FOLFIRI (fluorouracil, leucovorin, and irinotecan) plus bevacizumab. However, the actual benefit of the upfront exposure to the three cytotoxic drugs compared with a preplanned sequential strategy of doublets was not clear, and neither was the feasibility or efficacy of therapies after disease progression. We aimed to compare a preplanned strategy of upfront FOLFOXIRI followed by the reintroduction of the same regimen after disease progression versus a sequence of mFOLFOX6 (fluorouracil, leucovorin, and oxaliplatin) and FOLFIRI doublets, in combination with bevacizumab. Methods TRIBE2 was an open-label, phase 3, randomised study of patients aged 18–75 years with an Eastern Cooperative Oncology Group (ECOG) performance status of 2, with unresectable, previously untreated metastatic colorectal cancer, recruited from 58 Italian oncology units. Patients were stratified according to centre, ECOG performance status, primary tumour location, and previous adjuvant chemotherapy. A randomisation system incorporating a minimisation algorithm was used to randomly assign patients (1:1) via a masked web-based allocation procedure to two different treatment strategies. In the control group, patients received first-line mFOLFOX6 (85 mg/m2 of intravenous oxaliplatin concurrently with 200 mg/m2 of leucovorin over 120 min; 400 mg/m2 intravenous bolus of fluorouracil; 2400 mg/m2 continuous infusion of fluorouracil for 48 h) plus bevacizumab (5 mg/kg intravenously over 30 min) followed by FOLFIRI (180 mg/m2 of intravenous irinotecan over 120 min concurrently with 200 mg/m2 of leucovorin; 400 mg/m2 intravenous bolus of fluorouracil; 2400 mg/m2 continuous infusion of fluorouracil for 48 h) plus bevacizumab after disease progression. In the experimental group, patients received FOLFOXIRI (165 mg/m2 of intravenous irinotecan over 60 min; 85 mg/m2 intravenous oxaliplatin concurrently with 200 mg/m2 of leucovorin over 120 min; 3200 mg/m2 continuous infusion of fluorouracil for 48 h) plus bevacizumab followed by the reintroduction of the same regimen after disease progression. Combination treatments were repeated every 14 days for up to eight cycles followed by fluorouracil and leucovorin (at the same dose administered at the last induction cycle) plus bevacizumab maintenance until disease progression, unacceptable adverse events, or consent withdrawal. Patients and investigators were not masked. The primary endpoint was progression-free survival 2, defined as the time from randomisation to disease progression on any treatment given after first disease progression, or death, analysed by intention to treat. Safety was assessed in patients who received at least one dose of their assigned treatment. Study recruitment is complete and follow-up is ongoing. This trial is registered with Clinicaltrials.gov , NCT02339116 . Findings Between Feb 26, 2015, and May 15, 2017, 679 patients were randomly assigned and received treatment (340 in the control group and 339 in the experimental group). At data cut-off (July 30, 2019) median follow-up was 35·9 months (IQR 30·1–41·4). Median progression-free survival 2 was 19·2 months (95% CI 17·3–21·4) in the experimental group and 16·4 months (15·1–17·5) in the control group (hazard ratio [HR] 0·74, 95% CI 0·63–0·88; p=0·0005). During the first-line treatment, the most frequent of all-cause grade 3–4 events were diarrhoea (57 [17%] vs 18 [5%]), neutropenia (168 [50%] vs 71 [21%]), and arterial hypertension (25 [7%] vs 35 [10%]) in the experimental group compared with the control group. Serious adverse events occurred in 84 (25%) patients in the experimental group and in 56 (17%) patients in the control group. Eight treatment-related deaths were reported in the experimental group (two intestinal occlusions, two intestinal perforations, two sepsis, one myocardial infarction, and one bleeding) and four in the control group (two occlusions, one perforation, and one pulmonary embolism). After first disease progression, no substantial differences in the incidence of grade 3 or 4 adverse events were reported between the control and experimental groups, with the exception of neurotoxicity, which was only reported in the experimental group (six [5%] of 132 patients). Serious adverse events after disease progression occurred in 20 (15%) patients in the experimental group and 25 (12%) in the control group. Three treatment-related deaths after first disease progression were reported in the experimental group (two intestinal occlusions and one sepsis) and four in the control group (one intestinal occlusion, one intestinal perforation, one cerebrovascular event, and one sepsis). Interpretation Upfront FOLFOXIRI plus bevacizumab followed by the reintroduction of the same regimen after disease progression seems to be a preferable therapeutic strategy to sequential administration of chemotherapy doublets, in combination with bevacizumab, for patients with metastatic colorectal cancer selected according to the study criteria. Funding The GONO Cooperative Group, the ARCO Foundation, and F Hoffmann–La Roche.

Summary Background Polycythaemia vera is a myeloproliferative neoplasm characterised by excessive proliferation of erythroid, myeloid, and megakaryocytic components in the bone marrow due to mutations in the Janus kinase 2 (JAK2) gene. Ruxolitinib, a JAK 1 and JAK 2 inhibitor, showed superiority over best available therapy in a phase 2 study in patients with polycythaemia vera who were resistant to or intolerant of hydroxyurea. We aimed to compare the long-term safety and efficacy of ruxolitinib with best available therapy in patients with polycythaemia vera who were resistant to or intolerant of hydroxyurea. Methods We report the 5-year results for a randomised, open-label, phase 3 study (RESPONSE) that enrolled patients at 109 sites across North America, South America, Europe, and the Asia-Pacific region. Patients (18 years or older) with polycythaemia vera who were resistant to or intolerant of hydroxyurea were randomly assigned 1:1 to receive either ruxolitinib or best available therapy. Patients randomly assigned to the ruxolitinib group received the drug orally at a starting dose of 10 mg twice a day. Single-agent best available therapy comprised hydroxyurea, interferon or pegylated interferon, pipobroman, anagrelide, approved immunomodulators, or observation without pharmacological treatment. The primary endpoint, composite response (patients who achieved both haematocrit control without phlebotomy and 35% or more reduction from baseline in spleen volume) at 32 weeeks was previously reported. Patients receiving best available therapy could cross over to ruxolitinib after week 32. We assessed the durability of primary composite response, complete haematological remission, overall clinicohaematological response, overall survival, patient-reported outcomes, and safety after 5-years of follow-up. This study is registered with ClinicalTrials.gov , NCT01243944 . Findings We enrolled patients between Oct 27, 2010, and Feb 13, 2013, and the study concluded on Feb 9, 2018. Of 342 individuals screened for eligibility, 222 patients were randomly assigned to receive ruxolitinib (n=110, 50%) or best available therapy (n=112, 50%). The median time since polycythaemia vera diagnosis was 8·2 years (IQR 3·9–12·3) in the ruxolitinib group and 9·3 years (4·9–13·8) in the best available therapy group. 98 (88%) of 112 patients initially randomly assigned to best available therapy crossed over to receive ruxolitinib and no patient remained on best available therapy after 80 weeks of study. Among 25 primary responders in the ruxolitinib group, six had progressed at the time of final analysis. At 5 years, the probability of maintaining primary composite response was 74% (95% CI 51–88). The probability of maintaining complete haematological remission was 55% (95% CI 32–73) and the probability of maintaining overall clinicohaematological responses was 67% (54–77). In the intention-to-treat analysis not accounting for crossover, the probability of survival at 5 years was 91·9% (84·4–95·9) with ruxolitinib therapy and 91·0% (82·8–95·4) with best available therapy. Anaemia was the most common adverse event in patients receiving ruxolitinib (rates per 100 patient-years of exposure were 8·9 for ruxolitinib and 8·8 for the crossover population), though most anaemia events were mild to moderate in severity (grade 1 or 2 anaemia rates per 100 patient-years of exposure were 8·0 for ruxolitinib and 8·2 for the crossover population). Non-haematological adverse events were generally lower with long-term ruxolitinib treatment than with best available therapy. Thromboembolic events were lower in the ruxolitinib group than the best available therapy group. There were two on-treatment deaths in the ruxolitinib group. One of these deaths was due to gastric adenocarcinoma, which was assessed by the investigator as related to ruxolitinib treatment. Interpretation We showed that ruxolitinib is a safe and effective long-term treatment option for patients with polycythaemia vera who are resistant to or intolerant of hydroxyurea. Taken together, ruxolitinib treatment offers the first widely approved therapeutic alternative for this post-hydroxyurea patient population. Funding Novartis Pharmaceuticals Corporation.

Body composition parameters (BCp) have been associated with outcome in different tumor types. However, their prognostic value in patients with HER2-positive metastatic breast cancer (BC) receiving first line treatment with dual anti-HER2 antibody blockade is unknown. Preclinical evidences suggest that adipocytes adjacent to BC cells can influence response to anti-HER2 treatments. We retrospectively analyzed Computed Tomography (CT)-based BCp from 43 patients with HER2-positive metastatic BC who received first line pertuzumab/trastuzumab-based treatment between May 2009 and March 2020. The impact of baseline CT-based BCp on progression-free survival (PFS) was tested using Kaplan–Meier estimates and univariate and multivariate Cox regression models. We found a significantly worse PFS for patients with high baseline subcutaneous fat index (median 7.9 vs 16.1 months, p = 0.047, HR = 2.04, 95%CI 1–4.17) and for those with high total abdominal fat index (8.1 vs 18.8 months, p = 0.030, HR = 2.17, 95%CI 1.06–4.46). Patients with baseline sarcopenia did not show shorter PFS compared to those without sarcopenia (10.4 vs 9.2 months, p = 0.960, HR = 0.98, 95%CI 0.47–2.03). Total abdominal fat index remained a significant predictor of PFS at multivariate analysis. Our findings suggest that a high quantity of total abdominal fat tissue is a poor prognostic factor in patients receiving trastuzumab/pertuzumab-based first-line treatment for HER2-positive metastatic BC.

The addition of venetoclax to hypomethylating agents (HMA-V) improved the outcome of patients with newly diagnosed acute myeloid leukemia (AML) ineligible for intensive treatment. The aim of our study was to confirm data reported in literature, in a real-life multicenter experience. We retrospectively evaluated 56 naïve AML patients who received HMA-V at 8 different collaborating Hematology Units in the North-East of Italy, from September 2018 to October 2020. Patients received azacitidine or decitabine at standard dose, adding venetoclax starting from cycle 1-3. The median time-to-response was 2 cycles and composite complete remission rate (CCR) was 67.9%. Thirteen out of 38 responders (34.2%) relapsed, with a median response duration of 13.7 months. Transfusion independence (TI) was obtained in 27 (87.0%) and 28 (90.3%) out of 31 patients for red blood cells and platelets, respectively. Median OS was 12.3 months (95% CI, 8.1-16.5), and median PFS was 11.3 months (95% CI, 4.6-17.9). Cytogenetic risk was the only variable impacting on survival, while no differences were observed stratifying patients by age, bone marrow blasts, WHO classification or type of HMA. In conclusion, our real-life multicenter experience indicates that HMA-V treatment allows achieving good response rates in naïve AML patients, ineligible for intensive chemotherapy.

Metronomic chemotherapy (mCHT) refers to the minimum biologically effective dose of a chemotherapy agent given as a continuous dosing regimen, with no prolonged drug-free breaks, that leads to antitumor activity. Aim of the present study is to describe the use of mCHT in a retrospective cohort of metastatic breast cancer (MBC) patients in order to collect data regarding the different types and regimens of drugs employed, their efficacy and safety. Between January 2011 and December 2016, data of 584 metastatic breast cancer patients treated with mCHT were collected. The use of VRL-based regimens increased during the time of observation (2011: 16.8% - 2016: 29.8%), as well as CTX-based ones (2011: 17.1% - 2016: 25.6%), whereas CAPE-based and MTX-based regimens remained stable. In the 1st-line setting, the highest ORR and DCR were observed for VRL-based regimens (single agent: 44% and 88%; combination: 36.7% and 82.4%, respectively). Assuming VRL-single agent as the referee treatment (median PFS: 7.2 months, 95% CI: 5.3–10.3), the longest median PFS were observed in VRL-combination regimens (9.5, 95%CI 88.8–11.3, HR = 0.72) and in CAPE-single agent (10.7, 95%CI 8.3–15.8, HR = 0.70). The VICTOR-6 study provides new data coming from the real-life setting, by adding new information regarding the use of mCHT as an option of treatment for MBC patients.

Background Several studies have suggested a survival benefit of neoadjuvant therapy (NAT) for pancreatic ductal adenocarcinoma (PDAC) in the pancreatic head. Data concerning NAT for PDAC located in pancreatic body or tail are lacking. Methods Post hoc analysis of an international multicenter retrospective cohort of distal pancreatectomy for PDAC in 34 centers from 11 countries (2007–2015). Patients who underwent resection after NAT were matched (1:1 ratio), using propensity scores based on baseline characteristics, to patients who underwent upfront resection. Median overall survival was compared using the stratified log-rank test. Results Among 1236 patients, 136 (11.0%) received NAT, most frequently FOLFIRINOX (25.7%). In total, 94 patients receiving NAT were matched to 94 patients undergoing upfront resection. NAT was associated with less postoperative major morbidity (Clavien–Dindo ≥ 3a, 10.6% vs. 23.4%, P = 0.020) and pancreatic fistula grade B/C (9.6% vs. 21.3%, P = 0.026). NAT did not improve overall survival [27 (95% CI 14–39) versus 31 months (95% CI 19–42), P = 0.277], as compared with upfront resection. In a sensitivity analysis of 251 patients with radiographic tumor involvement of splenic vessels, NAT (n = 37, 14.7%) was associated with prolonged overall survival [36 (95% CI 18–53) versus 20 months (95% CI 15–24), P = 0.049], as compared with upfront resection. Conclusion In this international multicenter cohort study, NAT for resected PDAC in pancreatic body or tail was associated with less morbidity and pancreatic fistula but similar overall survival in comparison with upfront resection. Prospective studies should confirm a survival benefit of NAT in patients with PDAC and splenic vessel involvement.

Muscle invasive bladder cancer (MIBC) is a widespread malignancy with a worse prognosis often related to a late diagnosis. For early-stage MIBC pts, a multidisciplinary approach is mandatory to evaluate the timing of neoadjuvant chemotherapy (NAC) and surgery. The current standard therapy is platinum-based NAC (MVAC-methotrexate, vinblastine, doxorubicin, and cisplatin or Platinum–Gemcitabine regimens) followed by radical cystectomy (RC) with lymphadenectomy. However, preliminary data from Vesper trial highlighted that dose-dense NAC MVAC is endowed with a good pathological response but shows low tolerability. In the last few years, translational-based research approaches have identified several candidate biomarkers of NAC esponsiveness, such as ERCC2, ERBB2, or DNA damage response (DDR) gene alterations. Moreover, the recent consensus MIBC molecular classification identified six molecular subtypes, characterized by different sensitivity to chemo- or targeted or immunotherapy, that could open a novel procedure for patient selection and also for neoadjuvant therapies. The Italian PURE-01 phase II Trial extended data on efficacy and resistance to Immune Checkpoint Inhibitors (ICIs) in this setting. In this review, we summarize the most relevant literature data supporting NAC use in MIBC, focusing on novel therapeutic strategies such as immunotherapy, considering the better patient stratification and selection emerging from novel molecular classification.

Background: Bortezomib-based induction followed by high-dose melphalan (200 mg/m2) and autologous stem-cell transplantation (MEL200-ASCT) and maintenance treatment with lenalidomide alone is the current standard of care for young and fit patients with newly diagnosed multiple myeloma. We aimed to evaluate the efficacy and safety of different carfilzomib-based induction and consolidation approaches with or without transplantation and of maintenance treatment with carfilzomib plus lenalidomide versus lenalidomide alone in newly diagnosed multiple myeloma. Methods: UNITO-MM-01/FORTE was a randomised, open-label, phase 2 trial done in 42 Italian academic and community practice centres. We enrolled transplant-eligible patients with newly diagnosed multiple myeloma aged 65 years or younger with a Karnofsky Performance Status of 60% or higher. Patients were stratified according to International Staging System stage (I vs II/III) and age (

FOLFIRINOX, a combination of chemotherapy drugs (Fluorouracil, Oxaliplatin, Irinotecan -FOI), provides the best clinical benefit in pancreatic ductal adenocarcinoma (PDAC) patients. In this study we explore the role of miRNAs (MIR) as modulators of chemosensitivity to identify potential biomarkers of response. We find that 41 and 84 microRNA inhibitors enhance the sensitivity of Capan1 and MiaPaCa2 PDAC cells respectively. These include a MIR1307-inhibitor that we validate in further PDAC cell lines. Chemotherapy-induced apoptosis and DNA damage accumulation are higher in MIR1307 knock-out (MIR1307KO) versus control PDAC cells, while re-expression of MIR1307 in MIR1307KO cells rescues these effects. We identify binding of MIR1307 to CLIC5 mRNA through covalent ligation of endogenous Argonaute-bound RNAs cross-linking immunoprecipitation assay. We validate these findings in an in vivo model with MIR1307 disruption. In a pilot cohort of PDAC patients undergoing FOLFIRONX chemotherapy, circulating MIR1307 correlates with clinical outcome., Understanding which patients will respond to FOLFIRINOX therapy is important for clinical outcome. Here, the authors show that the MIR1307 is increased pancreatic cancer cell lines and inhibition of the microRNA sensitises cells to treatment.’ stratifying patients to achieve the best clinical outcome. Here, the authors show that the MIR1307 is increased in a subgroup of human pancreatic cancers and inhibition of the microRNA in in vitro and in vivo models of pancreatic cancer sensitises cells to treatment.

PURPOSE To address the role of consolidation treatment for newly diagnosed, transplant eligible patients with multiple myeloma in a controlled clinical trial. PATIENTS AND METHODS The EMN02/HOVON95 trial compared consolidation treatment with two cycles of bortezomib, lenalidomide, and dexamethasone (VRD) or no consolidation after induction and intensification therapy, followed by continuous lenalidomide maintenance. Primary study end point was progression-free survival (PFS). RESULTS Eight hundred seventy-eight eligible patients were randomly assigned to receive VRD consolidation (451 patients) or no consolidation (427 patients). At a median follow-up of 74.8 months, median PFS with adjustment for pretreatment was prolonged in patients randomly assigned to VRD consolidation (59.3 v 42.9 months, hazard ratio [HR] = 0.81; 95% CI, 0.68 to 0.96; P = .016). The PFS benefit was observed across most predefined subgroups, including revised International Staging System (ISS) stage, cytogenetics, and prior treatment. Revised ISS3 stage (HR, 2.00; 95% CI, 1.41 to 2.86) and ampl1q (HR, 1.67; 95% CI, 1.37 to 2.04) were significant adverse prognostic factors. The median duration of maintenance was 33 months (interquartile range 13-86 months). Response ≥ complete response (CR) after consolidation versus no consolidation before start of maintenance was 34% versus 18%, respectively ( P < .001). Response ≥ CR on protocol including maintenance was 59% with consolidation and 46% without ( P < .001). Minimal residual disease analysis by flow cytometry in a subgroup of 226 patients with CR or stringent complete response or very good partial response before start of maintenance demonstrated a 74% minimal residual disease–negativity rate in VRD-treated patients. Toxicity from VRD was acceptable and manageable. CONCLUSION Consolidation treatment with VRD followed by lenalidomide maintenance improves PFS and depth of response in newly diagnosed patients with multiple myeloma as compared to maintenance alone.

Machine learning (ML) algorithms have been used to forecast clinical outcomes or drug adverse effects by analyzing different data sets such as electronic health records, diagnostic data, and molecular data. However, ML implementation in phase I clinical trial is still an unexplored strategy that implies challenges such as the selection of the best development strategy when dealing with limited sample size. In the attempt to better define prechemotherapy baseline clinical and biomolecular predictors of drug toxicity, we trained and compared five ML algorithms starting from clinical, blood biochemistry, and genotype data derived from a previous phase Ib study aimed to define the maximum tolerated dose of irinotecan (FOLFIRI (folinic acid, fluorouracil, and irinotecan) plus bevacizumab regimen) in patients with metastatic colorectal cancer. During cross-validation the Random Forest algorithm achieved the best performance with a mean Matthews correlation coefficient of 0.549 and a mean accuracy of 80.4%; the best predictors of dose-limiting toxicity at baseline were hemoglobin, serum glutamic oxaloacetic transaminase (SGOT), and albumin. The feasibility of a prediction model prototype was in principle assessed using the two distinct dose escalation cohorts, where in the validation cohort the model scored a Matthews correlation coefficient of 0.59 and an accuracy of 82.0%. Moreover, we found a strong relationship between SGOT and irinotecan pharmacokinetics, suggesting its role as surrogates’ estimators of the irinotecan metabolism equilibrium. In conclusion, the potential application of ML techniques to phase I study could provide clinicians with early prediction tools useful both to ameliorate the management of clinical trials and to make more adequate treatment decisions.

In locally advanced pancreatic cancer (LAPC), the combination of chemotherapy and radiotherapy is a widely used treatment option. We performed a pooled analysis, including an exploratory analysis for prognostic and predictive factors, of two phase 2 trials including 73 patients with LAPC, treated with gemcitabine and oxaliplatin (GEMOX) and hypofractionated tomotherapy. With a median follow-up of 36 months (range 1–65), median progression-free (PFS) and overall survival (OS) were 10.2 (95% confidence interval [CI] 7.8–13.2) and 14.3 (95% CI 12.0–18.1) months, respectively. The overall resectability rate was 23.3% (95% CI 13.6–33.0), and the R0 resection rate was 13.7% (95% CI 5.8–21.6). In the multivariate analysis, ECOG performance status (PS) 0 and low levels of CA 19–9 were associated with improved OS and PFS. Concerning OS, log(CA19–9) resulted in a hazard ratio (HR) of 1.20 (95% CI 1.02–1.42), p = 0.027. For ECOG PS 0, HR was 1.00, for PS 1, HR was 2.69 (95% CI 1.46–4.96), for PS 2, HR was 4.18 (95% CI 0.90–19.46), p = 0.003. Low CA19–9 levels were also predictive for resection, with an odds ratio of 0.71 (95% CI 0.52–0.97), p = 0.034. In conclusion, GEMOX and hypofractionated radiotherapy is a treatment option in LAPC. Further studies are needed to identify differences in tumor biology, which may help to predict resectability and prognosis.

Systemic immunoglobulin light-chain (AL) amyloidosis is characterized by deposition of amyloid fibrils of light chains produced by clonal CD38+ plasma cells. Daratumumab, a human CD38-targeting antibody, may improve outcomes for this disease.We randomly assigned patients with newly diagnosed AL amyloidosis to receive six cycles of bortezomib, cyclophosphamide, and dexamethasone either alone (control group) or with subcutaneous daratumumab followed by single-agent daratumumab every 4 weeks for up to 24 cycles (daratumumab group). The primary end point was a hematologic complete response.A total of 388 patients underwent randomization. The median follow-up was 11.4 months. The percentage of patients who had a hematologic complete response was significantly higher in the daratumumab group than in the control group (53.3% vs. 18.1%) (relative risk ratio, 2.9; 95% confidence interval [CI], 2.1 to 4.1; P0.001). Survival free from major organ deterioration or hematologic progression favored the daratumumab group (hazard ratio for major organ deterioration, hematologic progression, or death, 0.58; 95% CI, 0.36 to 0.93; P = 0.02). At 6 months, more cardiac and renal responses occurred in the daratumumab group than in the control group (41.5% vs. 22.2% and 53.0% vs. 23.9%, respectively). The four most common grade 3 or 4 adverse events were lymphopenia (13.0% in the daratumumab group and 10.1% in the control group), pneumonia (7.8% and 4.3%, respectively), cardiac failure (6.2% and 4.8%), and diarrhea (5.7% and 3.7%). Systemic administration-related reactions to daratumumab occurred in 7.3% of the patients. A total of 56 patients died (27 in the daratumumab group and 29 in the control group), most due to amyloidosis-related cardiomyopathy.Among patients with newly diagnosed AL amyloidosis, the addition of daratumumab to bortezomib, cyclophosphamide, and dexamethasone was associated with higher frequencies of hematologic complete response and survival free from major organ deterioration or hematologic progression. (Funded by Janssen Research and Development; ANDROMEDA ClinicalTrials.gov number, NCT03201965.).

We aimed to compare real-world outcomes, resource use, and costs for patients with newly diagnosed multiple myeloma (NDMM) treated with continuous first-line (1 L) lenalidomide or fixed bortezomib in Europe. We performed a multicenter, retrospective, observational chart review of transplant-ineligible NDMM patients across 7 countries. Of 453 eligible patients, 220 received 1 L lenalidomide-based regimens; 105 (47.7%) received second-line (2 L) treatment, of which 50 (47.6%) received 2 L bortezomib. 233 patients received 1 L bortezomib-based regimens; 142 (60.9%) had 2 L treatment, of which 104 (73.2%) received 2 L lenalidomide. Patients receiving 1 L lenalidomide-based regimens had better progression-free survival than patients receiving 1 L bortezomib-based regimens (p =.002) and a longer time to 2 L or third-line treatment (both p

Minimal residual disease (MRD) by multiparameter flow cytometry (MFC) is the most effective tool to define a deep response in multiple myeloma (MM). We conducted an MRD correlative study of the EMN02/HO95 MM phase III trial in newly diagnosed MM patients achieving a suspected complete response before maintenance and every 6 months during maintenance. Patients received high-dose melphalan (HDM) versus bortezomib-melphalan-prednisone (VMP) intensification, followed by bortezomib-lenalidomide-dexamethasone (VRd) versus no consolidation, and lenalidomide maintenance. Bone marrow (BM) samples were processed in three European laboratories, applying EuroFlow-based MFC protocols (eight colors, two tubes) with 10−4−10−5 sensitivity. At enrollment in the MRD correlative study, 76% (244/321) of patients were MRD-negative. In the intention-to-treat analysis, after a median follow-up of 75 months, 5-year progression-free survival was 66% in MRD-negative versus 31% in MRD-positive patients (HR 0.39; p p

Aim: This subgroup analysis of the RAINBOW study evaluated the efficacy and safety of ramucirumab in patients with gastric cancer/gastroesophageal junction adenocarcinoma who received prior trastuzumab therapy. Patients & methods: Of adult patients enrolled in the RAINBOW study, 39 had received prior trastuzumab therapy. Of these, 20 patients were treated with ramucirumab plus paclitaxel and 19 patients with placebo plus paclitaxel within the RAINBOW trial. Results: Overall survival was longer with ramucirumab plus paclitaxel (11.4 months; 95% CI: 7.0–17.9) versus placebo plus paclitaxel (7.0 months; 95% CI: 3.4–14.6), hazard ratio: 0.68 (0.33–1.41); p = 0.30. Longer progression-free survival, higher objective response were observed in ramucirumab combination group. Conclusion: Ramucirumab plus paclitaxel demonstrated efficacy benefits with manageable safety profile in a subgroup of patients pretreated with trastuzumab. Clinical trial registration number: NCT01170663.

Introduction: Despite clinical efforts, pancreatic ductal adenocarcinoma (PDAC) has a dismal prognosis. The scarcity of effective therapies can be reflected by the lack of reliable biomarkers to adapt anticancer drugs prescription to tumors’ and patients’ features. Areas covered: Pharmacogenetics should provide the way to select patients who may benefit from a specific therapy that best matches individual and tumor genetic profile, but it has not yet led to gains in outcome. This review describes PDAC pharmacogenetics findings, critically reappraising studies on polymorphisms and -omics profiles correlated to response to gemcitabine, FOLFIRINOX, and nab-paclitaxel combinations, as well as limitations of targeted therapies. Further, we question whether personalized approaches will benefit patients to any significant degree, supporting the need of new strategies within well-designed trials and validated genomic tests for treatment decision-making. Expert opinion: A major challenge in PDAC is the identification of subgroups of patients who will benefit from treatments. Minimally-invasive tests to analyze biomarkers of drug sensitivity/toxicity should be developed alongside anticancer treatments. However, progress might fall below expectations because of tumor heterogeneity and clonal evolution. Whole-genome sequencing and liquid biopsies, as well as prospective validation in selected cohorts, should overcome the limitations of traditional pharmacogenetic approaches.

PubMed: 31209238, The effectiveness of most cancer targeted therapies is short-lived. Tumors often develop resistance that might be overcome with drug combinations. However, the number of possible combinations is vast, necessitating data-driven approaches to find optimal patient-specific treatments. Here we report AstraZeneca’s large drug combination dataset, consisting of 11,576 experiments from 910 combinations across 85 molecularly characterized cancer cell lines, and results of a DREAM Challenge to evaluate computational strategies for predicting synergistic drug pairs and biomarkers. 160 teams participated to provide a comprehensive methodological development and benchmarking. Winning methods incorporate prior knowledge of drug-target interactions. Synergy is predicted with an accuracy matching biological replicates for >60% of combinations. However, 20% of drug combinations are poorly predicted by all methods. Genomic rationale for synergy predictions are identified, including ADAM17 inhibitor antagonism when combined with PIK3CB/D inhibition contrasting to synergy when combined with other PI3K-pathway inhibitors in PIK3CA mutant cells. © 2019, The Author(s)., National Institute for Health Research, NIHR Wellcome Trust, WT: 102696, 206194 Magyar Tudományos Akadémia, MTA Bayer 668858 PrECISE AstraZeneca, We thank the Genomics of Drug Sensitivity in Cancer and COSMIC teams at the Wellcome Trust Sanger Institute for help with the preparation of the molecular data, Denes Turei for help with Omnipath, and Katjusa Koler for help with matching drug names across combination screens. We thank AstraZeneca for funding and provision of data to the DREAM Consortium to run the challenge, and funding from the European Union Horizon 2020 research (under grant agreement No 668858 PrECISE to J.S.R.), the Joint Research Center for Computational Biomedicine (which is partially funded by Bayer AG) to J.S.R., National Institute for Health Research (NIHR) Sheffield Biomedical Research Center, Premium Postdoctoral Fellowship Program of the Hungarian Academy of Sciences. M.G lab is supported by Wellcome Trust (102696 and 206194)., Competing interests: K.C.B., Z.G., G.Y.D., E.K.Y.T., S.F., and J.R.D. are AstraZeneca employees. K.C.B., Z.G., E.K.Y.T., S.F., and J.R.D. are AstraZeneca shareholders. Y.G. receives personal compensation from Eli Lilly and Company, is a shareholder of Cleerly, Inc., and Ann Arbor Algorithms, Inc. M.G. receives research funding from AstraZeneca and has performed consultancy for Sanofi. The remaining authors declare no competing interests.

Introduction: Metronomic chemotherapy (mCHT) is a treatment regimen in which drugs are administered frequently or continuously and that maintains low, prolonged, and pharmacologically active plasma concentrations of drugs to avoid toxicity associated with traditional chemotherapy regimens, while achieving tumor response. Despite the increasing use of mCHT in patients with metastatic breast cancer (MBC) and the endorsement of mCHT in guidelines, no consensus exists about which patients may substantially benefit from mCHT, which agents can be recommended, and in which treatment setting mCHT is most appropriate. Methods: In October 2017, ten international experts in the management of breast cancer convened to develop a report describing the current status of the use of mCHT for the treatment of advanced breast cancer, based not only on current literature but also on their opinion. The Delphi method was used to reach consensus. Results: A full consensus was reached concerning the acknowledgement that mCHT is not simply a different way of administering chemotherapy but a truly new treatment option. The best-known effect of mCHT is on angiogenesis inhibition, but exciting new data are on the way regarding potential activity on immune system activation. The experts strongly suggest that the ideal patients for mCHT are those with hormone receptor (HR)-positive tumors or those with triple-negative disease. Independently of HR status, mCHT could be an advantageous option for elderly patients, who are often under-treated simply because of their age. Conclusion: Current data support the use of mCHT in selected patients with MBC. Funding: Pierre Fabre.

Background: Chemotherapy plus 1-year trastuzumab is the standard adjuvant treatment of HER2-positive breast cancer. The efficacy of less extended trastuzumab exposure is under investigation. The short-HER study was aimed to assess the non-inferiority of 9 weeks versus 1 year of adjuvant trastuzumab combined with chemotherapy. Patients and methods: HER2-positive breast cancer patients with node-positive or, if node negative, with at least one risk factor (pT>2 cm, G3, lympho-vascular invasion, Ki-67 > 20%, age 35 years, or hormone receptor negativity) were randomly assigned to receive sequential anthracycline-taxane combinations plus 1-year trastuzumab (arm A, long) or plus 9 weeks trastuzumab (arm B, short). This study was designed as a non-inferiority trial with disease-free survival (DFS) as primary end point. A DFS hazard ratio (HR)

Hairy-cell leukemia (HCL) is a CD20+ indolent B-cell cancer in which a BRAF V600E kinase-activating mutation plays a pathogenetic role. In clinical trials involving patients with refractory or relapsed HCL, the targeting of BRAF V600E with the oral BRAF inhibitor vemurafenib led to a response in 91% of the patients; 35% of the patients had a complete response. However, the median relapse-free survival was only 9 months after treatment was stopped.In a phase 2, single-center, academic trial involving patients with refractory or relapsed HCL, we assessed the safety and efficacy of vemurafenib (960 mg, administered twice daily for 8 weeks) plus concurrent and sequential rituximab (375 mg per square meter of body-surface area, administered for 8 doses over a period of 18 weeks). The primary end point was a complete response at the end of planned treatment.Among the 30 enrolled patients with HCL, the median number of previous therapies was 3. A complete response was observed in 26 patients (87%) in the intention-to-treat population. All the patients who had HCL that had been refractory to chemotherapy (10 patients) or rituximab (5) and all those who had previously been treated with BRAF inhibitors (7) had a complete response. Thrombocytopenia resolved after a median of 2 weeks, and neutropenia after a median of 4 weeks. Of the 26 patients with a complete response, 17 (65%) were cleared of minimal residual disease (MRD). Progression-free survival among all 30 patients was 78% at a median follow-up of 37 months; relapse-free survival among the 26 patients with a response was 85% at a median follow-up of 34 months. In post hoc analyses, MRD negativity and no previous BRAF inhibitor treatment correlated with longer relapse-free survival. Toxic effects, mostly of grade 1 or 2, were those that had previously been noted for these agents.In this small study, a short, chemotherapy-free, nonmyelotoxic regimen of vemurafenib plus rituximab was associated with a durable complete response in most patients with refractory or relapsed HCL. (Funded by the European Research Council and others; HCL-PG03 EudraCT number, 2014-003046-27.).

Cancer immunotherapy has produced an unprecedented durable response rate, thus shifting from traditional doublet chemotherapy to immunotherapy-based treatments with and without chemotherapy as the first line strategies for advanced non-small cell lung cancer patients without a molecular driver. However, the majority of patients do not benefit from the treatment or may relapse after a period of response. As few treatment options are available after failure of cancer immunotherapy, including the combination of chemotherapy and anti-angiogenic drugs, a better understanding of the mechanisms limiting cancer immunotherapy may be of help in the definition of the best second line. Whereas only retrospective data support an immunotherapy rechallenge approach, new combination strategies including immunotherapy and cell-signaling inhibitors or double immunotherapy represent the newest and most promising strategy to overcome primary or acquired resistance to first line immunotherapy.

FOLFIRINOX (FFX) and gemcitabine + nab-paclitaxel (GN) are the most common chemotherapy regimens in first-line treatment of metastatic pancreatic cancer (PC). They have not been compared each other in a prospective trial, but only in retrospective studies, which can thus be affected by several biases. In order to overcome these biases, we took advantage of matching-adjusted indirect comparison (MAIC), that allows an indirect comparison by reducing cross-trial differences, and compared data from 268 patients treated with GN in a real-world setting with data from the 171 patients included in the FFX arm of the PRODIGE trial. Survival outcomes did not differ between the two populations. Overall survival was 11.1 months for both treatments (hazard ratio (HR) of FFX 1.10, 95% confidence interval (CI) 0.81–1.49, p = 0.527). Progression-free survival was 6.0 months with GN and 6.4 months with FFX (HR of FFX 1.11, 95% CI 0.82–1.50, p = 0.520). On the other hand, we observed a difference in the toxicity profiles: grade 3/4 anemia was more frequent with GN, whereas a higher occurrence of grade 3/4 vomiting and diarrhea was reported with FFX. FFX and GN show an equivalent efficacy but different safety profiles in the first-line therapy of metastatic pancreatic cancer. Searching for reliable predictive biomarkers is advised in order to improve therapeutic strategy in metastatic PC.

Combining oral PI3K inhibitors with immunochemotherapy for indolent B-cell lymphoma has been associated with toxicity. In the Phase III CHRONOS-4 safety run-in, 21 patients received intravenous copanlisib plus rituximab-based immunochemotherapy. There were no dose-limiting toxicities, and preliminary objective response rates were 90% to 100%. Copanlisib is the first PI3K inhibitor to demonstrate safe, tolerable, and effective combinability with immunochemotherapy, with evaluation ongoing. Background: When treating indolent B-cell lymphoma, combining continuously administered oral phosphatidylinositol 3-kinase (PI3K) inhibitors with immunochemotherapy has been associated with toxicity. CHRONOS-4 (Phase III; NCT02626455) investigates the intravenous, intermittently administered pan-class I PI3K inhibitor copanlisib in combination with rituximab plus bendamustine (R-B) or rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) in patients with relapsed indolent B-cell lymphoma. We report safety run-in results. Patients and Methods: Patients aged >= 18 years with relapsed CD20-positive indolent B-cell lymphoma received copanlisib (45 mg, increasing to 60 mg if no dose-limiting toxicities) weekly on an intermittent schedule with R-B or R-CHOP. Primary objective was to identify a recommended Phase III dose (RP3D). We also assessed objective response, safety, and tolerability. Results: Ten patients received copanlisib plus R-B and 11 received copanlisib plus R-CHOP. No dose-limiting toxicities were reported; RP3D was 60 mg. All patients had >= 1 treatment-emergent adverse event (TEAE), most commonly (all grade/grade 3/4) for copanlisib plus R-B: decreased neutrophil count (80%/50%), nausea (70%/0%), decreased platelet count (60%/10%), hyperglycemia (60%/50%); for copanlisib plus R-CHOP: hyperglycemia (82%/64%), hypertension (73%/64%), decreased neutrophil count (64%/64%). Two and 8 patients had serious TEAEs with copanlisib plus R-B and R-CHOP, respectively. Among evaluable patients, objective response rates were 90% (5 complete, 4 partial) and 100% (3 complete, 7 partial) with copanlisib plus R-B and R-CHOP, respectively. Conclusion: Copanlisib is the first PI3K inhibitor to demonstrate safe, tolerable, and effective combinability with immunochemotherapy in patients with relapsed indolent B-cell lymphoma at full dose (60 mg). Further evaluation is ongoing. (C) 2021 The Author(s). Published by Elsevier Inc.

Therapeutic regimens for previously treated multiple myeloma (MM) may not provide prolonged disease control and are often complicated by significant adverse events, including peripheral neuropathy. In patients with previously treated MM in the Phase 3 BOSTON study, once weekly selinexor, once weekly bortezomib, and 40 mg dexamethasone (XVd) demonstrated a significantly longer median progression-free survival (PFS), higher response rates, deeper responses, a trend to improved survival, and reduced incidence and severity of bortezomib-induced peripheral neuropathy when compared with standard twice weekly bortezomib and 80 mg dexamethasone (Vd). The pre-specified analyses described here evaluated the influence of the number of prior lines of therapy, prior treatment with lenalidomide, prior proteasome inhibitor (PI) therapy, prior immunomodulatory drug therapy, and prior autologous stem cell transplant (ASCT) on the efficacy and safety of XVd compared with Vd. In this 1:1 randomized study, enrolled patients were assigned to receive once weekly oral selinexor (100 mg) with once weekly subcutaneous bortezomib (1.3 mg/m2) and 40 mg per week dexamethasone (XVd) versus standard twice weekly bortezomib and 80 mg per week dexamethasone (Vd). XVd significantly improved PFS, overall response rate, time-to-next-treatment, and showed reduced all grade and grade ≥ 2 peripheral neuropathy compared with Vd regardless of prior treatments, but the benefits of XVd over Vd were more pronounced in patients treated earlier in their disease course who had either received only one prior therapy, had never been treated with a PI, or had prior ASCT. Treatment with XVd improved outcomes as compared to Vd regardless of prior therapies as well as manageable and generally reversible adverse events. XVd was associated with clinical benefit and reduced peripheral neuropathy compared to standard Vd in previously treated MM. These results suggest that the once weekly XVd regimen may be optimally administered to patients earlier in their course of disease, as their first bortezomib-containing regimen, and in those relapsing after ASCT.Trial registration: ClinicalTrials.gov (NCT03110562). Registered 12 April 2017. https://clinicaltrials.gov/ct2/show/NCT03110562.

Subcutaneous (SC) bortezomib-based regimens represent the standard induction therapy prior to autologous stem cell transplantation (ASCT) in newly diagnosed multiple myeloma patients. Published data are based principally on intravenous (IV) administration: this retrospective observational study aimed to define patients’ outcomes upon SC bortezomib administration, before and after ASCT. Of 131 enrolled patients, 86% received bortezomib-dexamethasone plus thalidomide (VTD), 5% plus cyclophosphamide (VCD), and 9% alone (VD), for a median of 4 cycles induction therapy, followed by single (52%) or double (48%) ASCT. 48 patients received consolidation with the same induction regimen. 35% had at least one adverse event, mainly gastrointestinal disorders and peripheral neuropathy (PN). ORR was 93.1%, 97.7% and 100%, after induction, ASCT(s) and consolidation, respectively. Median PFS and PFS2 were 55.8 months and 72 months, respectively, (median follow-up 45.3 months), while median OS was unreached. Concluding, SC bortezomib has similar efficacy with reduced PN than IV administration.

A few months ago, results from two randomised phase III trials of total neoadjuvant therapy (TNT) in locally advanced rectal cancer were presented (RAPIDO and PRODIGE 23), consistently showing better short- and long-term outcomes with TNT as compared with standard neoadjuvant long-course chemoradiotherapy (CRT) or short-course radiotherapy (SCRT). These results represent corroborating evidence in support of a practice that many centres had already implemented based on promising preliminary data. Also, they provide new, high-level evidence to endorse TNT as a new management option in the treatment algorithm of stage II-III rectal cancer in those centres where CRT and SCRT have long remained the only accepted standard neoadjuvant treatments. Having two consistently positive trials is certainly reassuring regarding the potential of TNT as a general treatment approach. Nevertheless, substantial differences between these trials pose important challenges in relation to the generalisability and applicability of their results, and translation of the same into practical clinical recommendations. In this article, we address a number of key questions that the RAPIDO and PRODIGE 23 trials have raised among the broad community of gastrointestinal oncologists, proposing an interpretation of the data that may help the decision making, and highlighting grey areas that warrant further investigation., SCOPUS: re.j, info:eu-repo/semantics/published

Background Copanlisib, an intravenous pan-class I PI3K inhibitor, showed efficacy and safety as monotherapy in patients with relapsed or refractory indolent non-Hodgkin lymphoma who had received at least two therapies. The CHRONOS-3 study aimed to assess the efficacy and safety of copanlisib plus rituximab in patients with relapsed indolent non-Hodgkin lymphoma. Methods CHRONOS-3 was a multicentre, double-blind, randomised, placebo-controlled, phase 3 study in 186 academic medical centres across Asia, Australia, Europe, New Zealand, North America, Russia, South Africa, and South America. Patients aged 18 years and older with an Eastern Cooperative Oncology Group performance status of no more than 2 and histologically confirmed CD20-positive indolent B-cell lymphoma relapsed after the last anti-CD20 monoclonal antibody-containing therapy and progression-free and treatment-free for at least 12 months, or at least 6 months for patients unwilling or unfit to receive chemotherapy, were randomly assigned (2:1) with an interactive voice-web response system via block randomisation (block size of six) to copanlisib (60 mg given as a 1-h intravenous infusion on an intermittent schedule on days 1, 8, and 15 [28-day cycle]) plus rituximab (375 mg/m(2) given intravenously weekly on days 1, 8, 15, and 22 during cycle 1 and day 1 of cycles 3, 5, 7, and 9) or placebo plus rituximab, stratified on the basis of histology, progression-free and treatment-free interval, presence of bulky disease, and previous treatment with PI3K inhibitors. The primary outcome was progression-free survival in the full analysis set (all randomised patients) by masked central review. Safety was assessed in all patients who received at least one dose of any study drug. This study is registered with ClinicalTrials.gov, NCT02367040 and is ongoing. Findings Between Aug 3, 2015, and Dec 17, 2019, 652 patients were screened for eligibility. 307 of 458 patients were randomly assigned to copanlisib plus rituximab and 151 patients were randomly assigned to placebo plus rituximab. With a median follow-up of 19.2 months (IQR 7.4-28.8) and 205 total events, copanlisib plus rituximab showed a statistically and clinically significant improvement in progression-free survival versus placebo plus rituximab; median progression-free survival 21.5 months (95% CI 17.8-33.0) versus 13.8 months (10.2-17.5; hazard ratio 0.52 [95% CI 0.39-0.69]; p, Bayer, Bayer.

[Background]: In the phase 3 ALCYONE study, daratumumab plus bortezomib/melphalan/prednisone (D-VMP) versus bortezomib/melphalan/prednisone (VMP) significantly improved progression-free survival (PFS) and overall survival (OS) in transplant-ineligible, newly diagnosed multiple myeloma (NDMM) patients. We present a subgroup analysis of ALCYONE by patient frailty status., [Patients and Methods]: Frailty assessment was performed retrospectively using age, Charlson comorbidity index, and baseline Eastern Cooperative Oncology Group performance status score. Patients were classified as fit (0), intermediate (1), or frail (≥2); a nonfrail category combined fit and intermediate patients., [Results]: Among randomized patients (D-VMP, n = 350; VMP, n = 356), 391 (55.4%) were nonfrail (D-VMP, 187 [53.4%]; VMP, 204 [57.3%]) and 315 (44.6%) were frail (163 [46.6%]; 152 [42.7%]). After 40.1-months median follow-up, nonfrail patients had longer PFS and OS than frail patients, but benefits of D-VMP versus VMP were maintained across subgroups: PFS nonfrail (median, 45.7 vs. 19.1 months; hazard ratio [HR], 0.36; P < .0001), frail (32.9 vs. 19.5 months; HR, 0.51; P < .0001); OS nonfrail (36-month rate, 83.6% vs. 74.5%), frail (71.4% vs. 59.0%). Improved greater than or equal to complete response and minimal residual disease (10−5)-negativity rates were observed for D-VMP versus VMP across subgroups. The 2 most common grade 3/4 treatment-emergent adverse events were neutropenia (nonfrail: 39.2% [D-VMP] and 42.4% [VMP]; frail: 41.3% and 34.4%) and thrombocytopenia (nonfrail: 32.8% and 36.9%; frail: 36.9% and 39.1%)., [Conclusion]: Our findings support the clinical benefit of D-VMP in transplant-ineligible NDMM patients enrolled in ALCYONE, regardless of frailty status., This study was sponsored by Janssen Research & Development, LLC.

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Background The combination of a microtubule inhibitor (eribulin) with a nucleoside analog (gemcitabine) may synergistically induce tumor cell death, particularly in triple negative breast cancer (TNBC) characterized by high cell proliferation, aggressive behavior, and chemo-resistance. Patients and methods This is an open-label, multicenter phase II study evaluating the combination of eribulin (0.88 mg/m2) plus gemcitabine (1000 mg/m2) on days 1 and 8 of a 21-day cycle as either first- or second-line treatment of locally advanced or metastatic TNBC. The primary endpoint was the objective response for evaluable patients. A prospective, molecular correlative study was carried out to assess the role of germinal BRCA pathogenic variants and single nucleotide polymorphisms (SNPs) in predicting efficacy and toxicity of the combination regimen. Results From July 2013 to September 2016, 83 evaluable patients were enrolled. They received a median number of six cycles of treatment. An overall response rate (ORR) of 37.3% (31 patients) was observed, with a complete response rate of 2.4% and a partial response rate of 34.9%; the clinical benefit rate was 48.8%. With a median follow-up of 28.8 months, the median response duration was 6.6 months, the median progression-free survival (PFS) was 5.1 months, and the median overall survival (OS) was 14.5 months. The most common grade 3-4 adverse events were aminotransferase elevation (in 25% of the patients) and neutropenia (in 23.8%). Women with BRCA1/2 pathogenic variants were associated with worse ORR, PFS, and OS than BRCA1/2 wild-type carriers. CYP3A4 and FGD4 SNPs were associated with increased risk of liver toxicity. Three different SNPs in CDA∗2, RRM1, and CYP2C8 genes were significantly associated with poorer OS. Conclusions The combination of eribulin and gemcitabine showed promising activity and a moderate toxicity profile in metastatic TNBC. BRCA status and pharmacogenetics tests may help identify patients with high probability of response with negligible toxicity. EudraCT number 2012-003505-10., Highlights • Eribulin plus gemcitabine showed a remarkable best ORR of 37.3% and a clinical benefit rate of 48.8%. • The most common grade 3/4 toxicities were liver toxicity and neutropenia without febrile neutropenia. • The study regimen partially lost its efficacy in patients harboring BRCA1/2 pathogenic variants. • SNPs in CYP3A4 and FGD4 genes were associated with increased risk of liver toxicity. • Three different SNPs in CDA∗2, RRM1, and CYP2C8 genes were significantly associated with poorer OS.

Background The current standard first-line treatment of human epidermal growth factor receptor 2 (HER2)-positive (+) metastatic breast cancer is the combination of pertuzumab, trastuzumab and a taxane (P + T + taxane), while standard second-line is ado-trastuzumab-emtansine (T-DM1). The registration trial of pertuzumab, however, did not include early-relapsing patients, defined as patients experiencing tumor relapse ≤12 months from the end of (neo)adjuvant anti-HER2 therapy. Conversely, the pivotal trial of T-DM1 included some patients relapsing ≤6 months after the end of (neo)adjuvant trastuzumab. Thus, a proportion of early-relapsing patients are currently eligible to receive T-DM1 as first-line treatment. Nevertheless, no direct comparison exists between the two regimens in this clinical setting. Patients and methods We retrospectively compared T-DM1 versus P + T + taxane as first-line treatment in two cohorts of early-relapsing patients in an Italian ‘real-world’ setting, involving 14 public health care institutions. The primary endpoint was progression-free survival. Secondary endpoints included patients' characterization, overall survival and post-progression survival. Univariate and multivariate analyses were carried out. All tests were two-sided and a P ≤ 0.05 was considered statistically significant. Results Among 1252 screened patients, 75 met the inclusion criteria. Forty-four (58.7%) received P + T + taxane and 31 (41.3%) received T-DM1. The two cohorts showed similar characteristics of aggressiveness and no significant differences in treatment history. T-DM1, compared with P + T + taxane was associated with worse progression-free survival (adjusted hazard ratio: 2.26, 95% confidence interval: 1.13-4.52, P = 0.021) and overall survival (adjusted hazard ratio: 3.95, 95% confidence interval: 1.38-11.32, P = 0.010), irrespective of previous (neo)adjuvant treatment, age, hormone receptors status, time-to-relapse (≤6 months or within 6-12 months) and presence of visceral/brain metastases. No differences were observed in post-progression survival (P = 0.095). Conclusions Our study suggests superiority for P + T + taxane over T-DM1 as up-front treatment of early-relapsing HER2+ metastatic breast cancer, which merits further assessment in larger and prospective trials., Highlights • This is the first study comparing pertuzumab + trastuzumab + taxane (P + T + taxane) with T-DM1 in early-relapsing HER2+ MBC. • The majority of early-relapsing HER2+ MBC have high-grade, node-positive, large primary tumors. • First-line T-DM1 compared with P + T + taxane is associated with worse progression-free survival. • First-line T-DM1 compared with P + T + taxane is associated with worse overall survival. • Post-progression survival does not differ between the two treatments cohorts.