Efficacy and safety of enasidenib and azacitidine combination in patients with IDH2 mutated acute myeloid leukemia and not eligible for intensive chemotherapy

Preclinically, enasidenib and azacitidine (ENA + AZA) synergistically enhance cell differentiation, and venetoclax (VEN), a small molecule Bcl2 inhibitor (i) is particularly effective in IDH2 mutated acute myeloid leukemia (IDH2^mutAML). This open label phase II trial enrolled patients (pts) with documented IDH2^mutAML. All patients received AZA 75 mg/m²/d x 7 d/cycle and ENA 100 mg QD continuously. Concomitant Bcl2i and FLT3i were allowed ({"type":"clinical-trial","attrs":{"text":"NCT03683433","term_id":"NCT03683433"}}NCT03683433).Twenty-six pts received ENA + AZA (median 68 years, range, 24–88); 7 newly diagnosed (ND) and 19 relapsed/refractory (R/R). In R/R AML patients, three had received prior ENA and none had received prior VEN. The composite complete remission rate (CRc) [complete remission (CR) or complete remission with incomplete hematologic recovery (CRi)] was 100% in ND AML, and 58% in R/R AML. Median OS was not reached in ND AML with median follow-up of 13.1 months (mo); Pts treated in first relapse had improved OS than those with ≥2 relapse (median OS not reached vs 5.2 mo; HR 0.24, 95% CI 0.07–0.79, p = 0.04). Two patients received ENA + AZA with a concomitant FLT3i, one responding ND AML patient and one nonresponding R/R AML patient. Seven R/R AML pts received ENA + AZA + VEN triplet, and with median follow up of 11.2 mo, median OS was not reached and 6-mo OS was 70%. The most frequent treatment-emergent adverse events include febrile neutropenia (23%). Adverse events of special interest included all-grade IDH differentiation syndrome (8%) and indirect hyperbilirubinemia (35%). ENA + AZA was a well-tolerated, and effective therapy for elderly pts with IDH2^mut ND AML as well as pts with R/R AML. The addition of VEN to ENA + AZA appears to improve outcomes in R/R IDH2^mutAML.Clinical trial registration information: https://clinicaltrials.gov/.{"type":"clinical-trial","attrs":{"text":"NCT03683433","term_id":"NCT03683433"}}NCT03683433Subject terms: Acute myeloid leukaemia, Drug development     

Obinutuzumab-atezolizumab-lenalidomide for the treatment of patients with relapsed/refractory follicular lymphoma: final analysis of a Phase Ib/II trial

We evaluated the triplet regimen obinutuzumab-atezolizumab-lenalidomide (G-atezo-len) for patients with relapsed/refractory (R/R) follicular lymphoma (FL) in an open-label, multicenter phase Ib/II study (BO29562; {"type":"clinical-trial","attrs":{"text":"NCT02631577","term_id":"NCT02631577"}}NCT02631577). An initial 3 + 3 dose‐escalation phase to define the recommended phase II dose of lenalidomide was followed by an expansion phase with G-atezo-len induction and maintenance. At final analysis, 38 patients (lenalidomide 15 mg, n = 4; 20 mg, n = 34) had completed the trial. Complete response rate for the efficacy population (lenalidomide 20 mg, n = 32) at end-of-induction was 71.9% (66.7% in double‐refractory patients [refractory to rituximab and alkylator] [n = 12]; 50.0% in patients with progressive disease within 24 months of first-line therapy [n = 12]). The 36-month progression-free survival rate was 68.4%. All treated patients had ≥1 adverse event (AE; grade 3–5 AE, 32 patients [84%]; serious AE, 18 patients [47%]; AEs leading to discontinuation of any study drug, 11 patients [29%]). There were 2 fatal AEs (1 merkel carcinoma, 1 sarcomatoid carcinoma; both unrelated to any study drug). The G‐atezo-len regimen is effective and tolerable in patients with R/R FL. AEs were consistent with the known safety profile of the individual drugs.Subject terms: Immunotherapy, Public health     

Randomised Phase 1b/2 trial of tepotinib vs sorafenib in Asian patients with advanced hepatocellular carcinoma with MET overexpression

Background This open-label, Phase 1b/2 study evaluated the highly selective MET inhibitor tepotinib in systemic anticancer treatment (SACT)-naive Asian patients with advanced hepatocellular carcinoma (aHCC) with MET overexpression.Methods In Phase 2b, tepotinib was orally administered once daily (300, 500 or 1,000 mg) to Asian adults with aHCC. The primary endpoints were dose-limiting toxicities (DLTs) and adverse events (AEs). Phase 2 randomised SACT-naive Asian adults with aHCC with MET overexpression to tepotinib (recommended Phase 2 dose [RP2D]) or sorafenib 400 mg twice daily. The primary endpoint was independently assessed time to progression (TTP).Results In Phase 1b (n = 27), no DLTs occurred; the RP2D was 500 mg. In Phase 2 (n = 90, 45 patients per arm), the primary endpoint was met: independently assessed TTP was significantly longer with tepotinib versus sorafenib (median 2.9 versus 1.4 months, HR = 0.42, 90% confidence interval: 0.26–0.70, P = 0.0043). Progression-free survival and objective response also favoured tepotinib. Treatment-related Grade ≥3 AE rates were 28.9% with tepotinib and 45.5% with sorafenib.Conclusions Tepotinib improved TTP versus sorafenib and was generally well tolerated in SACT-naive Asian patients with aHCC with MET overexpression.Trial registration ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT01988493","term_id":"NCT01988493"}}NCT01988493.Subject terms: Hepatocellular carcinoma, Molecularly targeted therapy     

The neutralizing antibody response post COVID-19 vaccination in patients with myeloma is highly dependent on the type of anti-myeloma treatment

Recent data suggest a suboptimal antibody response to COVID-19 vaccination in patients with hematological malignancies. Neutralizing antibodies (NAbs) against SARS-CoV-2 were evaluated in 276 patients with plasma cell neoplasms after vaccination with either the BNT162b2 or the AZD1222 vaccine, on days 1 (before the first vaccine shot), 22, and 50. Patients with MM (n = 213), SMM (n = 38), and MGUS (n = 25) and 226 healthy controls were enrolled in the study ({"type":"clinical-trial","attrs":{"text":"NCT04743388","term_id":"NCT04743388"}}NCT04743388). Vaccination with either two doses of the BNT162b2 or one dose of the AZD1222 vaccine leads to lower production of NAbs in patients with MM compared with controls both on day 22 and on day 50 (p < 0.001 for all comparisons). Furthermore, MM patients showed an inferior NAb response compared with MGUS on day 22 (p = 0.009) and on day 50 (p = 0.003). Importantly, active treatment with either anti-CD38 monoclonal antibodies (Mabs) or belantamab mafodotin and lymphopenia at the time of vaccination were independent prognostic factors for suboptimal antibody response following vaccination. In conclusion, MM patients have low humoral response following SARS-CoV-2 vaccination, especially under treatment with anti-CD38 or belamaf. This underlines the need for timely vaccination, possibly during a treatment-free period, and for continuous vigilance on infection control measures in non-responders.Subject terms: Myeloma, Antibodies     

Oral ixazomib-dexamethasone vs oral pomalidomide-dexamethasone for lenalidomide-refractory,proteasome inhibitor-exposed multiple myeloma: a randomized Phase 2 trial

Multiple myeloma (MM) patients typically receive several lines of combination therapy and first-line treatment commonly includes lenalidomide. As patients age, they become less tolerant to treatment, requiring convenient/tolerable/lenalidomide-free options. Carfilzomib and/or bortezomib-exposed/intolerant, lenalidomide-refractory MM patients with ≥2 prior lines of therapy were randomized 3:2 to ixazomib-dexamethasone (ixa-dex) (n = 73) or pomalidomide-dexamethasone (pom-dex) (n = 49) until progression/toxicity. Median progression-free survival (mPFS) was 7.1 vs 4.8 months with ixa-dex vs pom-dex (HR 0.847, 95% CI 0.535–1.341, P = 0.477; median follow-up: 15.3 vs 17.3 months); there was no statistically significant difference between arms. In patients with 2 and ≥3 prior lines of therapy, respectively, mPFS was 11.0 vs 5.7 months (HR 1.083, 95% CI 0.547–2.144) and 5.7 vs 3.7 months (HR 0.686, 95% CI 0.368–1.279). Among ixa-dex vs pom-dex patients, 69% vs 81% had Grade ≥3 treatment-emergent adverse events (TEAEs), 51% vs 53% had serious TEAEs, 39% vs 36% had TEAEs leading to drug discontinuation, 44% vs 32% had TEAEs leading to dose reduction, and 13% vs 13% died on study. Quality of life was similar between arms and maintained during treatment. Ixa-dex represents an important lenalidomide-free, oral option for this heavily pretreated, lenalidomide-refractory, proteasome inhibitor-exposed population.Trial registration: ClinicalTrials.gov number, {"type":"clinical-trial","attrs":{"text":"NCT03170882","term_id":"NCT03170882"}}NCT03170882.Subject terms: Disease-free survival, Myeloma, Adverse effects, Combination drug therapy, Phase II trials     

Lenalidomide and dexamethasone with or without clarithromycin in patients with multiple myeloma ineligible for autologous transplant: a randomized trial

Although case-control analyses have suggested an additive value with the association of clarithromycin to continuous lenalidomide and dexamethasone (Rd), there are not phase III trials confirming these results. In this phase III trial, 286 patients with MM ineligible for ASCT received Rd with or without clarithromycin until disease progression or unacceptable toxicity. The primary endpoint was progression-free survival (PFS). With a median follow-up of 19 months (range, 0–54), no significant differences in the median PFS were observed between the two arms (C-Rd 23 months, Rd 29 months; HR 0.783, p = 0.14), despite a higher rate of complete response (CR) or better in the C-Rd group (22.6% vs 14.4%, p = 0.048). The most common G3–4 adverse events were neutropenia [12% vs 19%] and infections [30% vs 25%], similar between the two arms; however, the percentage of toxic deaths was higher in the C-Rd group (36/50 [72%] vs 22/40 [55%], p = 0.09). The addition of clarithromycin to Rd in untreated transplant ineligible MM patients does not improve PFS despite increasing the ≥CR rate due to the higher number of toxic deaths in the C-Rd arm. Side effects related to overexposure to steroids due to its delayed clearance induced by clarithromycin in this elderly population could explain these results. The trial was registered in clinicaltrials.gov with the name GEM-CLARIDEX: Ld vs BiRd and with the following identifier {"type":"clinical-trial","attrs":{"text":"NCT02575144","term_id":"NCT02575144"}}NCT02575144. The full trial protocol can be accessed from ClinicalTrials.gov. This study received financial support from BMS/Celgene.Subject terms: Randomized controlled trials, Myeloma     

Low-fat dietary pattern and breast cancer mortality by metabolic syndrome components: a secondary analysis of the Women’s Health Initiative (WHI) randomised trial

Background In the Women’s Health Initiative (WHI) dietary modification (DM) randomised trial, the low-fat dietary intervention reduced deaths from breast cancer (P = 0.02). Extending these findings, secondary analysis examined dietary intervention influence on breast cancer mortality by metabolic syndrome (MS) components.Methods In total, 48,835 postmenopausal women with no prior breast cancer were randomised to a low-fat dietary intervention or comparison groups. Four MS components were determined at entry in 45,833 participants: (1) high waist circumference, (2) high blood pressure, (3) high cholesterol and (4) diabetes history. Forest plots of hazard ratios (HRs) were generated with P-values for interaction between randomisation groups and MS component score. Primary outcome was death from breast cancer by metabolic syndrome score.Results HRs and 95% confidence intervals (CI) for dietary intervention influence on death from breast cancer were with no MS components (n = 10,639), HR 1.09, 95% CI 0.63–1.87; with 1–2 MS components (n = 30,948), HR 0.80, 95% CI 0.62–1.02; with 3–4 MS components (n = 4,246), HR 0.31, 95% CI 0.14–0.69 (interaction P = 0.01).Conclusions While postmenopausal women with 3–4 MS components were at higher risk of death from breast cancer, those randomised to a low-fat dietary intervention more likely had reduction in this risk.Registry ClinicalTrials.gov ({"type":"clinical-trial","attrs":{"text":"NCT00000611","term_id":"NCT00000611"}}NCT00000611).Subject terms: Cancer prevention, Breast cancer     

Circulating androgen receptor gene amplification and resistance to 177Lu-PSMA-617 in metastatic castration-resistant prostate cancer: results of a Phase 2 trial

Background In a Phase 2 clinical trial, we aimed to determine the lutetium-177 [¹⁷⁷Lu]-PSMA-617 activity and the clinical utility of levels of plasma androgen receptor (AR) gene in patients with heavily pretreated metastatic castration-resistant prostate cancer (mCRPC).Methods We determined AR copy number in pretreatment plasma samples. We used logistic regression to estimate the odds ratio (OR) and 95% confidence intervals (95% CIs) in order to evaluate the independent relevance of AR status and to evaluate patients with early progressive disease (PD) defined as treatment interruption occurring within 4 months after the start of ¹⁷⁷Lu-PSMA-617.Results Twelve of the 15 (80%) with AR gene gain and 5 of the 25 (20%) patients with no gain of AR had early PD (p = 0.0002). The OR for patients without PSA response having AR gain was 3.69 (95% CI 0.83–16.36, p = 0.085). The OR for patients with early PD having AR gain was 16.00, (95% CI 3.23–79.27, p = 0.0007). Overall, median PFS and OS were 7.5 and 12.4 months, respectively. AR-gained had a significant shorter OS compared to AR-normal patients (7.4 vs 19.1 months, p = 0.020). No treatment interruptions due to adverse effects were reported.Discussion Plasma AR status helped to indicate mCRPC with early resistance to ¹⁷⁷Lu-PSMA-617.Trial registration {"type":"clinical-trial","attrs":{"text":"NCT03454750","term_id":"NCT03454750"}}NCT03454750.Subject terms: Predictive markers, Prostate cancer     

Phase 1A/1B dose-escalation and -expansion study to evaluate the safety,pharmacokinetics, food effects and antitumor activity of pamiparib in advanced solid tumours

Background Pamiparib, a PARP1/2 inhibitor, demonstrated antitumor activity in preclinical models.Methods This Phase 1A/1B dose-escalation/dose-expansion study enrolled adults (≥18 years) with advanced/metastatic cancer. The dose-escalation phase evaluated the recommended Phase 2 dose (RP2D), maximum tolerated dose (MTD), and pharmacokinetics; the dose-expansion phase evaluated the antitumor activity and food effects.Results Patients (N = 101) were enrolled in dose-escalation (n = 64) and dose-expansion (n = 37). During BID dose-escalation, dose-limiting toxicities were Grade 2 nausea (n = 1, 40 mg; n = 1, 80 mg); Grade 2 nausea and Grade 2 anorexia (n = 1, 120 mg), Grade 2 nausea, Grade 3 fatigue and Grade 3 paraesthesia (n = 1, 120 mg); MTD was 80 mg BID and RP2D was 60 mg BID. Common adverse events (AEs) were nausea (69.3%), fatigue (48.5%) and anaemia (35.6%); the most common Grade ≥3 AE was anaemia (24.8%). There was a dose-proportional increase in pamiparib exposure; no food effects on pharmacokinetics were observed. In the efficacy-evaluable population (n = 77), objective response rate (ORR) was 27.3% (95% CI, 17.7–38.6%). Median duration of response was 14.9 months (95% CI, 8.7–26.3). In the epithelial ovarian cancer (EOC)-evaluable population (n = 51), ORR was 41.2% (95% CI, 27.6–55.8%).Conclusions Pamiparib was tolerated with manageable AEs, and antitumor activity was observed in patients with EOC.ClinicalTrials.gov Identifier {"type":"clinical-trial","attrs":{"text":"NCT02361723","term_id":"NCT02361723"}}NCT02361723.Subject terms: Ovarian cancer, Drug development     

Phase 1b/2 trial of tepotinib in sorafenib pretreated advanced hepatocellular carcinoma with MET overexpression

Background This Phase 1b/2 study evaluated tepotinib, a highly selective MET inhibitor, in US/European patients with sorafenib pretreated advanced hepatocellular carcinoma (aHCC) with MET overexpression.Methods Eligible adults had aHCC, progression after ≥4 weeks of sorafenib, and, for Phase 2 only, MET overexpression. Tepotinib was administered once daily at 300 or 500 mg in Phase 1b (‘3 + 3’ design), and at the recommended Phase 2 dose (RP2D) in Phase 2. Primary endpoints were dose-liming toxicities (DLTs; Phase 1b) and 12-week investigator-assessed progression-free survival (PFS; Phase 2).Results In Phase 1b (n = 17), no DLTs occurred and the RP2D was confirmed as 500 mg. In Phase 2 (n = 49), the primary endpoint was met: 12-week PFS was 63.3% (90% CI: 50.5–74.7), which was significantly greater than the predefined null hypothesis of ≤15% (one-sided binomial exact test: P < 0.0001). Median time to progression was 4 months. In Phase 2, 28.6% of patients had treatment-related Grade ≥3 adverse events, including peripheral oedema and lipase increase (both 6.1%).Conclusions Tepotinib was generally well tolerated and the RP2D (500 mg) showed promising efficacy and, therefore, a positive benefit–risk balance in sorafenib pretreated aHCC with MET overexpression.Trial Registration ClinicalTrials.gov: {"type":"clinical-trial","attrs":{"text":"NCT02115373","term_id":"NCT02115373"}}NCT02115373.Subject terms: Hepatocellular carcinoma, Molecularly targeted therapy     

Safety and impact of dose reductions on efficacy in the randomised MONALEESA-2, -3 and -7 trials in hormone receptor-positive,HER2-negative advanced breast cancer

Background This pooled analysis of MONALEESA trials evaluated the safety of ribociclib plus endocrine therapy (RIB + ET) with a focus on dose reductions in first-line patients.Methods In the dose reduction analysis, data were pooled from MONALEESA-2 (all patients), MONALEESA-3 (patients receiving treatment as first-line ET) and MONALEESA-7 (patients receiving combination therapy with an NSAI as initial ET). Efficacy was analysed by ribociclib relative dose intensity (DI). Safety was analysed in all patients in the trials (except those receiving tamoxifen in MONALEESA-7) and those with/without ≥1 ribociclib dose reduction.Results Of 818 women who received first-line RIB + ET, 41.8% required ≥1 dose reduction due to AEs (most commonly, neutropenia). Median RIB relative DI in patients without and with dose reductions was 99.3% and 65.6% in MONALEESA-2, 98.4% and 67.8% in MONALEESA-3 and 98·0% and 66·3% in MONALEESA-7. Median PFS was 24.8, 24.9 and 29.6 months for patients who received ≤71% (30th percentile), 72–96% (60th percentile) and 97–100% (90th percentile) RIB relative DI, respectively. No new safety signals emerged in the pooled safety analysis.Conclusions This analysis provides reassuring data showing that the clinical benefit of RIB is preserved when dose modifications are undertaken to manage AEs.Trial registration MONALEESA-2 ({"type":"clinical-trial","attrs":{"text":"NCT01958021","term_id":"NCT01958021"}}NCT01958021) first posted October 8, 2013; MONALEESA-3 ({"type":"clinical-trial","attrs":{"text":"NCT02422615","term_id":"NCT02422615"}}NCT02422615) first posted April 21, 2015; MONALEESA-7 ({"type":"clinical-trial","attrs":{"text":"NCT02278120","term_id":"NCT02278120"}}NCT02278120) first posted October 29, 2014.Subject terms: Breast cancer, Cancer     

Efficacy and safety of cabozantinib for patients with advanced hepatocellular carcinoma based on albumin-bilirubin grade

Background Albumin-bilirubin (ALBI) grade is an objective measure of liver function for patients with hepatocellular carcinoma (HCC). The tyrosine kinase inhibitor cabozantinib is approved for patients with advanced HCC who have received prior sorafenib based on the phase 3 CELESTIAL trial ({"type":"clinical-trial","attrs":{"text":"NCT01908426","term_id":"NCT01908426"}}NCT01908426). Cabozantinib improved overall survival (OS) and progression-free survival (PFS) versus placebo in patients with previously treated HCC.Methods Patients were randomised 2:1 to receive cabozantinib 60 mg or placebo orally every day. Clinical outcomes in patients with ALBI grade 1 or 2 at baseline were evaluated in CELESTIAL. ALBI scores were retrospectively calculated based on baseline serum albumin and total bilirubin, with an ALBI grade of 1 defined as  ≤ −2.60 score and a grade of 2 as a score of > −2.60 to  ≤ −1.39.Results Cabozantinib improved OS and PFS versus placebo in both ALBI grade 1 (hazard ratio [HR] [95% CI]: 0.63 [0.46–0.86] and 0.42 [0.32–0.56]) and ALBI grade 2 (HR [95% CI]: 0.84 [0.66–1.06] and 0.46 [0.37–0.58]) subgroups. Adverse events were consistent with those in the overall population. Rates of grade 3/4 adverse events associated with hepatic decompensation were generally low and were more common among patients in the ALBI grade 2 subgroup.Discussion These results provide initial support of cabozantinib in patients with advanced HCC irrespective of ALBI grade 1 or 2.Trial registration number ClinicalTrials.gov number, {"type":"clinical-trial","attrs":{"text":"NCT01908426","term_id":"NCT01908426"}}NCT01908426.Subject terms: Drug development, Hepatocellular carcinoma     

Anlotinib vs placebo as third- or further-line treatment for patients with small cell lung cancer: a randomised,double-blind,placebo-controlled Phase 2 study

Background This study aimed to evaluate the efficacy and safety of anlotinib as a third-line and subsequent treatment for patients with small cell lung cancer (SCLC).Methods We conducted this Phase 2 trial at 11 institutions in China. Patients with pathologically confirmed SCLC who failed at least two lines of chemotherapy were enrolled. Subjects were randomly assigned in a 2:1 ratio to receive either anlotinib 12 mg orally once daily for 14 days every 3 weeks or placebo. The primary endpoint was progression-free survival (PFS).Results Between March 30, 2017 and June 8, 2018, a total of 82 and 38 patients were randomly assigned to receive anlotinib and placebo. The median PFS was significantly longer in the anlotinib group compared with the placebo group (4.1 months [95% confidence interval (CI), 2.8–4.2] vs 0.7 months [95% CI, 0.7–0.8]; hazard ratio (HR) 0.19 [95% CI, 0.12–0.32], p < 0.0001). Overall survival (OS) was significantly longer with anlotinib than placebo (7.3 months [95% CI, 6.1–10.3] vs 4.9 months [95% CI, 2.7–6.0]; HR 0.53 [95% CI, 0.34–0.81], p = 0.0029).Conclusions Anlotinib as a third-line or subsequent treatment for Chinese patients with SCLC showed improved PFS and OS than placebo with favourable safety profile.Clinical Trial Registration ClinicalTrials.gov, number {"type":"clinical-trial","attrs":{"text":"NCT03059797","term_id":"NCT03059797"}}NCT03059797.Subject terms: Tumour angiogenesis, Small-cell lung cancer     

Phase II trial of 7 days on/7 days off temozolmide for recurrent high-grade glioma

Background

A phase II trial was performed to evaluate the efficacy of a dose-dense, 7 days on/7 days off schedule of temozolomide for patients with recurrent high-grade gliomas (HGG).

Methods

Sixty patients with recurrent HGG received temozolomide at 150 mg/m²/day on days 1–7 and days 15–21 during each 4-week cycle. The primary endpoint was 6-month progression-free survival (PFS-6), with a secondary endpoint of overall survival (OS). A further exploratory objective included the investigation of whether methylation status of the O(6)-methylguanine-DNA methyltransferase (MGMT) promoter within tumor tissue predicted outcomes.

Results

Among patients with glioblastoma (n = 40), PFS-6 was 10% (95% CI, 3%–24%) with median OS of 21.6 weeks (95% CI, 16.9–30.6 weeks). PFS-6 for grade III glioma patients (n = 20) was 50% (95% CI, 27%–73%), and median OS was 100.6 weeks (95% CI, 67 weeks to not reached). There were trends towards longer PFS and OS with MGMT promoter methylation (log-rank test; P = .06 for PFS; P = .07 for OS). Additionally, bevacizumab-naïve glioblastoma patients had significantly longer PFS and OS (median PFS was 8.07 weeks [95% CI, 8 weeks to not reached] vs 7.57 weeks [95% CI, 7.29–8.29 weeks], log-rank test, P < .001; median OS was 62 weeks [26.1 weeks to not reached] vs 18.2 weeks [13.9–27.3 weeks], log-rank test, P < .001).

Conclusions

The dose-dense temozolomide regimen was well tolerated, although it has no significant activity in this population. Clinical trials.gov identified. {"type":"clinical-trial","attrs":{"text":"NCT00619112","term_id":"NCT00619112"}}NCT00619112 (available at http://clinicaltrials.gov/ct2/show/{"type":"clinical-trial","attrs":{"text":"NCT00619112","term_id":"NCT00619112"}}NCT00619112).     

First-line trifluridine/tipiracil + bevacizumab in patients with unresectable metastatic colorectal cancer: final survival analysis in the TASCO1 study

Background Therapeutic options are limited in patients with unresectable metastatic colorectal cancer (mCRC) ineligible for intensive chemotherapy. The use of trifluridine/tipiracil plus bevacizumab (TT-B) in this setting was evaluated in the TASCO1 trial; here, we present the final overall survival (OS) results.Methods TASCO1 was an open-label, non-comparative phase II trial. Patients (n = 153) were randomised 1:1 to TT-B (trifluridine/tipiracil 35 mg/m² orally twice daily on days 1–5 and 8–12, and bevacizumab intravenously 5 mg/kg on days 1 and 15 of each 28-day cycle) or capecitabine plus bevacizumab (C-B; capecitabine, 1250 mg/m² orally twice daily on days 1–14 and bevacizumab 7.5 mg/kg intravenously on day 1 of each 21-day cycle). Final OS was analysed when all patients had either died or withdrawn from the study. Adjusted multivariate regression was used to investigate the effects of pre-specified variables on OS.Results At 1 September 2020, median OS was 22.3 months (95% CI: 18.0–23.7) with TT-B and 17.7 months (95% CI: 12.6–19.8) with C-B (adjusted HR 0.78; 95% CI: 0.55–1.10). No variables negatively affected OS with TT-B. Safety results were consistent with prior findings.Conclusions TT-B is a promising therapeutic regimen in mCRC patients ineligible for intensive chemotherapy.Clinical trial information {"type":"clinical-trial","attrs":{"text":"NCT02743221","term_id":"NCT02743221"}}NCT02743221 (clinicaltrials.gov)Subject terms: Colorectal cancer, Colorectal cancer     

Selecting first-line bevacizumab-containing therapy for advanced breast cancer: TURANDOT risk factor analyses

Background:

The randomised phase III TURANDOT trial compared first-line bevacizumab–paclitaxel (BEV–PAC) vs bevacizumab–capecitabine (BEV–CAP) in HER2-negative locally recurrent/metastatic breast cancer (LR/mBC). The interim analysis revealed no difference in overall survival (OS; primary end point) between treatment arms; however, progression-free survival (PFS) and objective response rate were significantly superior with BEV–PAC. We sought to identify patient populations that may be most appropriately treated with one or other regimen.

Methods:

Patients with HER2-negative LR/mBC who had received no prior chemotherapy for advanced disease were randomised to either BEV–PAC (bevacizumab 10 mg kg⁻¹ days 1 and 15 plus paclitaxel 90 mg m⁻² days 1, 8 and 15 q4w) or BEV–CAP (bevacizumab 15 mg kg⁻¹ day 1 plus capecitabine 1000 mg m⁻² bid days 1–14 q3w). The study population was categorised into three cohorts: triple-negative breast cancer (TNBC), high-risk hormone receptor-positive (HR+) and low-risk HR+. High- and low-risk HR+ were defined, respectively, as having ⩾2 vs ⩽1 of the following four risk factors: disease-free interval ⩽24 months; visceral metastases; prior (neo)adjuvant anthracycline and/or taxane; and metastases in ⩾3 organs.

Results:

The treatment effect on OS differed between cohorts. Non-significant OS trends favoured BEV–PAC in the TNBC cohort and BEV–CAP in the low-risk HR+ cohort. In all three cohorts, there was a non-significant PFS trend favouring BEV–PAC. Grade ⩾3 adverse events were consistently less common with BEV–CAP.

Conclusions:

A simple risk factor index may help in selecting bevacizumab-containing regimens, balancing outcome, safety profile and patient preference. Final OS results are expected in 2015 (ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT00600340","term_id":"NCT00600340"}}NCT00600340).     

Clinical utility of circulating tumour cell-based monitoring of late-line chemotherapy for metastatic breast cancer: the randomised CirCe01 trial

Background CirCe01 trial aimed to assess the clinical utility of circulating tumour cell (CTC)-based monitoring in metastatic breast cancer (MBC) patients beyond the third line of chemotherapy (LC).Methods CirCe01 was a prospective, multicentre, randomised trial ({"type":"clinical-trial","attrs":{"text":"NCT01349842","term_id":"NCT01349842"}}NCT01349842) that included patients with MBC after two systemic LC. Patients with ≥5 CTC/7.5 mL (CellSearch®) were randomised between the CTC-driven and the standard arm. In the CTC arm, changes in CTC count were assessed at the first cycle of each LC; patients in whom CTC levels predicted early tumour progression had to switch to a subsequent LC.Results Greater than or equal to 5 CTC/7.5 mL were observed in N = 101/204 patients. In the CTC arm (N = 51), 43 (83%) and 18 (44%) patients completed CTC monitoring in the third and fourth lines, respectively, and 18 (42%) and 11 (61%) of these patients, respectively, had no CTC response. Thirteen (72%) and 5 (46%) of these patients underwent early switch to the next LC. Overall survival was not different between the two arms (hazard ratio = 0.95, 95% confidence interval = [0.6;1.4], p = 0.8). In subgroup analyses, patients with no CTC response who switched chemotherapy experienced longer survival than patients who did not.Conclusions Due to the limited accrual and compliance, this trial failed to demonstrate the clinical utility of CTC monitoring.Clinical Trial Registration NCT, {"type":"clinical-trial","attrs":{"text":"NCT01349842","term_id":"NCT01349842"}}NCT01349842, https://clinicaltrials.gov/ct2/show/{"type":"clinical-trial","attrs":{"text":"NCT01349842","term_id":"NCT01349842"}}NCT01349842, registered 9 May 2011.Subject terms: Breast cancer, Prognostic markers     

KarMMa-RW: comparison of idecabtagene vicleucel with real-world outcomes in relapsed and refractory multiple myeloma

Patients with relapsed and refractory multiple myeloma (RRMM) who are triple-class exposed (to an immunomodulatory agent, proteasome inhibitor, and anti-CD38 antibody) have limited treatment options and there is no standard of care. Idecabtagene vicleucel (ide-cel, bb2121), a BCMA-directed CAR T-cell therapy, demonstrated efficacy in triple-class exposed RRMM patients in the KarMMa trial ({"type":"clinical-trial","attrs":{"text":"NCT03361748","term_id":"NCT03361748"}}NCT03361748). In this retrospective study (KarMMa-RW), patient-level data from triple-class exposed RRMM patients were merged into a single data model and compared with KarMMa using trimmed stabilized inverse probability of treatment weighting. Endpoints included overall response rate (ORR; primary), rate of very good partial response or better (≥VGPR), progression-free survival (PFS), and overall survival (OS). Of 1949 real-world triple-class exposed RRMM patients, 190 received subsequent (index) line of therapy and met KarMMa eligibility criteria (Eligible RRMM cohort). With a median follow-up of 13.3 months in KarMMa and 10.2 months in Eligible RRMM, ORR, and ≥VGPR were significantly improved in KarMMa versus Eligible RRMM (ORR, 76.4% vs 32.2%; ≥VGPR, 57.9% vs 13.7%; both P < 0.0001) as were PFS (11.6 vs 3.5 months; P = 0.0004) and OS (20.2 vs 14.7 months; P = 0.0006). This study demonstrated that ide-cel significantly improved responses and survival compared with currently available therapies in triple-class exposed RRMM.Subject terms: Cancer, Medical research     

Preventive effect of sensorimotor exercise and resistance training on chemotherapy-induced peripheral neuropathy: a randomised-controlled trial

Background Chemotherapy-induced peripheral neuropathy (CIPN) is a common, unpleasant and usually long-lasting side effect of neurotoxic chemotherapeutic agents. This study aimed to investigate the preventive potential of sensorimotor- (SMT) and resistance training (RT) on CIPN.Methods Patients (N = 170) were randomised to SMT, RT or usual care (UC). Both exercise groups trained 3×/week for a total of 105 min/week during neurotoxic chemotherapy (mean length: 20 weeks). Before and 3 weeks after neurotoxic chemotherapy, CIPN signs/symptoms were assessed via Total Neuropathy Score (TNSr; primary endpoint) and EORTC QLQ-CIPN15 questionnaire. In addition, balance (centre of pressure), muscle strength (isokinetic), quality of life (QoL, EORTC QLQ-C30) and relative chemotherapy dose intensity (RDI) were investigated. The follow-up period covered 6 months after the end of chemotherapy.Results Intention-to-treat analyses (N = 159) revealed no differences regarding CIPN signs/symptoms. Exploratory per-protocol analyses (minimum training attendance rate 67%; N = 89) indicated that subjectively perceived sensory symptoms in the feet increased less during chemotherapy in the adherent exercisers (pooled group: SMT+RT) than in the UC group (−8.3 points (−16.1 to −0.4); P = 0.039, ES = 1.27). Furthermore, adherent exercisers received a higher RDI (96.6 ± 4.8 vs. 92.2 ± 9.4; P = 0.045), showed a better course of muscular strength (+20.8 Nm (11.2–30.4); P < 0.001, ES = 0.57) and QoL (+12.9 points (3.9–21.8); P = 0.005, ES = 0.64). During follow-up, CIPN signs/symptoms persisted in all groups.Conclusions This study demonstrates that SMT and/or RT alleviate subjectively perceived sensory CIPN symptoms in the feet and other clinically relevant cancer therapy-related outcomes, if an appropriate training stimulus is achieved.Clinical trial registration {"type":"clinical-trial","attrs":{"text":"NCT02871284","term_id":"NCT02871284"}}NCT02871284.Subject terms: Neurological manifestations, Breast cancer, Randomized controlled trials, Quality of life, Lifestyle modification