FOLFIRI plus cetuximab or bevacizumab for advanced colorectal cancer: final survival and per-protocol analysis of FIRE-3, a randomised clinical trial

Background Cetuximab plus FOLFIRI improved overall survival compared with bevacizumab plus FOLFIRI in KRAS wild-type metastatic colorectal cancer (mCRC) in FIRE-3, but no corresponding benefit was found for progression-free survival. This analysis aimed to determine whether cetuximab improves response and survival versus bevacizumab among response-evaluable patients receiving first-line FOLFIRI for RAS wild-type mCRC and the effect of primary tumour side on outcomes.Methods The intent-to-treat population included 593 patients with KRAS exon 2 wild-type mCRC. Further testing identified 400 patients with extended RAS wild-type disease; of these, 352 (88%) who received ≥3 cycles of therapy and had ≥1 post-baseline scan were evaluable for response and constituted the per-protocol population (169 cetuximab and 183 bevacizumab). Patients received 5-fluorouracil, folinic acid and irinotecan (FOLFIRI) with either weekly cetuximab or biweekly bevacizumab given on day 1 of each 14-day cycle until response, progression or toxicity occurred. The primary endpoint was the objective response rate (ORR) in the per-protocol population. Secondary endpoints included overall survival (OS) and progression-free survival (PFS). The effect of primary tumour location was evaluated.Results Median OS in the RAS wild-type population was 31 vs 26 months in the cetuximab and bevacizumab groups, respectively (HR 0.76, P = 0.012). In the per-protocol population, outcomes favoured cetuximab for ORR (77% vs 65%, P = 0.014) and median OS (33 vs 26 months, HR 0.75, P = 0.011), while PFS was comparable between groups. The advantage of cetuximab over bevacizumab occurred only in patients with left-sided primary tumours.Conclusions FOLFIRI plus cetuximab resulted in a significantly higher ORR and longer OS compared to FOLFIRI plus bevacizumab among patients with left-sided tumours. The superior response associated with cetuximab may particularly benefit patients with symptomatic tumours or borderline-resectable metastases.ClinicalTrials.gov identifier {"type":"clinical-trial","attrs":{"text":"NCT00433927","term_id":"NCT00433927"}}NCT00433927.Subject terms: Oncology, Biomarkers     

Serum alpha-fetoprotein and clinical outcomes in patients with advanced hepatocellular carcinoma treated with ramucirumab

Background Post hoc analyses assessed the prognostic and predictive value of baseline alpha-fetoprotein (AFP), as well as clinical outcomes by AFP response or progression, during treatment in two placebo-controlled trials (REACH, REACH-2).Methods Serum AFP was measured at baseline and every three cycles. The prognostic and predictive value of baseline AFP was assessed by Cox regression models and Subpopulation Treatment Effect Pattern Plot method. Associations between AFP (≥ 20% increase) and radiographic progression and efficacy were assessed.Results Baseline AFP was confirmed as a continuous (REACH, REACH-2; p < 0.0001) and dichotomous (≥400 vs. <400 ng/ml; REACH, p < 0.01) prognostic factor, and was predictive for ramucirumab survival benefit in REACH (p = 0.0042 continuous; p < 0.0001 dichotomous). Time to AFP (hazard ratio [HR] 0.513; p < 0.0001) and radiographic (HR 0.549; p < 0.0001) progression favoured ramucirumab. Association between AFP and radiographic progression was shown for up to 6 (odds ratio [OR] 5.1; p < 0.0001) and 6–12 weeks (OR 1.8; p = 0.0065). AFP response was higher with ramucirumab vs. placebo (p < 0.0001). Survival was longer in patients with an AFP response than patients without (13.6 vs. 5.6 months, HR 0.451; 95% confidence interval, 0.354–0.574; p < 0.0001).Conclusions AFP is an important prognostic factor and a predictive biomarker for ramucirumab survival benefit. AFP ≥ 400 ng/ml is an appropriate selection criterion for ramucirumab.Clinical Trial Registration ClinicalTrials.gov, REACH ({"type":"clinical-trial","attrs":{"text":"NCT01140347","term_id":"NCT01140347"}}NCT01140347) and REACH-2 ({"type":"clinical-trial","attrs":{"text":"NCT02435433","term_id":"NCT02435433"}}NCT02435433).Subject terms: Oncology, Biomarkers     

6-month follow-up of VIALE-C demonstrates improved and durable efficacy in patients with untreated AML ineligible for intensive chemotherapy

VIALE-C compared the safety and efficacy of venetoclax or placebo plus low-dose cytarabine (+LDAC) in patients with untreated AML ineligible for intensive chemotherapy. Overall, 211 patients were enrolled (n = 143, venetoclax; n = 68, placebo). At the primary analysis, the study did not meet its primary endpoint of a statistically significant improvement in overall survival (OS), however, ~60% of patients had been on study for ≤6-months. Here, we present an additional 6-months of follow-up of VIALE-C (median follow-up 17.5 months; range 0.1–23.5). Median OS was (venetoclax +LDAC vs. placebo +LDAC) 8.4 vs. 4.1 months (HR = 0.70, 95% CI 0.50,0.99; P = 0.040); a 30% reduction in the risk of death with venetoclax. Complete response (CR)/CR with incomplete hematologic recovery (CRi) rates were 48.3% vs. 13.2%. Transfusion independence rates (RBC) were 43% vs.19% and median event-free survival was 4.9 vs. 2.1 months (HR = 0.61; 95% CI 0.44,0.84; P = 0.002). These results represent improved efficacy over the primary analysis. Incidence of grade ≥3 adverse events were similar between study arms and overall safety profiles were comparable to the primary analysis. These data support venetoclax +LDAC as a frontline treatment option for patients with AML ineligible for intensive chemotherapy.This trial was registered at www.clinicaltrials.gov as #{"type":"clinical-trial","attrs":{"text":"NCT03069352","term_id":"NCT03069352"}}NCT03069352.Subject terms: Targeted therapies, Acute myeloid leukaemia     

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     

A multicentre,randomised, open-label,parallel-group Phase 2b study of belotecan versus topotecan for recurrent ovarian cancer

Background This Phase 2b study compared the efficacy and toxicity of belotecan and topotecan in recurrent ovarian cancer.Methods Patients with platinum-sensitive recurrent or platinum-resistant recurrent ovarian cancer (PRROC) were randomised 1:1 to receive belotecan 0.5 mg/m² or topotecan 1.5 mg/m² for five consecutive days every 3 weeks. The primary endpoint was overall response rate (ORR); secondary endpoints were progression-free survival (PFS), overall survival (OS), and toxicity.Results A total of 140 (belotecan, n = 71; topotecan, n = 69) and 130 patients (belotecan, n = 66; topotecan, n = 64) were included in the intention-to-treat (ITT) and per-protocol (PP) populations. ORR did not differ significantly between the belotecan and topotecan groups (ITT, 29.6% versus 26.1%; PP, 30.3% versus 25%). Although PFS did not differ between the groups, belotecan was associated with improved OS compared with topotecan in the PP population (39.7 versus 26.6 months; P = 0.034). In particular, belotecan showed longer OS in PRROC and non-high-grade serous carcinoma (non-HGSC; PP, adjusted hazard ratios, 0.499 and 0.187; 95% confidence intervals 0.255–0.977 and 0.039–0.895). Furthermore, there were no differences in toxicities between the two groups.Conclusions Belotecan was not inferior to topotecan in terms of overall response for recurrent ovarian cancer.Clinical trial registration {"type":"clinical-trial","attrs":{"text":"NCT01630018","term_id":"NCT01630018"}}NCT01630018.Subject terms: Ovarian cancer, Chemotherapy     

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     

Adding cetuximab to paclitaxel and carboplatin for first-line treatment of carcinoma of unknown primary (CUP): results of the Phase 2 AIO trial PACET-CUP

Background Patients with carcinoma of unknown primary (CUP) have a dismal prognosis, even when treated with multi-agent chemotherapy. We hypothesised that adding the epidermal growth-factor receptor (EGFR) inhibitor cetuximab to standard first-line chemotherapy with paclitaxel and carboplatin would improve PFS and RR in unfavourable CUP.Methods This open-labelled, multicentre Phase 2 study included patients with unfavourable, untreated adeno- or undifferentiated CUP. Patients were randomised to receive either paclitaxel/carboplatin (group A) or paclitaxel/carboplatin plus cetuximab (group B) every 3 weeks for a maximum of 6 cycles followed by cetuximab maintenance in group B. The primary endpoint was PFS in the two groups. Secondary endpoints were RR, toxicity and overall survival (OS).Results One-hundred-and-fifty patients were randomised (group A = 72, group B = 78). The median PFS and OS for all patients were 3.8 and 8.1 months (95% confidence interval (CI): 2.9–4.8 and 6.8–9.5). There was no significant difference in PFS (3.7 vs 4.6 months, HR 0.98) or OS (8.1 vs 7.4, HR 1.1) between the two treatment groups. Response rate tended to be better for chemotherapy plus cetuximab compared to chemotherapy alone (22% vs 15%). Adverse events grade ≥3 were comparable between the two groups, except for significantly increased skin toxicity in the cetuximab arm.Conclusions Cetuximab plus paclitaxel/carboplatin did not improve PFS, OS and RR in metastatic CUP compared to paclitaxel/carboplatin alone. Addition of cetuximab resulted in additional skin toxicity.Clinical trial registration The study was registered at clinicaltrials.gov as {"type":"clinical-trial","attrs":{"text":"NCT00894569","term_id":"NCT00894569"}}NCT00894569.Subject terms: Cancer therapy, Cancer     

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     

The effect of geriatric intervention in frail older patients receiving chemotherapy for colorectal cancer: a randomised trial (GERICO)

Background Older patients with colorectal cancer (CRC) experience chemotherapy dose reductions or discontinuation. Comprehensive geriatric assessment (CGA) predicts survival and chemotherapy completion in patients with cancer, but the benefit of geriatric interventions remains unexplored.Methods The GERICO study is a randomised Phase 3 trial including patients ≥70 years receiving adjuvant or first-line palliative chemotherapy for CRC. Vulnerable patients (G8 questionnaire ≤14 points) were randomised 1:1 to CGA-based interventions or standard care, along with guideline-based chemotherapy. The primary outcome was chemotherapy completion without dose reductions or delays. Secondary outcomes were toxicity, survival and quality of life (QoL).Results Of 142 patients, 58% received adjuvant and 42% received first-line palliative chemotherapy. Interventions included medication changes (62%), nutritional therapy (51%) and physiotherapy (39%). More interventional patients completed scheduled chemotherapy compared with controls (45% vs. 28%, P = 0.0366). Severe toxicity occurred in 39% of controls and 28% of interventional patients (P = 0.156). QoL improved in interventional patients compared with controls with the decreased burden of illness (P = 0.048) and improved mobility (P = 0.008).Conclusion Geriatric interventions compared with standard care increased the number of older, vulnerable patients with CRC completing adjuvant chemotherapy, and may improve the burden of illness and mobility.Trial registration ClinicalTrials.gov ID: {"type":"clinical-trial","attrs":{"text":"NCT 02748811","term_id":"NCT02748811"}}NCT 02748811.Subject terms: Geriatrics, Colorectal cancer     

A first-in-human phase 1 and pharmacological study of TAS-119, a novel selective Aurora A kinase inhibitor in patients with advanced solid tumours

Background This is a first-in-human study with TAS-119, an Aurora A kinase (AurA) inhibitor.Methods Patients with advanced, refractory, solid tumours were enrolled into 5 dose escalation cohorts (70–300 mg BID, 4 days on/3 days off, 3 out of 4 weeks or 4 out of 4 weeks). The expansion part consisted of patients with small-cell lung cancer, HER2-negative breast cancer, MYC-amplified/β-catenin-mutated (MT) tumours or other (basket cohort).Results In the escalation part (n = 34 patients), dose-limiting toxicities were one grade 3 nausea, two grade 2 and one grade 3 ocular toxicity and a combination of fatigue, ocular toxicity and nausea in one patient (all grade 2) at dose levels of 150, 200, 250 and 300 mg, respectively. Most frequent treatment-related adverse events were fatigue (32%), diarrhoea (24%) and ocular toxicity (24%). Toxicity grade ≥3 in ≥10% of patients were diarrhoea (15%) and increased lipase (12%). The maximum tolerated dose was 250 mg BID. Due to one additional grade 1 ocular toxicity, the RP2D was set at 200 mg BID (4 days on/3 days off, 3 out of 4 weeks), which was further explored in the expansion part (n = 40 patients). Target inhibition in paired skin biopsies was shown.Conclusions TAS-119 has a favourable and remarkably distinct safety profile from other AurA inhibitors.Clinical trial registration {"type":"clinical-trial","attrs":{"text":"NCT02448589","term_id":"NCT02448589"}}NCT02448589.Subject terms: Drug development, Drug safety     

A Phase 1 study of gefitinib combined with durvalumab in EGFR TKI-naive patients with EGFR mutation-positive locally advanced/metastatic non-small-cell lung cancer

Background EGFR tyrosine kinase inhibitors (TKIs) induce cytolysis and release of tumour proteins, which can stimulate antigen-specific T cells. The safety and efficacy of durvalumab and gefitinib in combination for TKI-naive patients with advanced EGFRm NSCLC was evaluated.Methods This Phase 1 open-label, multicentre trial ({"type":"clinical-trial","attrs":{"text":"NCT02088112","term_id":"NCT02088112"}}NCT02088112) was conducted in 56 patients with NSCLC. Dose expansion permitted TKI-naive patients, primarily with activating L858R or Ex19del EGFRm. Arms 1 + 1a received concurrent therapy; Arm 2 received 4 weeks of gefitinib induction followed by concurrent therapy.Results From dose escalation, the recommended dose of durvalumab was 10 mg/kg Q2W with 250 mg QD gefitinib. Pharmacokinetics were as expected, consistent with inhibition of soluble PD-L1 and no treatment-emergent immunogenicity. In dose expansion, 35% of patients had elevated liver enzymes leading to drug discontinuation. In Arms 1 + 1a, objective response rate was 63.3% (95% CI: 43.9–80.1), median progression-free survival (PFS) was 10.1 months (95% CI: 5.5–15.2) and median response duration was 9.2 months (95% CI: 3.7–14.0).Conclusions Durvalumab and gefitinib in combination had higher toxicity than either agent alone. No significant increase in PFS was detected compared with historical controls. Therefore, concurrent PD-L1 inhibitors with gefitinib should be generally avoided in TKI-naive patients with EGFRm NSCLC.Subject terms: Tumour biomarkers, Cancer immunotherapy, Non-small-cell lung cancer, Targeted therapies     

Human papilloma virus (HPV) integration signature in Cervical Cancer: identification of MACROD2 gene as HPV hot spot integration site

Background Cervical cancer (CC) remains a leading cause of gynaecological cancer-related mortality with infection by human papilloma virus (HPV) being the most important risk factor. We analysed the association between different viral integration signatures, clinical parameters and outcome in pre-treated CCs.Methods Different integration signatures were identified using HPV double capture followed by next-generation sequencing (NGS) in 272 CC patients from the BioRAIDs study [{"type":"clinical-trial","attrs":{"text":"NCT02428842","term_id":"NCT02428842"}}NCT02428842]. Correlations between HPV integration signatures and clinical, biological and molecular features were assessed.Results Episomal HPV was much less frequent in CC as compared to anal carcinoma (p < 0.0001). We identified >300 different HPV-chromosomal junctions (inter- or intra-genic). The most frequent integration site in CC was in MACROD2 gene followed by MIPOL1/TTC6 and TP63. HPV integration signatures were not associated with histological subtype, FIGO staging, treatment or PFS. HPVs were more frequently episomal in PIK3CA mutated tumours (p = 0.023). Viral integration type was dependent on HPV genotype (p < 0.0001); HPV18 and HPV45 being always integrated. High HPV copy number was associated with longer PFS (p = 0.011).Conclusions This is to our knowledge the first study assessing the prognostic value of HPV integration in a prospectively annotated CC cohort, which detects a hotspot of HPV integration at MACROD2; involved in impaired PARP1 activity and chromosome instability.Subject terms: Oncology, Molecular medicine, Biomarkers, Molecular biology     

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     

Comparative Efficacy of Teclistamab Versus Physician's Choice of Therapy in the Long-term Follow-up of APOLLO,POLLUX, CASTOR,and EQUULEUS Clinical Trials in Patients With Triple-class Exposed Relapsed or Refractory Multiple Myeloma

BackgroundThe efficacy and safety of teclistamab in patients with RRMM who received ≥3 prior lines of therapy and were triple-class exposed (TCE) are being evaluated in the single-arm, multicohort, phase I/II MajesTEC-1 trial (NCT04557098). We evaluated the comparative effectiveness of teclistamab versus physician's choice (PC) of therapy in TCE RRMM patients.MethodsIndividual patient-level data from MajesTEC-1 patients who received teclistamab (1.5 mg/kg weekly; clinical cutoff March 16, 2022) were included. An external control arm was created from patients in long-term follow-up of 4 clinical trials of daratumumab who were treated with PC therapy after discontinuation of trial treatments. In the primary analysis, inverse probability of treatment weighting was used to adjust for imbalances in 9 baseline covariates. A fully adjusted model included 5 additional prognostic factors. Outcomes included overall response rate (ORR), very good partial response or better (≥VGPR) rate, overall survival (OS), progression-free survival (PFS), and time to next treatment (TTNT).ResultsAfter adjustment, baseline characteristics were balanced between cohorts. In the primary analysis, outcomes were significantly improved with teclistamab versus PC: ORR (OR [95% CI] 4.81 [3.04-7.72]; P < .0001); ≥VGPR rate (OR, 12.07 [6.91-22.11]; P < .0001); OS (HR, 0.54 [0.40-0.73]; P < .0001); PFS (HR, 0.59 [0.46-0.78]; P = .0001); and TTNT (HR, 0.32 [0.24-0.42]; P < .0001). Results of the fully adjusted model were consistent with the primary analysis.ConclusionTeclistamab showed significantly improved effectiveness versus PC on all outcomes, highlighting its clinical benefit in patients with TCE RRMM and limited treatment options.     

Phase I study of olaparib in combination with liposomal doxorubicin in patients with advanced solid tumours

Background:

Olaparib, an oral PARP inhibitor, has shown antitumour activity as monotherapy in patients with germline BRCA1/2 (gBRCA)-mutated breast and ovarian cancer. This study evaluated olaparib capsules in combination with liposomal doxorubicin (PLD) in patients with advanced solid tumours ({"type":"clinical-trial","attrs":{"text":"NCT00819221","term_id":"NCT00819221"}}NCT00819221).

Methods:

Patients received 28-day cycles of olaparib, continuously (days 1–28) or intermittently (days 1–7), plus PLD (40 mg m⁻², day 1); seven olaparib dose cohorts (50–400 mg bid) were explored to determine the recommended dose. Assessments included safety, pharmacokinetics, pharmacodynamics and preliminary efficacy (objective response rate (ORR)).

Results:

Of 44 patients treated (ovarian, n=28; breast, n=13; other/unknown, n=3), two experienced dose-limiting toxicities (grade 3 stomatitis and fatal pneumonia/pneumonitis (200 mg per 28-day cycle); grade 4 thrombocytopenia (400 mg per 7-day cycle)). The maximum tolerated dose was not reached using continuous olaparib 400 mg bid plus PLD. Grade ⩾3 and serious AEs were reported for 27 (61%) and 12 (27%) patients, respectively. No major pharmacokinetic interference was observed between olaparib and PLD. The ORR was 33% (n=14 out of 42; complete response, n=3). A total of 13 responders had ovarian cancer: 10 were platinum-sensitive, 11 had a gBRCA mutation.

Conclusions:

Continuous/intermittent olaparib (up to 400 mg bid) combined with PLD (40 mg m⁻²) was generally tolerated and showed evidence of antitumour activity in ovarian cancer.     

Impact of early response on outcomes in AL amyloidosis following treatment with frontline Bortezomib

The outcomes in systemic AL amyloidosis are dependent on the depth of haematologic response. However, there is limited data on the impact of the speed of response on outcomes. Here we report the impact of speed of response in a cohort of AL patients treated with upfront Bortezomib. Patients seen from February 2010 until August 2019 are included in the present analysis. 1194 & 1133 patients comprised the ITT and 1-month landmark cohorts. In the landmark cohort, 137 (11.5%), 270 (22.6%), 252 (21.1%) and 352 (31.1%) patients had a CR, VGPR, PR and NR at 1-month. Patients with ≥ VGPR at 1-month had significantly better survival (median not reached; at the end of 1, 2, 5,10 years, 87%/92%, 83%/87%, 68%/72% and 63%/58% of patients in CR/VGPR, respectively, were alive) compared to those with a PR (median OS 60 months) or NR (median OS 32 months) (p < 0.005). At 1-month, patients with CR and iFLC < 20 mg/l had a significantly better survival compared to CR and iFLC > 20 mg/l (p = 0.005). Reaching ≥ VGPR at 1-month significantly improved survival in all Mayo disease stages. In conclusion, patients achieving an early deep haematologic response have a significantly superior survival irrespective of cardiac involvement.Subject terms: Myeloma, Prognosis     

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     

Intermittent high dose proton pump inhibitor enhances the antitumor effects of chemotherapy in metastatic breast cancer

Background

Acidity is a hallmark of malignant tumor, representing a very efficient mechanism of chemoresistance. Proton pump inhibitors (PPI) at high dosage have been shown to sensitize chemoresistant human tumor cells and tumors to cytotoxic molecules. The aim of this pilot study was to investigate the efficacy of PPI in improving the clinical outcome of docetaxel + cisplatin regimen in patients with metastatic breast cancer (MBC).

Methods

Patients enrolled were randomly assigned to three arms: Arm A, docetaxel 75 mg/m² followed by cisplatin 75 mg/m² on d4, repeated every 21 days with a maximum of 6 cycles; Arm B, the same chemotherapy preceded by three days esomeprazole (ESOM) 80 mg p.o. bid, beginning on d1 repeated weekly. Weekly intermittent administration of ESOM (3 days on 4 days off) was maintained up to maximum 66 weeks; Arm C, the same as Arm B with the only difference being dose of ESOM at 100 mg p.o. bid. The primary endpoint was response rate.

Results

Ninety-four patients were randomly assigned and underwent at least one injection of chemotherapy. Response rates for arm A, B and C were 46.9, 71.0, and 64.5 %, respectively. Median TTP for arm A (n = 32), B (n = 31), C (n = 31) were 8.7, 9.4, and 9.7 months, respectively. A significant difference was observed between patients who had taken PPI and who not with ORR (46.9 % vs. 67.7 %, p = 0.049) and median TTP (9.7 months vs. 8.7 months, p = 0.045). Exploratory analysis showed that among 15 patients with triple negative breast cancer (TNBC), this difference was bigger with median TTP of 10.7 and 5.8 months, respectively (p = 0.011). PPI combination showed a marked effect on OS as well, while with a borderline significance (29.9 vs. 19.2 months, p = 0.090). No additional toxicity was observed with PPI.

Conclusions

The results of this pilot clinical trial showed that intermittent high dose PPI enhance the antitumor effects of chemotherapy in MBC patients without evidence of additional toxicity, which requires urgent validation in a multicenter, randomized, phase III trial.

Trial registration

Clinicaltrials.gov identifier: {"type":"clinical-trial","attrs":{"text":"NCT01069081","term_id":"NCT01069081"}}NCT01069081.

Electronic supplementary material

The online version of this article (doi:10.1186/s13046-015-0194-x) contains supplementary material, which is available to authorized users.     

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