Rituximab and trastuzumab were the first therapeutic monoclonal antibodies (mAbs) approved in oncology. Both antibodies are delivered by the intravenous (IV) route, but recently subcutaneous (SC) ...formulations have been developed. Subcutaneous administration of mAbs can offer substantial patient and resource benefits compared with IV, but SC administration of some mAbs can be limited by drug volume. Recombinant human hyaluronidase (rHuPH20) temporarily degrades hyaluronan, allowing SC delivery of drug volumes that might not otherwise be feasible.
Clinical trials assessing coformulation of rituximab or trastuzumab with rHuPH20 for SC administration were reviewed.
Phase I trials of rituximab SC maintenance therapy in patients with follicular lymphoma and trastuzumab SC in healthy volunteers and patients with early breast cancer have demonstrated substantially shorter administration times and comparable tolerability and pharmacokinetics compared with IV formulations. Rituximab SC 1400-mg and trastuzumab SC 600-mg doses were identified for further study. Phase III clinical data for rituximab SC 1400 mg have shown comparable efficacy to rituximab IV, and initial clinical data suggest comparable efficacy of trastuzumab SC 600 mg and the IV formulation.
Coformulation with rHuPH20 may enable effective, well-tolerated, cost-effective, and convenient SC administration of rituximab and trastuzumab. Additional studies are ongoing.
In the neoadjuvant GeparSixto study, adding carboplatin to taxane- and anthracycline-based chemotherapy improved pathological complete response (pCR) rates in patients with triple-negative breast ...cancer (TNBC). Here, we present survival data and the potential prognostic and predictive role of homologous recombination deficiency (HRD).
Patients were randomized to paclitaxel plus nonpegylated liposomal doxorubicin (Myocet®) (PM) or PM plus carboplatin (PMCb). The secondary study end points disease-free survival (DFS) and overall survival (OS) were analyzed. Median follow-up was 47.3 months. HRD was among the exploratory analyses in GeparSixto and was successfully measured in formalin-fixed, paraffin-embedded tumor samples of 193/315 (61.3%) participants with TNBC. Homologous recombination (HR) deficiency was defined as HRD score ≥42 and/or presence of tumor BRCA mutations (tmBRCA).
A significantly better DFS (hazard ratio 0.56, 95% CI 0.34–0.93; P = 0.022) was observed in patients with TNBC when treated with PMCb. The improvement of OS with PMCb was not statistically significant. Additional carboplatin did not improve DFS or OS in patients with HER2-positive tumors. HR deficiency was detected in 136 (70.5%) of 193 triple-negative tumors, of which 82 (60.3%) showed high HRD score without tmBRCA. HR deficiency independently predicted pCR (ypT0 ypN0) odds ratio (OR) 2.60, 95% CI 1.26–5.37, P = 0.008. Adding carboplatin to PM significantly increased the pCR rate from 33.9% to 63.5% in HR deficient tumors (P = 0.001), but only marginally in HR nondeficient tumors (from 20.0% to 29.6%, P = 0.540; test for interaction P = 0.327). pCR rates with carboplatin were also higher (63.2%) than without carboplatin (31.7%; OR 3.69, 1.46–9.37, P = 0.005) in patients with high HRD score but no tmBRCA. DFS rates were improved with addition of carboplatin, both in HR nondeficient (hazard ratio 0.44, 0.17–1.17, P = 0.086) and HR deficient tumors (hazard ratio 0.49, 0.23–1.04, P = 0.059).
The addition of carboplatin to neoadjuvant PM improved DFS significantly in TNBC. Long-term survival analyses support the neoadjuvant use of carboplatin in TNBC. HR deficiency in TNBC and HRD score in non-tmBRCA TNBC are predictors of response. HRD does not predict for carboplatin benefit.
Combining immune-checkpoint inhibitors with chemotherapy yielded an increased response rates in patients with metastatic triple-negative breast cancer (TNBC). Therefore, we evaluated the addition of ...durvalumab to standard neoadjuvant chemotherapy (NACT) in primary TNBC.
GeparNuevo is a randomised phase II double-blind placebo-controlled study randomising patients with TNBC to durvalumab or placebo given every 4weeks in addition to nab-paclitaxel followed by standard EC. In the window-phase durvalumab/placebo alone was given 2 weeks before start of nab-paclitaxel. Randomisation was stratified by stromal tumour-infiltrating lymphocyte (sTILs). Patients with primary cT1b-cT4a-d disease, centrally confirmed TNBC and sTILs were included. Primary objective was pathological complete response (pCR) (ypT0 ypN0).
A total of 174 patients were randomised, 117 participated in the window-phase. Median age was 49.5years (range 23–76); 47 patients (27%) were younger than 40years; 113 (65%) had stage ≥IIA disease, 25 (14%) high sTILs, 138 of 158 (87%) were PD-L1-positive. pCR rate with durvalumab was 53.4% (95% CI 42.5% to 61.4%) versus placebo 44.2% (95% CI 33.5% to 55.3%; unadjusted continuity corrected χ2P=0.287), corresponding to OR=1.45 (95% CI 0.80–2.63, unadjusted Wald P=0.224). Durvalumab effect was seen only in the window cohort (pCR 61.0% versus 41.4%, OR=2.22, 95% CI 1.06–4.64, P=0.035; interaction P=0.048). In both arms, significantly increased pCR (P<0.01) were observed with higher sTILs. There was a trend for increased pCR rates in PD-L1-positive tumours, which was significant for PD-L1-tumour cell in durvalumab (P=0.045) and for PD-L1-immune cell in placebo arm (P=0.040). The most common immune-related adverse events were thyroid dysfunction any grade in 47%.
Our results suggest that the addition of durvalumab to anthracycline-/taxane-based NACT increases pCR rate particularly in patients treated with durvalumab alone before start of chemotherapy.
ClinicalTrials.gov number: NCT02685059.
Mein damaliger Chef hatte mir relativ viel Freiraum gegeben, und so konnte ich dort das Studienzentrum für klinische Studien in der Gynäko-Onkologie aufbauen. best practice onkologie: Mittlerweile ...kann der Genexpressionstest Oncotype DX® (Genomic Health, Redwood City, CA, USA) genutzt werden, um das Risiko für Fernrezidive zu bestimmen und dient somit als Entscheidungshilfe für oder gegen eine adjuvante Chemotherapie. In der TAILORx-Studie hat sich gezeigt, dass erst Frauen ab einem Rückfallrisiko von mehr als 26 nach dem „21-gene recurrence-score assay“ (Oncotype DX®) von einer Chemotherapie profitieren. Eine Study Nurse des Netzwerks überprüft daraufhin, ob die Patientin tatsächlich in die Studie passt.
Addition of immune checkpoint inhibitors to neoadjuvant chemotherapy (NACT) is a promising strategy in early breast cancer, but the optimal duration of therapy is currently unknown. In the GeparNuevo ...(NCT02685059) trial, addition of durvalumab to NACT as previously reported led to a moderate increase in pathological complete response (pCR) rate by an absolute 9% (P = 0.287).
Patients with cT1b-cT4a-d triple-negative breast cancer (TNBC) received durvalumab 1.5 g or placebo every 4 weeks added to nab-paclitaxel 125 mg/m2 weekly for 12 weeks, followed by durvalumab/placebo every 4 weeks plus epirubicin/cyclophosphamide every 2 weeks followed by surgery. Durvalumab was not continued after surgery. The primary objective was pCR. Secondary endpoints included invasive disease-free survival (iDFS), distant disease-free survival (DDFS) and overall survival (OS).
A total of 174 patients were randomised between June 2016 and October 2017. After a median follow-up of 43.7 months, 34 events had occurred. Despite a non-significant increase in the pCR rate, significant differences were observed for 3-year iDFS, DDFS and OS: iDFS was 85.6% with durvalumab versus 77.2% with placebo hazard ratio (HR) 0.48, 95% confidence interval (CI) 0.24-0.97, stratified log-rank P = 0.036; DDFS 91.7% versus 78.4% (HR 0.31, 95% CI 0.13-0.74, P = 0.005); OS 95.2% versus 83.5% (HR 0.24, 95% CI 0.08-0.72, P = 0.006). pCR patients had 3-year iDFS of 95.5% with durvalumab and 86.1% without (HR 0.22, 95% CI 0.05-1.06). In the non-pCR cohort 3-year iDFS was 76.3% versus 69.7% (HR 0.67, 95% CI 0.29-1.54). Multivariable analysis confirmed a durvalumab effect independent of the pCR effect. No new safety signals occurred.
Durvalumab added to NACT in TNBC significantly improved survival despite a modest pCR increase and no adjuvant component of durvalumab. Additional studies are needed to clarify the optimal duration and sequence of checkpoint inhibitors in the treatment of early TNBC.
•Significant improvement of secondary endpoints iDFS, DDFS and OS by adding durvalumab to neoadjuvant chemotherapy.•Survival improvement although no adjuvant checkpoint inhibitor therapy was given.•Long-term effect is seen in pCR as well as non-pCR patients.•The improved survival outcome with checkpoint inhibitor therapy is only partially explained by the increased pCR rate.•Our results suggest that additional long-term antitumour effects are present.
The proliferation marker Ki67 has been suggested as a promising cancer biomarker. As Ki67 needs an exact quantification, this marker is a prototype of a new generation of tissue-based biomarkers. In ...this study, we have systematically evaluated different cut points for Ki67 using three different clinical end points in a large neoadjuvant study cohort.
We have evaluated pretherapeutic Ki67 levels by immunohistochemistry in 1166 breast cancer core biopsies from the neoadjuvant GeparTrio trial. We used the standardized cutoff-finder algorithm for three end points response to neoadjuvant chemotherapy (pCR), disease-free (DFS) and overall-survival (OS). The analyses were stratified for hormone receptor (HR) and HER2 status by molecular subtype radar diagrams (MSRDs).
A wide range of Ki67 cut points between 3%–94% (for pCR), 6%–46% (for DFS) and 4%–58% (for OS) were significant. The three groups of Ki67 ≤ 15% versus 15.1%–35% versus >35% had pCR-rates of 4.2%, 12.8%, and 29.0% (P < 0.0005), this effect was also present in six of eight molecular subtypes. In MSRD, Ki67 was significantly linked to prognosis in uni- and multivariate analysis in the complete cohort and in HR-positive, but not triple-negative tumors.
Ki67 is a significant predictive and prognostic marker over a wide range of cut points suggesting that data-derived cut point optimization might not be possible. Ki67 could be used as a continuous marker; in addition, the scientific community could define standardized cut points for Ki67. Our analysis explains the variability observed for Ki67 cut points in previous studies; however, this should not be seen as weakness, but as strength of this marker. MSRDs are an easy new approach for visualization of biomarker effects on outcome across molecular subtypes in breast cancer. The experience with Ki67 could provide important information regarding the development and implementation of other quantitative biomarkers.
The efficacy and toxicity of olaparib as combination therapy in early breast cancer (BC) patients with homologous recombinant deficiency (HRD) score high and/or germline (g) or tumour (t) BRCA1/2 ...mutation is not well described. GeparOLA (ClinicalTrials.gov, NCT02789332) investigated olaparib in combination with paclitaxel in HER2-negative early BC with HRD.
Patients with untreated primary HER2-negative cT2-cT4a-d or cT1c with either cN+ or pNSLN+ or cT1c and triple-negative breast cancer (TNBC) or cT1c and Ki-67>20% BC with HRD were randomised either to paclitaxel (P) 80 mg/m2 weekly plus olaparib (O) 100 mg twice daily for 12 weeks or P plus carboplatinum (Cb) area under the curve 2 weekly for 12 weeks, both followed by epirubicin/cyclophosphamide (EC). Stratification factors were hormone receptor (HR) status (HR+ versus HR−) and age (<40 versus ≥40 years). The primary endpoint was pathological complete response (pCR; ypT0/is ypN0). A two-sided one-group χ2-test was planned to exclude a pCR rate of ≤55% in the PO-EC arm. Secondary end points were other pCR definitions, breast conservation rate, clinical/imaging response, tolerability and safety.
A total of 107 patients were randomised between September 2016 and July 2018; 106 (PO N = 69; PCb N = 37) started treatment. Median age was 47.0 years (range 25.0-71.0); 36.2% had cT1, 61.0% cT2, 2.9% cT3, and 31.8% cN-positive tumours; grade 3 tumours: 86.8%; Ki-67>20%: 89.6%; TNBC: 72.6%; confirmed gBRCA1/2 mutation: 56.2%. The pCR rate with PO was 55.1% 90% confidence interval (CI) 44.5% to 65.3% versus PCb 48.6% (90% CI 34.3% to 63.2%). Analysis for the stratified subgroups showed higher pCR rates with PO in the cohorts of patients <40 years and HR+ patients.
GeparOLA could not exclude a pCR rate of ≤55% in the PO arm. PO was significantly better tolerated and the combination merits further evaluation.
•Randomised phase II GeparOLA study investigated olaparib plus paclitaxel (PO) in early HER2-negative HRD breast cancer.•Addition of olaparib to chemotherapy could not exclude pCR ≤55% but was significantly better tolerated than carboplatinum.•Stratified subgroup analysis shows higher pCR rates with PO in cohorts <40 years and those with HR-positive tumours.•Overall, pCR rate in the gBRCA1/2 carriers was significantly higher than in non-carriers.•Combination of olaparib with paclitaxel prompts further investigation of olaparib as part of NACT in primary HRD tumours.
The predictive value of tumor mutational burden (TMB), alone or in combination with an immune gene expression profile (GEP), for response to neoadjuvant therapy in early triple negative breast cancer ...(TNBC) is currently not known, either for immune checkpoint blockade (ICB) or conventional chemotherapy.
We obtained both whole exome sequencing and RNA-Seq data from pretreatment samples of 149 TNBC of the recent neoadjuvant ICB trial, GeparNuevo. In a predefined analysis, we assessed the predictive value of TMB and a previously developed immune GEP for pathological complete remission (pCR).
Median TMB was 1.52 mut/Mb (range 0.02–7.65) and was significantly higher in patients with pCR (median 1.87 versus 1.39; P = 0.005). In multivariate analysis, odds ratios for pCR per mut/Mb were 2.06 95% confidence intervals (CI) 1.33–3.20, P = 0.001 among all patients, 1.77 (95% CI 1.00–3.13, P = 0.049) in the durvalumab treatment arm, and 2.82 (95% CI 1.21–6.54, P = 0.016) in the placebo treatment arm, respectively. We also found that both continuous TMB and immune GEP (or tumor infiltrating lymphocytes) independently predicted pCR. When we stratified patients in groups based on the upper tertile of TMB and median GEP, we observed a pCR rate of 82% (95% CI 60% to 95%) in the group with both high TMB and GEP in contrast to only 28% (95% CI 16% to 43%) in the group with both low TMB and GEP.
TMB and immune GEP add independent value for pCR prediction. Our results recommend further analysis of TMB in combination with immune parameters to individually tailor therapies in breast cancer.
•Tumor mutational burden (TMB) predicts pCR after neoadjuvant treatment in early triple negative breast cancer.•The predictive value of TMB was found both for immune checkpoint inhibition with chemotherapy and for chemotherapy alone.•Both TMB and an immune gene expression profile add independent value for pCR prediction in multivariate analysis.
HannaH revealed consistent overall safety profiles between fixed-dose subcutaneous (s.c.) and weight-based intravenous (i.v.) trastuzumab (median follow-up 20 months). Event-free survival rates were ...balanced between i.v. and s.c. There was no association between toxicity and exposure or body weight. Similar pathologic complete response rates were observed in higher weight patients in i.v. and s.c.
HannaH (NCT00950300) was a phase III, randomized, international, open-label study that compared pharmacokinetics (PK), efficacy, and safety of two different trastuzumab formulations subcutaneous (s.c.) and intravenous (i.v.) in HER2-positive, operable, locally advanced, or inflammatory breast cancer in the neoadjuvant/adjuvant setting. The co-primary end points, to show noninferiority of s.c. versus i.v. trastuzumab in terms of serum concentration (Ctrough) and pathologic complete response (pCR) were met; safety profiles were comparable at 12 months' median follow-up. Secondary end points included safety and tolerability, PK profile, immunogenicity, and event-free survival (EFS). We now report updated safety and efficacy data after a median follow-up of 20 months.
Patients (N = 596) were treated with eight cycles of neoadjuvant chemotherapy, administered concurrently with 3-weekly s.c. trastuzumab (fixed dose of 600 mg) or the standard weight-based i.v. method. Following surgery, patients continued trastuzumab treatment to complete 1 year of therapy. Updated analyses of PK, efficacy, safety, and immunogenicity data were carried out.
s.c. trastuzumab was generally well tolerated and the incidence of adverse events (AEs), including grade 3 or 4 AEs, between treatment groups was comparable. A slightly higher incidence of serious AEs (SAEs), mainly due to infections, was reported with s.c. treatment {64 21.5%; 95% confidence interval (CI) 17.0%–26.7% versus 42 (14.1%; 95% CI 10.4%–18.6%) in the i.v. group}; however, the differences were small and often based on rare events, with no observable pattern across reported events. An early analysis of EFS showed rates of 95% in both groups 1 year postrandomization. Exploratory analyses did not reveal an association between toxicity and body weight or exposure.
Overall, the safety profile of s.c. trastuzumab was consistent with the previously published data from HannaH and the known safety profile of i.v. trastuzumab. EFS rates were comparable between the i.v. and s.c. groups.
NCT00950300.
According to Dooge (1986) intermediate-scale catchments are systems of organized complexity, being too organized and yet too small to be characterized on a statistical/conceptual basis, but too large ...and too heterogeneous to be characterized in a deterministic manner. A key requirement for building structurally adequate models precisely for this intermediate scale is a better understanding of how different forms of spatial organization affect storage and release of water and energy. Here, we propose that a combination of the concept of hydrological response units (HRUs) and thermodynamics offers several helpful and partly novel perspectives for gaining this improved understanding. Our key idea is to define functional similarity based on similarity of the terrestrial controls of gradients and resistance terms controlling the land surface energy balance, rainfall runoff transformation, and groundwater storage and release. This might imply that functional similarity with respect to these specific forms of water release emerges at different scales, namely the small field scale, the hillslope, and the catchment scale. We thus propose three different types of "functional units" - specialized HRUs, so to speak - which behave similarly with respect to one specific form of water release and with a characteristic extent equal to one of those three scale levels. We furthermore discuss an experimental strategy based on exemplary learning and replicate experiments to identify and delineate these functional units, and as a promising strategy for characterizing the interplay and organization of water and energy fluxes across scales. We believe the thermodynamic perspective to be well suited to unmask equifinality as inherent in the equations governing water, momentum, and energy fluxes: this is because several combinations of gradients and resistance terms yield the same mass or energy flux and the terrestrial controls of gradients and resistance terms are largely independent. We propose that structurally adequate models at this scale should consequently disentangle driving gradients and resistance terms, because this optionally allows equifinality to be partly reduced by including available observations, e.g., on driving gradients. Most importantly, the thermodynamic perspective yields an energy-centered perspective on rainfall-runoff transformation and evapotranspiration, including fundamental limits for energy fluxes associated with these processes. This might additionally reduce equifinality and opens up opportunities for testing thermodynamic optimality principles within independent predictions of rainfall-runoff or land surface energy exchange. This is pivotal to finding out whether or not spatial organization in catchments is in accordance with a fundamental organizing principle.
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