Background

Modified FOLFIRINOX (mFOLFIRINOX) is a standard treatment in advanced pancreatic cancer (aPC). Because of the presence of either loss-of-function mutations in DPYD (c.1679T>G, IVS14 + 1G>A, c.2194G>A, c.2846A>T) or UGT1A1*28 variant associated with reduced UGT1A1 expression, deficiency of DPD and UGT may result in drug accumulation and severe toxicities caused by fluoropyrimidines and irinotecan, respectively.

Methods

The present study analyzes the association between DPYD and UGT variants and adverse drug reactions (ADRs) in aPC patients (pts) treated with mFOLFIRINOX. Blood samples were collected from 104 pts, and analyses of DPYD c.1679T>G, IVS14 + 1G>A, c.2194G>A, c.2846A>T and UGT1A1*28 were performed by automatic sequencing. Statistical analysis was performed by chi-square, Mann-Whitney and Spearman's rho tests on SPSS v.23s.

Results

None of the pts was carrier of the c.1679G and c.2846T alleles. Only one IVS14 + 1GA was found and 8 pts had c.2194GA genotype. ADRs grade (G) ≥3 were neutropenia (42.3%), diarrhea (7.7%) and stomatitis (7.7%). The statistical analysis of the IVS14 + 1GA has not been performed due to the extremely low frequency of the mutant allele (0.96%), however IVS14 + 1GA patient experienced G4 hematological and gastrointestinal ADRs after the first cycle. We observed a trend toward significant association between c.2194GA genotype and the risk of thrombocytopenia (p = 0.080) and hand-foot syndrome (HFS) (p = 0.096). The UGT1A1*28 allele was found in 56 (54.4%) pts (*1/*28, n = 38; *28/*28, n = 18) and it was correlated with the risk of developing thrombocytopenia (p = 0.006) and neutropenia (p = 0.044). Moreover, this risk increased as the number of *28 alleles increased (*28/*28 > *1/*28 > *1/*1, p = 0.003). No significant correlation with diarrhea was found.

Conclusions

Our data confirm that DPYD IVS14 + 1A is associated with life-threatening toxicities and that the c.2194A allele could be possibly associated with thrombocytopenia and HFS, but validation in larger cohorts is needed. UGT1A1*28 allele is associated with a higher risk of G3/4 thrombocytopenia and neutropenia, and should be implemented in routine practice to personalize treatment in aPC.

Legal entity responsible for the study

University of Pisa

Funding

Institutional fundings

Disclosure

All authors have declared no conflicts of interest.

Background

Breast cancer (BC) is an important cause of morbidity and mortality. Most BC are hormone-receptor positive and can be treated with endocrine treatment (ET), until resistance or toxicity is developed. Specifically, H3K27m3, an epigenetic marker of gene repression, has been associated with prognosis in ET resistant BC. Herein, we aim to further understand its potential role as predictive marker of ET resistance before exposure to treatment.

Methods

A cohort of BC patients diagnosed between 1995 and 2002 at our institution were enrolled after informed consent. Expression of H3K27me3 was determined by immunohistochemistry (IHC) in formalin fixed paraffin embedded tissues. GenASIs^TM software was used to assess cell-positivity using a custom profile from positive control. Pre-specified conditions: ≥ 5 frames ≥ 3000 cells analyzed/case. SPSS v24 was used for statistical purposes.

Results

A total of 102 cases were assessed for H3K27me3 immunoexpression. Median of 6 frames/case (range 5-10) and 3311 cells/case (range 3017-5292) were obtained. Of the total cases analyzed, a median of 80% of cells showed positivity (range 9-100%). Using a negative/positive 50% cut-off, 81% were considered positive (pos.). The analyzed cohort displayed a median age of 60 years (33-82 years), 89% were classified as ductal carcinoma (DC) and 38% were grade 3. Concerning IHC subtyping, 43% classified as Luminal A-like, whereas 57% Luminal B-like. Around 66% of the cases evaluated for H3K27me3 expression were treated with adjuvant Tamoxifen exclusively. BC cases with H3K27me3 50-60% positivity were associated with higher cancer-related death (CI 95% 1.10-34.38, p = 0.05), although not reaching significance. Grade 3 BC significantly associated with increased risk of death (p = 0.024). An intermediate H3K27me3 expression (60-70% pos.) was observed in non-DC BC (CI 95% 1.42-13.92, p = 0.04).

Conclusions

In this preliminary retrospective cohort, H3K27m3 positivity was not found to be a pre-treatment endocrine resistance biomarker. However, statistical trends were observed between H3K27m3 expression and increased cancer-related death risk. Thus, further studies with extended cohort of patients are warranted.

Legal entity responsible for the study

Cancer Biology and Epigenetics Group, IPO Porto Research Center (CI-IPOP), Portuguese Oncology Institute of Porto (IPO Porto), Porto, Portugal

Funding

None

Disclosure

All authors have declared no conflicts of interest.

Background

B12019 is being developed as a biosimilar to Neulasta® (INN pegfilgrastim), a pegylated, long-acting form of recombinant human granulocyte-colony stimulating factor (G-CSF) for the prevention of chemotherapy-induced neutropenia. A clinical development program was conducted with B12019 in comparison to EU-authorised Neulasta to confirm the biosimilarity as established by analytical, functional and preclinical data.

Methods

The clinical development program for B12019 consisted of two clinical studies. Study B12019-101 investigated pharmacokinetics (PK) and pharmacodynamics (PD) comparability of B12019 to Neulasta. The 6mg single-dose, randomised, double-blind, two-way crossover study enrolled 172 healthy volunteers. The primary PK endpoints were the area under the plasma concentration-time curve (AUC_0-last) and the maximum concentration (C_max) as well as the area under the effect curve (AUEC_0-last) for absolute neutrophil count (ANC) for PD. In study B12019-102 immunogenicity and PD comparability of B12019 and Neulasta were investigated in a 3mg multiple-dose, randomised, double-blind, three-period, two-sequences crossover study in 96 healthy volunteers. Primary endpoints were AUEC_0-last for PD and anti-drug antibody rate (ADA) for immunogenicity.

Results

Study B12019-101, using 6 mg, confirmed PK and PD comparability (compare also Roth et al, Blood, Dec 2016). In study B12019-102, 82 subjects were included in the model-based PD comparison. PD comparability was demonstrated, with the AUEC_0-last geometric mean ratio with a CI of 99.6; 103.6 being within the pre-specified acceptance range. In both studies, no imbalance of ADA-positive samples after single or repeated dosing were observed. Neither anti-G-CSF nor neutralising antibodies were detected for B12019 or Neulasta.

Conclusions

· The clinical program confirmed the biosimilarity of B12019 and Neulasta in highly sensitive clinical study settings. · PK comparability of B12019 and Neulasta was demonstrated at the clinical dose of 6 mg. · PD comparability of B12019 and Neulasta was shown at the clinical dose of 6 mg and the reduced dose of 3 mg. · The safety and immunogenicity profile of B12019 did not show any clinically meaningful differences to Neulasta.

Clinical trial identification

NCT02912377 NCT02629562

Legal entity responsible for the study

Cinfa Biotech S.L., Olloki, Spain

Funding

Cinfa Biotech S.L., Olloki, Spain

Disclosure

K. Roth, H. Wessels, R. Jankowsky: Employee of Cinfa Biotech J. Hoefler: Employee of Staburo GmbH, statistical consultancy

Background

Several patients progressed with their cancer disease despite treatment and eventually they become refractory. We selected patients from several malignancies with PD despite standard of care treatment (n = 30) and performed a pilot clinical study to evaluate the effect of two intravenously, two oral and one subcutaneously agent. With this in mind and with a systematic review and immunomodulatory, anti-angiogenic and anti-tumoral validation of each drug was studied. We tested the preexisting CD8 and Th1 antigen specific immune response against several clinically relevant peptides from bad prognosis proteins.

Methods

30 subjects were included after the CICS ethics committee approved the protocol. The inclusion criteria include ECOG=0, complete CT scan from neck, thorax, abdomen and pelvis, laboratory tests such as CBC, phase acute proteins, etc. The patients were accepted after initial IFN-gamma and Elispot assays were done to make sure we have only patients with Th1 and CD8 immune response, as we know that ipilimumab unleashes every T cell. The tumors included were PDAC (n = 5), HGSOC (n = 12), TNBC (n = 10) and MM (3). The patients received the oral and the IV treatment biweekly for 4 months.

Results

We had 60% of CR and 40% of PR. The tumor with more significant response was ovarian (90%). There was an immunological correlation of CD8 immune response between in both CR (p = 0.001) and PR (p = 0.05). The combination was well tolerated and after 16 months of stopping the treatment some patients have persistent CD8 antigen specific immune response.

Conclusions

The combination is clinically feasible, looks promising and we now understand the importance of preserving the immune response and the use of biomarkers to improve the rational and generate new combinations with this approach to improve clinical outcomes.

Clinical trial identification

DOES NOT APPLY

Legal entity responsible for the study

CENTRO DE INVESTIGACION DE CANCER EN SONORA CAMPUS CIUDAD OBREGON, SONORA, MEXICO

Funding

Fundacion del centro de investigacion de cancer en sonora (cics) campus ciudad obregon, sonora, Mexico.

Disclosure

All authors have declared no conflicts of interest.

Background

Patients (pts) with metastatic renal cell carcinoma (mRCC) may present with primary metastases (synchronous disease) or develop metastases during follow-up (metachronous disease). The impact of timing of metastatic disease outbreak on outcomes from targeted therapy (TKI) is unclear.

Methods

We used the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) to assess overall survival (OS) and time to treatment failure (TTF) on first line TKI, and performed Cox regression analyses comparing synchronous (metastases ≤ 3 mo of initial diagnosis of cancer) vs metachronous disease (metastasis diagnosed post initial diagnosis, evaluated by intervals >3-12 mo, >1-2 yrs, >2-7 yrs, and >7yrs).

Results

In 7386 pts with mRCC treated with first line TKI, 3906 pts (53%) had synchronous and 3480 pts (47%) had metachronous metastases. Synchronous vs metachronous disease by intervals >3-12 mo, >1-2 yrs, >2-7 yrs, >7yrs correlated with lower age at TKI initiation (mean 61 yrs vs 61, 62, 63, 66 yrs, respectively, p < 0.0001), higher rate of non-clear cell histology (14% vs 12%, 10%, 10%, 7%, respectively, p < 0.0001), and higher rate of IMDC risk features (mean 2.3 vs 1.6, 0.9, 0.9, 0.8, p < 0.0001). Compared with synchronous disease, the longer time to metastases was significantly associated with improved OS and TTF from TKI therapy initiation in multivariable Cox regression, adjusted for nephrectomy status, histology (cc vs ncc), IMDC risk factors (Hgb, Corrected calcium, Neutrophil, platelets, Karnofsky performance status), number of metastasis (1 vs > 1), age at TKI initiation and year of TKI initiation (2003-2007, 2008-2012, 2013-2016).Table:

883P Association of time to metastases with OS and TTF from TKI initiation

Conclusions

Timing of metastases post initial RCC diagnosis impacts outcome with targeted therapy in mRCC. This may need to be taken into consideration in clinical trial designs.

Legal entity responsible for the study

The International Metastatic Renal Cell Carcinoma Database Consortium (IMDC)

Funding

The International Metastatic Renal Cell Carcinoma Database Consortium (IMDC)

Disclosure

F. Donskov: Research funding (to institution) from Novartis, GSK and Pfizer. C. Porta: Consulting or advisory role: Novartis, Bristol-Myers Squib, Pfizer, Jannsen, Eisai, Pelefon, Ipsen, Speaker bureau: Novartis, Bristol-Myers Squib, Pfizer, Ipsen; Eisai Research funding: Pfizer. J.L. Lee: Honoraria from Pfizer and Astellas; consulting fees from Astellas; research funding from Pfizer, Bayer, Janssen, Novartis, and Exelixis. T. Yuasa: Honoraria from Astellas, Novartis, and Pfizer. I.D. Davis: Supported by an Australian National Health and Medical Research Council Practitioner Fellowship (APP1102604) and research funding from Astellas and Exelixis. C. Pezaro: Honoraria from Janssen, Pfizer, Sanofi, Novartis, and Astellas; consulting fees from Novartis; and travel and accommodation funding from Pfizer and Sanofi. R. Kanesvaran: Honoraria from Pfizer, Novartis, Bayer, Astellas, Janssen, Mundipharma, and Sanofi; research funding from Sanofi; and travel and accommodation expenses from Pfizer and Astellas. N. Agarwal: Consulting fees from Pfizer, Exelixis, Cerulean, Argos, and Medivation. C.M. Canil: Advisory Boards for Janssen, Pfizer, Astellas and Amgen; speaking fees from Janseen and Astellas and travel grants from Novartis and Janssen. T.K. Choueiri: Consulting or advisory role for Bayer, Bristol-Myers Squib (institutional), GSK, Merck, Novartis, and Pfizer; and institutional research funding from AstraZeneca, Bristol-Myers Squib, Exelixis, GSK, Merck, Novartis, Peloton Therapeutics, Pfizer, Roche/Genentech, and TRACON Pharma. D.Y.C. Heng: Advisory boards Pfizer, Novartis, Bristol-Myers Squib, Exilexis. All other authors have declared no conflicts of interest.

Background

Evidence is increasing that severe skeletal muscle (SM) loss (sarcopenia) is associated with reduced overall survival (OS) in mCRC pts. We recently found, using data of the randomized phase 3 CAIRO3 study (Lancet, 2015), that SM loss was related to shorter time to progression during first line maintenance treatment (Tx) with capecitabine+bevacizumab (CAP-B) or observation. Subsequently, SM loss during more intensive reinduction Tx by adding oxaliplatin (CAPOX-B) was associated to shorter overall survival (ASCO, 2017). As a potential risk factor for reduced survival we explored whether sarcopenia was associated with dose reductions at start of CAPOX-B reinduction Tx and dose limiting toxicities (DLT) during CAPOX-B reinduction Tx.

Methods

Here, CAIRO3 pts were included who received CAPOX-B reinduction Tx. DLT were defined as any dose delay, reduction, or discontinuation of systemic treatment because of reported CTCAE (v3.0) toxicities at start or during Tx. Poisson regression models adjusted for relevant confounders were used to study the association between sarcopenia and DLT.

Results

A total of 254 pts received CAPOX-B reinduction Tx. 39% of pts were sarcopenic and compared to normal SM pts we found no statistically significant differences in age and sex (sarcopenic vs normal SM: mean age 63.6±9.1 vs 61.9±8.5 yrs, p=.20 and 39% vs 31% females p=.31). BMI was significantly lower in sarcopenic pts, but pts were on average still overweight (25.9±3.8 vs 27.2±3.8 p=.01). Overall, 67% experienced ≥1 DLT. At start of CAPOX-B, 25% had already received a dose reduction and the risk of dose reduction at start was significantly higher for sarcopenic compared to normal SM pts (RR 1.8 95%CI 1.08-2.90). Despite more frequent dose reductions at start, sarcopenic pts did not have a significantly lower risk of DLT during CAPOX-B Tx (RR sarcopenic vs normal SM pts 0.86 95% CI 0.46-1.45).

Conclusions

Sarcopenia was significantly associated with dose reductions at start of CAPOX-B reinduction Tx, and not with DLT during CAPOX-B reinduction Tx. Possible explanations for dose reductions at start might be more frequent toxicities during previous Tx including neuropathy.

Clinical trial identification

NCT00442631

Legal entity responsible for the study

Dutch Colorectal Cancer Group (DCCG)

Funding

Province of Utrecht, The Netherlands

Disclosure

B. Dorresteijn, M. Jourdan: Employee of Nutricia Research All other authors have declared no conflicts of interest.

Background

Extramedullary plasmacytomas (EMPs) is a rare presentation of plasma cell neoplasm and accounts for 7 to 15% of all plasma cell neoplasm. Fluorescence in-situ hybridization (FISH)-detected abnormalities, including del(17p), del(13q), and t(4;14), have been associated with inferior prognosis. However, there are few data about the prognostic significance of cytogenetic abnormalities in multiple myeloma (MM) patients with extramedullary plasmacytoma (EMP). This study aimed the clinical features, FISH data and outcome of patients with EMPs.

Methods

The data were collected from 70 patients with EMPs, retrospectively. We excluded skeletal plasmacytomas. The clinic-pathologic variables and treatment outcome retrospectively reviewed.

Results

Seventeen patients had solitary EMPs. Most common site of solitary EMP was nasal cavity and most patients received radiotherapy (n = 7) and surgery (n = 6). A total of 905 patients with newly diagnosed MM were included, and 53 patients (8.7%) had EMPs at diagnosis. Thirty-three patients had conventional FISH data. By conventional cytogenetic analysis and FISH, 35.8% (19/53) and 54.5% (18/33) patients were identified genetic abnormalities, respectively. By comprehensive cytogenetic/FISH approach, the most common genetic aberration was 1q21 amplification and/or 1p32 deletion (42.4%, 14/33), followed by -13 or del (13q) (24.3%, 8/33), del (17p) (15.2%, 5/33), IGH/FGFR3 rearrangement (15%, 2/33) and IGH/CCND1 rearrangement (12%, 2/33). Patients with initial EMPs had significantly worse overall survival compared to those without initial EMPs. Del(13q), and t (4;14) have been associated with inferior prognosis.

Conclusions

In the current study, del(13q), and t (4;14) were associated with worse survival in MM patients with EMP.

Legal entity responsible for the study

Hyun Ae Jung

Funding

None

Disclosure

All authors have declared no conflicts of interest.