Differences In Toxicity Profiles Research Articles

Bendamustine Bridging Versus Standard of Care Chemotherapy on Toxicity Profile for Multiple Myeloma Patients Undergoing CAR T Cell Therapy

Introduction Multiple myeloma (MM) remains an incurable malignancy arising from plasma cells, however great promise has been seen with the use of Chimeric Antigen Receptor (CAR) T cells. Autologous CAR-T products require bridging therapy, however little is known about different agents used in this manner. Some studies indicate decrease in disease burden is crucial, while others note an association with higher rates of toxicity and negative effect on survival. As commercial CAR T cell therapy is indicated after failure of at least 4 prior treatments, careful consideration of bridging therapy is crucial, particularly in patients with aggressive and high-risk disease. This study aims to compare the impact of bendamustine to standard of care (SOC) bridging therapy in MM patients undergoing CAR T cell therapy. Methods A single-center retrospective chart review of 19 adult patients with relapsed/refractory multiple myeloma treated with CAR T cells, who also received bridging therapy with either bendamustine (n=9) or SOC/Other (n=10) was conducted at Mount Sinai Hospital. Patient demographic information (gender, race, MM subtype, history of prior transplant) was collected and toxicity profiles (infection, pancytopenia, cytokine release syndrome (CRS), and immune effector cell-associated neurotoxicity syndrome (ICANS)) were compared. Descriptive statistics were used to analyze demographic characteristics and toxicity profiles between the two cohorts. Results Comparative analysis of demographics showed that both cohorts were predominantly males with IgG MM subtype, and varied in terms of race ( Figure 1a). The Other cohort had a higher proportion of patients with a history of autologous stem cell transplant (ASCT) (70%) compared to the bendamustine group. In the SOC group, two patients developed infections, whereas none were observed in the bendamustine cohort ( Figure 1b). Pancytopenia was observed in both groups, but interestingly, 100% of patients experienced it in the SOC cohort. CRS and ICANS were comparable between the two groups ( Figure 1b). Comparative statistics demonstrated no significant difference between the two groups ( Figure 1c). Conclusion Our study findings indicate that there was no significant difference in toxicity profiles between the two pre-conditioning therapy groups. Given our limited sample size, future studies with a larger are indicated to validate these results.

Switch to generic formulation of temozolomide results in statistically significant increase in grade 3 and 4 bone marrow toxicity in glioma patients in the province of Alberta.

Temozolomide (TMZ) is an oral, systemic chemotherapy used chiefly for treating high-grade glioma. Due to the rising costs of systemic chemotherapy, many jurisdictions have replaced brand name with generic formulations. The aim of this study was to determine whether or not there was difference in the incidence of grade 3 or 4 bone marrow toxicity and median overall survival in patients treated with brand name versus generic TMZ in the province of Alberta, Canada. The province suspended the use of generic TMZ based on preliminary data pointing to excess toxicity. This multicenter, retrospective study included data from patients with newly diagnosed high-grade glioma that received treatment with TMZ in Alberta. Multivariate logistic regression analysis was performed to determine the association between grade 3 or 4 toxicity to generic versus brand name TMZ exposure, ECOG score, and age. Kaplan-Meier survival estimates and log-rank testing were used to determine differences in overall survival between the brand name and generic TMZ cohorts, as well as the cytopenic versus non-cytopenic patients. Furthermore, a screening analysis for grade 3 or 4 bone marrow toxicity was conducted on all de novo glioma patients treated with brand name TMZ after Alberta preemptively stopped generic TMZ. Grade 3 or 4 neutropenia and thrombocytopenia were observed in 15% and 19% of patients treated with generic TMZ (n = 156) as compared to 3% and 5% of patients (n = 100) treated with brand name TMZ-treated patients; P= .003 and .001. A trend toward increased median overall survival in glioblastoma patients treated with generic TMZ (13.7 months) versus brand name (15.8 months, P = .178.) was also observed through meeting statistical significance. Based on these results, the province stopped the use of generic TMZ and reverted to the Merck TMZ. An initial review of all new glioma patients (n = 89) treated with Merck TMZ since the province stopped the generic drug demonstrated 3.4% and 10.1% grade 3 or 4 neutropenia, respectively. The statistically significant difference in toxicity profile has prompted the province of Alberta to replace generic TMZ with brand name TMZ in high-grade glioma patients pending more detailed analysis. Our study provides evidence supporting the importance of conducting prospective studies on long-term safety for generic chemotherapies.

8-Day Versus 12-Day Manufactured LV20.19 CAR T-Cells for B-Cell Non-Hodgkin Lymphoma

Introduction: CD19 CAR T-cell therapy has revolutionized outcomes for patients (pts) with relapsed, refractory (R/R) B-cell non-Hodgkin lymphoma (NHL). However, the vein-to-vein time for commercially approved CAR-T cell products and downregulation of the target receptor with CD19 CAR-T remain limitations of therapy. To improve clinical outcomes we utilized a lentiviral, bispecific, tandem anti-CD20/anti-CD19 (LV20.19) CAR T-cell in pts with R/R B-cell NHL with point of care manufacturing (MF) to limit time to infusion. For MF, we used IL-7+IL-15 for cell expansion with two arms comparing a flexible 8/12 day MF process versus (vs) a fixed 12 day platform. We hypothesized shorter MF would produce a more naïve CAR T-cell population improving clinical responses for R/R B-cell NHL. Methods: We conducted a Phase 1/2, multi-cohort, single center, prospective trial (NCT04186520) evaluating LV20.19 CAR T-cells at a fixed dose of 2.5x10e6 cells/kg for pts with R/R diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma (FL). Cells were manufactured via CliniMACS Prodigy device. Pts were sequentially enrolled on the two arms: fixed 12-day MF vs flexible 8/12 day MF where cells were harvested on day 8 if target dose was met. The goal was fresh infusion for all pts with lymphodepletion initiated during the MF process. After safety run-in, we opened two Phase 1b expansion cohorts. Descriptive statistics were utilized for baseline characteristics and Fischer's exact test for comparison of categorical variables. Survival analyses were calculated utilizing the Kaplan-Meier method and differences between groups were evaluated via log-rank test. Results: In total, there were 21 pts with DLBCL or FL treated with LV20.19 CAR-T cells with 11 pts treated on the flexible 8/12 MF arm and 10 pts treated on the fixed 12-day MF arm. MF success was 100% and 18 (86%) pts received fresh cells without cryopreservation. All 11 pts on the flexible 8/12 arm met goal target dose at Day 8 of MF. The median age of all pts was 66 years (41-78). Median prior lines of therapy were 3 (2-11). Nine (43%) pts progressed after prior autologous transplant and 2 pts progressed after anti-CD19 CAR T-cell therapy (Table 1). By cohort, there was no difference in day 28 overall response rates: 82% with an 8-day process vs 70% with a 12-day process (p=0.64). Both prior CAR treated pts progressed at day 28. Day 28 complete response (CR) rates trended higher in the 8-day arm (64% vs 20%, p=0.08). There was no difference in median duration of response (DOR); 6 months in the 8-day arm vs not reached in the 12-day arm (p=0.64). The 1-year OS for all pts was 61%. There were 4 non-relapse mortality events in responding pts beyond day 28 (1=therapy related MDS, 1=covid, 1=line associated sepsis, 1=pneumonia). More pts in the 8-day arm had CRS, 100% (n=11) with 1 grade 3 vs 70% (n=7) in the 12-day arm, all grade 1-2 (p=0.08). Immune effector cell associated neurotoxicity syndrome (ICANS) occurred in 2 pts in the 8-day arm, both grade 1-2 and in 4 pts in the 12-day arm (2=grade 2 and 2=grade 3). Immunophenotypically CAR T-cells harvested at day 8 had significantly higher numbers of central memory (CM) T-cells and lower terminally differentiated effector memory re-expressing CD45RA (EMRA) T-cells in both CD4 and CD8 compartments than CAR T-cells harvested at day 12 (Figure 1). Intra-patient immunophenotyping of 3 pts assigned to the 12-day MF arm demonstrated a similar shift with decreasing CM T-cells and increasing EMRA T-cells between day 7 (in-process testing) and day 12 (harvest). Conclusions: Bispecific LV20.19 CAR T-cells are safe and efficacious for pts with R/R B-cell NHL. Shorter MF produced a more naïve CAR T-cell product with no difference in toxicity profile. Higher percentage of CM T-cells and lower EMRA T-cells were observed earlier in the MF process both between the two cohorts and intra-patient. While CR rates were higher in the 8-day arm, duration of response was similar in both groups. These data confirm that a shorter MF process is feasible and improves immunophenotype of the final CAR product without impacting safety. Future studies will utilize an 8-day MF process. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

COMPARISON OF TOXICITIES OF SAMPLES OF CRUDE OIL FROM DIFFERENT SOURCES IN NIGERIA

The use of crude oil in the treatment of diseases is gaining popularity in several parts of Nigeria. The impact of handling and storage on the toxicity profile of the Nigeria Crude oil has not been determined. A few hepatic and renal parameters were used in this study to assess the toxicity of crude oil samples found in different parts of Nigeria. Three different crude oil samples from Onitsha market, Lagos markets and NNPC refinery Port Harcourt were administered orally for 30 days at three dose levels (750, 1500 and 3000 mg/kg) while the control was given water (10 ml/kg). There was a rise in serum BUN of 1500 mg/kg and 3000 mg/kg for both NNPC (Groups C & D) and Lagos (Groups I & J) samples while for Onitsha, a significant rise was observed only in the 3000 mg/kg dose group (Group G). Similarly, a significant percentage rise in creatinine was observed in 1500 mg/kg and 3000 mg/kg doses for both NNPC (Groups C & D) and Lagos (Groups I & J) samples, while all doses of crude oil from Onitsha showed no significant increase. Furthermore, all doses of the three samples of crude oil showed a significant percentage increase in serum levels of AST, whereas only the 1500 mg/kg dose of crude oil from NNPC showed a significant percentage rise in the serum levels of ALT. The results of the histological studies for the liver and kidney tissues demonstrated more abnormality in NNPC and Lagos samples than in the Onitsha samples. Conclusively, crude oil from the NNPC refinery and Lagos market was more toxic than the samples from the Onitsha market. Factors likely to contribute to differences in toxicity profiles could be exposure, environmental conditions, and time.

CT and MRI Based Gross Tumor Volume Comparison in Pharyngeal and Laryngeal Carcinoma

Background: Different other imaging modalities help in accurate gross tumor volume delineation. Studies have shown conflicting results for intermodality GTV comparison. Since in our institute we routinely take planning CT and planning MRI for laryngeal and pharyngeal tumors treated with definitive radiotherapy, with this study we intent to compare the gross tumor volume (GTV) with these modalities in these tumors. Materials & Methods: Study population included pharyngeal and laryngeal carcinoma patients treated. Planning CT and planning MRI images of these patients were retrieved. Gross tumor volume (GTV) was delineated by a Radiation Oncologist in both these image sets and GTVs were documented. Results: Out of 87 patients analysed, the overall median GTV with planning CT and planning MRI were 20.4 cc & 18.2 cc respectively. Median GTV with planning CT & MRI for different sites like Nasopharynx, Oropharynx, Larynx and Hypopharynx were 32.85 & 27.75 cc, 22.1 & 20.9 cc, 8.25 & 10.35cc and 20.55 & 20.6 cc respectively with no statistically significant difference. Median GTVs with CT & MRI for different primary tumor stages like T2, T3, T4a, T4b were 14.3 & 14.3 cc, 20.45 & 19 cc, 16.55 & 27.45 cc and 50.75 & 52.4 cc respectively. Analysis showed 94.6 % correlation between GTVs with CT & MRI. Conclusion: This study showed comparable median GTVs with planning CT & MRI for pharyngeal and laryngeal carcinomas. Subset analysis did not show any significant difference in GTVs with two modalities for different primary tumor site. As expected there was good correlation between GTVs of two modalities. Even though the results does not show significant intermodality variation for GTV delineation. With the results of this study we cannot question the use of multiple modalities for GTV delineation as subtle variation in GTV can result in differences in target volumes resulting in differences in toxicity profile.

Postoperative Adjuvant Chemoradiotherapy Versus Chemotherapy Alone for Stage III Endometrial Cancer: A Multicenter Retrospective Study

IntroductionWe aimed to evaluate the efficacy and toxicity of the combination of 6 cycles of chemotherapy and radiation therapy compared with chemotherapy alone as postoperative adjuvant therapy for patients with stage III endometrial cancer.MethodsThis retrospective cohort study included patients with stage III endometrial cancer who received postoperative chemoradiotherapy or chemotherapy alone at 6 hospitals between January 2009 and December 2019. The progression-free survival (PFS) and overall survival (OS) for each treatment group were analyzed using the Kaplan–Meier method. We also assessed differences in toxicity profiles between the treatment groups.ResultsA total of 133 patients met the inclusion criteria. Of these, 80 patients (60.2%) received adjuvant chemoradiotherapy and 53 (39.8%) received chemotherapy alone. The PFS and OS did not differ significantly between the groups. For patients with stage IIIC endometrioid subtype, the chemoradiotherapy group had significantly longer PFS rate than did the chemotherapy alone group (log-rank test, P = .019), although there was no significant difference in the OS (log-rank test, P = .100). CRT was identified as a favorable prognostic factor for PFS in multivariate analysis (adjusted HR, .37; 95% CI, .16-.87; P = .022). Patients treated with chemoradiotherapy more frequently suffered from grade 4 neutropenia (73.8% vs 52.8%; P = .018) and grade 3 or worse thrombocytopenia (36.3% vs 9.4%; P = .001) compared with the chemotherapy alone group. There were no differences between the 2 treatment groups in the frequency of toxicity-related treatment discontinuation or dose reduction.ConclusionWe confirmed that chemoradiotherapy yields longer progression-free survival than does chemotherapy alone for patients with stage IIIC endometrioid endometrial cancer, with an acceptable toxicity profile.

“CO in a pill”: Towards oral delivery of carbon monoxide for therapeutic applications

Along with the impressive achievements in understanding the endogenous signaling roles and mechanism(s) of action of carbon monoxide (CO), much research has demonstrated the potential of using CO as a therapeutic agent for treating various diseases. Because of CO’s toxicity at high concentrations and the observed difference in toxicity profiles of CO depending on the route of administration, this review analyzes and presents the benefits of developing orally active CO donors. Such compounds have the potential for improved safety profiles, enhancing the chance for developing CO-based therapeutics. In this review, the difference between inhalation and oral administration in terms of toxicity, CO delivery efficiency, and the potential mechanism(s) of action is analyzed. The evolution from CO gas inhalation to oral administration is also extensively analyzed by summarizing published studies up to date. The concept of “CO in a pill” can be achieved by oral administration of novel formulations of CO gas or appropriate CO donors.

Chemosensitive Disease Better Predicts Outcome Than Age Following Autologous Heamatopoietic Stem Cell Transplantation in Elderly Patients with Multiple Myeloma

High-dose chemotherapy followed by autologous hematopoietic stem cell transplantation (AHSCT) is considered the standard of care as first-line therapy for eligible multiple myeloma patients(Barlogie et al. 1987; McElwain & Powles 1983). Median age at diagnosis of multiple myeloma is 69 years old (SEER 18 2010-2014). Data from the CIBMTR revealed that the number of transplants done per year and the age of recipients are still rising(D'Souza & Zhu 2016). With an expected myeloma prevalence rising by 57% from 2010 to 2030(Smith et al. 2009), the number of older patients considered for AHSCT will increase significantly. Best treatment options for those older patients must therefore be addressed. The assessment of hematopoietic cell transplant comorbidity index score (HCT-CI) (Sorror et al. 2005; Sorror et al. 2009) can be helpful in the selection of candidates for AHSCT. The goal of this study was to identify factors impacting the safety and efficacy of AHCT in older multiple myeloma patients in order to better select those who will benefit from such an intervention.This single center, retrospective study examines outcomes of AHSCT in elderly patients (≥60 years old) with multiple myeloma compared to younger patients (<60 years old). Between January 1, 2011, and September 1, 2015, 93 patients met the inclusion criteria and were included in the study. Patients signed an informed consent and the ethics committee of our institution approved the study. Toxicity was analyzed according to age and HCT-CI. Progression-free-survival (PFS) and overall survival (OS) were analyzed according to age at the time of transplantation, HCT-CI, Revised International Staging System (R-ISS) and disease status at the time of transplant.From the 93 patients included in the study, 49(53%) were included in the younger patient group with a median age at transplant of 54 years-old (range 34 to 59). Forty-four (44) patients were included in the older patient group with a median age at transplant of 65 years-old (range 60 to70). Two thirds (66%) of patients were male. Based on the R-ISSS score, 46% were stage I, 54% were stage II and none were stage III. HCT-CI score was low, intermediate and high in 40%, 32% and 28% of patients respectively. Median karnofsky index was 90 (range 70 to 100). Acute renal failure was more frequent in the older group (p=0,028) at multiple myeloma diagnostic. Light chain disease was more frequent in the younger patient group with 19% compared to 3% (p=0,09). Mucositis was similar in occurrence in both groups with only 5% of grade ≥3 mucositis. No parenteral alimentation was required in the older patient group while 4 patients required it in the younger patient group(p=0,053). The incidence of febrile neutropenia was universal in all patients (100%) within the cohort. The incidence of septic shock and admission to intensive care unit was only 1%. Delirium was diagnosed in 2 older patients (p=0,131). There was no difference in toxicity profile when comparing both groups. Median engraftment for neutrophils was 14 days and 16 days for platelets. Median hospital stay duration was 21 days. Intravenous antibiotics were used a median time of 8 days. There was no difference in resources used during transplant in both groups. Median CD4 count was comparable in both groups at 3 months and at 1 year after transplant. With a median follow-up of 37 months (range 2 to 70), our cohort had a PFS of 24 months with no difference between younger and older patient groups(p=0,234). The median OS was not reached at the time of evaluation for both groups. Estimated 4 years PFS was 21% and OS was 81%. There was no difference between our younger and older patient cohorts (figure 1 and 2). Being in stable or progressive disease was associated with worse PFS (median of 9 months versus 26 months, p<0,0005)(figure 3). Our 1 year NRM was 0% in both groups.In conclusion, AHSCT is a good treatment option in well-selected patients. Comorbidities must be considered and HCT-CI can help clinicians choose carefully those patients. Our study demonstrates that age should not be the limiting factor when considering ASCT in older patients. Toxicity and survival were comparable in both groups. Best timing when to proceed to ASCT is still in investigation. Considering the significantly worse PFS with chemoresistant disease, other treatment options should be considered before AHSCT without age being a consideration. [Display omitted] DisclosuresDelage:AbbVie: Research Funding; Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Research Funding; Pfizer: Research Funding.

Dual immune check point blockade or immune check point-tyrosine kinase inhibitor combination: as a first-line treatment in metastatic renal cell carcinoma?

To discuss treatment decisions in the first-line setting of metastatic renal cell carcinoma (mRCC). Immune check point inhibitor (ICI) combinations have replaced sunitinib as the standard of care in the first-line treatment of mRCC. Dual ICI treatment with nivolumab and ipilimumab was shown to significantly improve overall survival and objective response rates. Similarly, the ICI-tyrosine kinase inhibitor combinations pembrolizumab and axitinib and nivolumab and cabozantinib have demonstrated superiority in terms of overall survival, objective response rates and progression-free survival versus sunitinib. The lack of both comparative trials and predictive markers impedes individualized treatment decisions. Clinicians are left to make treatment choices based on clinical and biological factors. These factors may include differences in toxicity profiles, the rate of complete remission, a clinical situation that requires urgent tumor shrinkage, the presence of inflammation, histological or immune-histochemical features and others. In the absence of comparative trials, clinical and biological factors may facilitate the choice between various treatment options in the first-line setting of mRCC. In addition, both the experience of the physician with a specific treatment together with patient's preferences and expectations of systemic therapy may be part of the decision-making process.

On the properties of the toxicity index and its statistical efficiency.

Cancer clinical trials typically generate detailed patient toxicity data. The most common measure used to summarize patient toxicity is the maximum grade among all toxicities and it does not fully represent the toxicity burden experienced by patients. In this article, we study the mathematical and statistical properties of the toxicity index (TI), in an effort to address this deficiency. We introduce a total ordering, (T‐rank), that allows us to fully rank the patients according to how frequently they exhibit toxicities, and show that TI is the only measure that preserves the T‐rank among its competitors. Moreover, we propose a Poisson‐Limit model for sparse toxicity data. Under this model, we develop a general two‐sample test, which can be applied to any summary measure for detecting differences among two population of toxicity data. We derive the asymptotic power function of this class as well as the asymptotic relative efficiency (ARE) of the members of the class. We evaluate the ARE formula empirically and show that if the data are drawn from a random Poisson‐Limit model, the TI is more efficient, with high probability, than the maximum and the average summary measures. Finally, we evaluate our method on clinical trial toxicity data and show that TI has a higher power in detecting the differences in toxicity profile among treatments. The results of this article can be applied beyond toxicity modeling, to any problem where one observes a sparse array of scores on subjects and a ranking based on extreme scores is desirable.

Evaluation of the anti-inflammatory effects of synthesised tanshinone I and isotanshinone I analogues in zebrafish.

During inflammation, dysregulated neutrophil behaviour can play a major role in a range of chronic inflammatory diseases, for many of which current treatments are generally ineffective. Recently, specific naturally occurring tanshinones have shown promising anti-inflammatory effects by targeting neutrophils in vivo, yet such tanshinones, and moreover, their isomeric isotanshinone counterparts, are still a largely underexplored class of compounds, both in terms of synthesis and biological effects. To explore the anti-inflammatory effects of isotanshinones, and the tanshinones more generally, a series of substituted tanshinone and isotanshinone analogues was synthesised, alongside other structurally similar molecules. Evaluation of these using a transgenic zebrafish model of neutrophilic inflammation revealed differential anti-inflammatory profiles in vivo, with a number of compounds exhibiting promising effects. Several compounds reduce initial neutrophil recruitment and/or promote resolution of neutrophilic inflammation, of which two also result in increased apoptosis of human neutrophils. In particular, the methoxy-substituted tanshinone 39 specifically accelerates resolution of inflammation without affecting the recruitment of neutrophils to inflammatory sites, making this a particularly attractive candidate for potential pro-resolution therapeutics, as well as a possible lead for future development of functionalised tanshinones as molecular tools and/or chemical probes. The structurally related β-lapachones promote neutrophil recruitment but do not affect resolution. We also observed notable differences in toxicity profiles between compound classes. Overall, we provide new insights into the in vivo anti-inflammatory activities of several novel tanshinones, isotanshinones, and structurally related compounds.

Yttrium-90 Radioembolization in Intrahepatic Cholangiocarcinoma: A Multicenter Retrospective Analysis

PurposeTo report outcomes of yttrium-90 (90Y) radioembolization in patients with unresectable intrahepatic cholangiocarcinoma (ICC). Materials and MethodsRetrospective review was performed of 115 patients at 6 tertiary care centers; 92 were treated with resin microspheres (80%), 22 were treated with glass microspheres (19%), and 1 was treated with both. Postintervention outcomes were compared between groups with χ2 tests. Survival after diagnosis and after treatment was assessed by Kaplan–Meier method. ResultsGrade 3 laboratory toxicity was observed in 4 patients (4%); no difference in toxicity profile between resin and glass microspheres was observed (P = .350). Clinical toxicity per Society of Interventional Radiology criteria was noted in 29 patients (25%). Partial response per Response Evaluation Criteria In Solid Tumors 1.1 was noted in 25% of patients who underwent embolization with glass microspheres and 3% of patients who were treated with resin microspheres (P = .008). Median overall survival (OS) from first diagnosis was 29 months (95% confidence interval [CI], 21–37 mo) for all patients, and 1-, 3-, and 5-year OS rates were 85%, 31%, and 8%, respectively. Median OS after treatment was 11 months (95% CI, 8–13 mo), and 1- and 3-year OS rates were 44% and 4%, respectively. These estimates were not significantly different between resin and glass microspheres (P = .730 and P = .475, respectively). Five patients were able to undergo curative-intent resection after 90Y radioembolization (4%). ConclusionsThis study provides observational data of treatment outcomes after 90Y radioembolization in patients with unresectable ICC.

204P - Evolution in the risk of adverse events of adjuvant endocrine therapy in postmenopausal women with early-stage breast cancer

BackgroundAdjuvant endocrine therapy is a gold standard in early-stage, hormone receptor-positive breast cancer. In postmenopausal women aromatase inhibitors (AIs) are associated with improved outcome compared to tamoxifen monotherapy. Differences in the toxicity profiles of these drugs are described, however, little is known about whether the risk of adverse events changes over time. MethodsSequential reports of large, randomized, adjuvant endocrine therapy trials comparing AIs to tamoxifen were reviewed. Data on pre-specified adverse events were extracted including cardiovascular events, bone fractures, cerebrovascular disease, endometrial cancer, other secondary malignancies, venous thrombosis and death without recurrence. Odds ratios (ORs) were calculated for serial publications over follow-up. The change in the ORs for adverse events over time was evaluated using weighted linear regression. ResultsAnalysis included 22 reports of 7 trials reporting outcomes between 25.8 and 120 months of follow-up. Over time, the differences in toxicity profiles between AIs and tamoxifen did not change significantly (Table). Compared to tamoxifen, longer duration of AI use was associated with a non-significant reduction in the OR for bone fracture and a non-significant increase in the OR for thromboembolic events.Table204PTableEventβpFractures-0.4310.084Cardiovascular events-0.1890.557Cerebrovascular disease0.0880.823Thromboembolic events0.3890.169Secondary cancer0.2270.365Endometrial cancer-0.1040.671Death without recurrence0.0430.852 ConclusionsDifferences in toxicity profiles between adjuvant AIs and tamoxifen do not change significantly over time. Drug-specific toxicity (e.g. bone fractures with AI and thromboembolism with tamoxifen) may fall over time and after discontinuation of treatment. Legal entity responsible for the studyThe authors. FundingHas not received any funding. DisclosureE. Amir: Speaker Bureau / Expert testimony: Genentech/Roche; Advisory / Consultancy: Apobiologix; Advisory / Consultancy: Agendia; Advisory / Consultancy: Myriad Genetics. H. Goldvaser: Honoraria (self): Roche. R. Yerushalmi: Honoraria (self): Roche; Honoraria (self): Medison; Honoraria (self): AstraZeneca; Honoraria (self): Novartis; Honoraria (self): Teva. All other authors have declared no conflicts of interest.

Systematic review and meta-analysis of selected toxicities of approved ALK inhibitors in metastatic non-small cell lung cancer

IntroductionAnaplastic lymphoma kinase (ALK) inhibitors are the mainstay treatment for patients with non-small cell lung carcinoma (NSCLC) harboring a rearrangement of the ALK gene or the ROS1 oncogenes. With the recent publication of pivotal trials leading to the approval of these compounds in different indications, their toxicity profile warrants an update.Materials and MethodsA systematic literature search was performed in July 2017. Studies evaluating US FDA approved doses of one of the following ALK inhibitors: Crizotinib, Ceritinib, Alectinib or Brigatinib as monotherapy were included. Data were analyzed using random effects meta-analysis for absolute risks (AR), study heterogeneity, publication bias and differences among treatments.ResultsFifteen trials with a total of 2,005 patients with evaluable toxicity data were included in this report. There was significant heterogeneity amongst different studies. The pooled AR of death and severe adverse events were 0.5% and 34.5%, respectively. Grade 3/4 nausea, vomiting, diarrhea, and constipation were uncommon: 2.6%, 2.5%, 2.7%, 1.2%, respectively.ConclusionsALK inhibitors have an acceptable safety profile with a low risk of treatment-related deaths. Important differences in toxicity profile were detected amongst the different drugs.

Oxygen content determines the bio-reactivity and toxicity profiles of carbon black particles

In spite of the considerable efforts invested to understand the environmental health and safety (EHS) impacts of ultrafine particles, such as the representative PM2.5, there are still significant knowledge gaps to be filled. No conclusive understandings have been obtained about the physicochemical determinants in accounting for differential adverse outcomes. Here we compared the cytotoxicity of four carbon black (CB) particles with similar physicochemical properties except for their oxygen contents (C824455 < C1864 < Printex U < SB4A). We found that these four CB particles manifested in vitro and in vivo cytotoxicity reversely related to their oxygen contents, namely a hierarchy of cytotoxicity: C824455 > C1864 > Printex U > SB4A. Among these CB particles, the most significant lung injury (e.g. collapses and inflammation) and macrophagic activation were found for C824455 and C1864, in particular for C824455. All these differences in toxicity profiles, including in vitro and in vivo cytotoxicity, pro-inflammatory effects and direct damages to the lung epithelia, should be (at least partially) ascribed to the oxygen content in these CB particles that in turn determined their transformation, i.e. the different aggregation states. Nonetheless, PM2.5 likewise caused severe in vivo and in vitro toxicities to the lung cells and macrophages. This study thus offers more insights into the structure-activity relationship (SAR) and opens a new avenue to elucidate the physicochemical determinants in evoking lung injuries by ultrafine airborne particles.

HLA-G 3'UTR Polymorphisms Predict Drug-Induced G3-4 Toxicity Related to Folinic Acid/5-Fluorouracil/Oxaliplatin (FOLFOX4) Chemotherapy in Non-Metastatic Colorectal Cancer.

Polymorphisms in drug-metabolizing enzymes might not completely explain inter-individual differences in toxicity profiles of patients with colorectal cancer (CRC) that receive folinic acid/5-fluorouracil/oxaliplatin (FOLFOX4). Recent data indicate that the immune system could contribute to FOLFOX4 outcomes. In light of the immune inhibitory nature of human leukocyte antigen-G (HLA-G), a non-classical major histocompatibility complex (MHC) class I molecule, we aimed to identify novel genomic markers of grades 3 and 4 (G3-4) toxicity related to FOLFOX4 therapy in patients with CRC. We retrospectively analyzed data for 144 patients with stages II-III CRC to identify HLA-G 3′ untranslated region (3′UTR) polymorphisms and related haplotypes and evaluate their impact on the risk of developing G3-4 toxicities (i.e., neutropenia, hematological/non-hematological toxicity, neurotoxicity) with logistic regression. The rs1610696-G/G polymorphism was associated with increased risk of G3-4 neutropenia (OR = 3.76, p = 0.015) and neurotoxicity (OR = 8.78, p = 0.016); rs371194629-Ins/Ins was associated with increased risk of neurotoxicity (OR = 5.49, p = 0.027). HLA-G 3′UTR-2, which contains rs1610696-G/G and rs371194629-Ins/Ins polymorphisms, was associated with increased risk of G3-4 neutropenia (OR = 3.92, p = 0.017) and neurotoxicity (OR = 11.29, p = 0.009). A bootstrap analysis confirmed the predictive value of rs1610696 and rs371194629, but the UTR-2 haplotype was validated only for neurotoxicity. This exploratory study identified new HLA-G 3′UTR polymorphisms/haplotypes as potential predictive markers of G3-4 toxicities in CRC.

Toxicity profile differences of adjuvant docetaxel/cyclophosphamide (TC) between Asian and Caucasian breast cancer patients.

For early-stage breast cancer, four cycles of docetaxel and cyclophosphamide (TC) was proven superior to doxorubicin plus cyclophosphamide in the US Oncology 9375 trial. Given primary prophylactic antibiotics, 5% febrile neutropenia was recorded in a population comprising 75.5% Caucasians. Smaller trials and retrospective studies reviewing TC use in Asian patients did not produce similar incidence rates. This study aims to discover the variable hematological toxicities with TC use in Caucasian and Asian patients. Breast cancer data was retrospectively reviewed for patients receiving adjuvant docetaxel 60-75 mg/m2 plus cyclophosphamide 600 mg/m2 from six countries (China, Hong Kong, Japan, Taiwan, Italy, and United States). Similar number of patients with relatively balanced baseline characteristics were chosen for analysis of hematological and nonhematological toxicities and survival data. From March 2004 to July 2013, data of 227 patients (127 Asians and 100 Caucasian) patients were analyzed for treatment-related toxicities. During the four cycles of TC, Asians had a significantly higher rate of grade ≥2 neutropenia than Caucasians (45.7% vs 6.0%; P <0.001) and significantly more grade ≥3 neutropenia events were documented (respectively 30.7% vs 4.0%, P <0.001). The prophylactic use of G-CSF was similar; 26.0% in Asians and 28.0% in Caucasian (P = 0.764). There were no differences in nonhematological toxicities. No significant difference in disease-free survival was observed between Asians and Caucasians (log-rank P = 0.910). Ethnic differences in toxicity profile exist between Asian and Caucasian patients given adjuvant TC. Over 30% Asians but less than 5% Caucasians experienced grade ≥3 neutropenia.

Cabozantinib for Renal Cell Carcinoma: Current and Future Paradigms.

Cabozantinib was approved by the FDA in April 2016 for the treatment of advanced renal cancer, pretreated with at least one prior antiangiogenic therapy. This is the first agent in the therapy of kidney cancer to show a statistically significant improvement in all three endpoints of clinical efficacy, response rate, progression free survival, and overall survival (OS), in a phase III randomized trial. The reporting of METEOR coincided with that of the Checkmate 025 study which randomized similarly eligible patients to receive nivolumab or everolimus 10mg daily. As the drug development has occurred in parallel for cabozantinib and nivolumab, no evidence exists for decision making regarding optimal sequencing of these agents. A third option of lenvatinib and everolimus was also rapidly approved based on a phase II randomized trial demonstrating promising magnitude of improvement in response, progression-free survival (PFS), and OS. The differences in toxicity profiles, duration and toxicities of prior therapy, presence of brain metastases, concomitant immunosuppressive therapies, or autoimmune conditions are the factors that are taken into account when choosing therapy. The patients who have demonstrated response, prolonged clinical benefit and tolerability, and with anti-VEGF therapy are likely to benefit from continued antiangiogenic activity combined with MET and HGF inhibition with cabozantinib at progression. The patients who have intolerance or poor response to anti-VEGF TKI should be switched to nivolumab as the preferential therapy of choice. Clearly, better predictors are required to aid in guiding therapeutic decisions. The CABOSUN trial will likely shift the entire paradigm. The CABOSUN trial demonstrated superior PFS and response rates favoring cabozantinib as compared to sunitinib in untreated, intermediate, or poor-risk RCC and can be predicted to become the front-line therapy of choice. Immune-based regimens such as the combinations of nivolumab+ipilimumab and bevacizumab+atezolizumab have completed phase III trials, comparing to sunitinib, and results are awaited. In the future, a similar clinical dilemma will be shifted to the front-line therapy and the nuances of trial eligibility, and patient comorbidities will remain important factors. Optimal sequencing and predictive biomarkers are the questions that need to be incorporated in future clinical trials within RCC.

Acute Toxicity and Quality of Life in Patients With Prostate Cancer Treated With Protons or Carbon Ions in a Prospective Randomized Phase II Study—The IPI Trial

The purpose of this study was to compare safety and feasibility of proton therapy with that of carbon ion therapy in hypofractionated raster-scanned irradiation of the prostate, in a prospective randomized phase 2 trial. In this trial, 92 patients with localized prostate cancer were enrolled. Patients were randomized to receive either proton therapy (arm A) or carbon ion therapy (arm B) and treated with a total dose of 66 Gy(relative biological effectiveness [RBE]) administered in 20 fractions (single dose of 3.3 Gy[RBE]). Patients were stratified by the use of antihormone therapy. Primary endpoint was the combined assessment of safety and feasibility. Secondary endpoints were specific toxicities, prostate-specific antigen progression-free survival (PFS), overall survival (OS), and quality of life (QoL). Ninety-one patients completed therapy and have had a median follow-up of 22.3 months. Among acute genitourinary toxicities, grade 1 cystitis rates were 34.1% (39.1% in A; 28.9% in B) and 17.6% grade 2 (21.7% in A; 13.3% in B). Seven patients (8%) required urinary catheterization during treatment due to urinary retention, 5 of whom were in arm A. Regarding acute gastrointestinal toxicities, 2 patients treated with protons developed grade 3 rectal fistulas. Grade 1 radiation proctitis occurred in 12.1% (13.0% in A; 11.1% in B) and grade 2 in 5.5% (8.7% in A; 2.2% in B). No statistically significant differences in toxicity profiles between arms were found. Reduced QoL was evident mainly in fatigue, pain, and urinary symptoms during therapy and 6 weeks thereafter. All European Organization for Research and Treatment of Cancer QLQ-C30 and -PR25 scores improved during follow-up. Hypofractionated irradiation using either carbon ions or protons results in comparable acute toxicities and QoL parameters. We found that hypofractionated particle irradiation is feasible and may be safe. Due to the occurrence of gel in the rectal wall and the consecutive occurrence of 2 rectal fistulas, we stopped using the insertion of spacer gel. Longer follow-up is necessary for evaluation of PFS and OS. (Ion Prostate Irradiation (IPI); NCT01641185; ClinicalTrials.gov.).

713P - Activity, Efficacy and Safety of Nab-Paclitaxel (Nab-P) and Gemcitabine (G) in Advanced Pancreatic Cancer (Apdac) Elderly Patients

ABSTRACT Aim: Nab-P and G combination represents a standard of care in APDAC first line therapy (CT) and it seems to be active and effective also in pretreated pts. Activity, efficacy and safety of Nab-P + G have not been established in elderly patients and clinical trials on APDAC treatment contain fewer elderly patients compared with everyday clinical practice. Aim of our retrospective analysis is to investigate outcomes and toxicities of elderly pts treated with Nab-P + G. Methods: 61 APDAC pts aged ≥65 receiving Nab-P 125 mg/m2 and G 1000 mg/m2 on days 1,8 and 15 of a 28 day cycle as first (39 pts, 64%) or further (22 pts, 36%) line of CT were included in our analysis for activity (Disease Control Rate, DCR: Stable Disease + Partial Response + Complete Response, SD + PR + CR), efficacy (Progression Free Survival, PFS and Overall Survival, OS) and safety. OS and PFS were estimated with Kaplan-Meyer method with 95% CI. Univariate and multivariate analysis were performed using Cox-regression model. Results: 61 pts, median age 69 (range 65-83; 48% pts ≥70 years) and ECOG Performance Status of 0/1/2: 24/26/11 respectively, were included in our analysis. 44 pts (72%) had liver metastases, 21 (34.4%) had multiple metastatic sites and biliary stent was present in 10 pts (16.4%). 14 SD, 9 PR (DCR: 59%) were observed in first line CT pts and 9 SD, 2 PR (DCR 50%) were recorded in pretreated pts. Median PFS was 6 months (mo) (95% CI 3.9-8.1) and 3.5 mo (95% CI 1.6-5.4) in first line and pretreated pts, with median OS of 9.5 (95% CI 7.3-11.7) and 6 mo (95% CI 4.2-7.8) in first line and pretreated pts respectively. Age ≥70 was not significantly associated to PFS and OS at univariate and multivariate analysis. Treatment was well tolerate with no G4 events, 15 (24.5%) G3 neutropenia, 6 (9.8%) G3 thrombocytopenia, 2 (3.2%) G3 anemia, 8 (13%) G3 fatigue, 4 (6.6%) G3 diarrhea and neurotoxicity. Dose reduction was needed in 18 (29.5%) pts. No significative differences in toxicity profile and dose reductions were observed in ≥70 years pts. Conclusions: These data show that APDAC elderly pts may benefit from Nab-P and G combination as well as younger population both in terms of responses and survival, in first line CT as well as further lines, experiencing a low toxicity profile. Disclosure: All authors have declared no conflicts of interest.