Maintaining Dose Intensity Research Articles

Use of empegfilgrastim for primary prevention of febrile neutropenia in patients receiving myelosuppressive therapy. Experience of the Arkhangelsk Clinical Oncological Dispensary

Background. Granulocyte colony-stimulating factors (G-CSFs) are used in oncology practice for prevention of febrile neutropenia caused by cytotoxic chemotherapy. Despite the proven safety of G-CSFs use in randomized clinical trials and in real clinical practice, clinicians have questions about the tolerability of this group of drugs.Aim. To demonstrate the safety profile of a long-acting G-CSF produced in Russia which was used to prevent febrile neutropenia and maintain dose intensity of drug therapy in patients with various solid tumors undergoing chemotherapy at the Arkhangelsk Clinical Oncological Dispensary.Materials and methods. The retrospective analysis included patients with a confirmed diagnosis of malignant neoplasm who received various chemotherapy regimens that required the inclusion of G-CSF. For primary prevention of febrile neutropenia, patients were prescribed empegfilgrastim (Extimia®) at a dose of 7.5 mg subcutaneously once per course of chemotherapy.Results. Data of 151 patients were analyzed for the period from July 2021 to April 2023. The average age was 57 years (28–75). The group of elderly patients (over 65 years) consisted of 38 (25 %) patients. The majority of patients were diagnosed with breast cancer (56 (37 %) patients) and gastric cancer (37 (25 %) patients). The number of empegfilgrastim injections over the entire observation period was 773. Adverse reactions associated with the use of empegfilgrastim were registered in 13 (8.6 %) patients, the most common of which was grade 1–2 leukocytosis according to the CTCAE v.5 classification. One patient developed a serious adverse reaction: grade 4 neutropenia according to the CTCAE v.5 classification. A subgroup of patients with metastatic pancreatic cancer treated with FOLFIRINOX was analyzed separately to assess the relative dose intensity of the chemotherapy courses. Nine patients with metastatic pancreatic cancer received FOLFIRINOX therapy with a median of 8 (5–12) courses. A total of 69 chemotherapy cycles were administered to 9 patients with a median of 7.5 (2–13) cycles. The relative dose intensity of the chemotherapy courses was 83.71 ± 19.33.Conclusion. Empegfilgrastim has shown a favorable safety and tolerability profile in patients with various solid tumors in real-world clinical practice including the highly toxic FOLFIRINOX regimen.

The importance of early-stage blood pressure control in thyroid cancer patients treated with lenvatinib from the perspective of dose intensity.

Lenvatinib (LEN) is a multikinase inhibitor that strongly inhibits tyrosine kinase receptors, especially VEGFR-2, which can cause hypertension, as well as strong tumor shrinkage. Though control of any side effects (SEs) is important for maintaining dose intensity (DI), hypertension is particularly important, because blood pressure (BP) can change quickly and respond to LEN administration and withdrawal, and it can be controlled with antihypertensive medications. Focusing on the early phase of treatment, the effect of BP 8 weeks after LEN initiation (BP8w) on DI at 8 weeks (DI8w) was investigated. The subjects were 85 thyroid cancer patients who started LEN at 24 mg/day and continued for ≥8 weeks. The BP at the start of LEN (BPbase), BP8w grade, and DI8w were examined. Median (range) systolic BP changed significantly from BPbase of 117 (84-167) mmHg to BP8w of 134 (103-168) mmHg (p<0.001). Antihypertensive treatment at baseline, systolic BPbase, and male sex were related to higher DI8w on multivariate analysis. The median DI8w of the 23 patients who required dose modification due to hypertension was 20.2 mg/day (n=6) in grade 1, 15.8 mg/day (n=13) in grade 2, and 14.5 mg/day (n=4) in grade 3, showing a trend toward lower DI8w as the grade level increased. LEN can increase BP by 20 mmHg at 8 weeks even with intensive antihypertensive management. Baseline antihypertensive treatment and BPbase can affect DI8w. A higher DI8w may be achieved by aiming for a low 8-week BP with more intensive antihypertensive therapy after LEN initiation.

An Analysis of Ruxolitinib Dosing for Myelofibrosis in Real-World Practice

Background: Myelofibrosis (MF) is a myeloid neoplasm characterized by splenomegaly, constitutional symptoms, and cytopenias. Notably, worsening cytopenias in MF patients is directly correlated with poor survival ( Coltro, et al. Blood Cancer J. 2022;12(8):116). The JAK1/2 inhibitor ruxolitinib (RUX) is effective in decreasing splenomegaly and improving symptom control at starting doses of 30-40 mg total daily dose (TDD), though drug-induced cytopenias often lead to significant dose reductions. Doses of ≤20 mg TDD are associated with decreased efficacy for spleen response, and doses of ≤10 mg TDD demonstrate minimal efficacy for spleen or symptom reduction ( Verstovsek, et al. Onco Targets Ther. 2014;7:13-21). Treating with less clinically effective doses may not be optimal in light of newer, less myelosuppressive JAK2 inhibitors that can be administered without dose reduction, regardless of baseline cytopenias. This study describes RUX dosing patterns in real-world community practice. Methods: This retrospective, observational study included deidentified data of adult patients from the IntegraConnect PrecisionQ database (~80% community practice) with MF treated with first-line RUX and with ≥2 office visits (with a criterion of 2 MF diagnosis codes reported within 180 days) from January 2016 to July 2022. Patients were stratified by baseline platelet count (PLT). Data on RUX TDD at initiation and at first dose modification were collected, with a focus on less clinically effective dosing of ≤20 mg TDD and ≤10 mg TDD. Results: Of 129 patients on RUX with a median age of 75 (range: 42-89) years, 61% (n=79) had PLT &amp;gt;200x10 9/L, 19% (n=24) had PLT 100-200x10 9/L, and 20% (n=26) had PLT &amp;lt;100x10 9/L. Across all PLT strata, 88% (n=114) were initiated on RUX at a TDD of ≤20 mg, and 51% (n=66) were started at a TDD ≤10 mg. Nearly half of patients with higher baseline platelet counts (&amp;gt;100 x 10 9/L) were started on doses ≤10 mg TDD (Fig 1). Among 79 patients with PLT &amp;gt;200x10 9/L, starting RUX TDD was ≤20 mg in 87% (n=69) and ≤10 mg in 43% (n=34). A total of 49 patients underwent subsequent dose modification (median time [min, max]: 47 days [10, 1336], with 19 dose increases vs 30 dose decreases. Of patients whose dose increased, only 4 escalated to a TDD &amp;gt;20 mg. Despite dose modification, RUX TDD remained ≤20 mg in 90% (44/49) and ≤10 mg in 43% (21/49) of patients. Similar to patients with baseline PLT &amp;gt;200x10 9/L, the majority of patients with PLT 100-200x10 9/L started on TDD ≤20 mg (87.5% [21/24]), with a high proportion on ≤10 mg (50% [12/24]). Among the 103 patients with PLT &amp;gt;100x10 9/L for whom a recommended starting dose is provided in the RUX package insert, 88% (91/103) initiated RUX below the recommended dose. Of the 61 patients who underwent subsequent dose modification (median time: 47 days [10, 1336], only 10% (6/61) were escalated to a dose recognized as clinically effective. Conclusions: These real-world data suggest that a majority of patients starting RUX, including those with PLT &amp;gt;200x10 9/L, are initiated on ≤20 mg TDD, and the majority of patients are not titrated up to the doses tested in the pivotal studies that led to RUX approval. These data suggest that clinicians are hesitant to prescribe RUX at doses known to be clinically effective. Together with the timing of dose modification, this suggests that there may be concerns related to toxicity or treatment-related cytopenias. Recognizing that JAK2 inhibition remains an important part of managing MF for patients, clinicians now have alternative treatment options. These newer treatments inhibit additional pathways (IRAK1/ACVR1), are less myelosuppressive, and can maintain dose intensity regardless of baseline platelet count. Study funded by CTI BioPharma Corp., a Sobi Company.

Autologous Stem Cell Transplant in Lymphoma Using a Noncryopreserved Platform: An Adapted Sequential Conditioning Maintaining Dose Intensity Does not Affect Transplantation Outcomes

Hematopoietic autologous stem cell transplantation (ASCT) is a validated therapeutic strategy for lymphoma treatment and precise well-tolerated conditioning. Several conditioning methods are available, but the most commonly used are CVB, BEAM, and ICE, which are conventionally administered in 6 to 7 days. Since 2015, our program has moved toward noncryopreserved platforms that require concise times; therefore, we have modified the conditioning by reducing it to 4 to 5 days. In this study, we show our experience. We compared ASCT performed in our program before and after 2015 in lymphoma patients. Between 2000 and 2014 and from 2015 to 2022, we performed 46 and 61 ASCT procedures, respectively. Since 2015, we observed a greater number of infused stem cells, fewer episodes of febrile neutropenia (60% vs. 37% P=.008), shorter hospitalizations (30 vs. 18 days P=.001), faster engraftment (20 vs. 14 days P=.001) and better progression-free survival (72 vs. 44 months P=.002). Additionally, a prolonged overall survival was observed at these results, and this prolonged survival is difficult to interpret due to the short follow-up. In conclusion, conditioning adjusted for a noncryopreserved strategy offers at least similar or even better results than the cryopreserved strategy. Prospective studies are warranted.

Long-term safety with ≥12 months of pirtobrutinib in relapsed/refractory (R/R) B-cell malignancies.

7513 Background: While Bruton tyrosine kinase inhibitors (BTKi) can induce sustained remissions, ongoing response requires continuous treatment and thus long-term safety/tolerability is critical for adherence, maintaining dose intensity, and delivering maximum efficacy. Pirtobrutinib is a highly selective, non-covalent (reversible) BTKi approved by the FDA in January 2023 for R/R mantle cell lymphoma after 2 prior lines of therapy including a BTKi. Pirtobrutinib has demonstrated promising efficacy with low discontinuation and dose reduction rates in patients (pts) with multiple subtypes of R/R B-cell malignancies. However, the long-term safety and tolerability of pirtobrutinib has not yet been reported. Here we report the clinical safety in pts with long-term (≥12 months) pirtobrutinib treatment from the phase 1/2 BRUIN trial. Methods: Pts with R/R B-cell malignancies who received ≥12 months of pirtobrutinib were included. Median time to onset, dose reduction, discontinuation, and cumulative incidence rates were determined for treatment emergent adverse event (TEAE) that occurred in ≥20% of pts and select AE of interest associated with BTKi. Results: As of 29 July 2022, 773 pts were enrolled, and 326 (42%) pts received treatment for ≥12 months. Among these 326 pts, median time on treatment was 19 months (IQR: 16,25), with 231 (71%) remaining on pirtobrutinib. The most common TEAE (all grade, regardless of attribution) in this long-term 326 pt cohort were fatigue (32%), diarrhea (31%), Covid-19 (29%), contusion (26%), cough (25%), and back pain (21%). TEAE leading to dose reduction or discontinuation occurred in 23 (7%) and 11 (3%) pts, respectively. Four (1%) pts discontinued due to a treatment-related AE, and 1 pt had a fatal treatment-related AE (Covid-19 pneumonia). Select AE of interest for the long-term pts are shown in the Table. Comprehensive safety analyses describing the frequency of TEAE over time will be presented. Conclusions: Prolonged pirtobrutinib therapy continues to demonstrate a safety profile amenable to long-term administration at the recommended dose without evidence of new or worsening toxicity signals. The safety and tolerability observed in pts on therapy for ≥12 months was similar to previously published safety analyses on all pts enrolled regardless of follow-up. Clinical trial information: NCT03740529 . [Table: see text]

442P Dose intensity and tolerance of modified FOLFIRINOX in patients with advanced cancer

Modified FOLFIRINOX is the standard of care for advanced pancreatic cancer and has expanded application in biliary tract and colorectal cancers. Despite its efficacy, real world data suggests nearly 75% of patients are unable to maintain dose intensity leading to reduction in efficacy and survival. We proposed to evaluate the dose intensity (DI) and toxicity of patients planned for mFOLFIRINOX.

Tivozanib (T) as first-line (1L) treatment of metastatic renal cell carcinoma (mRCC): A real-world outcome review in North-West of England (NWE), UK.

335 Background: The TIVO-1 study demonstrated improved PFS in mRCC patients (pts) undergoing 1L treatment with T compared with sorafenib. We previously presented outcomes of our experience of T in 4 cancer centres in NWE. Here we present updated outcomes with longer follow-up (FU). Methods: mRCC pts commencing 1L T March 2017- May 2019 were identified. Outcomes of interest included overall response rate (ORR), survival (OS, PFS) and toxicity. Data cut off for this update was 30/11/2020. Results: 113 pts were identified with characteristics as in the table. Median FU was 25.9 mo (18.3-44.7mo), 18% pts remain on treatment at data cut-off. 88.5% commenced T at full dose, of which 67% maintained dose intensity. 11.5% commenced T with dose reduction due to prior TKI toxicities or comorbidities. Median number of cycles was 7 (1-33). In terms of efficacy, ORR was 29% (CR 0%, PR29%, SD39%, PD26%, NE 6%) and median PFS was 9.0 months (95% C.I. 6.0-12.1mo). Median PFS by IMDC risk group was: F= 23.0 months (95% C.I. 7.6-38.4mo); I= 10.0 months (95% C.I. 6.3-13.7mo); P= 3.0 months (95% C.I. 1.5.- 4.5mo), p value&lt;0.0001. Median OS was 25.0 months (95% C.I. 15.4-34.6mo). Median OS by IMDC risk group was: F= NR with 72% alive at data cut-off; I= 26.0 months (95% C.I. 17.9-34.1mo); P= 7.0 months (95% C.I. 4.4-9.6mo), p value&lt;0.0001. Adverse events (AEs) of any grade occurred in 77% (≥G3 13%) including fatigue 42% (≥G3 0%), diarrhoea 19% (≥G3 &lt; 1%), mucositis 24% ( ≥G3 2%), anorexia 12% (≥G3 &lt; 1%); and hypertension 7% (≥G3 2%). Notable ≥G3 events included abnormal liver function 3%; vascular events 2% and seizure &lt; 1%. 18% of patients discontinued treatment due to toxicity with no treatment-related deaths. Conclusions: Our real world experience of 1L T suggests comparable activity with randomized data and other TKIs, particularly in F and I IMDC risk groups. The low incidence of serious AEs makes it an attractive option if unsuitable for combination therapies. [Table: see text]

Clinical Impact of the Administration of FOLFIRINOX Beyond Six Months in Advanced Pancreatic Adenocarcinoma: A Cohort Study.

BackgroundAlthough a toxic regimen, FOLFIRINOX is one of the most efficient chemotherapy regimens in advanced pancreatic adenocarcinoma. There is no standard number of cycles in locally advanced or metastatic stages.Materials and methodThe present retrospective study reports the experience of a single center with this regimen administered until disease progression or unacceptable toxicity. The authors of this retrospective study analyzed the data on patients with this diagnosis treated in our clinic during 2017-2021. Forty-two patients were included in the study, 21 who received six courses or less and 21 who received more than six courses. Progression-free survival (PFS) and overall survival (OS) were analyzed according to this stratification. The oncological response was also reported according to dose reduction and treatment delay, irrespective of the number of courses administered.ResultsMedian PFS was 7.5 months, and median OS was 13.6 months in the entire studied population. When patients were compared according to the number of courses received (under six vs. over six), there were obvious differences (PFS: 5.17 months vs. 11.2, p = 0.8, OS: 8 months vs. 17.3 months, p = 0.6). However, when stratifying survival by treatment delay and the presence or absence of dose reduction, better results were seen with lower doses (p<0.001) and treatment temporization (p=0.03). The general incidence of hematologic and neurologic toxicity was higher than the ones reported in the literature.ConclusionThe study revealed that patients benefit from the administration of FOLFIRINOX for more than six months, but that the administration of full dose and the maintaining dose intensity does not necessarily favor the patient.

A phase II study of FOLFIRINOX with primary prophylactic pegfilgrastim for chemotherapy-na\xefve Japanese patients with metastatic pancreatic cancer

BackgroundAlthough FOLFIRINOX is currently one of the standard therapies for chemotherapy-naïve patients with metastatic pancreatic cancer (MPC), the high rate of febrile neutropenia (FN) presents a clinical problem. This study aimed to evaluate the safety and efficacy of primary prophylactic pegfilgrastim with FOLFIRINOX in Japanese MPC patients.MethodsFOLFIRINOX (intravenous oxaliplatin 85 mg/m2, irinotecan 180 mg/m2, levofolinate 200 mg/m2, 5-fluorouracil (5-FU) bolus 400 mg/m2 and 5-FU 46 h infusion 2400 mg/m2) and pegfilgrastim 3.6 mg on day 4 or 5, every 2 weeks was administered to previously untreated MPC patients. The primary endpoint was the incidence of FN during the first 3 cycles. The planned sample size was 35 patients, but the trial was predefined to discontinue enrollment for safety if 4 patients developed FN.ResultsAt the enrollment of 22 patients, 4 patients developed FN in the first cycle, resulting in an incidence of FN of 18% {95% confidence interval [CI], 0.5–40.3%}, and enrollment was discontinued early. The incidence of grade 3 or higher neutropenia was 36.4%. Median relative dose intensities during the initial 3 cycles of oxaliplatin, irinotecan, bolus 5-FU, infusional 5-FU, and levofolinate maintained high (100%, 89.0%, 100%, 66.0%, and 100%, respectively). Response rate and median overall survival were 54.5% (95% CI 32.7–74.9) and 15.7 months (95% CI 7.9–18.8), respectively.ConclusionsThis phase II study could not demonstrate any reduction in the incidence of FN, nevertheless some patients experience benefits for efficacy by maintaining dose intensity using prophylactic pegfilgrastim.Trial registrationhttp://www.umin.ac.jp/ctr/index-j.htm, UMIN000017538. Date of registration: May/13/2015

Impact of BMI on chemotherapy dosing and survival in endometrial cancer

Impact of BMI on chemotherapy dosing and survival in endometrial cancer

A cross-sectional study on effectiveness of antiemetic regimens for chemotherapy-induced nausea and vomiting: A single-center retrospect study of 1,000 patients.

e24100 Background: Chemotherapy-induced nausea and vomiting (CINV) is a common symptom in patients who undergoing chemotherapy, it is very important to control CINV to maintain dose intensity and patients' quality of life. To analyse the current situation of CINV for the tumor patients who undergoing chemotherapy, we used a cross-sectional survey to assess CINV status in those patients, and whether the drugs used by doctors in each department met the guidelines, and compared the efficacy of different antiemetic regimens on acute and delayed CINV overall post-chemotherapy periods. Methods: 1,000 patients were randomly selected from 5,468 patients with chemotherapy discharged from different departments of Zhejiang cancer hospital in China between April 1 and April 30, 2019, and there were 87 responses totally. Medical records were collected on patient’s department (internal medicine, surgery, radiotherapy, interventional), chemotherapy regimens, anti-vomiting program, etc. Patients' feedbacks were recorded by CTCAE4.03 standard using MASCC antiemetic tool (Mat). Participants reported the frequency, severity, and impact on daily life of CINV from the day of chemotherapy administration up to 5 days thereafter and nausea and vomiting, as well as pharmacologic and chemotherapy used. Results: A total of 66 antineoplastic drugs were investigated, of which 52 were given intravenously and 14 orally.There were 9, 7, 50 drugs with high, moderate and low emetic risk respectively.The most prescribed prophylactic regimens for the management of CINV were aprepitant, 5-HT3R, H1-RA and dexamethasone and metoclopramide. The overall incidence of CINV were 44.34%, 24.57% and 39.66% patients reported nausea or vomiting in the acute and delayed phases. 19.89% patients had both acute and delayed CINV. The consistency rate of antiemetic with guideline was 63.19% in internal medicine department, 61.41% in surgery department and 52.91% in radiotherapy department, which showed a significant gap between the actual use of drugs and the recommended guidelines(P = 0.001). In 875 patients, 518 patients received guideline recommended antiemetic regimen, the CINV rates of complete response (CR), defined as no vomiting with no rescue medication, were 61.58%. While the CR rates in other 357 patients were 47.06%(P &lt; 0.001). Nausea was more frequent across the overall observation period (43.77% VS 18.86%). However, vomiting was more sever and had a greater impact on life than nausea. Conclusions: Overall, adherence to the guideline recommendations in different departments were poor with varying degrees. Future studies should set hard outcomes, such as the absence of any symptoms, as a primary end point. The standardized management of CINV in patients need to be further strengthened and doctors need to use drugs more regularly to reduce the occurrence of CINV in patients.

A cross-sectional study on the effectiveness of antiemetic regimens for chemotherapy-induced nausea and vomiting: A single center retrospect study of 1,000 patients.

e24055 Background: Chemotherapy-induced nausea and vomiting (CINV) is a common symptom in patients who undergoing chemotherapy, it is very important to control CINV to maintain dose intensity and patients' quality of life. To analyse the current situation of CINV for the tumor patients who undergoing chemotherapy, we used a cross-sectional survey to assess CINV status in those patients, and whether the drugs used by doctors in each department met the guidelines, and compared the efficacy of different antiemetic regimens on acute and delayed CINV overall post-chemotherapy periods. Methods: 1,000 patients were randomly selected from 5,468 patients with chemotherapy discharged from different departments of Zhejiang cancer hospital in China between April 1 and April 30, 2019, and there were 87 responses totally. Medical records were collected on patient’s department (internal medicine, surgery, radiotherapy, interventional) , chemotherapy regimens, anti-vomiting program, etc. Patients' feedbacks were recorded by CTCAE4.03 standard using MASCC antiemetic tool (Mat). Participants reported the frequency, severity, and impact on daily life of CINV from the day of chemotherapy administration up to 5 days thereafter and nausea and vomiting, as well as pharmacologic and chemotherapy used. Results: A total of 66 antineoplastic drugs were investigated, of which 52 were given intravenously and 14 orally.There were 9, 7, 50 drugs with high, moderate and low emetic risk respectively.The most prescribed prophylactic regimens for the management of CINV were aprepitant, 5-HT3R, H1-RA and dexamethasone and metoclopramide. The overall incidence of CINV were 44.34%, 24.57% and 39.66% patients reported nausea or vomiting in the acute and delayed phases. 19.89% patients had both acute and delayed CINV. The consistency rate of antiemetic with guideline was 63.19% in internal medicine department, 61.41% in surgery department and 52.91% in radiotherapy department, which showed a significant gap between the actual use of drugs and the recommended guidelines(P = 0.001). In 875 patients, 518 patients received guideline recommended antiemetic regimen, the CINV rates of complete response (CR), defined as no vomiting with no rescue medication, were 61.58%. While the CR rates in other 357 patients were 47.06%(P &lt; 0.001). Nausea was more frequent across the overall observation period(43.77% VS 18.86%). However, vomiting was more sever and had a greater impact on life than nausea. Conclusions: Overall, adherence to the guideline recommendations in different departments were poor with varying degrees. Future studies should set hard outcomes, such as the absence of any symptoms, as a primary end point.The standardized management of CINV in patients needs to be further strengthened and doctors need to use drugs more regularly to reduce the occurrence of CINV in patients.

Abstract PS13-06: Lower rates of neuropathy with oral paclitaxel and encequidar (oPac+E) compared to IV paclitaxel (IVPac) in treatment of metastatic breast cancer (mBC): Study KX-ORAX-001

Abstract Background: Chemotherapy-induced peripheral neuropathy (CIPN) is a common dose-limiting toxicity associated with IVPac. Primarily sensory, CIPN is an often irreversible condition primarily affecting the hands and feet associated with pain, numbness, tingling, and sensitivity to cold and has a significant impact on quality of life and treatment tolerance. Risk of CIPN increases with age, dose intensity, cumulative dose, and preexisting conditions including diabetes. Methods: Study KX-ORAX-001 was a phase III, randomized, international study in women with mBC for whom treatment with IVPac was recommended. Eligible patients were randomized 2:1 to receive oPac+E or IVPac. Patients continued treatment until discontinuation due to progressive disease or toxicity. oPac 205 mg/m2 was given once daily for 3 days weekly. E 12.9 mg was given 1 hour before each dose of oPac. IVPac 175 mg/m2 was infused over 3 hours every 3 weeks. The primary endpoint was efficacy defined as tumor response confirmed by BICR at two consecutive evaluations. Key secondary endpoints included PFS, OS. Safety was monitored throughout the study. Results: A total of 402 mBC patients were enrolled, 265 randomized to oPac+E and 137 to IVPac (ITT population). 399 patients were treated and comprise the safety population. The confirmed response rate was significantly greater in the oPac+E group vs IVPac (35% vs 23%) for the ITT population. Median overall survival was (27.7 vs 16.7 months, ITT) at the time of the analysis. Long-term follow up for final determination of PFS and OS is ongoing.Incidence of neuropathy-related TEAEs were lower in patients receiving oPac+E vs IVPac: Overall (21% vs 64%; all grades), grade ≥3 (2% vs 15%). Cumulative risk for neuropathy with IVPac was &amp;gt;50% by week 8 and was 83% at week 88. In contrast, the cumulative risk of neuropathy with oPac+E rose slowly and plateaued at 34% at week 88. Treatment discontinuations due to neuropathy occurred only in the IVPac arm (8%). Dose reductions due to neuropathy were reported in 8% of IVPac treated patients and in 2% of oPac+E treated patients. In agreement with the lower rates of peripheral neuropathy in patients treated with oPac+E, there was lower use of medications used for the treatment of neuropathic symptoms. Use of gabapentin or pregabalin was 12% for patients receiving oPac+E vs 40% for IVPac treated patients. Conclusions: oPac+E was associated with greater efficacy in the treatment of patients with mBC and a lower incidence of neuropathy, slower onset and lesser severity of neuropathic events compared to IVPac 175mg/m2 administered every three weeks. Fewer patients receiving oPac+E required dose reduction due to neuropathy and no patients receiving oPac+E discontinued treatment due to neuropathy. Reduction in neuropathy may improve quality of life and allow longer administration of effective therapy while maintaining dose intensity. Citation Format: H S Rugo, G Umanzor, F J Barrios, R H Vasallo, M A Chivalan, S Bejarano, J R Ramirez, L Fein, R D Kowalyszyn, D L Cutler, D Kramer, J Goldfinch, H Wang, T Moore, R MF Kwan. Lower rates of neuropathy with oral paclitaxel and encequidar (oPac+E) compared to IV paclitaxel (IVPac) in treatment of metastatic breast cancer (mBC): Study KX-ORAX-001 [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS13-06.

Tolerability of Highly Protein Bound Targeted Oral Oncolytic Drugs in Patients With Hypoalbuminemia: A Retrospective Analysis.

Hypoalbuminemia is commonly observed in cancer patients. Given the pharmacokinetic interactions between serum proteins and protein bound medications, administration of highly protein bound targeted oral oncolytic drugs may result in elevated unbound drug levels and decreased tolerability in those with hypoalbuminemia. To describe the impact of hypoalbuminemia on oral oncolytic drug tolerability. A retrospective study was conducted of adult patients receiving treatment with targeted oral oncolytic drugs with ≥95% protein binding. The primary end point of this study was to compare time to discontinuation resulting from documented toxicity in those with and without hypoalbuminemia. The study included 143 patients receiving 16 targeted oral oncolytic drugs (42% with hypoalbuminemia, 58% without hypoalbuminemia). Adverse events were common, with similar incidence among patients with and without hypoalbuminemia (73% vs 76%, respectively; P = 0.727). Median time to therapy discontinuation resulting from documented toxicity was significantly shorter in those with hypoalbuminemia (22 months vs not reached; P = 0.003). Cox regression demonstrated that hypoalbuminemia was the only significant risk factor for shorter time to discontinuation resulting from documented adverse effects (hazard ratio = 3.0; 95% CI = 1.15-8.0; P = 0.025). This represents the first report of the impact of hypoalbuminemia on tolerability of highly protein bound oral oncolytic drugs, demonstrating that patients with hypoalbuminemia may be at increased risk for early discontinuation resulting from toxicity. Given the importance of maintaining dose intensity in patients receiving oncolytic therapy, albumin levels should be monitored throughout treatment and supportive care maximized in those developing hypoalbuminemia.

Pegfilgrastim Maintains Relative Dose Intensity and Decreases Hospitalisations in Patients With Endometrial Cancer.

Data are limited regarding the use of pegfilgrastim in gynaecologic oncology. We evaluated its efficacy for maintaining dose intensity during chemotherapy. We retrospectively examined the data of 65 women (26 pegfilgrastim users) who underwent primary surgical treatment for stages IB-IV endometrial cancer and had adjuvant chemotherapy containing platinum and taxane; the primary outcome was a relative dose intensity ≥85%. In the pegfilgrastim vs. the control group, body mass index (26.6±5.9 vs. 23.4±4.4), rate of relative dose intensity ≥85% (88.5% vs. 15.4%), plus other adverse event incidences were significantly higher; rate of neutropenia, total hospital visits during chemotherapy (11.0±2.1 vs. 18±5.6 days), unscheduled hospital visits (1.1±1.8 vs. 5.8±5.1 days), and unscheduled granulocyte colony-stimulating factor injections (0.58±1.7 vs. 6.4±5.1 days) were significantly lower. Pegfilgrastim can maintain a dose intensity of ≥85% during chemotherapy for the treatment of gynaecologic cancers and decrease hospital-visit frequency.

466P - Interim results from trial of SL-801, a novel XPO-1 inhibitor, in patients with advanced solid tumours

BackgroundSL-801 is a novel, oral, small molecule that reversibly inhibits Exportin-1 (XPO-1), a nuclear export protein, overexpressed in a variety of solid and hematologic malignancies. XPO-1 is a mediator of nuclear-cytoplasmic transport of over 200 nuclear proteins and has been associated with aggressive tumor behavior and poor prognosis. SL-801 has demonstrated potent in vitro and in vivo activity. Interim results from the dose-escalation stage are reported. MethodsSTML-801-0115 is a first-in-human, multicenter dose and schedule finding study in patients with localized unresectable, or metastatic solid tumors that are refractory to or are relapsed after treatment with standard therapy. Objectives are to identify the maximum tolerated dose or optimal dose/schedule, and assess pharmacokinetics, pharmacodynamics, and preliminary anti-tumor activity. SL-801 was initially orally administered on days 1-4 and 8-11 of a 21-day cycle (Schedule A). The dosing schedule has been amended to potentially allow a longer recovery time between dosing periods while maintaining dose intensity. Patients are now receiving SL-801 once daily on days 1-2, 8-9, 15-16 and 22-23 of a 28-day cycle (Schedule B). The starting dose in the study was 5mg/day in Schedule A; current study dose level is 70mg/day in Schedule B. Results45 patients received 5-65mg/day of SL-801 in Schedule A (median age 63 YO [range: 39-83], 51% females, median number of prior systemic therapies, 4 [range: 2-10]; 57% received 3 or more. Common treatment-emergent adverse events (TEAEs) were nausea (62%), vomiting (64%), fatigue (44%), decreased appetite (33%), and diarrhea (29%). Grade 3 TEAEs included nausea (9%), anemia (7%), and fatigue, diarrhea, hyponatremia and hypophosphatasemia (each 4%). Most TEAEs were grade 1-2; no grade 4-5 toxicities reported. 12 patients (27%) had stable disease (SD) and remained on study for 2-11 months including 5 with SD for 4+ months. 1 patient with basal cell carcinoma had SD for 11 months. 3 patients had radiographic tumor shrinkage of 14-20% in target lesions. ConclusionsSL-801 reversibly binds XPO1, a clinically validated target in oncology. To date 27% of heavily pre-treated patients have achieved SD as best response. Enrollment and dose escalation continue. Clinical trial identificationNCT02667873. Legal entity responsible for the studyStemline Therapeutics. FundingStemline Therapeutics. DisclosureJ. Wang: Speaker Bureau / Expert testimony: AstraZeneca. E. Chiorean: Research grant / Funding (institution): Boehringer-Ingelheim, Merck, BMS, Lilly, Stemline, Ignyta/Roche, Incyte, Halozyme; Advisory / Consultancy: AstraZeneca, Array, Ipsen, Eisai, Halozyme, Seattle Genetics, Vicus, Five Prime. P. LoRusso: Advisory / Consultancy: abbvie; Advisory / Consultancy, data safety monitoring board: agios; Advisory / Consultancy: alexion; Advisory / Consultancy: ariad; Advisory / Consultancy, data safety monitoring committee: Five prime; Advisory / Consultancy: GenMab; Advisory / Consultancy: Glenmark; Advisory / Consultancy, data safety monitoring: Halozyme; Advisory / Consultancy: Menarini; Advisory / Consultancy: Novartis; Advisory / Consultancy: Genentech; Advisory / Consultancy: CytomX; Advisory / Consultancy: Omniox; Advisory / Consultancy: Ignyta; Advisory / Consultancy: Takeda; Advisory / Consultancy: Sotio; Advisory / Consultancy, data safety monitoring committee: Tyme. K. Courtney: Advisory / Consultancy: Janssen; Research grant / Funding (institution): Astellas Pharma; Research grant / Funding (institution): Lilly; Research grant / Funding (institution): Medivation; Research grant / Funding (institution): Aragon; Research grant / Funding (self): Astellas Pharma; Research grant / Funding (institution): PSMA Development; Research grant / Funding (institution): Stemline; Research grant / Funding (institution): Peloton; Research grant / Funding (institution): Merck Sharp & Dohme; Research grant / Funding (institution): Corvus Pharmaceuticals; Research grant / Funding (institution): Clovis Oncology; Research grant / Funding (institution): Proacta; Spouse / Financial dependant, Receives patent royalties: Athena Diagnostics, Inc. D. Qi: Advisory / Consultancy: stemline. J. Bullington: Shareholder / Stockholder / Stock options, Full / Part-time employment: Stemline. M. Sardone: Shareholder / Stockholder / Stock options, Full / Part-time employment: Stemline. J. Chen: Shareholder / Stockholder / Stock options, Full / Part-time employment: Stemline. C. Brooks: Shareholder / Stockholder / Stock options, Full / Part-time employment: Stemline. S. Shemesh: Shareholder / Stockholder / Stock options, Full / Part-time employment: Stemline. T.M. Bauer: Full / Part-time employment: Tennessee Oncology; Advisory / Consultancy: Ignyta; Advisory / Consultancy: Guardant Health; Advisory / Consultancy: Loxo; Advisory / Consultancy, Research grant / Funding (institution): Pfizer; Speaker Bureau / Expert testimony: Bayer; Research grant / Funding (institution): Daiichi Sankyo; Research grant / Funding (institution): Medpacto, Inc; Research grant / Funding (institution): Incyte; Research grant / Funding (institution): Mirati Therapeutics; Research grant / Funding (institution): MedImmune; Research grant / Funding (institution): AstraZeneca; Research grant / Funding (institution): MabVax; Research grant / Funding (institution): Stemline Therapeutics; Research grant / Funding (institution): Merck; Research grant / Funding (institution): Lilly; Research grant / Funding (institution): GlaxoSmithKline; Research grant / Funding (institution): Novartis; Research grant / Funding (institution): Bristol-Myers Squibb; Research grant / Funding (institution): Amgen. All other authors have declared no conflicts of interest.

Sequential gemcitabine (G), oxaliplatin (O), and irinotecan (I) based weekly metronomic chemotherapy (MC) regimens for the treatment of metastatic pancreatic cancer (mPC): A community cancer clinic experience.

284 Background: mPC has a poor prognosis with a median overall survival (mOS) ranging from 8.5 to 11.1 months (mo) with standard treatment, outlining the need for new innovative treatments. MC regimens utilize lower doses of chemotherapy that are administered more frequently which can maintain dose intensity while reducing toxicity. MC with paclitaxel (P) or nab-paclitaxel (N) may have effects on the tumor microenvironment. Methods: A retrospective analysis of treatment regimens and survival of patients (pts) with biopsy proven mPC who received treatment between August 2004 and August 2018 was performed. Results: 30 pts with biopsy proven mPC were identified. 14 pts received prior chemotherapy. mOS of this cohort was 18.9 mo after diagnosis and 14.2 mo after beginning MC. 70% of pts (21/30) survived longer than 12 mo, 37% (11/30) greater than 24 mo, and 27% (8/30) greater than 30 mo. All MC regimens were given on a weekly basis and included: P 60 mg/m² and G 600 mg/m² (PaG); P 60 mg/m², O 50 mg/m², folinic acid (L) 20 mg/m², and 5-fluorouracil (F) 425 mg/m² (POLF); P 60 mg/m², I 100 mg/m², and cisplatin (C) 20 mg/m² (PIC) or P 60 mg/m², I 100 mg/m², L 20 mg/m², and F 425 mg/m² (PILF). 21 pts received N instead of P at some point during their treatment. PaG, POLF, and PIC or PILF were purposely switched before disease progression after a median length of 13, 11 and 13 weeks respectively. 16 pts received PaG as their first regimen. 12 of these 16 pts then received POLF as their second regimen, and 7 of these 12 pts subsequently received PIC or PILF as their third regimen. These 7 pts had a mOS of 21.7 mo after diagnosis and 19.1 mo after beginning MC. 10 pts were successfully able to receive PaG, POLF, or PIC/PILF more than once. Conclusions: Weekly MC regimens such as PaG, POLF, and PIC/PILF that are given sequentially are an effective treatment for mPC. Switching regimens may prevent the development of chemotherapy resistance, allowing for chemotherapy regimens to be used again in the future. There are limitations of retrospective studies so further investigation of this treatment strategy should be done with a large randomized clinical trial.

High-Dose Chemotherapy in Relapsed or Refractory Metastatic Germ-Cell Cancer: The Scotland Experience.

To report outcomes from high-dose chemotherapy (HDCT) and autologous stem-cell transplantation (ASCT) for metastatic germ-cell cancer in Scotland. All patients who underwent this treatment between the years 2001 and 2016 at the Beatson West of Scotland Cancer Centre in Glasgow were identified. Information regarding baseline patient and tumor characteristics, prognostic features, HDCT delivery, and survival outcomes were obtained retrospectively from patients' medical records. Eighteen patients (15 male and 3 female subjects) received HDCT and ASCT in the salvage setting. Of the 14 male patients who had relapsed disease, 8 (57%) were high or very high risk according to the International Prognostic Factor Study Group (IPFSG) risk categorization. The mean time interval between HDCT cycles was 8.6 weeks, which is longer than the specified 3 to 4 weeks in the literature. A total of 67% of patients had no biochemical or radiologic evidence of disease after salvage treatment, including surgery. Progression-free survival and overall survival rates at 2 years were 67% and 72%, respectively. However, 12 patients (67%) and 6 patients (39%) had long-term neurotoxicity and ototoxicity, respectively. Delivery of HDCT and ASCT as salvage treatment for metastatic germ-cell cancer is feasible within a tertiary cancer center with survival outcomes comparable to published literature, although maintaining dose intensity is a challenge. We hope to recruit subjects to the international TIGER trial (ClinicalTrials.gov, NCT02375204), which will attempt to clarify if HDCT is superior to conventional-dose chemotherapy in the salvage setting.

Effectiveness of Antiemetic Regimens for Highly Emetogenic Chemotherapy-Induced Nausea and Vomiting: A Systematic Review and Network Meta-Analysis.

It is important to control chemotherapy-induced nausea and vomiting (CINV) to maintain dose intensity and patients' quality of life. The National Comprehensive Cancer Network guidelines suggest combination therapy of antiemetic agents. The growing number of antiemetic regimens, and in particular the growing use of regimens containing antagonists to the Nk-1 receptor (NK1RAs) and the antipsychotic drug olanzapine (OLZ), call for the re-evaluation of the optimal regimen for CINV. This study assessed the efficacy and safety of antiemetic regimens for highly emetogenic chemotherapy, using Bayesian network meta-analysis. Randomized trials that compared different antiemetic regimens were included. We strictly followed Preferred Reporting Items for Systematic Reviews and Meta-Analysis guidelines. The main outcomes were the odds ratio (OR) for overall complete response (absence of vomiting). We conducted network meta-analysis within a Bayesian model to combine the direct and indirect evidence. Safety was assessed from the trial description. All statistical tests were two-sided. We systematically reviewed 27 randomized control trials (13,356 participants), which compared 12 different antiemetic regimens: serotonin-3 receptor antagonist (5HT3), 5HT3 + dexamethasone (Dex), palonosetron (PAL), PAL + Dex, PAL at 0.75 mg (PAL0.75), PAL0.75 + Dex, NK1RA + 5HT3 + Dex, NK1RA + PAL + Dex, an oral combination of netupitant and palonosetron (NEPA) + Dex, OLZ + 5HT3 + Dex, OLZ + PAL + Dex, and OLZ + NK1RA + 5HT3 + Dex. An NK1RA + 5HT3 + Dex regimen and an NK1RA + palonosetron + Dex regimen gave a higher complete response (CR) rate than the reference regimen, 5HT3 + Dex (OR, 1.75; 95% credibility interval [95% CrI], 1.56-1.97, and OR, 2.25; 95% CrI, 1.66-3.03, respectively). A regimen containing NEPA was more effective in producing CR than conventional regimens without NEPA or olanzapine. Further analysis, based on the surface under the cumulative ranking probability curve, indicated that olanzapine-containing regimens were the most effective in producing CR. Our meta-analysis supports the conclusion that olanzapine-containing regimens are the most effective for CINV of highly emetogenic chemotherapy. We confirmed that NK1RA + PAL + Dex is the most effective of conventional regimens. Substituting olanzapine for an Nk-1 receptor antagonist may offer a less costly and more effective alternative for patients. Nausea and vomiting during chemotherapy often pose difficulties for patients and doctors, making it hard to continue the proper therapy and to maintain the quality of life. This article gives insights into the optimal choice of medicine to treat nausea during chemotherapy. The findings reported here provide readers with a robust efficacy ranking of antinausea medicine, which can be used as a reference for the best possible treatment. Furthermore, the 70% less costly drug, olanzapine, is suggested to be equally effective to aprepitant in reducing nausea and vomiting. The possibility of offering a cost-effective treatment to a wider range of the population is discussed.

Intensity-modulated radiotherapy for paranasal sinuses and base of skull tumors

Paranasal sinus and skull base tumors are rare aggressive head and neck cancers, and typically present in the locally advanced stages. As a result, achieving wide surgical resection with clear margins is a challenge for these tumors, and radiotherapy is thus usually indicated as an adjuvant modality following surgery to optimize local control. Given the integral role of radiotherapy in the management of this subgroup of head and neck tumors, the advent of intensity-modulated radiotherapy (IMRT) has led to substantial improvement of clinical outcomes for these patients. This is primarily driven by the improvement in radiation dosimetry with IMRT compared to conventional two dimensional (2D)- and 3D-techniques, in terms of ensuring dose intensity to the tumor target coupled with minimizing dose exposure to critical organs. Consequently, the evident clinical benefits of IMRT have been in reduction of normal tissue toxicities, ranging from critical neurological symptoms to less debilitating but bothersome symptoms of eye infections and radiation-induced skin changes. Another domain where IMRT has potential clinical utility is in the management of a subset of non-resectable T4 paranasal sinus and skull base tumors. For these inoperable lesions, the steep dose-gradient between tumor and normal tissue is even more advantageous, given the crucial need to maintain dose intensity to the tumor. Innovative strategies in this space also include the use of induction chemotherapy for patient selection. In this review, we summarized the data for the aforementioned topics, including specific discussions on the different histologic subtypes of paranasal sinus and skull base tumors.