Dose Intensity Research Articles

Assessing the feasibility and cost-effectiveness of all oral adjuvant chemotherapy (cyclophosphamide, methotrexate, capecitabine) in high-risk hormone receptor positive breast cancer.

TPS616 Background: Women with high-risk HR+/HER2- breast cancer (BCA) receive additional chemotherapy to reduce disease recurrence. Preferred Taxane and Anthracycline based chemotherapy regimens have debilitating side effects such as cardiotoxicity, leukemia, peripheral neuropathy, severe fatigue, alopecia, downtime which are more common in black women thereby necessitating dose reductions. Metronomic cyclophosphamide, methotrexate, 5-fluourouracil (CMF) is an option but less preferred due to frequent dosing and longer therapy duration. Head-to-head comparison of CMF to anthracycline-based chemotherapy conducted 3 decades ago in early-stage BCA showed anthracycline benefit was driven by HER2+ disease with no benefit for HR+/HER2- BCA. Head-to-head comparison trials of CMF and Taxane-based regimen have not been conducted but single institution data suggest similar disease-free and similar overall survival but different toxicity profiles favoring CMF. In our ongoing trial, we converted all three chemotherapy drugs in CMF regimen to an all-oral regimen namely oral Cyclophosphamide, oral Methotrexate, oral Capecitabine (CMC) with the potential benefit of increased patient convenience, decreased costs (oral agents are generic; no chair time; no growth factors), and improved toxicity profile (low rates of grade III neutropenia, no port complications, no alopecia). This trial in progress aims to evaluate the feasibility of oral CMC by measuring the relative dose intensity in addition to the safety and tolerability of oral CMC. We hypothesize that 80% of patients will receive >85% of the intended dose of oral CMC. Methods: This is a Phase II, single arm, non-randomized study enrolling 25 patients with high-risk early-stage HR+ HER2- breast cancer to receive oral CMC regimen based on dose conversion equivalent bioavailability with conventional metronomic CMF chemotherapy. Enrolled patients will receive adjuvant therapy of oral cyclophosphamide 60 mg/m2 PO days 1-21 continuously, Methotrexate 15 mg/m2 PO Day 1, 8, and 15 and Capecitabine 650 mg/m2 PO BID Day 1- 14 to be given every 21 days for 8 cycles. The primary objective is to assess feasibility which is defined as 80% of patients (greater than 20 patients) maintaining a relative dose intensity (RDI) > 85%. The RDI is calculated as the ratio of the actual dose intensity/standard dose intensity; the average RDI for oral CMC regimen is the sum of RDI for each drug divided by 3. This study will be stopped if >25% of patients report Grade 4+ toxicity on oral CMC. The secondary objectives will assess quality of life as reported by the patients and report adverse effects. Clinical trial information: NCT06085742 . [Table: see text]

Clinical prognostic factors to guide treatment strategy for HPV-positive oropharyngeal cancer from treatment outcomes of induction chemotherapy: A real-world experience.

e18014 Background: The role of induction chemotherapy (IC) in locally advanced oropharyngeal cancer (OPC) remains a topic of debate and suitable candidates for de-escalation treatment in these patients have not been fully identified. This study aimed to identify high-risk groups for HPV-positive OPC by analyzing patients who underwent IC followed by chemoradiotherapy (CRT) to guide optimal treatment strategies. Methods: Between 2004 and 2020, we reviewed patients with OPC diagnosed with stage III-IVA who underwent a treatment regimen comprising a minimum of two cycles of IC followed by CRT.In this study, all patients were re-staged according to the American Joint Committee on Cancer (AJCC) 8th edition, and we analyzed the overall response rate and survival outcomes associated with clinical factors based on HPV status by utilizing univariate and multivariate analyses. Results: This study analyzed 105 patients with a median age of 60 years (range: 40–76 years). Among 105 patients, 40 (38.1%) were HPV-negative, and 65 (61.9%) were HPV-positive. Through a median follow-up of 60.0 months (range, 5–60 months), no significant differences in progression-free survival (PFS) (p = 0.172) and overall survival (OS) (p = 0.064) were observed based on HPV status, regardless of no differences in relative dose intensity of IC and cumulative dose of radiation and cisplatin in CRT. In all patients, survival outcomes were notably poorer in patients aged ≥ 60 years ( p = 0.006) and those who did not achieve complete response (non-CR) post-CRT ( p < 0.001), irrespective of HPV status. All have received sufficient IC with a median RDI of 80% or more in both age < 60 years and age ≥ 60 years. Unlike HPV-negative OPC, where age and T stage showed no significant correlation, in HPV-positive OPC, age ≥ 60 years ( p = 0.011) and T4 stage ( p = 0.019) emerged as substantial poor prognostic factors for survival outcomes despite IC and CRT. Utilizing these results, we categorized HPV-positive OPC patients into three groups based on the number of clinical risk factors at diagnosis (age, T4 stage), the PFS and OS showed significant stratification across each group as the number of clinical risk factors increased. Conclusions: This study revealed that age and T stage significantly influenced on prognosis in HPV-positive OPC but not in HPV-negative OPC. Considering our result, HPV-positive OPC exhibiting these risk factors requires a careful treatment strategy, and combined treatments, including immunotherapy, may be considered to enhance treatment outcomes for these patients.

Effect of AVM0703 treatment on the limitations of R-CHOP and survival in a model applicable to ABC subtype DLBCL.

e19060 Background: The current treatment regimen for DLBCL consisting of rituximab-cyclophosphamide-doxorubicin-vincristine-prednisone (RCHOP), is challenged by molecular and prognostic characterization of DLBCL. Activated B-cell (ABC) lymphoma has a significantly worse prognosis (5 yr OS rate: 45% - 56%) than germinal center B-cell (GCB) lymphoma (78% - 80%) after RCHOP treatment. Around 40% of patients ultimately relapse and/or develop primary refractory disease, cardiotoxicity and long-term secondary malignancies. Efforts are being made to improve the RCHOP backbone by including dose intensification and by the addition of new agents to increase the efficacy and reduced toxicity of RCHOP (McKelvey EM Cancer 1976; Wilson WH Blood 2002; Molina TJ JCO 2014; Coiffier B Hematology 2016). AVM0703, an immunomodulatory drug, mobilizes bispecific γδ and inv-TCR double-positive novel T and NKT cells. In a previous study employing an aggressive, immune resistant A20 mouse lymphoma model (Bascuas T J Transl Med. 2016), neoadjuvant AVM0703 was additive/synergistic, when cyclophosphamide/fludarabine (CyFlu) was dosed 3 and 24 hr later, with no additional toxicities. In the present study we combined AVM0703 with RCHOP to evaluate the efficacy in A20 mice model. Methods: 10 week old Balb/c mice were injected with 2x106 murine A20 B-cells in the flank and were randomized (1:1 male: female) into 1) Placebo 2) 3 cycles RCHOP 3) 3 cycles AVM0703 (18mg/kg HED) 4) 3 cycles AVM0703+RCHOP, when tumor size reached ~100 mm3. Mice who achieved complete remission (CR) were re-challenged at 21-25 wks later. Pre and post re-challenge, presence of memory cells was analyzed using flow cytometer. All mice were monitored continuously as per the IACUC protocol. Results: Mice treated with the combination of AVM0703+RCHOP achieved superior CR compared to RCHOP alone, which was not curative in any mice. In first phase of the study, 3 out of 11 AVM0703 +RCHOP treated mice showed CR after only 1-cycle. In second phase, 2 of 12 mice survived in CR for >150 days after 3 cycles, whereas no RCHOP mice survived beyond 2 cycles. AVM0703+RCHOP treated mice in long-term CR, had memory cells (CD44hi-Cd62low) pre- and post re-challenge, and no A20 engraftment, suggesting strong immunological memory induced by AVM0703+RCHOP. Conclusions: AVM+RCHOP demonstrated anti-tumor activity in A20 lymphoma mice, with reduced toxicity, compared to RCHOP. Larger preclinical studies are underway to confirm the activity of AVM0703+RCHOP against RCHOP resistant ABC DLBCL, and the potential to reduce total RCHOP exposure to only 3 cycles while maintaining or improving efficacy. [Table: see text]

Acupuncture for preventing progression of taxane-induced peripheral neuropathy (ATP): A phase II randomized, placebo-controlled trial.

TPS12154 Background: Chemotherapy-induced peripheral neuropathy (CIPN) from chemotherapy drugs such as taxanes can be detrimental to cancer survival, increasing the risk of falls and worsening physical functions. The current management of worsening and persistent CIPN during chemotherapy is dose reduction or discontinuation of chemotherapy. There is no effective treatment or preventative measure for CIPN. Methods: Trial design: The ATP trial is a two-arm, parallel, randomized controlled trial comparing weekly real acupuncture (RA) versus sham acupuncture (SA) during preplanned curative intent taxane containing regimens in patients with breast cancer. Eligibility criteria: English or Spanish-proficient; aged ≥18 years; histological diagnoses of invasive carcinoma of the breast; and plan to receive curative intent chemotherapy regimen containing paclitaxel or nab-paclitaxel weekly or biweekly as standard of care, developed CIPN grade ≥1 based on the NCI-CTCAE version 5.0, while receiving taxane; ≥ four weeks of paclitaxel or nab-paclitaxel weekly or biweekly planned, as standard of care and at treating physician’s discretion; willing to adhere to requirement that no new pain medication or dose changes be taken throughout the first 12 weeks of the study period; and willing to adhere to all study-related procedures. Specific aims: The primary aim is to evaluate the effectiveness of RA versus SA in preventing taxane-induced peripheral neuropathy progression as measured by Neuropathic Pain Scale (NPS) in patients with early-stage breast cancer who are receiving curative intent neurotoxic chemotherapy. The secondary aim is to evaluate the effectiveness of RA versus SA on chemotherapy relative dose intensity (RDI) and CIPN-related chemotherapy discontinuation. Statistical methods: We will randomize 80 patients, 40 to each arm. All randomized patients will be evaluable in the Intent to Treat (ITT) analyses because all will have completed the baseline assessment before randomization. We will use a linear mixed model (LMM) to compare the change in NPS between the arms from baseline to week 4. Based on our pilot data, a difference in CIPN grade from 1 to 2 corresponded to a difference in NPS from 12 to 22, a difference of ten points in 27 patients. The NPS standard deviation (SD) in patients with grade 1 CIPN was 17. With 80 patients we will have 80% power to detect a difference between arms as small as 10 points on the NPS, assuming a one-sided test, type I error of 5%, correlation between baseline and follow-up measurements of 0.5, SD of 17, and 15% attrition at week 4. Present accrual and target accrual: We accrued 43 participants in the intervention phase by the end of January 2024; the target accrual is 80 participants. Clinical trial information: NCT05458284 .

Phase 3 randomized study of isatuximab (Isa) plus lenalidomide and dexamethasone (Rd) with bortezomib versus isard in patients with newly diagnosed transplant ineligible multiple myeloma (NDMM TI).

7501 Background: CD38 targeting immunotherapy is approved in combination with lenalidomide and dexamethasone in NDMM TI and considered the current standard of care (SOC). The best treatment combinations are important in NDMM TI, as outcomes worsen with successive line of therapy. To improve current SOC, we evaluated the added value of prolonged use of bortezomib for 18 months with reduced intensity weekly schedule to IsaRd, with the intent to demonstrate the impact of a PI in a quadruplet regimen to improve depth of response. In BENEFIT/IFM2020-05 study (NCT04751877), we investigated efficacy and safety of IsaRd vs Isa-VRd in NDMM TI. Methods: BENEFIT is a prospective, multicenter, randomized, parallel trial. Patients aged 65-79, non-frail, with NDMM TI were randomized 1:1 and stratified by age, high-risk cytogenetic and center. Isa-VRd arm received V (1.3 mg/m2 SC weekly up to c12 (c), bimonthly up to c18); both arms received Isa (10 mg/kg IV weekly and bimonthly up to c12, then monthly), R (25 mg), and d (20 mg up to c12). The primary endpoint was minimal residual disease (MRD) 10-5 negative rate (NGS) at 18 months from treatment start analyzed in ITT. Key secondary endpoints included survival times (OS, PFS, EFS, TTNT), response rates and durations, MRD endpoints, and safety (using NCI CTCAE v5.0). Results: At data cutoff date (02 Feb 2024), 270 patients (135 per arm) were recruited. Patients baseline characteristics were well balanced across arms, overall median age was 73.2 years [IQR. 71;76], 90 patients (33%) were >75 years, 23 (9%) had high-risk cytogenetic (IFM score >1), 181 (76%) had R-ISS2+3, and 47 (17%) had impaired renal function (eGFR <60 mL/min). MRD negativity rates at 10-5 at 18 months were significantly higher in Isa-VRd arm compared to IsaRd arm (47% vs 24%, OR for negative MRD =2.96 [95%CI. 1.73 – 5.07, p<0.001]. The MRD benefit was consistent across subgroups. At 21.2 months median follow-up, 33 (12%) patients had relapsed and 20 (7%) had died, and no significant difference were observed across arms, yet. The addition of weekly “light” schedule of bortezomib did not significantly affect relative dose intensity of IsaRd. Forty-four (33%) patients presented with neurological adverse events grade ≥2 in the Isa-VRd vs 27 (20%) in IsaRd arm. Conclusions: Isa-VRd significantly deepened responses including a significant increase of the MRD negative rate at 10-5 vs IsaRd. The safety profile is consistent with addition of bortezomib. This study supports Isa-VRd as a new standard of care for NDMM TI non-frail patients. Clinical trial information: NCT04751877 . [Table: see text]

Phase II trial of biologically optimized schedule of gemcitabine and nab-paclitaxel in metastatic pancreatic cancer.

e16325 Background: Metastatic pancreatic adenocarcinoma (PDAC) has a poor prognosis and limited therapeutic options. In addition to efforts to develop novel agents, there is a need to optimize and maximize the benefit of currently approved drugs such as gemcitabine (G) + nab-paclitaxel (NP). NP is albumin–bound, hence albumin uptake is critical for its effect. Caveolae are small membrane invaginations essential for transendothelial albumin uptake. Cav-1 is the principal structural component of caveolae. We have shown that tumor cell-specific Cav-1 expression directly correlates with albumin and albumin-bound chemotherapy uptake and subsequent apoptotic response in tumor cells. In vitro studies showed that exposure of PDAC cells to G resulted in up-regulation of Cav-1 peaking 48 hours after G exposure. This Cav-1 up-regulation correlated with increased temporal albumin cellular uptake. In addition, we noted that exposure of PDAC cells to G resulted in a time–specific re-entry of cells into the G2/M phase (NP cytotoxicity phase) between 48-60 hours after G treatment. Collectively this data suggest that infusing NP 48 hours after G infusion would be optimal for both increased uptake as well as increased susceptibility to apoptosis of tumor cells. We have shown this effect on multiple cell lines and mouse models. Methods: This is a phase II trial (NCT04115163) where patients (pts) receive G + NP every 2 weeks with modification of the schedule to deliver NP 48 hours (2 days) after G infusions. The primary endpoint is ORR, with a null hypothesis of 20% vs a target of 35%. Employing a 2-stage minimax design minimax and assuming 80% power and a 0.05 significance level, a total of 53 pts are required. In the first stage, if at least 7/31 pts respond to therapy, an additional 22 pts will be added for a total of 53 pts. The study will be terminated early if ≤ 6 pts respond in the first stage. Observation of response in at least 16/53 pts would be required to warrant further investigation of this infusion schedule. Secondary endpoints include safety of the regimen schedule, relative dose intensity, disease control rate, PFS, and OS. The trial opened to enrolment in June 2020. Results: Interim analysis was conducted after 43 pts had been enrolled. 29 pts were found to be evaluable for the primary endpoint of response. Objective response was seen in 11 out of 29 (37.9%) evaluable pts thus meeting statistical criteria to continue enrolment on stage 2 of the study. The regimen was well tolerated with no new safety signals. Toxicities are summarized in table. Conclusions: Biologically optimized G + NP was well tolerated with interim analysis revealing response rate of 37.9%. Enrolment is ongoing with plans for correlative analysis related to Cav-1. Clinical trial information: NCT04115163 . [Table: see text]

Eribulin and irinotecan for refractory or recurrent Ewing sarcoma: A retrospective study.

e23502 Background: The effectiveness of eribulin and irinotecan in treatment of xenograft models of Ewing sarcoma is well-established but little clinical data has been reported. Encouraging results from preclinical models and a shortage of temozolomide in our hospital have prompted the administration of the eribulin as substitute for temozolomide and vincristine in combination of irinotecan at our institution from 2022 to 2023 in an off-label way. Methods: We retrospectively reviewed the medical records of patients treated for refractory or recurrent Ewing sarcoma with 1.4mg/m2 D1,8 eribulin and 20mg/m2/d D1-5,8-12 irinotecan at 21 day intervals (ERII) at Peking University People’s Hospital. Results: Finally, a total of 17 patients with median age 18.6 years were treated with a total of 77 courses of ERII between February 2022 and February 2023. The objective response rate was 35.3%, the disease control rate 58.9% and the median event-free survival (EFS) 2.07 months. 35.3% patients had 6 months EFS and overall survival was 66.9%. Grade 3 or 4 toxicities were observed in 37.6% courses and in 64.7% of the patients, with myelosuppression, especially neutropenia, being the most common and diarrhea / abdominal pain the second most common. In the dx5x2 VIT protocol the later portion was given two days after the end of early portion. However, in this substitute regimen of eribulin, the median time interval between the end of the early portion to the start of later portion was 5 days. The dose intensity of the regimen was reduced by 21% per cycle. The later portion was delayed mostly because of unrecovered myelosuppression. Conclusions: The efficacy and safety of eribulin and irinotecan as a second-line regimen was inferior to historical reports of temozolomide and irinotecan in the same institute. There was no need for further prospective trials on this combination unless mechanisms of synergy and biomarkers are identified. [Table: see text]

Efficacy of a combined diet and exercise intervention in patients with breast cancer undergoing chemotherapy: A meta-analysis of randomized controlled trials.

e12517 Background: Breast cancer treatment presents challenging side effects that may compromise patients’ health and quality of life (QoL). While exercise programmes have been shown to improve survival, the impact of combined exercise and dietary interventions compared to usual practices alongside chemotherapy remains controversial. Methods: PubMed, Embase, Cochrane Central, and ClinicalTrials.gov were systematically searched up to October 2023. We included randomized controlled trials (RCTs) involving adult breast cancer patients undergoing chemotherapy and comparing combined diet and exercise interventions with usual care. Outcomes of interest included weight change, relative dose intensity (RDI), and Functional Assessment of Cancer Therapy-General scale (FACT-G) score for QoL. Statistical analysis was performed using Review Manager 5.4.1 and RStudio version 4.1.2. The protocol was registered on PROSPERO (ID: CRD42023463543). Results: Seven RCTs with 960 patients undergoing breast cancer therapy were included, of whom 506 (53%) were assigned to combined exercise and dietary interventions. Participants had a mean BMI of 26.6 kg/m2, and approximately 52% were postmenopausal. Combined exercise and dietary interventions resulted in significant reductions in weight loss (MD -1.06 kg, 95% CI -1.68 to -0.44; p<0.01), BMI (MD -0.44; 95% CI -1.76 to -0.13; p<0.01), body fat (MD -2.12%; 95% CI -3.99 to -0.26; p=0.03), and FACT-G (MD -3.40; 95% CI -6.25 to -0.55; p=0.02) compared to usual care. No significant differences were observed in waist circumference (p=0.05), RDI (p=0.23), or fatigue levels (p=0.98) between groups. Conclusions: In this meta-analysis of randomized trials, combined exercise and dietary interventions improved weight management in breast cancer patients undergoing chemotherapy but did not significantly impact chemotherapy completion, fatigue levels, and worsened FACT-G score (QoL). Findings can help to further holistic cancer care, taking into account both physical and psychosocial dimensions of patient health.

First-in-human study of ABBV-400, a novel c-Met–targeting antibody-drug conjugate, in advanced solid tumors: Results in colorectal cancer.

3515 Background: c-Met (MET protein) is frequently overexpressed in several advanced solid tumors including colorectal cancer (CRC). There are no approved therapies specific for c-Met–overexpressing tumors in CRC. The antibody-drug conjugate ABBV-400 comprises c-Met–targeting antibody telisotuzumab conjugated to a novel topoisomerase 1 inhibitor payload. A phase 1 study of ABBV-400 was initiated for adults with advanced solid tumors and progression on standard therapies (NCT05029882); results from dose escalation (ESC) at doses 1.6–6.0 mg/kg once every 3 weeks (Q3W) were previously presented and showed preliminary efficacy (Sharma et al. ASCO 2023. Abstract 3015). We present data from dose ESC and expansion (EXP) cohorts in CRC. Methods: During EXP, patients (pts) with CRC were randomized to receive ABBV-400 at 1.6, 2.4, or 3.0 mg/kg Q3W. Primary objectives were to evaluate the safety, tolerability, pharmacokinetics, preliminary efficacy, and the recommended phase 2 dose of ABBV-400. Results: As of Oct 2023, 122 pts (ESC: 29; EXP: 93) were included. Median age: 56 years; 65 (53%) males. Median prior treatments was 4. Follow-up was longer in ESC vs EXP (14.8 vs 3.8 months). Seventy-eight (64%) pts had a grade (G)≥3 treatment-emergent adverse event (TEAE); 41% had a serious TEAE. Most frequent hematologic TEAEs were anemia (52%; G≥3: 30%), neutropenia (37%; G≥3: 25%), leukopenia (25%; G≥3: 12%), and thrombocytopenia (23%; G≥3: 12%); nonhematologic TEAEs were nausea (57%, G≥3: 3%), fatigue (43%; G≥3: 2%), and vomiting (39%, G≥3: 4%). G≥3 diarrhea was < 1%. Unadjudicated interstitial lung disease/pneumonitis rate was 7% (G≥3: 2%). Treatment-related AEs leading to discontinuation occurred in 11 (9%) pts. Preliminary efficacy outcomes are shown in the Table. The majority of tissues expressed c-Met. In pts with higher c-Met expression, an increased ORR of > 30% was observed at efficacious doses (≥2.4 mg/kg). Activity was also seen at lower c-Met expression levels (10–15% ORR). Conclusions: ABBV-400 at 2.4 and 3.0 mg/kg Q3W has a tolerable and manageable safety profile, with promising antitumor activity. Long-term tolerability appears improved at 2.4 relative to 3.0 mg/kg, with higher relative dose intensity and generally lower TEAEs. The study is also evaluating ABBV-400 with bevacizumab in pts with CRC. Clinical trial information: NCT05029882 . [Table: see text]

Symptom management through electronic patient-reported outcome (ePRO)-based intervention in patients with breast cancer treated with abemaciclib: Primary results from the LIBRA study, a phase II randomized controlled trial.

11110 Background: We have developed a system using LINE, a widely-used social network service in Japan, for rapid collection of ePROs based on the PRO-CTCAE criteria. To evaluate the effectiveness of intervention through this system in reducing diarrhea frequency and enhancing quality of life (QOL) in patients treated with abemaciclib, we conducted a randomized controlled trial. Methods: Patients with hormone receptor-positive advanced breast cancer scheduled to begin abemaciclib treatment were randomized to the intervention and control arms with 1:1 ratio. The LINE-ePRO system was used to monitor symptoms daily in both arms. In the intervention arm, expert medical staffs contacted patients via phone when symptoms met certain criteria, whereas patients in the control arm received standard care. The primary endpoint was the increase in the number of defecations from baseline during 28 days. The secondary endpoints included the increase in the number of defecations from baseline during 56 days, other symptoms monitored via the LINE-ePRO system, QOL evaluated by EORTC QLQ C-30 and EQ-5D-5L, relative dose intensity (RDI), treatment interruption rate, progression-free survival (PFS), and overall survival (OS). This study (LIBRA, UMIN000045432) is funded by Eli Lilly. Results: Between Jan 2022 and Apr 2023, 60 women were enrolled and 58 (29 in each arm) were analyzed in this study. Median age was 57.5 years (range 43-80), 93% of patients were post-menopausal, 71% received abemaciclib as first-line treatment, and 74% were treated in combination with aromatase inhibitors. The increase in the number of defecations from baseline was significantly lower in the intervention arm compared to the control arm both during 28 days (0.64 vs. 1.21 per day, p=0.003) and during 56 days (0.55 vs. 1.18 per day, p=0.0004). No significant difference was observed in other symptoms between the arms. In the EORTC QLQ C-30 scales, global health status/QOL (mean score change from baseline to after one cycle of abemaciclib treatment: 0 vs. -13.5, p=0.038) and diarrhea (20.7 vs. 32.2, p=0.049) were better in the intervention arm. The treatment interruption and dose reduction rates were 41.4 and 31.0% in the intervention arm, and 31.0 and 27.6% in the control arm, respectively. The mean RDI of abemaciclib was numerically lower in the intervention arm (73.5% vs. 84.8%). Conclusions: This study is the first randomized trial to demonstrate that the intervention based on daily ePROs reduces the frequency of diarrhea in patients with advanced breast cancer treated with abemaciclib. Clinical trial information: UMIN000045432.

Final safety results from ATHENA–MONO (GOG-3020/ENGOT-ov45), a randomized, placebo-controlled, double-blind, phase 3 trial evaluating rucaparib monotherapy as maintenance treatment in patients with newly diagnosed ovarian cancer.

5554 Background: Rucaparib provided a sustained progression-free survival benefit in patients (pts) with newly diagnosed advanced ovarian cancer after first-line treatment in the phase 3 ATHENA-MONO study (NCT03522246). We report final safety analyses (data cutoff 09 Mar 2023). Methods: Rucaparib was administered in 28-day cycles. Eligible pts were randomized 4:1 to oral rucaparib 600 mg BID (N=427) or placebo (N=111), with a treatment cap defined as 24 months. The safety population included randomized pts who received at least 1 dose of study drug (rucaparib, n=425; placebo, n=110). Results: All ATHENA-MONO pts discontinued treatment as of 24 Nov 2022 with a median treatment duration of 15 months and 35% of pts reaching the 24-month treatment cap. The median (range) relative dose intensity was 89% (30-110) for rucaparib. The rate of treatment-emergent adverse events (TEAEs), grade ≥3 TEAEs, TEAEs leading to interruption, dose reduction, or discontinuation with rucaparib remained consistent with the primary endpoint analysis with some minor changes (see Table below). Most common grade ≥3 TEAEs were anemia/decreased hemoglobin (28.7%), neutropenia/decreased neutrophils (14.6%), increased ALT/AST (10.6%), and thrombocytopenia/decreased platelets (7.3%). The most common TEAEs leading to discontinuation were anemia/decreased hemoglobin (3.5%), asthenia/fatigue (4.9%), and nausea (2.1%). Hypertension continued to be the most common TEAE observed in the placebo group (3.6%) compared with 1.6% in the rucaparib group. There were no changes in the incidence of serious adverse events or TEAEs leading to death since the primary endpoint analysis. Myelodysplastic syndromes (MDS)/acute myeloid leukemia (AML) were reported in a total of 3 pts in the rucaparib group (1 MDS during treatment [0.2%] and 1 AML and 1 MDS during long-term follow-up [0.5%]), of which the latter occurred since the primary readout. The initial MDS event that occurred during treatment, included in these incidence numbers, was considered resolved by the investigator since the initial analysis. Conclusions: Long-term maintenance treatment with rucaparib demonstrates a consistent and manageable safety profile in a broad population of pts with newly diagnosed ovarian cancer. No new safety signals were identified. Adverse events were generally manageable and led to discontinuation in a low proportion of pts. Clinical trial information: NCT03522246 . [Table: see text]

Real-World Impact of an In-House Dihydropyrimidine Dehydrogenase (DPYD) Genotype Test on Fluoropyrimidine Dosing, Toxicities, and Hospitalizations at a Multisite Cancer Center.

Fluoropyrimidine-related toxicity and mortality risk increases significantly in patients carrying certain DPYD genetic variants with standard dosing. We implemented DPYD genotyping at a multisite cancer center and evaluated its impact on dosing, toxicity, and hospitalization. In this prospective observational study, patients receiving (reactive) or planning to receive (pretreatment) fluoropyrimidine-based chemotherapy were genotyped for five DPYD variants as standard practice per provider discretion. The primary end point was the proportion of variant carriers receiving fluoropyrimidine modifications. Secondary end points included mean relative dose intensity, fluoropyrimidine-related grade 3+ toxicities, and hospitalizations. Fisher's exact test compared toxicity and hospitalization rates between pretreatment carriers, reactive carriers, and wild-type patients. Univariable and multivariable logistic regression identified factors associated with toxicity and hospitalization risk. Kaplan-Meier methods estimated time to event of first grade 3+ toxicity and hospitalization. Of the 757 patients who received DPYD genotyping (median age 63, 54% male, 74% White, 19% Black, 88% GI malignancy), 45 (5.9%) were heterozygous carriers. Fluoropyrimidine was modified in 93% of carriers who started treatment. In 442 patients with 3-month follow-up, 64%, 31%, and 30% of reactive carriers, pretreatment carriers, and wild-type patients had grade 3+ toxicity, respectively (P = .085); 64%, 25%, and 13% were hospitalized (P < .001). Reactive carriers had 10-fold higher odds of hospitalization compared with wild-type patients (P = .001), whereas no significant difference was noted between pretreatment carriers and wild-type patients. Time-to-event of toxicity and hospitalization were significantly different between genotype groups (P < .001), with reactive carriers having the earliest onset and highest incidence. DPYD genotyping prompted fluoropyrimidine modifications in most carriers. Pretreatment testing reduced toxicities and hospitalizations compared with reactive testing, thus normalizing the risk to that of wild-type patients, and should be considered standard practice.

First-in-human phase 1 trial of the safety, tolerability, pharmacokinetics of BY101298: Initial report from dose escalation cohort.

e15132 Background: Radiotherapy (RT) is a cornerstone of cancer treatment, leveraging the effect of ionizing radiation to induce DNA damage, primarily through DNA double-strand breaks (DSBs). Non-homologous end joining (NHEJ) stands as the predominant pathway for repairing DSBs, with DNA-dependent protein kinases (DNA-PK) playing a pivotal role in NHEJ pathway. DNA damage repair can compromise tumor cells sensitivity to RT, potentially leading to the development of radiation resistance. BY101298, an innovative and highly selective DNA-PK inhibitor, works to diminish DSBs repair. In synergy with RT or chemotherapy, BY101298 enhances tumor cells eradication, preventing local recurrence and metastasis, thereby improving clinical benefits for cancer patients. Methods: This phase Ⅰa multicenter, open-label, dose-escalation study assessed the safety, tolerability, and clinical efficacy of BY101298. Oral doses ranged from (50 mg to 400 mg once/day [QD]) in continuous 28-day cycles. Primary outcome was safety and tolerability; secondary outcome was PK; exploratory outcome was DNA-PK phosphorylation (PD). Adverse events (AEs) were monitored per the Common Terminology Criteria for Adverse Events (CTCAE version5.0). Responses were assessed every other cycle using Response Evaluation Criteria in Solid Tumors (RECIST version 1.1). Results: Data from 9 pts with advanced solid tumors (cutoff: 26 December 2023; 2 men, 7 women; median age 58.0) revealed a linear increase in BY101298 AUC exposure and Cmax with dose escalation. Daily dosing for 15 consecutive days showed no AUC increase. Serum drug concentration correlated significantly with DNA-PK phosphorylation. All pts, previously systemic treated, received doses of 50 mg QD (n = 2), 100 mg QD (n = 3), and 200 mg QD (n = 4). Median treatment duration was 30 days (range: 1-57), with one patient (11.1%) continuing. Median relative dose intensity was 100%. Common treatment-related AEs (≥25%), primarily grade 1, included hypoalbuminemia (n = 5, 55.56%); anemia (n = 4, 44.44%); nausea (n = 3, 33.33%); weight decreased (n = 3, 33.33%). No pts experienced ≥Gr3 AEs. Two pts experienced serious AEs (none of which were considered treatment-related). No treatment discontinuations, dose reductions, or deaths attributed to treatment-related. The final dose group, representing the fourth cohort, is scheduled to commence shortly and is expected to conclude in April as per our estimation. Conclusions: In pts with advanced solid tumors, BY101298 exhibits a favorable safety profile and manageable toxicity. Vomiting was noted as a potential risk associated with BY101298. Further studies are imperative to elucidate the efficacy of BY101298 in combination with radiotherapy among pts with advanced solid tumors. Research Sponsor: This study received support from Chengdu Baiyu Pharmaceutical Co., Ltd. Clinical trial information: CTR20230997.

106P Retrospective analysis of the impact of relative dose intensity on outcomes of colorectal cancer patients treated with 5-FU-based chemotherapy

106P Retrospective analysis of the impact of relative dose intensity on outcomes of colorectal cancer patients treated with 5-FU-based chemotherapy

Assessing response and adherence to neoadjuvant treatment in soft tissue sarcomas of the extremities.

e23559 Background: The standard treatment for large, intermediate, and high-grade extremity soft tissue sarcoma (ESTS) involves surgery and radiotherapy. The addition of chemotherapy has improved oncological outcomes, such as reduced recurrence and prolonged survival. However, the relationship between neoadjuvant treatment and tumor response in ESTS is not well understood. Pathological evaluation of viable tumor cells after treatment is an indicator of tumor response, yet the proportion of viable tumor cells remains high, particularly in high-risk sarcomas. Combining radiotherapy with chemotherapy may enhance the response of tumor cells. Objective: This study aims to evaluate the effects of neoadjuvant chemotherapy (NCT) and chemoradiotherapy (CRT) on patients with high-risk ESTS and to determine its impact on the pathological response. Methods: We enrolled adult patients with high-risk ESTS (SARCULATOR OS &lt; 60%) at a single center in Latin America. The study was designed to analyze the pathological response in patients with high-risk sarcomas who underwent neoadjuvant CRT and resection and to correlate these responses with various variables. The treatment response was evaluated using the EORTC–STBSG criteria. Results: Thirty-four patients were recruited, with a median age of 44 years (IQR 23-74). Fifty-two percent had T3 tumors (mean size 18 cm), and 79.4% were diagnosed at stage III. The predominant histological subtypes were synovial sarcoma (35.3%) and dedifferentiated liposarcoma (29.4%). The most used NCT regimen was doxorubicin/ifosfamide (84.4%), with 62.5% receiving a dosage intensity of Q4W, affected by overcapacity, and 25% received Q3W. Concurrent CRT was administered to 64.7% of patients, with a median delay to onset of 36 days due to overcapacity (43.5%). Only 79.4% completed three preoperative cycles of treatment. As for the response, 41.2% had an EORTC-E response, and 17.6% had an EORTC-D response. Grade 3 neutropenia and anemia occurred in 17.2% and 8.8% of patients, respectively. Disease progression during NCT was observed in six patients. No significant difference was found in the pathological response between the Q4W and Q3W dosage intensities (p = 0.62). Conclusions: The impact of NCT on pathological responses was not significantly high, which may be due to the predominant histological type in our series. The main cause of treatment delay at our center was due to overcapacity; however, this did not influence the pathological response relative to dose intensity. Additional follow-up assessments are required to determine the influence on relapse-free and overall survival based on the response after preoperative CRT.

Neoadjuvant sintilimab, albumin-bound paclitaxel, and carboplatin for locally advanced resectable esophageal squamous cell carcinoma: A prospective phase 2 study.

e16097 Background: Whether combined immunotherapy on the basis of neoadjuvant chemotherapy is beneficial for locally advanced esophageal squamous cell carcinoma (ESCC) remain to be inconclusive. This phase 2 study (ChineseClinical Trial Registry: ChiCTR2000041081) evaluate the efficacy and safety of neoadjuvant sintilimab, albumin-bound paclitaxel, and carboplatin in locally advanced ESCC. Methods: Patients with locally advanced ESCC (T2N+M0, T3N0-2M0, T4aN0-2M0, or no distant metastases, or viable or potentially viable) were enrolled and received 3 cycles of neoadjuvant sintilimab, albumin-bound paclitaxel, and carboplatin. Surgery was scheduled within four to six weeks of completing the neoadjuvant treatment. Three additional cycles of adjuvant sintilimab monotherapy or sintilimab plus chemotherapy were scheduled after a multidisciplinary discussion. The primary endpoint was the MPR rate. Results: From November 2020 to November 2021, twenty-four patients (median age: 64.5 years, men: 21/24,lower segment tumor location12/24,stage IV disease 15/24) were included in this study. All patients completed three cycles of neoadjuvant treatment and surgery. The median dose intensities for sintilimab, carboplatin and albumin-bound paclitaxel were 100% (range, 66.7–105.0%), 98.4% (range, 64.1–104.0%), and 100% (range, 38.1–105.8%), respectively. The R0 resection rate was 100%. The pCR rate and MPR rate was 33.3% and 41.7%. Among the 10 patients with PD-L1 CPS of ≥1, the pCR and MPR rates were 40% and 50%. 20 (83.1%) had TNM downstaging. The median DFS and median OS had not been reached yet, 500 days DFS and OS rate was 85.3% (95%CI 85.4%-97.2%) and 94.1% (95%CI 94.8%-100.0%). PD-L1 protein expression showed a higher life expectancy trend in the post-neoadjuvant therapy esophageal tissue samples than in the pre-therapy samples. The most common grade 3-4 treatment-related adverse events were anemia (29.2%), increased gamma-glutamyl transferase level (4.2%) and hyponatremia (4.2%). Emergency reoperation and intensive care were not required, and there were no postoperative mortalities. Conclusions: Neoadjuvant sintilimab, albumin-bound paclitaxel, and carboplatin preliminarily demonstrate encouraging clinical benefits and acceptable safety. Preoperative immunotherapy combined with chemotherapy alters the immune microenvironment of locally advanced resectable ESCC. Clinical trial information: ChiCTR2000041081.

Effect of nivolumab combined with definitive chemoradiotherapy on response rate for esophageal cancer: An immune active intrinsic subtype could be its biomarker—The NOBEL trial.

4068 Background: The usefulness of combined therapy with immune checkpoint inhibitors (ICI) and chemoradiotherapy (CRT) and its potential biomarker of treatment efficacy for esophageal cancer remains unclear. We investigated the safety, efficacy, and associated biomarkers of combined therapy with ICI and definitive CRT in operable and inoperable esophageal squamous cell carcinoma (ESCC). Methods: This prospective single-arm phase 2 trial was performed at five hospitals in Japan. Patients aged 20–75 years with histologically confirmed ESCC, an ECOG PS score of 0 or 1, and adequate organ and bone marrow functions were eligible. Inoperable patients did not have distant organ metastasis. Patients did not receive any chemotherapy or surgical resection as an initial therapy. Concurrent radiotherapy (50.4 Gy/28 fractions to the primary lesion and 41.4 Gy/23 fractions to the regional LN area) consisted of 4 courses of CF (cisplatin, 75 mg/m2/day, day 1; 5-fluorouracil, 1000 mg/m2/day, days 1–4) plus nivolumab (240 mg/m2/day, every 2 weeks for up to 1 year). The primary endpoint was safety. The incidence rates of nonhematological toxicity grade ≥ 4 and pneumonitis grade ≥ 3 were ≤10% and ≤15%, respectively. The secondary endpoints included overall survival (OS), progression-free survival (PFS), complete response (CR) rate, and time to esophagectomy-free survival (EFS). Sixty patients were to be accrued, but the trial enrollment was terminated because of slow accrual. This trial was registered as jRCT1091220408. Results: Between January 2019 and September 2021, 42 patients were enrolled. Twenty-five patients had operable disease and 16 had inoperable disease. Two patients (4.8%) experienced grade 3 pneumonitis, suggesting that the primary endpoint was met. The median relative dose intensity of nivolumab was 92.4%. One-year OS, PFS, and EFS rates in all cases were 92.7%, 65.4%, and 78.0%, respectively. One-year OS, PFS, and EFS rates in operable and inoperable cases were 100%, 79.6%, and 84.0% and 81.3%, 43.8%, and 68.8%, respectively. The CR and objective response rates were 73.2% (95% confidence interval [CI]: 58.1%–84.3%) and 87.8% (95% CI: 74.5%–94.7%), respectively. The CR rates in operable and inoperable cases were 84% (95% CI: 65.3%–93.6%) and 56.3% (95% CI: 33.2%–76.9%), respectively. Immune high-active intrinsic subtype before treatment (n=4) with an expression score &gt; 80 of 51 immune-related genes showed a high CR rate (100%, n=4), whereas the immune low-active intrinsic subtype (n=37) with an expression score &lt; 80 showed a relatively high CR rate (70%). Conclusions: Nivolumab combined with definitive CRT provided encouraging efficacy and acceptable toxicity in patients with ESCC. Immune high-active intrinsic subtype before treatment has the potential to predict a high CR rate for this combination treatment. Clinical trial information: jRCT1091220408 .

DEFENDOR: Real-world evidence of primary prolonged G-CSF prophylaxis by empegfilgrastim for relative dose intensity compliance in patients with solid tumors—The final analysis.

e24109 Background: Myelosuppression management under chemotherapy (CT) is crucial for maintaining the relative dose intensity (RDI) of therapy and ensuring effective treatment of patients with solid tumors (ST). RDI &gt; 85% is associated with better overall survival for the most ST. Granulocyte colony stimulating factors (G-CSF) have been the standard of care for the prevention of chemotherapy-induced neutropenia (CIN). Here we present the final results of a multicenter prospective observational post-marketing study of safety and efficacy of pegylated G-CSF Extimia (INN: empegfilgrastim, JSC BIOCAD) in pts with ST who receive cytotoxic therapy. Methods: The primary endpoint was the RDI of CT courses (4-8 cycles per course are allowed) with empegfilgrastim support. RDI was calculated for each single agent in the chemotherapy-based (CTb) regimen and for the CTb regimen in total. Extimia (7,5 mg) was administered subcutaneously once per chemotherapy cycle. Results: The study included 3218 pts with various tumor types across 41 centers in Russia. 3217 (99.97%) pts received at least one dose of the study drug. 2663 (82.8%) pts were included in the RDI assessment population per protocol. The average age of pts was 56.9 (18–84) y.o. Individuals aged ≥65 y.o accounted for almost one third of all pts. RDI ≥ 85% was achieved in 2415 (90.7%) pts (Table 1). 1447 (54.3%) pts have at least one FN risk factor whereas age ≥ 65 years is the most common (763/2663 (28.6%) pts). 91.5% RDI was registered in pts &lt; 65 y.o and 88.7% RDI - in pts ≥ 65 y.o. Neutropenia was reported in 19 (0.7%) cases as a reason of RDI decrease. Grade 3-4 AEs were recorded in 74 (1.8%) cases in 59 pts whereas neutropenia (n = 22), anemia (n = 8) and diarrhea (n = 6) were the most common (CTCAE (v. 5.0)). Conclusions: Primary prolonged G-CSF prophylaxis by empegfilgrastim allows effectively maintaining RDI across various tumor types (TT) and treatment groups in pts with ST in routine clinical practice. Clinical trial information: NCT0481144 . [Table: see text]

Neoadjuvant nivolumab plus paclitaxel/cisplatin- chemo-radiotherapy (neo-NTP-CRT) followed by esophagectomy for locally advanced esophageal squamous cell carcinoma (ESCC): A phase II study.

e16098 Background: Adjuvant nivolumab has shown efficacy in reducing recurrence in patients (pts) with locoregional esophageal cancer harboring pathologic residual disease following neoadjuvant chemoradiotherapy (CRT). However, the efficacy of adding nivolumab to neoadjuvant CRT remains unclear. Methods: We conducted a phase II trial of neoadjuvant nivolumab (240mg IV on D-14, 1, 15, 29), paclitaxel (50mg/m2 IV on D1, 8, 15, 22, 29), cisplatin (30mg/m2 IV on D1, 8, 15, 22, 29) and RT (45Gy given in 25 fractions) followed by esophagectomy 6 to 8 weeks after finishing CRT in pts with locally advanced ESCC, defined as clinical stage cT3-4aN0M0 or cT1-3N1-3M0 according to the AJCC Cancer Staging System 8th ed. (ClinicalTrials.gov Identifier: NCT05130684). The study, in a Simon’s two-stage design, used pathological complete response (pCR) rate as the primary endpoint. Secondary endpoints included feasibility, safety, recurrence free survival (RFS), progression free survival (PFS), and overall survival (OS). Results: Between Jan 2021 and Apr 2023, we enrolled a total of 17 pts. Fifteen were male. The median age was 52 years (range: 44~69). The clinical stage was I, II, and III in 1, 1, and 15 pts, respectively. All pts received neo-NTP-CRT with the following dose-intensities (mean dose intensity [range]): nivolumab (95% [50%~ 100%]), paclitaxel (75% [48%~ 100%], cisplatin (97% [80%~ 100%]), and radiotherapy (100%). Fourteen pts received esophagectomy, and 4 of them achieved pCR (24%). Because pCR for the first stage did not meet the efficacy criteria to move forward to second-stage, the enrollment was discontinued after enrolling 17 pts. During neo-NTP-CRT, the most common treatment-related adverse events (TRAEs) were leukopenia (76%), neutropenia (59%), thrombocytopenia (35%), and skin rash (35%); and the most common grade 3 and 4 TRAEs were leukopenia (24%), neutropenia (6%), and nausea and vomiting (6%). Among 14 pts receiving esophagectomy, 4 experienced surgical complications, including 2 with anastomotic leakage, 1 with subclavian artery rupture, and 1 with pneumonitis; one pt died 263 days after surgery, followed by a prolonged hospital stay due to refractory anastomotic leakage, infectious complications, and tumor progression. The median follow-up duration was 18 months. Median RFS, PFS and OS was 8, 12, and 16 months, respectively. Conclusions: Our data indicate that adding nivolumab to neoadjuvant paclitaxel and cisplatin-based CRT is feasible but does not improve pCR rate in locally advanced ESCC pts. Clinical trial information: NCT05130684 .

A first-in-human (FIH), phase 1/2, dose-escalation, dose-optimization, and dose-expansion study of PARP1-selective inhibitor IMP1734 in participants with advanced solid tumors.

TPS3191 Background: PARP inhibitors (PARPi) selectively kill tumor cells harboring genetic mutations in critical DNA repair genes (e.g., BRCA1/2). While several approved nonselective PARPi have provided robust anti-tumor activity, they are associated with significant hematologic toxicities that limit dose intensity and clinical benefit. Drugs that selectively inhibit PARP1 but spare PARP2 may improve the risk-benefit profile for this class of therapies by retaining anti-tumor activity while avoiding PARP2-related toxicities. IMP1734 (EIK1003) is a potent PARP1-selective inhibitor that inhibits tumor growth in nonclinical models and may widen the therapeutic index in tumors where non-selective PARPi have demonstrated efficacy. Methods: Study EIK1003-001 (IMP1734-101) is a global, multi-center, Phase 1/2 study evaluating the safety and potential antitumor activity of IMP1734 in participants with advanced solid tumors. The study has 3 parts: Part 1 (FIH; Dose Escalation), Part 2 (Dose Optimization), and Part 3 (Dose Expansion at the recommended dose for expansion [RDE]). Part 1 of this study is currently enrolling and consists of dose escalation of IMP1734 in study participants with advanced/recurrent/metastatic ovarian, breast, or prostate cancer with suspected deleterious/deleterious mutations in a pre-specified panel of homologous recombination repair (HRR) genes (n = 70). Eligible participants must be ≥ 18 years of age, have histologically or cytologically confirmed tumors as indicated in each study part, and at least 1 RECIST v1.1-measurable lesion and/or pre-specified serum tumor-specific marker. All participants must have a deleterious or suspected deleterious mutation in select HRR genes. Primary endpoints include safety and tolerability (evaluation of dose-limiting toxicities and determining the maximum tolerated dose, maximum achievable dose, and RDE). Secondary endpoints include evaluation of the pharmacokinetic parameters of IMP1734 and measures of efficacy, including overall response rate, duration of response, progression-free survival, and overall survival. Exploratory endpoints include analysis of pharmacodynamic biomarkers, serial ctDNA measurements, and patient quality-of-life measures. This study opened on 11 Dec 2023. Clinical trial information: NCT06253130 .