Dose Chemotherapy Research Articles

The phase 3 INTerpath-002 study design: Individualized neoantigen therapy (INT) V940 (mRNA-4157) plus pembrolizumab vs placebo plus pembrolizumab for resected early-stage non–small-cell lung cancer (NSCLC).

TPS8116 Background: Pembrolizumab (pembro; anti–PD-1) is indicated as adjuvant monotherapy following resection and adjuvant chemotherapy in patients (pts) with stage IB (T2a ≥4 cm), II, or IIIA NSCLC (per AJCC v7). However, many pts experience disease recurrence, and have limited treatment options available. V940 (mRNA-4157) is a novel individualized neoantigen therapy that encodes up to 34 neoantigens that is specifically tailored and manufactured for each pt derived from their tumor. V940 as monotherapy and in combination with pembro has shown preliminary antitumor activity in the phase 1 KEYNOTE-603 study in several solid tumor types, including NSCLC. Additionally, in pts with completely resected, high-risk stage IIIB/C/D and IV cutaneous melanoma in the KEYNOTE-942 primary analysis, V940 plus pembro demonstrated significant improvements in recurrence-free survival (HR, 0.561 [95% CI, 0.309–1.017]; P = 0.0266) and distant metastasis-free survival (HR, 0.347 [95% CI, 0.145–0.828]; P = 0.0063) vs pembro alone. Here we present the design of the phase 3, randomized, double-blind INTerpath-002 study (NCT06077760) of adjuvant V940 plus pembro vs placebo plus pembro in pts with completely resected and chemotherapy-treated stage II–IIIB (N2) NSCLC (AJCC v8). Methods: Eligible pts aged ≥18 years with completely resected stage II, IIIA, or IIIB (N2) squamous or nonsquamous NSCLC (per AJCC v8.0) where EGFR-directed therapy is not indicated as primary therapy (ie, absence of sensitizing EGFR mutations e.g. DEL19 or L858R), who have received 1–4 doses of adjuvant platinum-doublet chemotherapy, have ECOG PS 0 or 1, and have available tumor tissue for next-generation sequencing and PD-L1 testing will be enrolled. Pts must not have received previous neoadjuvant therapy for NSCLC and must not have received or be candidates for adjuvant radiotherapy. Pts will be randomized 1:1 to receive V940 1 mg IM or placebo Q3W for up to 9 doses plus pembro 400 mg IV Q6W for up to 9 cycles or until disease recurrence, pt withdrawal, unacceptable toxicity, or an additional malignancy requiring treatment. Randomization will be stratified by histology (squamous vs nonsquamous), PD-L1 TPS ( < 1% vs 1%–49% vs ≥50%), disease stage (II vs III), and geographic location (North America/Western Europe/Australia vs rest of world). The primary endpoint is disease-free survival per investigator review. Secondary endpoints include distant metastasis-free survival per investigator assessment, OS, lung cancer‒specific survival, patient-reported outcomes, and safety. Tumor imaging will occur at baseline, every 12 wk until wk 48, every 24 wk through year 3, and every 48 wk thereafter. Enrollment began in October 2023 and is ongoing globally (NCT06077760). The abstract was originally presented and published in: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT281. Clinical trial information: NCT06077760 .

A prospective multicenter trial of dose escalation for weekly gemcitabine concurrent with intensity-modulated radiotherapy following cisplatin and gemcitabine induction chemotherapy in patients with locally advanced nasopharyngeal carcinoma.

6071 Background: Gemcitabine and cisplatin induction chemotherapy, followed by cisplatin-based concurrent chemoradiotherapy, constitutes the standard treatment for locally advanced nasopharyngeal carcinoma (LANPC). However, the substantial cumulative dosage of cisplatin used in this approach renders it intolerable for many patients due to advanced age or compromised renal function. Therefore, identifying alternative chemotherapeutic agents is crucial. Gemcitabine is a potent radiosensitizer with an overall favorable safety profile. Despite extensive research on the maximum tolerated dose (MTD) of concurrent gemcitabine chemotherapy in head and neck cancer, its MTD as a single-agent chemotherapy concurrently administered with intensity-modulated radiotherapy (IMRT) in LANPC remains uncertain. Methods: Patients diagnosed with stage III-IVa nasopharyngeal carcinoma were prospectively enrolled in three hospitals located within the largest NPC endemic area in southern China. After two cycles of cisplatin plus gemcitabine induction chemotherapy, patients underwent combined concurrent radiochemotherapy (70 Gy/6-7 weeks) with weekly gemcitabine. The initial dose level was set at 25mg/m2 and subsequently escalated in a sequential manner to higher doses of 50mg/m2, 100mg/m2, 200mg/m2, and 300mg/m2 etc. Our study employed a dose escalation strategy in which the dosage was incremented to the next group only if no more than one out of six patients experienced Dose-Limiting Toxicity (DLT), until DLT occurred in at least two patients. Patients underwent follow-up evaluations every three months. This study is registered with ClinicalTrials.gov under NCT04522050. Results: Between October 2018 and December 2023, a total of 39 Chinese patients were enrolled, 36 (27 males, 9 females) patients were considered evaluable. The incidence of DLT was observed in two out of six patients receiving a dosage level of 300 mg/m², with both cases presenting Grade 3 oral mucositis. Subsequently, the study was replicated using the same dosage level, resulting again in two instances of DLT: one case with Grade 3 radiation dermatitis and another case with oral mucositis. Consequently, a reduced dosage level of 200mg/m² was determined as MTD. No significant hematological toxicity or serious gastrointestinal adverse events were observed. Tumor response evaluation by MRI after twelve weeks of IMRT showed a complete response rate of 100%. To date, only two cases (5.56%) have been reported exhibiting tumor recurrence. Conclusions: The MTD for weekly gemcitabine with IMRT following induction chemotherapy in LANPC is determined to be 200 mg/m2. The DLT associated with this treatment regimen primarily consists of radiation dermatitis and/or oral mucositis. Clinical trial information: NCT04522050 .

AN0025 in combination with definitive chemoradiotherapy (dCRT) in unresectable locally advanced or locally recurrent esophageal cancer (EC): A single-arm, open-label, multicenter, phase Ib study.

e16076 Background: AN0025 is a selective EP4 inhibitor that demonstrates antitumor activity by modulating the accumulation and function of macrophages and immunosuppressive myeloid cells in tumor microenvironment. The combination of AN0025 with CRT as neoadjuvant therapy has shown synergistic antitumor efficacy in locally advanced rectal cancer in a prior clinical trial (NCT03152370). Methods: This Phase Ib study includes a dose escalation phase followed by an expansion phase to evaluate the safety, tolerability, and feasibility of AN0025 plus dCRT for unresectable locally advanced or locally recurrent EC or esophagogastric junction cancer. Antitumor efficacy was assessed per RECIST v1.1. The eligible patients (pts) are candidates for dCRT, who received RT (2.0 Gy/fraction, totally 50-60 Gy) with concurrent weekly paclitaxel and carboplatin for 4 weeks, followed by two doses of consolidation chemotherapy on Week 8 and Week 12. AN0025 (250 mg or 500 mg QD) was administered orally for 15 weeks concurrently with dCRT. At the beginning of Week 17, pts would start AN0025 monotherapy in the maintenance phase. Results: As of Jan 12, 2024, 12 pts (11 males and 1 female, median age 62) with histologically confirmed esophageal squamous cell carcinoma (ESCC) were enrolled and received the study treatment, 5 at the 250 mg dose level and 7 at the 500 mg dose level. Among those 12 pts, 11 were locally advanced ESCCs and 1 was locally recurrent ESCC. The most common AN0025-related adverse events (AEs) were weight decreased (33%), anemia (33%), and white blood cell count decreased (25%). Two pts (17%) experienced Grade ≥3 AN0025-related AEs (one Grade 3 weight decreased and one Grade 3 esophageal fistula). No dose-limiting toxicity occurred at either dose level, and the maximum tolerated dose was not reached. The median follow-up was 14.2 months, with 8 pts remaining on study treatment and a maximum time on treatment of 2 years. The disease control rate (DCR) was 92% (11/12). The median progression-free survival (PFS) was not reached, with 6-month and 1-year PFS rates of 91% and 73%, respectively. The 1-year overall survival (OS) rate was 82%. Additionally, among the 8 pts with measurable lesion(s) at baseline, 1 (13%) achieved confirmed complete response (CR), and 6 achieved partial response (PR), including 5 confirmed PRs, giving an unconfirmed overall response rate (ORR) of 88% (7/8) and a confirmed ORR of 75% (6/8). AN0025 PK approached linearity at both 250 mg and 500 mg QD. AN0025 PK in combination with dCRT showed no interactions. Conclusions: This Phase Ib study suggests that AN0025 plus dCRT exhibits favorable safety and encouraging preliminary efficacy in unresectable locally advanced or locally recurrent EC, warranting further investigation. Clinical trial information: NCT05191667 .

A phase I clinical study to evaluate the safety, tolerability, immunogenicity, pharmacokinetics and preliminary efficacy of SCB-219M in patients with chemotherapy-induced thrombocytopenia (CIT): An interim analysis.

e15015 Background: CIT is a serious, chemotherapy-associated complication observed in a wide range of cancer patients with various types of cancer. Incidence of CIT can occur in about 15-25% of patients undergoing standard chemotherapy regiments with platinum, taxane and/or gemcitabine-based regimen. CIT can lead to chemotherapy dose delay or dose reduction, and potentially bleeding events. Currently, there is no FDA-approved therapy for CIT. SCB-219M, a thrombopoietin receptor agonist (TPO-RA) mimetic bispecific Fc-fusion protein produced from CHO cells can efficiently raise PLT count under normal and pathological conditions in laboratory animals. Methods: This is a single-arm, multi-center, open-label, dose escalation Phase Ia clinical study to evaluate the safety, tolerability, and immunogenicity, PK profile and preliminary efficacy of a single ascending dose of SCB-219M administered one day after a chemotherapy in prior CIT patients with malignant solid tumors and lymphoma. The study design of accelerated titration combined with "3 + 3" is used, and the number of subjects planned to enroll is 12 to be assigned to 4 cohorts with 2, 6, 10 and 15 mg/kg subcu administration of SCB-219M, respectively. Enrollment criteria include episode of CIT experienced (<75 × 109/L in PLT count) in prior cycle of chemotherapies and PLT count has recovered to >75 × 109/L prior to initiation of this study . The chemotherapy regimen allowed include either mono or combination chemotherapy (including targeted therapy and/or immunotherapy). The observation period of dose-limiting toxicities (DLTs) is 21 days. Chemotherapy is planned at each study site. There will be no change in the planned dose or frequency of chemotherapy in the study. Results: As of Dec 20, 2023, 9 prior CIT patients including 3 at 15 mg/kg were enrolled. SCB-219M was well tolerated. There were no SAEs or AESIs (Adverse Event of Special Interest) observed. DLT was not reached. A favorable PK profile, in particular in serum availability (AUC) and half-life (T1/2) was obtained. All 9 prior CIT patients in the study maintained PLT counts >75 x 109/L from 1-week following chemotherapies with a single dose of SCB-219M, and durable responses experienced through at least 3 weeks. Conclusions: In this interim analysis, drug safety, PK profile and durable efficacy are expected to support SCB-219M dosing interval of ≥2-weeks or a single dosing regimen within a chemotherapy cycle. Accordingly, a Phase Ib trial evaluating repeated dosing of SCB-219M is planned to initiate in 2024. Clinical trial information: NCT05426369 .

Relative dose intensity of first-line triplet chemotherapy in metastatic colorectal cancer

PurposeRelative dose intensity (RDI) is a measurement of chemotherapy (CT) dose defined as the actual dose received divided by the standard calculated dose during a set period. The study objective was to assess the impact of a RDI ≥ 80% on response and survival of patients treated in first line CT by FOLFOXIRI or FOLFIRINOX ± Bevacizumab (BV) for an unresectable metastatic colorectal cancer (mCRC). Materials and methodsIt was a retrospective, non-interventional, multicenter study calculating RDI from the first cycles of CT to the first CT-scan evaluation (CT-scan1). Objective response and disease control rates (ORR and DCR), progression-free survival (PFS) and overall survival (OS) were compared between patients with RDI ≥ 80% and <80% and results were adjusted for age, gender, ECOG, tumor location, number of metastatic sites, RAS and BRAF status, the CT regimen, the use of BV, the delay from C1 to CT scan1. ResultsAmong 152 screened patients, 100 met inclusion criteria, with a mean (± standard deviation) age at 59.0 (± 10.7) years. The ECOG performance status was 0–1 in 96 (96%) patients; metastases were synchronous in 95 (95%), RAS and BRAF were mutated in 60 (60%) and 22 (22%), respectively. ORR was observed in 51 (51%) at CT-scan1 with median PFS and OS of 10.5 and 21.9 months, respectively. A RDI ≥ 80% was observed in 44 (44%) patients without impact on ORR (ORa: 1.04, 95% CI: 0.37 to 2.89, p = 0.94) but was significantly associated to improved PFS and OS with HRa 0.50 (95%CI: 0.29 to 0.87, p = 0.013) and 0.52 (95% CI: 0.29 to 0.91, p = 0.023), respectively. ConclusionOur results suggest a low level of FOLFOXIRI or FOLFIRINOX +/- BV exposure in first-line mCRC is associated with a significant trend on PFS and OS.

Safety and efficacy of PEG-rhG-CSF as primary prophylaxis against neutropenia induced by combination chemotherapy regimens involving oral chemotherapy agents in gastrointestinal cancer patients: A prospective, exploratory, non-randomized controlled study.

e24107 Background: The safety and efficacy of PEGylated recombinant human granulocyte colony-stimulating factor (PEG-rhG-CSF) for prevention of chemotherapy-induced neutropenia (CIN) in patients undergoing oral chemotherapy remain unclear. This study investigated the safety and efficacy of PEG-rhG-CSF as primary prophylaxis against CIN in gastrointestinal (GI) cancer patients receiving combination chemotherapy regimens involving oral chemotherapy agents. Methods: This is a prospective, single-center, open-label, exploratory, non-randomized controlled study. GI cancer patients receiving two consecutive cycles of IV oxaliplatin (150mg/m2 on day 1) combined with oral capecitabine 1000mg/m2 or tegafur gimeracil oteracil potassium capsule 40-60mg twice daily on days 1-14 every 3 weeks. PEG-rhG-CSF (6mg) was administered subcutaneously 24 hours post-oxaliplatin treatment in the PEG-rhG-CSF group, while the control group did not receive it. The primary endpoint was safety, and secondary endpoints included CIN incidence and neutropenic complications. The study was registered with the Chinese Clinical Trial Registry (registration number ChiCTR2100054854). Results: Between March 2022 and January 2023, a total of 49 patients was screened, and 43 patients completed the treatment (26 in PEG-rhG-CSF group and 17 in control group). The average age was 61.4 years, with 90.7% males and 83.7% having gastric cancer. Baseline characteristics were similar between the two groups. The overall adverse events (AE) did not differ statistically (88.5% vs. 88.2%, p = 1.000), with grade £2 fatigue and nausea being the most common AEs. Grade 3 platelet reduction showed no significant difference between the two groups (7.69% vs. 17.65%, p = 0.432). Four cases of bone pain (15.4%) and five cases of injection site reactions below grade 3 (19.2%) were observed in the PEG-rhG-CSF group. Grade ≥2 CIN was significantly lower in the PEG-rhG-CSF group (3.84% vs. 58.82%, p &lt; 0.001). One case in the PEG-rhG-CSF group required antibiotic treatment due to febrile neutropenia. Regarding neutropenic complications, the PEG-rhG-CSF group exhibited lower proportion of chemotherapy delay (3.85% vs. 35.29%, p &lt; 0.001) and dose reduction (1.92% vs. 23.53%, p = 0.002). Rescue treatment with rhG-CSF for grade 3/4 CIN was significantly less frequent in the PEG-rhG-CSF group (1.92% vs. 23.53%, p = 0.002). Conclusions: Primary prophylaxis with PEG-rhG-CSF in GI cancer patients undergoing oral capecitabine/tegafur gimeracil oteracil potassium may be safe, without an increased chemotherapy-related AEs, and is associated with a reduced grade ≥2 CIN. Clinical trial information: ChiCTR2100054854.

SOGUG-Vexillum: Phase II non-randomized clinical trial of nivolumab/ipilimumab maintenance following first-line chemotherapy in unresectable locally advanced or metastatic urothelial cancer.

4576 Background: Nivolumab (nivo) 1mg/kg plus ipilimumab (ipi) 3mg/kg achieved the highest ORR (42.4%) in refractory metastatic urothelial carcinoma (mUC) with a manageable safety profile. The addition of nivo and ipi subsequently to first-line chemotherapy (CT) could consolidate the clinical benefit. Methods: This single arm, open-label, multicenter study evaluates the effectiveness of ipi 3 mg/kg and nivo 1 mg/kg (Q3W) for 4 cycles followed by nivo maintenance therapy (Q4W) in delaying disease progression in patients with unresectable urothelial cancer that did not progress after first-line platinum-based CT (at least 4-6 cycles of CT). Autoimmune disease, immune deficiency, and symptomatic brain metastasis were excluded. The primary endpoint is Progression Free Survival (PFS) in intention-to-treat and PD-L1 populations. Secondary endpoints include: objective response rate (ORR), duration of response (DoR), overall survival (OS), overall survival from 1st dose of CT (cOS), progression-free survival from 1st dose of CT (cPFS), safety and translational biomarker analysis. Sample size was estimated using a Simon II stage design for 4-months PFS rate (H0= 40%; H1= 60; α= 0.05; β= 80%; attrition 10%), requiring 25 patients in the 1st stage and up to 66 in total. Here we report the interim analysis for 1st stage. Results: As of January 2024, the 1st accrual stage was completed with 25 evaluable patients. Baseline characteristics are outlined in the table. With a median follow-up of 6.8 months (95% CI: 6.2-10.5), the 4-m PFS rate was 64% (95% CI: 47.7-85.9) and the median PFS was 4.3 months (95% CI: 3.2-NR). The median cPFS was 9.4 months (95% CI: 8-NR). The 6-m OS rate was 76.4% (95% CI: 60-97.2), while median cOS was 15.4 months (95% CI: 15.4-NR). The median duration of treatment was 2.6 months (95% CI: 2.1, 5.7). Nivo and ipi were permanently discontinued due to toxicity in 3 (12%) and 1 (4.2%) patients, respectively. Nivo doses were delayed in 8 (32%) patients and ipi in 3 (12%) for management of toxicity. Grade ≥3 toxicities were reported in 8 (32%) patients, being the most common: Immune-mediated hepatitis (8%), ALT/AST increased (8%) and diarrhea (8%). Conclusions: Maintenance treatment with nivo and ipi showed preliminary efficacy consolidating clinical benefit to CT with a manageable safety profile. The 4-m PFS rate surpassed the futility threshold in the interim analysis and the accrual in Stage II is underway. Final survival results are awaited. Clinical trial information: NCT05219435 . [Table: see text]

Effect of DeltaRex-G ± DeltaRex-G Plus (an FDA-approved drug) on advanced chemoresistant pancreatic cancer, sarcoma, and breast cancer.

e15086 Background: Expanded access for DeltaRex-G, a tumor targeted retrovector encoding a CCNG1 inhibitor, is being studied for advanced cancers. Methods: 137 archived tumor specimens were analyzed with AI RNA sequencing to identify CCNG1 expression levels, reported as: Low = 17%, Medium-low = 17%-49%, Medium-high = 50%-83%, High = 83%. Nine patients with advanced solid malignancies, whose CCNG1 levels were identified, received DeltaRex-G (2-3 x 10e11 cfu/dose one to three times a week), either without an FDA-approved drug, or with an FDA-approved drug (“DeltaRex-G Plus”). Overall survival, duration of treatment, and responses were evaluated. Results: All analyzed tumors showed enhanced CCNG1 expression. Thirty (22%) tumors exhibited High CCNG1 expression, 48 (35%) showed Medium-High CCNG1 expression, 53 (39%) displayed Medium-Low CCNG1 expression, and six (4%) had Low CCNG1 expression. One hundred (73%) patients had metastatic disease, and 37 (27%) had localized disease. There was no correlation between CCNG1 expression and disease stage. Four patients with advanced pancreatic cancer (n = 1), Stage 1 HR+Her2+ invasive breast cancer (n = 1), Stage 1 triple negative breast cancer (n = 1), and squamous cell carcinoma of skin (n = 1), received DeltaRex-G alone or DeltaRex-G Plus between 2008 and 2021 and are alive 15, 3, 2.5, and 2.5 years since treatment initiation, respectively. Retrospective analysis of their respective tumors showed CCNG1 expression levels of 24%, 23%, 74%, and 40%. Three of the patients are in sustained remission and the patient with squamous cell carcinoma had a partial response. Of the five patients currently being treated with DeltaRex-G Plus: one patient with advanced breast cancer had a partial response (n = 1), one patient with advanced pancreatic cancer (n = 1) and three patients with soft tissue sarcoma (n = 3) had stable disease. Four of five patients had previously progressed with standard doses of chemotherapy. All patients are alive from 11 to 22 weeks since treatment initiation. No serious treatment-related adverse events have been reported. Conclusions: Taken together, the data shows that (1) 100% of 137 tumors tested have enhanced CCNG1 expression, further reinforcing the 2021 FDA-CBER authorization for use of DeltaRex-Plus, and (2) DeltaRex-G Plus is a promising therapy for advanced pancreatic cancer, sarcoma, and breast cancer. Randomized Phase 2/3 studies are warranted to confirm the efficacy and safety of DeltaRex-G Plus. Clinical trial information: NCT04091295 .

Follow-Up of Patients Diagnosed With Germinal Testicular Tumors (Seminomas and Non-seminomatous) Treated With a Bone Marrow Transplant and a High Dose of Chemotherapy.

Germinal testicular tumors are the most common malignant neoplasm in men around 20 to 34 years. Even though they are unusual, they have increased incidence in the last decade; they have an excellent prognosis and overall survival at five years, approximately 95%. Divergent data exists regarding treatment options in patients with first, second, and third relapses with conventional therapy. Some studies describe the possible benefit of using high-dose chemotherapy associated with a bone marrow transplant with variable results. The present study describes clinical outcomes, clinical response, mortality, overall survival, and progression-free survival to two years in a group of patients with germinal malignant tumors, seminoma versus non-seminomatous with evidence of progression of the disease at first, second, or third conventional chemotherapy regimens,and who received high dose chemotherapy and bone marrow transplantation at the National Cancer Institute between 2010 and 2021. A retrospective observational study of case series showed that 57% of patients in third-line therapy received high-dose chemotherapy and bone marrow transplantation, with progression disease median time from diagnosis more than two years. Patients in the post-graft period presented infectious complications (71%). The most common were febrile neutropenia (29%) with a mortality rate of 71% (n=5), progression-free survival of 2.3 months, and overall survival of 7.4 months. These results show that in this group of patients, regimens with high-dose chemotherapy associated with bone marrow transplants, have a worse prognosis compared to other cohorts of patients, and may not be the best candidates for this rescue therapy.

Racial differences in degrees of side effects to taxane based chemotherapy in patients with breast cancer.

e13726 Background: Taxane-based chemotherapy is well-established as a backbone of treatment for patients with breast cancer. While highly effective, all taxanes are known to cause peripheral neuropathy, with a high prevalence in obese patients. Other risk factors to developing peripheral neuropathy include older age, smoking, and hyperglycemia. Prior studies have shown that obesity is more prevalent in Black women compared with other racial group in the United States. Obese women have higher body surface areas and thus, tend to receive higher doses of chemotherapy. The higher total doses of taxanes received by obese women puts them at higher risks for developing peripheral neuropathy. We sought to evaluate the racial and BMI differences in rates of neuropathy in patients with breast cancer receiving taxanes. Methods: We created a 2-year database (2021-2022) of women diagnosed with breast cancer who received a taxane across a single health system. Data collected included age at diagnosis, self-identified race, breast cancer subtype, BMI, type of taxane, neuropathy, smoking and diabetes. Stratification analysis was performed using SAS Software 9.4. Results: The rate of neuropathy was 65.2% in White patients and 71.01% in Black patients (p=0.4649). The risk ratio between Black patients with neuropathy to White patients with was 1.26, 95% Cl (0.73-2.17), p=0.6525. In the total cohort of patients, regardless of neuropathy, 60.6% of Black patients had a BMI &gt;30 compared with only 39.5% of White patients. Of those who had neuropathy, obesity was present in 64% of White patients and 65% of Black patients. Conclusions: The data presented here suggest that in a population of breast cancer patients treated with taxanes, there was a trend towards increased neuropathy in Black patients, but no increase in neuropathy based on BMI. Black women were more obese, which suggests that they are at increased risk for developing neuropathy. Factors such as universal effects of chemotherapy across races, comorbid conditions and insufficient sample size could have masked potential significant differences. Further research is needed to understand the complex elements influencing treatment responses in a diverse population. [Table: see text]

Analysis of risk factors for recurrence within 12 months after surgery in patients with breast cancer receiving neoadjuvant therapy at a Brazilian cancer center.

e13039 Background: Early recurrence following treatment for localized breast cancer typically occurs within 5 years, and is commonly linked to high-risk clinicopathologic factors. However, literature focusing on risk factors for earlier recurrence timeframes is scarce, particularly within the neoadjuvant treatment population. Therefore, this study aims to investigate potential predictors for recurrence within 12 months post-surgery in breast cancer patients submitted to neoadjuvant therapy. Methods: This is an observational, descriptive, retrospective study involving 310 patients with recurrent breast cancer who received neoadjuvant therapy between January 2007 and March 2022, at AC Camargo Cancer Center in São Paulo, Brazil. Patients were compared based on relapse time after surgery (&lt;12 months or ≥12 months), and risk factors were analyzed using the Chi-Square test or Fisher’s Exact test. Results: From 310 patients analyzed, 108 relapsed within 12 months and 202 after this period. Factors predicting recurrence in less than 12 months included: Histologic grade (HG) III ( p &lt; 0.01); nuclear grade (NG) III ( p &lt; 0.001); mitotic counts &gt;20/mm2 ( p = 0.02); Ki67 &gt; 20% ( p = 0.010); triple negative breast cancer (TNBC) and HER2+/HR- subtypes ( p &lt; 0.001); interruption of neoadjuvant therapy due to disease progression or toxicity ( p &lt; 0.001); chemotherapy dose reduction or delay ( p = 0.001); omission of adjuvant radiotherapy ( p &lt; 0.001) and interruption of adjuvant HER2 targeted therapy ( p &lt; 0.001). Menopausal status, Residual Cancer Burden (RCB) index, type of surgery and clinical stage showed no significant correlation with the outcome. Conclusions: Recurrence in less than 12 months was associated with intrinsic factors, such as HG III, NG III, high mitotic counts, Ki67 &gt; 20%, TNBC, as well as interruption or delay of neoadjuvant therapy, omission of adjuvant radiotherapy and interruption or delay of HER2 targeted therapy, pointing out potential risk factors in this population.

Patient factors associated with chemotherapy modifications: Results from the Optimal Breast Cancer Chemotherapy Dosing (OBCD) study.

520 Background: Understanding patient factors associated with an increased likelihood of receiving chemotherapy modifications is important for treatment planning and anticipating which patient groups might require extra support through the course of treatment. Methods: We have evaluated patient and tumor factors associated with chemotherapy modifications in a cohort of 9700 women receiving adjuvant chemotherapy for breast cancer at Kaiser Permanente Northern California (KPNC) and Kaiser Permanente Washington (KPWA) in the Optimal Breast Cancer Chemotherapy Dosing (OBCD) Study diagnosed between 2005-2019. The outcome variable, receipt of a ‘chemotherapy modification’ is defined as a composite representing any of the following deviations from the intended regimen: dose reduction &gt;10% (first cycle or overall), extensive delay (any single delay &gt;14 days), regimen change, or receipt of fewer cycles of any given drug than intended in the original chemotherapy plan. Multivariable-adjusted prevalence ratios (PR) and corresponding 95% confidence intervals (95% CI) were calculated using generalized linear models of the Poisson family with a log link-function and robust standard errors. Results: Several factors were associated with chemotherapy modifications. Notably, older age was associated with an increased likelihood of modifications (p-trend&lt;0.001), with adults aged 80+ years at diagnosis 1.93-fold more likely to experience modification than adults 18-39 years (95% CI: 1.50-2.50). Increased comorbidity and BMI were also associated with increased likelihood of modification (p-trend for both:&lt;0.001), with patients with a Charlson Comorbidity Index of 3+ (vs 0) having an PR of 1.33 (95% CI: 1.19-1.48) and those with a BMI of 35+ kg/m2 (vs &lt;25 kg/m2) having an PR of 1.53 (95% CI: 1.41-1.65). HER2+ status (PR HER2+ vs HER2-: 1.99 95% CI: 1.89-2.10) and higher stage of disease (PR IIIA vs I:1.24; 95% CI: 1.13-1.35; p-trend&lt;0.001) were associated with increased likelihood of chemotherapy modification, while hormone receptor positivity was associated with lower likelihood of modification (PR ER+ and/or PR+ vs ER-/PR-: 0.93; 95% CI: 0.88-0.99). Diagnosis in more recent years was also associated with decreased likelihood of modification (PR 2015-2019 vs 2004-2009: 0.70; 95% CI: 0.66-0.75), as was higher neighborhood income (PR Q4 vs Q1: 0.78; 95% CI: 0.72-0.84). Conclusions: Several patient-level and clinical factors were associated with chemotherapy modifications, including age, comorbidity, BMI, and ER/PR/HER2 status. Future research might focus on the groups noted to have increased risk of treatment modification to better understand the factors underlying these changes, as well as the impact on patient outcomes.

Romiplostim for chemotherapy induced thrombocytopenia in solid tumors: A meta-analysis.

e24137 Background: Chemotherapy-induced thrombocytopenia (CIT), defined as platelets &lt; 100,000/mcL persisting for ≥3-4 weeks post-chemotherapy affects 20-25% of cases necessitating platelet transfusions or dose reductions leading to treatment delays and impacting patient outcomes. (1,2) Despite multiple studied agents, there are no established guidelines. Romiplostim, a thrombopoietin receptor agonist approved for immune thrombocytopenic purpura, stands out. NCCN suggests its use, but pooled analyses are lacking. Our meta-analysis addresses this gap, exploring romiplostim's efficacy in CIT management. Methods: We performed a systematic search of PUBMED, EMBASE, and COCHRANE databases for studies that evaluate the use of romiplostim in the setting of CIT for solid tumors. The primary endpoint was the proportion of patients that showed improvement in platelet counts in response to romiplostim. Secondary endpoints were the proportion of patients that continued full dose chemotherapy dose on romiplostim and incidence of thromboembolic events. Pooled proportions were calculated along with 95% confidence intervals (CI) using a random-effects model. I2 statistic was used to depict inter-study heterogeneity. Results: A total of 10 single arm studies - 3 prospective studies, 3 case series, and 4 retrospective studies were included. The pooled outcomes were: significant improvement of platelet count above 100K with response to romiplostim therapy in 80.53% patients [95 % CI 72.47 - 87.48, I2 = 69%], proportion of patients that continued full dose chemotherapy on romiplostim was 70.89% [95% CI 63.40 - 77.84, I2 = 0%], and incidence of thromboembolic events was 6.81% [ 95% CI 3.64 – 10.89, I2 = 35%]. Variables like platelet transfusions, bleeding events, type and stage of cancer were not reported uniformly and hence subgroup analyses could not be performed. Conclusions: Our analysis reveals that romiplostim improved the platelet counts in majority of patients with underlying CIT associated with solid tumors. It also shows that a majority of the patients were able to resume their full dose chemotherapy when maintained on romiplostim. The incidence rate of thromboembolic events with romiplostim believed to be consistent with what expected of this population with majority having advanced/high-risk malignancies. Given its efficacy, romiplostim may be used for routinely managing CIT in solid tumors. This analysis is limited by lack of comparative studies and warrant further randomized trials to confirm the safety and efficacy of romiplostim in this patient population.

Clinical impact and financial feasibility of remote oncology pharmacists' roles in community oncology practices.

1545 Background: The clinical and financial impact of oncology-trained pharmacists in the community oncology setting has not been well documented. The US Oncology Network has introduced a novel remote oncology pharmacist model which provides clinical services to oncology community practices to alleviate the burden on oncologists, enhance patient care, and improve workflows. Methods: Oncology-trained pharmacists remotely reviewed chemotherapy regimens across 12 community oncology practices. Pharmacists identified opportunities to modify therapy based on clinical criteria, waste reduction, and/or financial stewardship. These modifications were discussed with the treatment team or implemented in accordance with practice-approved policies. Clinical and financial metrics were tracked to assess the overall impact of the pharmacist interventions and provider time saved. Results: From January 1, 2023, through December 31, 2023, 27,938 reviews were documented for 19,962 patients. Among these reviews, the majority (14,572, 73%) required modification by the pharmacist, and many (3,005, 21%) were deemed clinically significant by the intervening pharmacist. The most common clinically significant interventions included changes to anticancer drug doses (1155, 38%), modifications to supportive care (742, 25%) and recommendations for additional monitoring (426, 14%). Across 12 practices, 63 drug-related workflow policies were implemented allowing pharmacists to autonomously auto-substitute products, order laboratory tests and adjust chemotherapy doses. These policies saved over 600 hours of physician time. Pharmacist involvement resulted in medication-related margin improvements totaling $9.3M. Practices also experienced a $4.3M reduction in the total cost of care in medication expenses. The cost of the pharmacists during this period was $1.4M, equating to a 560% return on investment compared to margin improvement. Conclusions: Community oncology practices operate within a resource-constrained model with limited access to oncology pharmacists. As invaluable members of the care team, pharmacists identified opportunities to significantly enhance clinical care by focusing on medication safety, dosing, and regimen optimization, while demonstrating a tremendous financial impact on small-scale budgets. Oncology-trained pharmacists play a vital role in alleviating care burden of the clinical team by collaboratively developing practice-approved policies and reviewing clinical orders in a high-risk patient population.

Patient characteristics associated with primary prophylactic granulocyte colony-stimulating factor (G-CSF) use among women treated for early-stage breast cancer.

e12605 Background: The National Comprehensive Cancer Network (NCCN) recommends several chemotherapy regimens for early-stage breast cancer that have elevated risk of neutropenia (&gt;20%). In these regimens, primary prophylactic use of granulocyte colony-stimulating factor (G-CSF) is recommended. Little is known about how patient-level factors relate to receipt of prophylactic G-CSF among women receiving these regimens. Methods: In the Optimal Breast Cancer Chemotherapy Dosing (OBCD) Study, we examined use of G-CSF among women with stage I-IIIA breast cancer between 2005-2019 in Kaiser Permanente Northern California (KPNC) and Kaiser Permanente Washington (KPWA). We evaluated the patient-level factors associated with primary prophylactic G-CSF use (≤7 days before to ≤3 days after first day of chemotherapy) among women receiving chemotherapy regimens with high risk of neutropenia, for which the NCCN guidelines recommend prophylactic G-CSF use. Multivariable-adjusted prevalence ratios (PR) and their corresponding 95% Confidence Intervals (95% CI) were calculated using generalized linear models of the Poisson family with a log link-function and robust standard errors. Results: Overall, while all 3,083 women receiving these regimens ultimately received G-CSF, 2412 (79%) received primary prophylactic G-CSF within the period 7 days prior to 3 days post first cycle. Younger women had higher prevalence of prophylactic G-CSF receipt (82.7% in ages 18-39 years vs. 58.1% in 70+ years). Black women had higher prevalence of receipt compared to white women (82.7% in non-Hispanic Black women vs 76.1% in White women). Women with a higher body mass index (BMI) had lower prevalence of receipt compared to normal weight women (73.3% in 35+ kg/m2 group vs 81.5% in 18.5-&lt;25 kg/m2 group). In multivariable models, older women were less likely to receive prophylactic G-CSF (PR70+ vs 18-39: 0.69; 95% CI: 0.57-0.84; p-trend&lt;0.001), as were those with a higher BMI (PRBMI 35+ vs 18.5-&lt;25: 0.92; 95% CI: 0.85, 0.97; p-trend=0.006), and a later year of diagnosis (PR2016-19 vs 2005-07: 0.81; 95% CI: 0.77, 0.85; p-trend&lt;0.001). Although race/ethnicity was not significantly associated with receipt of prophylactic G-CSF use overall in multivariable models, we observed Non-Hispanic Black women to experience slightly higher likelihood of G-CSF receipt than Non-Hispanic White women (PR: 1.08; 95% CI: 1.02, 1.15). Conclusions: Women of older age and those with higher BMI were less likely to receive primary prophylactic G-CSF, as were women treated in later years. Further research looking at timing of G-CSF use is warranted, as are studies examining provider/facility-level factors in relation to patterns of G-CSF use, G-CSF’s impact on survival outcomes, and the real-world impact of decisions around G-CSF use across age, BMI, and racial/ethnic groups.

Implementing DPYD/UGT1A1testing to prevent treatment related adverse events (TRAE) in patients with gastrointestinal (GI) cancer: Results of a pragmatic implementation trial.

10599 Background: Fluoropyrimidines (FP), 5-FU and capecitabine, are standard treatments for many GI cancers. Irinotecan may be used with FPs in both the curative and palliative settings. 30-40% of patients experience severe TRAEs which can lead to treatment interruption and hospitalization. TRAE risk is higher in patients with pharmacogenetic variants in DPYD and/or UGT1A1. Methods: This is a non-randomized, open-label implementation study at 3 cancer care sites within an academic health system to determine feasibility of integrating DPYD/UGT1A1 testing into clinical care (IMPACT-GI; NCT#04736472). Test ordering and discrete variant resulting were available within the Electronic Health Record. The lab detected 5 DPYD variants with reduced or no function (c.1905+1G&gt;A, c.2846A&gt;T, c.1679T&gt;G, c.1236G&gt;A, c.557A&gt;G) and 2 UGT1A1 (*6, *28) alleles. Patients with a GI cancer initiating treatment with 5-FU, capecitabine, or irinotecan underwent testing along with preemptive chemotherapy dose modifications. Carriers of 1 DPYD variant (i.e., intermediate metabolizers [IM]) and UGT1A1 homozygous carriers (i.e., poor metabolizers [PM]) were recommended a 50% and 30% dose reduction, respectively. The primary endpoints were feasibility (proportion of results available prior to cycle 1) and fidelity (genotype concordant dose modifications). Secondary endpoints included severe TRAE (requiring emergency room visit or hospitalization) comparing variant carriers vs. wildtype over the first 6 cycles. Results: From 3/2021- 12/2022, 224 patients received testing (54% male, 74% White, 18% Black, mean age 62 ±17 years. The most common diagnoses were 47% colorectal and 30% pancreatic cancers. The median lab turnaround time was 10 (IQR 9-13) calendar days with 57.2% of results available prior to cycle 1. Results available prior to cycle 1 varied by distance to lab (64.7% near sites vs. 32.7% far site, p&lt;0.001). We identified 7 (3%) DPYD intermediate metabolizers (IM) and 33 (15%) UGT1A1 poor metabolizers (PM). Four (2%) patients carried a variant in both DPYD and UGT1A1. Chemotherapies were preemptively dose reduced for 6 of 7 DPYD carriers receiving FP and 5 of 8 UGT1A1 PMs receiving irinotecan. 2 (28%) DPYD carriers vs. 71 (33%) wildtype carriers had a severe TRAE. 4 (50%) UGT1A1 PMs vs. 11 (36%) UGT1A1 wildtype carriers experienced a severe TRAE. Conclusions: DPYD/UGT1A1 testing is feasible with oncology providers following the genotype guided dose reductions when results were available prior to cycle 1. Pretreatment DPYD/UGT1A1 testing in conjunction with preemptive dose reductions resulted a similar proportion of severe TRAE as compared with wild-type patients. Further workflow modifications are required to decrease test turnaround time to ensure results are available prior to chemotherapy initiation. Clinical trial information: NCT04736472 .

A retrospective study of first line atezolizumab-carboplatin-etoposide in extensive-stage small cell lung cancer: Real world data from a Spanish tertiary center.

e20100 Background: The association of immune checkpoint inhibitors (ICIs) with Platinum-Etoposide (PE) has been established as the standard treatment in extensive stage Small Cell Lung Cancer (ES-SCLC). We present a real-world analysis, conducted in a Spanish tertiary hospital, that assesses the efficacy and safety of Atezolizumab combined to Carboplatin-Etoposide (Atezo-CE) in first-line ES-SCLC treatment, based on the Impower-133 Clinical Trial (CT). Methods: In this longitudinal, retrospective study, we analysed the patients (pts) diagnosed with ES-SCLC and treated at our center from July 2020 to June 2023, comparing outcomes of PE chemotherapy and Atezo-CE regime. Primary endpoints were overall survival (OS), progression-free survival (PFS) and safety. We contrasted our findings to those obtained in trials that used different ICIs: Impower-133 (Atezolizumab), CASPIAN (Durvalumab) or KEYNOTE-604 (Pembrolizumab). Data analysis employed Chi-square, Kaplan-Meier and Log-Rank. Results: Over 35 months (m), 41 pts with ES-SCLC were treated in our center: 19 pts received PE (57.9% Cisplatin and 42.1% Carboplatin), and 22 received Atezo-CE. In the PE group: 42.1% completed 6 cycles, 21.1% 4 cycles, and 36.8% less than 4. In the Atezo-CE cohort: 81.8% completed 4 cycles, and 18.2% less than 4. Regarding Performance Status (PS) in the PE cohort vs the Atezo-PE group: PS 0 0 vs 4.5%; PS 1 47.4 vs 77.3%; PS 2 42.1 vs 18.2%; PS 3 10.5 vs 0%. Corticosteroid therapy was ongoing in 52.6% vs 50% of PE vs Atezo-CE pts, respectively, adding the ICI in later cycles without affecting total cycles of Atezo received (6.8 in our study vs 7 in the Impower-133). Adverse effects (AEs) occurred in 73.7% of PE pts vs 100% of Atezo-CE pts (68.2% chemo-induced and 31.8% immune-related). Common AEs in both groups were anemia, thrombopenia, leukopenia, asthenia and vomiting. Skin and thyroid AEs were the most frequent ICI-related. Chemotherapy dose reduction occurred in 47.4% vs 27.3% and suspension in 5.3% vs 13.3% of PE pts vs Atezo-CE pts, respectively. OS was higher in the Atezo-CE group, 11.7m (95% CI: 9.2-14.2m) compared to 6.8m (95% CI: 3.8-9.8m) in the PE cohort, p-value 0.008. PFS also favoured Atezo-CE pts, 6.9m (95% CI: 5-8.7m) vs 5m (95% CI: 2.8-7.2m) in the PE cohort, though not statistically significant, p-value 0.249. Compared to the CTs Impower-133, CASPIAN and KEYNOTE-604, which reported OS of 12.3m, 12.9m and 10.8m, respectively, and PFS of 5.2m (Impower-133) and 4.2m (KEYNOTE-604), our study with pts with worse PS and needing corticosteroids at treatment initiation (exclusion criteria in CTs), showed comparable outcomes. Conclusions: Our study underscores the importance of adding ICIs to ES-SCLC first-line treatment. It further emphasizes the need for a deeper knowledge in molecular profiling and biomarker-driven strategies to tailor ES-SCLC therapy more effectively.

Chemotherapy Regimen Optimization Using a Two-Archive Multi-Objective Squirrel Search Algorithm

Chemotherapy is one of the most effective treatments for cancer, but the efficacy of standard chemotherapy regimens is often limited by toxicities and the individual heterogeneity of cancers. Precise dosing is an important tool to improve efficacy and reduce significant differences in toxicity. However, most of the existing studies on chemotherapy optimization fail to fully consider the toxic side effects, drug resistance, and drug combinations, and thus the chemotherapy regimens obtained may face difficulty in achieving the expected efficacy and also affect the subsequent treatment. Therefore, this paper establishes a tumor growth model for the combination chemotherapy of cell cycle-specific and non-cycle-specific drugs and includes the factors of acquired drug resistance and toxic side effects, proposing an improved multi-objective Squirrel Search Algorithm, the TA-MOSSA, to solve the problem of accurate chemotherapy drug optimization. In this paper, experiments were conducted to analyze the efficacy of chemotherapy dosing regimens obtained by the TA-MOSSA based on the tumor growth model, and the results show that the TA-MOSSA can provide effective chemotherapy regimens for patients who take different treatment approaches.

Chemotherapy Primary Dose Reduction in Older Cancer Patients: A Retrospective Cohort

Primary dose reduction (PDR) in the first course of chemotherapy is an empirical practice, commonly used in older population. Patients over 70 years old receiving a first course of chemotherapy for a solid tumor were enrolled. A total of 179 patients were included. Standard dose was used in 69.8% of patients, while 30.2% received PDR of chemotherapy. Only 29.6% received a standardized geriatric assessment. Patients receiving standard doses presented 83.2% of toxicities, while 68% of toxicities were reported in patients receiving PDR. The toxicity rate was significantly decreased in patients treated with reduced first-cycle dose of chemotherapy.

Assessment of efficacy and safety of dose-dense doxorubicin and cyclophosphamide (ddAC) in combination with immunotherapy in early-stage triple-negative breast cancer

PurposeThis study aimed to assess safety and efficacy of a modified KEYNOTE 522 protocol, which incorporated pembrolizumab every 6 weeks, allowing for concomitant dose-dense (14 day) doxorubicin and cyclophosphamide (ddAC). By optimizing this dosing, the intention of this modified protocol was to improve pathologic complete response (pCR) rates in a population associated with a poorer prognosis.MethodsThis was a retrospective, single-center, cohort study. Patients were included if they had early stage, triple-negative breast cancer, and received at least one dose of AC. The entire cohort received neoadjuvant chemotherapy including weekly carboplatin and paclitaxel with pembrolizumab every 3 weeks for 12 weeks (4 cycles). The group then received either ddAC with pembrolizumab 400 mg every 6 weeks, or AC with pembrolizumab 200 mg every 3 weeks. The primary objective was pCR rate at time of surgery.ResultsThis study assessed outcomes in 25 patients over 34 months. The pCR rate in the pembrolizumab, AC 3-week cohort was 64.3% versus 81.8% in the ddAC and 6-week pembrolizumab group. No pembrolizumab-associated grade 3–4 adverse events occurred in the either cohort. Despite seeing an increased incidence of grade 3–4 toxicities in the ddAC arm, this did not result in additional chemotherapy delays or dose reductions.ConclusionThis study demonstrated tolerability and a potential for favorable outcomes with this patient population, making this modified KEYNOTE 522 protocol a reasonable treatment approach. Larger, prospective studies are warranted to assess the feasibility of this dosing and true optimization of patient outcomes given the small sample size of this study.