Weekly Paclitaxel Research Articles

Comparison of Weekly Paclitaxel Regimens in Recurrent Platinum-Resistant Ovarian Cancer: A Single Institution Retrospective Study.

Weekly paclitaxel (WP) is a chemotherapeutic cornerstone in the management of patients with platinum-resistant ovarian carcinoma. Multiple WP dosing regimens have been used clinically and studied individually. However, no formal comparison of these regimens is available to provide objective guidance in clinical decision making. The primary objective of this study was to compare the cumulative dose of paclitaxel delivered using 80 mg/m2/week, administered using either a 3 weeks out of 4 (WP3) or a 4 weeks out of 4 (WP4) regimen. The secondary objective was to evaluate the clinical outcomes associated with both regimens, including efficacy and toxicity parameters. Our retrospective cohort comprised 149 patients harboring platinum-resistant ovarian cancer treated at the CHU de Québec from January 2012 to January 2023. WP3 and WP4 reached a similar cumulative dose (1353.7 vs. 1404.2 mg/m2; p = 0.29). No significant differences in the clinical outcomes were observed. The frequency of dose reduction was significantly higher for WP4 than WP3 (44.7% vs. 4.9%; p < 0.01), mainly due to treatment intolerance from toxicity (34.0% vs. 3.9%; p < 0.01). Our data suggest that a WP3 regimen delivers a similar cumulative dose to WP4, hence offering a better tolerability profile without compromising efficacy.

Pegylated recombinant human granulocyte colony-stimulating factor for primary prophylaxis of neutropenia in patients with cervical cancer receiving concurrent chemoradiotherapy: a prospective study

BackgroundThis study aimed to investigate the efficacy and safety of pegylated recombinant human granulocyte colony-stimulating factor (PEG-rhG-CSF) for primary prophylaxis of neutropenia in patients with cervical cancer receiving concurrent chemoradiotherapy.MethodsIn this prospective, single-center, single-arm study, we enrolled patients (18–70 years) with 2018 International Federation of Gynecology and Obstetrics (FIGO) stage IIIC1r-IVA and IVB (distant metastasis only with inguinal lymph node metastasis) cervical cancer. Eligible patients should have normal function of the bone marrow (absolute neutrophil count (ANC) ≥ 2.0 × 109/L) and adequate hepatic and renal functions. Key exclusion criteria included: previous chemotherapy and/or radiotherapy; a history of bone marrow dysplasia or other hematopoietic abnormalities. All patients underwent radical radiotherapy (pelvic radiotherapy or extended-field irradiation) plus brachytherapy. The chemotherapy regimen included four cycles of 3-weekly paclitaxel and cisplatin. PEG-rhG-CSF was administered 48–72 h after each treatment cycle. Salvage granulocyte colony-stimulating factor (G-CSF) was only permitted in certain circumstances. The primary endpoint was the incidence of grade 3–4 neutropenia. The secondary endpoints included frequency of febrile neutropenia (FN), chemotherapy completion rate in cycles 2–4, time to complete radiotherapy, and safety.ResultsOverall, 52 patients were enrolled in this study from July 2019 to October 2020. The incidence of grade 3–4 neutropenia was 28.8%, with an average duration of grade 3–4 neutropenia persistence of 3.85 days (1–7 days). The incidence rate of FN was 3.8%. The chemotherapy completion rate was 94.2%, 82.7%, and 75.0% for cycles 2–4, respectively. The incidences of grade 3–4 neutropenia for cycles 1–4 were 9.6% (5/52), 8.2% (4/49), 14.0% (6/43), and 2.6% (1/39), respectively. All patients completed radiotherapy within 8 weeks (median, 48 days; range: 41–56 days), except one patient who withdrew consent and did not receive radiotherapy. Severe non-hematologic toxicity was not observed in any patient.ConclusionPEG-rhG-CSF is an effective and safe prophylactic treatment for neutropenia in patients with cervical cancer undergoing concurrent chemoradiotherapy.Trial registrationChinese Clinical Trial Registry, ChiCTR1900024494. Date of Registration:13/July/2019.

ECOG-ACRIN EAZ171: Prospective validation trial of germline variants and taxane type in association with taxane-induced peripheral neuropathy (TIPN) in Black women with early-stage breast cancer.

LBA503 Background: Black women experience higher rates of TIPN compared to White women when receiving weekly paclitaxel (WP) for early-stage breast cancer. This disparity impacts health equity, as TIPN leads to more frequent dose reductions and higher recurrence rates in Black women. Conversely, disparities in TIPN by race are not seen in women receiving every three-week docetaxel (3D). Further, retrospective analyses have identified specific genotypes associated with differential risk of grade 2-4 TIPN in women of African ancestry receiving WP . The primary aim of EAZ171 was to prospectively validate germline predictors of TIPN in Black women receiving WP. Secondary objectives included comparing rates of TIPN and dose reductions in Black women receiving WP compared to 3D. Methods: Women with early-stage breast cancer who self-identified as Black and were planned by physician choice to receive (neo)adjuvant WP (80mg/m2 x 12 doses) or 3D (75 mg/m2 x 4-6 doses) were eligible. Genotyping determined germline neuropathy risk, defined as high ( FCAMR homozygous wt or SBF2 mutated) or low (variant allele in FCAMR and SBF2 wt). Grade 2-4 TIPN by physician-reported CTCAE v.5 was compared between high vs. low risk genotypes, and between the WP vs. 3D arms at one year using Fisher exact tests with two-sided alpha of 0.1. Patient-rated TIPN was captured using PRO-CTCAE items, and patient-reported outcomes (PROs) assessed TIPN symptoms and functional interference (FACT/GOG-NTx, EORTC CIPN20). Results: 249 patients were enrolled between 6/27/19-3/31/22, including 121 receiving at least one dose of WP and 118 receiving a dose of 3D. Of those with genotype data, 91/117 (77.8%) in the WP arm and 87/118 (73.7%) in the 3D arm were classified as high risk. Physician-reported grade 2-4 TIPN was not significantly different in the high vs. low risk genotype groups with WP (47% vs. 35% p=0.27) nor with 3D (28% vs. 19% p=0.47). Grade 2-4 TIPN was significantly higher in the WP vs. 3D arm by physician-rated CTCAE (45% vs. 29% p=0.02) and PRO-CTCAE (40% vs. 24% p=0.03). Trends in worsening neuropathy scores were similar over time using the FACT/GOG-NTx and EORTC CIPN20 questionnaires, but were not significantly different between the two arms at 1 year. Patients receiving WP required more dose reductions due to TIPN (28% vs. 9% p&lt;0.001) or due to any cause (39% vs. 25% p=0.02) than patients receiving 3D. Conclusions: In this prospective trial enrolling only Black women with breast cancer, germline variation did not significantly impact risk of TIPN with WP or 3D. However, 3D was more tolerable evidenced by less grade 2-4 TIPN and fewer dose reductions compared to WP. Given the disparate burden of TIPN and its potential impact on cure rates, this trial suggests docetaxel should be considered the preferred taxane for Black women with early-stage breast cancer. Clinical trial information: NCT04001829 .

A phase III randomized, open-label study to establish the superiority of triple oral metronomic therapy (OMCT) used in addition to chemotherapy regimen (paclitaxel + carboplatin) over chemotherapy alone for the treatment of advanced unresectable head and neck cancer squamous cell cancer (HNSCC).

LBA6053 Background: Advanced HNSCC has poor outcomes and limited treatment options, especially in resource-constrained settings. Immunotherapy is affordable for less than 5% of patients in lower-middle-income countries (LMICs). Triple OMCT, employing low-dose continuous chemotherapy, shows promise, but its safety and efficacy along with chemotherapy remain unproven. We aimed to assess whether the addition of OMCT to first-line chemotherapy can improve overall survival (OS) as compared to chemotherapy alone. Methods: This phase 3 randomized, prospective, open-label, superiority design study enrolled patients with advanced HNSCC who were planned for palliative intent platinum-based chemotherapy. The patients were stratified for the site of the tumor and ECOG PS, and were randomly assigned 1:1 to receive either triple OMCT (Erlotinib 150 mg OD, Celecoxib 200 mg BD and Methotrexate 9mg/m2 once weekly) in addition to 3-weekly paclitaxel carboplatin (PC) chemotherapy (Arm A) or, PC chemotherapy alone (Arm B). Sample size calculation assumed no OS improvement with OMCT+PC (5% type I error, 80% type II error). The primary endpoint was OS, while secondary endpoints included PFS, quality of life (QoL) assessments, and safety. OS and PFS were analyzed via Kaplan-Meier and log-rank test; HR estimated via Cox proportional hazard models. QoL was assessed using EORTC QLQ-C30. The study was approved by Institutional Ethics Committee and registered with the Clinical Trials Registry India (CTRI/2022/10/046520). Results: Between Nov 02, 2022, and Dec 20, 2023, 238 patients were randomly assigned with 119 in each arm. Median age was 47 years, with 97.8% being males, and 78% of patients had ECOG PS 0-1. The median OS for patients in Arm A was 8.3 months (95% CI, 6.3-10.4) while it was 6.1 months (95% CI, 4.7-7.4), in Arm B (HR 0.63; 95% CI, 0.47–0.83; p=0.00011). The corresponding median PFS was 7.6 months (95% CI, 6.3-8.8) and 3.5 months (95% CI, 2.2-4.7) (HR, 2.79; 95% CI, 1.98-3.93; P&lt;0.000). Significant differences in EORTC-C30 were found for the physical functioning domain between baseline and 1-month follow-up visit. PC chemotherapy combined with triple OMCT showed good tolerability, with common toxicities including fatigue (40.3%), and hyponatremia (25.4%), similar to the incidence observed with PC chemotherapy alone. Conclusions: This study demonstrates that the addition of triple OMCT to paclitaxel and carboplatin chemotherapy is an effective and safe treatment option for patients with advanced HNSCC in platinum-sensitive settings. This treatment option is particularly valuable in LMICs, where cetuximab and pembrolizumab are not feasible. Clinical trial information: CTRI/2022/10/046520 . [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 .

An Open-Label Phase II Trial NCT03812393 to Evaluate the Efficacy and Safety of Neoadjuvant Neratinib Followed by Weekly Paclitaxel and Carboplatin Plus Neratinib in Early-Stage Triple-Negative Breast Cancer (TNBC) Patients Who Exhibit Enhanced HER2 Signaling by Live Cell HER2 Signaling Transduction Analysis (FACT-2)

An Open-Label Phase II Trial NCT03812393 to Evaluate the Efficacy and Safety of Neoadjuvant Neratinib Followed by Weekly Paclitaxel and Carboplatin Plus Neratinib in Early-Stage Triple-Negative Breast Cancer (TNBC) Patients Who Exhibit Enhanced HER2 Signaling by Live Cell HER2 Signaling Transduction Analysis (FACT-2)

Abstract PO1-18-03: Chemokine-modulating regimen (rintatolimod, IFN-α2b, celecoxib): New strategy to drive CD8+T-cells into triple negative breast cancer

Abstract BACKGROUND: Pathologic complete response (pCR) is critical for positive long-term outcomes after neoadjuvant chemotherapy (NAC) in triple negative breast cancer (TNBC) but is achieved only in 40-50% of patients. Combination of NAC with pembrolizumab, the new standard of care in TNBC, increases the pCR rate to 65% but is associated with significant and often permanent immune-related toxicities. Higher levels of CD8+ cytotoxic T-lymphocytes (CTLs) and low levels of regulatory T-cells (Treg) and myeloid derived suppressor cells (MDSC) in the tumor microenvironment (TME) predict improved relapse-free survival (RFS), overall survival (OS) and pCR, a surrogate marker for RFS. Locally produced chemokines CCL5, CXCL9, CXCL10 and CXCL11 are critical for CTL infiltration, while CCL22 is responsible for Treg attraction, with high CXCL9 being associated with a 3-fold higher rate of pCR after NAC. Our preclinical data show that Chemokine-modulatory (CKM) regimen, combining rintatolimod (TLR3 agonist), interferon (IFN)α2b and celecoxib (COX-2 inhibitor), eliminates the suppressive aspects of paclitaxel-induced inflammation and induces CTL-attractants but decreases MDSC- and Treg-attractants in the TME. We hypothesized that the combination of CKM with paclitaxel-based NAC will promote selective CTL infiltration into TNBC, and along with doxorubicin/cyclophosphamide (AC), will result in higher rate of pCR, translating into improved RFS and OS. METHODS: In this phase I study NCT04081389, 9 pts with stage I-III TNBC and median age of 47 (37-55) years received 3 weeks of paclitaxel with CKM, followed by 9 weeks of paclitaxel alone, followed by standard dose-dense AC and surgery. Paclitaxel was given weekly IV at 80 mg/m2 for 12 weeks, rintatolimod 200 mg IV, IFN-α2b and celecoxib 200 mg oral twice daily on days 1-3 of each of the initial 3 weeks. IFN-α2b was administered in an accelerated titration design at doses 0 or 5 million units (MU)/m2 [Dose Level (DL) 1 and 2, respectively] in the first 2 pts (no intra-patient dose escalation), then 10 MU/m2 [DL3] in 4 pts and then 20 MU/m2 [DL4] in 3 pts. Day 1 pre- and post-treatment blood samples were drawn. Pre- and post-treatment (at 3 weeks) biopsies were obtained from 5 pts at DL3 and DL4. Dose-limiting toxicity (DLT) was defined as grade 3 or higher within the first 3 weeks of treatment. Primary endpoint was safety and tolerability, to determine the recommended phase II dose (RP2D) of CKM for extended efficacy study. Secondary endpoints included efficacy (pCR), along with RFS and OS. Biomarkers were analyzed in exploratory studies. RESULTS: Treatment was well-tolerated with mostly grade 1 or 2 treatment-related adverse events (TRAEs) and no DLTs. Grade 3 TRAE were neutropenia (3/9), attributed to CKM (1/9) or paclitaxel (3/9), pneumonia (1/9) and anemia (1/9) attributed to AC. Paclitaxel- or AC-related toxicities were not higher than expected. There were no delayed or immune-related toxicities beyond treatment. 5/9 (56%) pts attained pCR, and 1 additional pt had ypTmic at the time of surgery. There was consistent (p=0.07) selective increase in CD8α (CTL marker) in post-treatment tumor biopsies with concomitant decrease in CD8α in the blood (p=0.04) measured by RT-PCR. RNA sequencing on the blood samples (7 pre- and post-treatment) showed that higher M2 macrophages and naïve B cells in the pre-treatment samples were associated with higher probability of non pCR (adjusted p=0.02 and 0.05, respectively). CKM treatment decreased CD8α and CD8β post-treatment in the blood samples. Higher CD8+ T cells and NK cells in the post-treatment blood samples, were associated with higher likelihood of pCR, although this trend did not reach statistical significance. CONCLUSIONS: We have observed preliminary indications of safety and good tolerability of the combination of CKM regimen with paclitaxel, with promising pCR + ypTmic of 66%. RNA sequencing indicates that CKM may drive CD8+ T cells from the blood into the tumor. Citation Format: Shipra Gandhi, Cayla Jones, Mateusz Opyrchal, Ronald Slomba, Kristopher Attwood, Jianmin Wang, Eduardo Cortes Gomez, Tracey O'Connor, Ellis Levine, Pawel Kalinski. Chemokine-modulating regimen (rintatolimod, IFN-α2b, celecoxib): New strategy to drive CD8+T-cells into triple negative breast cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO1-18-03.

Abstract PO1-20-03: Acupuncture for Preventing Progression of Taxane-Induced PeripheralNeuropathy (ATP): A Phase II Randomized, Placebo Controlled Trial

Abstract 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. However, there is no effective treatment or preventative measure for CIPN. The current management of worsening and persistent CIPN during chemotherapy is dose reduction or discontinuation of chemotherapy. Our group previously completed a single-arm phase IIA pilot trial of women who developed National Cancer Institution Common Terminology Criteria for Adverse Events (NCI-CTCAE) grade 2 CIPN during weekly paclitaxel for stage I-III breast cancer. The result suggested an acupuncture intervention for grade 2 CIPN might slow CIPN progression during chemotherapy. However, the role of acupuncture still needs to be better defined. 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. The study will include two phases: screening and intervention. In the screening phase, eligible patients will consent and receive CIPN screening each week. Patients who develop grade 1 CIPN or higher based on NCI-CTCAE version 5.0 will be consented to the intervention phase and randomized to receive either weekly RA or SA using a standardized, semi-fixed protocol developed in our preliminary studies to improve CIPN pain. Eligibility criteria for the screening phase: 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. Eligibility criteria for the intervention phase: in additional to the screening phase eligibility criteria, 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, including randomization to one of the two possible acupuncture treatments. 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 20 participants in the intervention phase by the end of June 2023; the target accrual is 80 participants. Contact information for people with a specific interest in the trial: W. Iris Zhi, MD, PhD, zhiw@mskcc.org. ClinicalTrails.gov Identifier: NCT05458284. Citation Format: W. Iris Zhi, Lauren Taylor, Raymond Baser, Matthew Weitzman, Qing Li, Christina Seluzicki, Ting Bao, Jun Mao. Acupuncture for Preventing Progression of Taxane-Induced PeripheralNeuropathy (ATP): A Phase II Randomized, Placebo Controlled Trial [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO1-20-03.

Abstract PO3-18-11: A011801 (CompassHER2 RD): Postneoadjuvant T-DM1 + tucatinib/placebo in patients with residual HER2-positive invasive breast cancer

Abstract Background: Patients with HER2+ early breast cancer (EBC) and invasive residual disease (RD) after neoadjuvant therapy (NAT) have a higher risk of relapse than patients who have a pathologic complete response (pCR). Escalation of therapy in patients with RD using post-neoadjuvant T-DM1 has become the new standard of care, leading to improved invasive disease-free survival (iDFS), but patients with estrogen receptor (ER)-negative or nodal RD have suboptimal outcomes, and central nervous system recurrences are a challenge. More effective treatment strategies are urgently needed. Alliance A011801 (CompassHER2 RD) is an escalation trial for patients with high-risk HER2+ RD after neoadjuvant systemic therapy, evaluating the addition of the HER2 selective tyrosine kinase inhibitor (TKI) tucatinib to post-neoadjuvant T-DM1. Methods: Eligibility and Intervention: Patients with high-risk HER2+ RD (i.e., ER-, node-positive, or both) after a predefined course of neoadjuvant HER2-directed treatment are randomized 1:1 to adjuvant T-DM1 + placebo, vs. T-DM1 and tucatinib with adjuvant RT +/- ET. Eligibility criteria include completion of ≥ 6 cycles of NAT, including ≥ 9 weeks of paclitaxel and trastuzumab +/- pertuzumab. All chemotherapy (CT) must be completed preoperatively unless participating in EA1181 (~15-30% will be participants in the CompassHER2 pCR de-escalation companion trial [NCT04266249]; these patients must receive postoperative CT to complete ≥ 6 cycles prior to enrollment on A011801). Patients who received prior HER2-targeted TKIs or antibody-drug conjugates are ineligible. Objectives: The primary objective is to determine if iDFS is improved with addition of tucatinib to T-DM1 in patients with HER2+ EBC with RD after neoadjuvant systemic therapy; secondary endpoints include overall survival, breast cancer free survival, distant recurrence-free survival, brain metastases-free survival and disease-free survival. Correlative objectives include the association of i) tumor infiltrating lymphocyte (TILs) levels in the primary tumor and RD with iDFS, ii) TILs with tucatinib benefit, iii) iDFS and circulating tumor cells (CTC) at serial timepoints and iv) the magnitude of benefit of tucatinib (iDFS) in patients with/without detectable pretreatment CTCs. Quality of life and pharmacokinetic endpoints are also being evaluated. Statistics: A011801 is a prospective, double-blind, randomized, phase III superiority trial; stratified by i) receipt of postoperative CT (Y/N), ii) hormone receptor-status (+/-), and iii) pathologic lymph node status (+/-). The study targets an absolute difference of 5% in iDFS (control vs. experimental arm 82% &amp; 87%, HR = 0.7), with a two-sided alpha of 0.05 and power of 80%. The sample size is 981; target accrual = 1031 patients; activation and estimated completion dates are 01/6/21 and ~ 01/2028. Accrual as of 7/10/2023: 438 patients. Support: U10CA180821, U10CA180882; Seagen Inc; https://acknowledgments.alliancefound.org. ClinicalTrials.gov Identifier: NCT04457596 Citation Format: Ciara O'Sullivan, Karla Ballman, Linda McCall, Tyler Zemla, Anna Weiss, Melissa Mitchell, Victoria Blinder, Nadine Tung, William Irvin, Myounghee Lee, Sailaja Kamaraju, Matthew Goetz, W. Fraser Symmans, Virginia Borges, Ian Krop, Ann Partridge, Lisa Carey. A011801 (CompassHER2 RD): Postneoadjuvant T-DM1 + tucatinib/placebo in patients with residual HER2-positive invasive breast cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO3-18-11.

Comparative Analysis of Weekly Cisplatin Versus Weekly Paclitaxel with Radiotherapy in Locally Advanced Head and Neck Cancer

Comparative Analysis of Weekly Cisplatin Versus Weekly Paclitaxel with Radiotherapy in Locally Advanced Head and Neck Cancer

Exploring the Efficacy of Pembrolizumab in Combination with Carboplatin and Weekly Paclitaxel for Frail Patients with Advanced Non-Small-Cell Lung Cancer: A Key Investigative Study.

Immune checkpoint blockers have revolutionized the first-line treatment of advanced non-small-cell lung cancer (NSCLC). Pembrolizumab, an anti-PD-1 monoclonal antibody, is a standard therapy either alone or in combination with chemotherapy (chemo-IO). The current study explores the efficacy and safety of pembrolizumab with carboplatin and weekly paclitaxel in a cohort of frail patients. A monocentric retrospective study was conducted between 22 September 2020 and 19 January 2023 regarding patients with stage IV NSCLC treated with chemo-IO combination: carboplatin (AUC 5 mg/mL/min; Q4W), weekly paclitaxel (90 mg/m2 on days 1, 8, and 15), and pembrolizumab (200 mg Q4W). The primary objective was real-world progression-free survival (rwPFS). Secondary objectives were overall survival (OS), toxicity profile, and outcomes based on histological subtype. A total of 34 patients (20 squamous and 14 non-squamous NSCLC) benefited from the chemo-IO regimen for frail patients; 41.9% had an ECOG-PS = 2. The median age was 75.5 years. We observed an overall response rate (ORR) of 55.9%. Notably, squamous NSCLC exhibited a significantly higher ORR (80%) than non-squamous NSCLC (21.4%); p = 0.001. The median rw-PFS was 10.6 months (95% CI [6.0, NA]), with 6- and 12-month rw-PFS rates of 69% and 45.8%, respectively. The median OS was not reached, with 12- and 18-month OS rates of 75.6% and 61.4%, respectively. The median number of maintenance cycles of pembrolizumab was 5 (0; 27). Nine patients (26.5%) experienced a toxicity related to chemotherapy leading to a reduction of the dose administered and, in five patients (14.7%), to the permanent discontinuation of chemotherapy. Six patients (17.6%) had an immune-related adverse event leading to the discontinuation of immunotherapy. Pembrolizumab plus carboplatin and weekly paclitaxel demonstrates promising efficacy and safety in frail patients with metastatic NSCLC, especially for ORR in sq-NSCLC. Prospective studies focusing on frail populations are warranted in order to validate these findings and optimize therapeutic strategies in the first-line setting.

Neoadjuvant therapy of HER2 directed conventional dendritic cell (DC1) intratumoral (IT) therapy plus weekly paclitaxel, trastuzumab, and pertuzumab in patients with HER-2 positive breast cancer: NATASHA trial.

596 Background: Early stage HER2 positive breast cancer (BC) patients (pts) are commonly treated with neoadjuvant HER2-targeted therapy. Optimizing neoadjuvant therapy by improving efficacy while reducing toxicity is a critical unmet need. IT DC 1 therapy combined with an IgG1 antibody mediating ADCC drives strong anti-HER-2 CD4 Th1 responses and complete tumor regression in preclinical models. We initiated a phase I/II neoadjuvant study to explore the efficacy and immune stimulation effects of an initial 6 weeks of immunotherapy phase (IP) using IT DC1 vaccine plus trastuzumab (H) and pertuzumab (P) (as source of IgG1) followed by 12 weeks of paclitaxel (T) and HP. Methods: Early stage HER2+ BC pts with tumor ≥ 1cm were eligible. Treatment included IT DC1 weekly x6 followed by paclitaxel 80 mg/m2 IV weekly x 12. Trastuzumab IV every (q) 3 weeks (8 mg/kg loading dose, then 6 mg/m2) and pertuzumab IV q 3 weeks (840 mg loading dose, then 420 mg) x 6 cycles starting from day 1. Two dose levels (DL) of IT DC1 (DL1 = 50 million and DL2 = 100 million cells) were evaluated including 6 pts in each DL. Once the optimal DL is determined based on toxicities, additional 22 patients will be enrolled in expansion phase 2 trial. The primary end point of the phase 1 is the safety, immune responses (measured by ELISPOT). MRI breast was performed at the baseline, post-immunotherapy and post-chemotherapy. Here we are reporting the safety and immune correlates in phase 1 study. Results: Twelve pts were enrolled between 10/2021 and 10/2022. Median age was 57 (range 34-74). Nine pts had hormone receptor positive disease with clinical stage I/II/III (5/5/2) and 4 pts had node positive disease. All pts completed IP and 10 patients completed THP chemotherapy as of 2/1/2023. Radiologic response per MRI breast on pre and post-IP showed 6 partial response, 3 complete response and 3 stable disease. Nine pts underwent surgery and 6 out of 9 pts had pCR (RCB 0). The most frequently observed toxicities were chills (50%), diarrhea (42%), nausea (42%), fatigue (42%), and headache (42%). ELISPOT demonstrated a significant decrease of HER2- specific T cell response following 6 weeks of DC1 IT injections in DL2 compared to DL1. Conclusions: The addition of IT DC1/HP to neoadjuvant chemotherapy was well tolerated with manageable toxicities. The 100 million DC1 led to a significant decrease in peripherally circulating anti-HER2 T cell response at week 6 following IP and improved radiologic tumor responses which correlates with a higher likelihood of pCR. Data from another IT DC1 trial suggests decreased circulating HER2 responsive T cells are due to increased trafficking of reactive T cells out of circulation into the tumor possibly leading to an enhanced anti-tumor effect. Updated results including correlative biomarkers will be presented at the meeting. Clinical trial information: NCT05325632 .

Efficacy of Endocrine Therapy Plus Trastuzumab and Pertuzumab vs De-escalated Chemotherapy in Patients with Hormone Receptor–Positive/ERBB2-Positive Early Breast Cancer

Combination of chemotherapy with (dual) ERBB2 blockade is considered standard in hormone receptor (HR)-positive/ERBB2-positive early breast cancer (EBC). Despite some promising data on endocrine therapy (ET) combination with dual ERBB2 blockade in HR-positive/ERBB2-positive BC, to our knowledge, no prospective comparison of neoadjuvant chemotherapy vs ET plus ERBB2 blockade in particular with focus on molecular markers has yet been performed. To determine whether neoadjuvant de-escalated chemotherapy is superior to endocrine therapy, both in combination with pertuzumab and trastuzumab, in a highly heterogeneous HR-positive/ERBB2-positive EBC. This prospective, multicenter, neoadjuvant randomized clinical trial allocated 207 patients with centrally confirmed estrogen receptor-positive and/or progesterone receptor-positive (>1%) HR-positive/ERBB2-positive EBC to 12 weeks of standard ET (n = 100) vs paclitaxel (n = 107) plus trastuzumab and pertuzumab. A total of 186 patients were required to detect a statistically significant difference in pathological complete response (pCR) (assumptions: 19% absolute difference in pCR; power, ≥80%; 1-sided Fisher exact test, 2.5% significance level). Standard ET (aromatase inhibitor or tamoxifen) or paclitaxel, 80 mg/m2, weekly plus trastuzumab and pertuzumab every 21 days. The primary end point was pCR (ypT0/is, ypN0). Secondary end points included safety, translational research, and health-related quality of life. Omission of further chemotherapy was allowed in patients with pCR. PAM50 analysis was performed on baseline tumor biopsies. Of the 207 patients included (median [range] age, 53 [25-83] years), 121 (58%) had cT2 to cT4 tumors, and 58 (28%) had clinically node-positive EBC. The pCR rate in the ET plus trastuzumab and pertuzumab arm was 23.7% (95% CI, 15.7%-33.4%) vs 56.4% (95% CI, 46.2%-66.3%) in the paclitaxel plus trastuzumab and pertuzumab arm (odds ratio, 0.24; 95% CI, 0.12-0.46; P < .001). Both immunohistochemical ERBB2 score of 3 or higher and ERBB2-enriched subtype were independent predictors for pCR in both arms. Paclitaxel was superior to ET only in the first through third quartiles but not in the highest ERBB2 quartile by messenger RNA. In contrast with the paclitaxel plus trastuzumab and pertuzumab arm, no decrease in health-related quality of life after 12 weeks was observed in the ET plus trastuzumab and pertuzumab arm. The WSG-TP-II randomized clinical trial is, to our knowledge, the first prospective trial comparing 2 neoadjuvant de-escalation treatments in HR-positive/ERBB2-positive EBC and demonstrated an excellent pCR rate after 12 weeks of paclitaxel plus trastuzumab and pertuzumab that was clearly superior to the pCR rate after ET plus trastuzumab and pertuzumab. ClinicalTrials.gov Identifier: NCT03272477.

Long-term outcomes of dual vs single HER2-directed neoadjuvant therapy in NSABP B-41.

The primary aim of this randomized neoadjuvant trial in operable, HER2-positive breast cancer, was to determine the efficacy on pathologic complete response (pCR) of substituting lapatinib (L) for trastuzumab (T) or adding L to T, in combination with weekly paclitaxel (WP) following AC. Results on pCR were previously reported. Here, we report data on planned secondary endpoints, recurrence-free interval (RFI) post-surgery, and overall survival (OS). All patients received standard AC q3 weeks × 4 cycles followed by WP (80mg/m2) on days 1, 8, and 15, q28 days × 4 cycles. Concurrently with WP, patients received either T (4mg/kg load, then 2mg/kg) weekly until surgery, L (1250mg) daily until surgery, or weekly T plus L (750mg) daily until surgery. Following surgery, all patients received T to complete 52 weeks of HER2-targeted therapy. 522 of 529 randomized patients had follow-up. Median follow-up was 5.1years. RFI at 4.5years was 87.2%, 79.4% (p = 0.34; HR = 1.37; 95% CI 0.80, 2.34), and 89.4% (p = 0.37; HR = 0.70; 0.37, 1.32) for arms T, L, and TL, respectively. The corresponding five-year OS was 94.8%, 89.1% (p = 0.34; HR = 1.46; 0.68, 3.11), and 95.8% (p = 0.25; HR = 0.58; 0.22, 1.51), respectively. Patients with pCR had a much better prognosis, especially in the ER-negative cohort: RFI (HR = 0.23, p < 0.001) and OS (HR = 0.28, p < 0.001). Although pCR, RFI, and OS were numerically better with the dual combination and less with L, the differences were not statistically significant. However, achievement of pCR again correlated with improved outcomes, especially remarkable in the ER-negative subset. NCT00486668.

Abstract P3-02-01: Chemotherapy plus immunotherapy in stage IV triple-negative breast cancer patient during pregnancy: a case report

Abstract Introduction Cancer during pregnancy is uncommon but the incidence is increasing, particularly in breast cancer, the most common tumor diagnosed in this scenario. The treatment decision in pregnant patients with triple-negative breast cancer is challenging, even more so in cases with advanced disease. Clinical case A 36-year-old woman was referred to our hospital in January, 2020 with the diagnosis of an early (T2N0M0, stage IIA) invasive carcinoma of no special type triple-negative tumor on the left breast and germinative CHEK2 mutation. She received neoadjuvant treatment with four cycles of ACdd followed by nine weeks of paclitaxel and carboplatin, interrupted for local disease progression. The patient underwent a nipple-sparing mastectomy plus sentinel lymph node biopsy without complications. The pathology report showed gross residual disease, so we decided on adjuvant treatment with radiotherapy followed by capecitabine. Twelve months after the end of the treatment, she received the diagnosis of second-trimester pregnancy but also presented suspicion of pulmonary, nodal, and liver relapse. The liver biopsy confirmed triple-negative histology with CPS &amp;gt; 10. The first-line chemotherapy was liposomal doxorubicin, which showed hepatic disease progression after two cycles. As second-line, we started carboplatin, gemcitabine, and pembrolizumab. The radiologic evaluation after two cycles showed a partial response in the lung and liver, with the patient presenting excellent tolerability without fetal complications. The treatment plan is to wait until the term for delivery and continue treatment until progression or toxicity. Conclusion We report the first stage IV triple-negative breast cancer case in a pregnant patient treated with chemotherapy plus immunotherapy. This case indicates that the treatment is feasible and should be considered in this scenario. Citation Format: Candice Lima, Thiago L. Apolinario. Chemotherapy plus immunotherapy in stage IV triple-negative breast cancer patient during pregnancy: a case report [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P3-02-01.

Impact of Anti-HER2 Therapy Alone and With Weekly Paclitaxel on the Ovarian Reserve of Young Women With HER2-Positive Breast Cancer.

The potential gonadotoxicity of anti-HER2 agents remains largely unknown, and limited, conflicting evidence exists for taxanes. Antimüllerian hormone (AMH) is an established biomarker of ovarian reserve that may aid in quantifying anticancer treatment-induced gonadotoxicity. The present biomarker analysis of the randomized phase III neoadjuvant NeoALTTO trial included premenopausal women aged ≤45 years at diagnosis of HER2-positive early breast cancer with available frozen serum samples at baseline (ie, before anticancer treatments), at week 2 (ie, the "biological window" of anti-HER2 therapy alone), and/or at the time of surgery (ie, after completing paclitaxel + anti-HER2 therapy, before starting adjuvant chemotherapy). The present analysis included 130 patients with a median age of 38 years (interquartile ratio [IQR], age 33-42 years). AMH values at the 3 time points differed significantly (P<.001). At baseline, median AMH levels were 1.29 ng/mL (IQR, 0.56-2.62 ng/mL). At week 2, a small but significant reduction in AMH levels was observed (median, 1.10 ng/mL; IQR, 0.45-2.09 ng/mL; P<.001). At surgery, a larger significant decline in AMH levels was observed (median, 0.01 ng/mL; IQR, 0.01-0.03 ng/mL; P<.001). Although the type of anti-HER2 treatment (trastuzumab and/or lapatinib) did not seem to impact the results, age and pretreatment ovarian reserve had a major influence on treatment-induced gonadotoxicity risk. This NeoALTTO biomarker analysis showed that anti-HER2 therapies alone had limited gonadotoxicity but that the addition of weekly paclitaxel resulted in marked AMH decline with possible negative implications for subsequent ovarian function and fertility.

Long-Term Outcomes of a Randomized Study of Neoadjuvant Induction Dual HER2 Blockade with Trastuzumab and Lapatinib Followed by Weekly Paclitaxel Plus Dual HER2 Blockade for HER2-Positive Primary Breast Cancer (Neo-Lath Study).

Simple SummaryWe conducted the Neo-LaTH study in which patients with HER2-positive breast cancer were randomized to different lengths of neoadjuvant induction anti-HER2 therapy with lapatinib and trastuzumab followed by weekly paclitaxel plus anti-HER2 therapy, and in estrogen receptor-positive patients, with or without concurrent endocrine therapy. Here, we report the survival outcomes. The duration of neoadjuvant induction therapy and/or the addition of endocrine therapy at randomization did not affect the pathological complete response (CpCR) rate after neoadjuvant treatment and long-term outcomes. The 5-year disease-free survival rate was significantly higher in patients who had CpCR plus ypN0 after neoadjuvant treatment than in those who did not (91.7% vs. 85.1%; p = 0.0387). The stratified analysis showed better survival outcomes in CpCRypN0 patients than non-CpCRypN0 patients, regardless of use of adjuvant anthracycline therapy. Favorable survival outcomes, regardless of adjuvant anthracycline, were particularly noted in patients with small size and clinically node-negative tumors.We conducted the Neo-LaTH study in which patients were randomized to different lengths of neoadjuvant induction anti-HER2 therapy with lapatinib and trastuzumab followed by weekly paclitaxel plus the anti-HER2 therapy, and in estrogen receptor (ER)-positive patients, with or without concurrent endocrine therapy. The use of endocrine therapy did not affect the response; comprehensive pathological complete response (CpCR) plus ypN0 rate was 57.6% and 30.3% in ER-negative and ER-positive patients, respectively. After surgery, patients received an anthracycline-based regimen based on physician’s choice, followed by trastuzumab for 1 year, and in ER-positive patients, endocrine therapy for 5 years. Here, we report the 5-year survival outcomes. Among the followed-up patients (n = 212), the 5-year disease-free survival (DFS), distant DFS, and overall survival rates were 87.8% [95% confidence interval (CI), 82.5–91.6%], 93.7% (95% CI, 89.3–96.3%), and 95.6% (95% CI, 91.7–97.7%), respectively, with no difference between ER-negative and ER-positive patients. The 5-year DFS rate was significantly higher in patients who had a CpCR plus ypN0 after neoadjuvant treatment than in those who did not (91.7% vs. 85.1%; p = 0.0387). The stratified analysis showed better survival outcomes in patients who had CpCRypN0 than in those who did not after neoadjuvant treatment, regardless of use of adjuvant anthracycline therapy.

A Phase II Study Evaluating the Safety and Efficacy of Sunitinib Malate in Combination With Weekly Paclitaxel Followed by Doxorubicin and Daily Oral Cyclophosphamide Plus G-CSF as Neoadjuvant Chemotherapy for Locally Advanced or Inflammatory Breast Cancer

IntroductionNeoadjuvant chemotherapy is standard treatment for locally advanced breast cancer (LABC) or inflammatory breast cancer (IBC). We hypothesized that adding sunitinib, a tyrosine kinase inhibitor with antitumor and antiangiogenic activity, to an anthracycline and taxane regimen would improve pathologic complete response (pCR) rates to a prespecified endpoint of 45% in patients with HER2-negative LABC or IBC. MethodsWe conducted a multicenter, phase II trial of neoadjuvant sunitinib with paclitaxel (S+T) followed by doxorubicin and cyclophosphamide plus G-CSF for patients with HER2-negative LABC or IBC. Patients received sunitinib 25 mg PO daily with paclitaxel 80 mg/m2 IV weekly ×12 followed by doxorubicin 24 mg/m2 IV weekly + cyclophosphamide 60 mg/m2 PO daily with G-CSF support. Response was evaluated using pCR in the breast and the CPS + EG score (clinical-pathologic scoring + estrogen receptor [ER] and grade). ResultsSeventy patients enrolled, and 66 were evaluable for efficacy. Eighteen patients (27%) had pCR in the breast (10 had ER+ disease and 8 had triple-negative disease). When defining response as pCR and/or CPS + EG score ≤2, 31 (47%) were responders. In pateints with ER positive disease, 23 (64%) were responders. The most common toxicities were cytopenias and fatigue. ConclusionsNeoadjuvant S+T followed by AC+G-CSF was safe and tolerable in LABC and IBC. The study did not meet the prespecified endpoint for pCR; however, 47% were responders using pCR and/or CPS + EG score ≤2. ER positive patients had the highest response rate (64%). The addition of sunitinib to neoadjuvant chemotherapy may provide promising incremental benefit for patients with ER positive LABC.

Efficacy and safety of weekly paclitaxel in elderly patients with heavily pretreated platinum-resistant ovarian carcinoma.

e17552 Background: In platinum-resistant ovarian cancer treatment, single-agent paclitaxel can be used alone or in combination with bevacizumab. We aimed to assess the efficacy and safety profile of a weekly paclitaxel (WP) scheme in heavily pretreated platinum-resistant high-grade serous ovarian carcinoma. Methods: We retrospectively analyzed 30 adult patients with platinum-resistant high-grade serous ovarian carcinoma treated with WP at our institution between 2015 and 2020. Patients with platinum-resistant ovarian, fallopian tube or primary carcinoma of the peritoneum who had received at least 3 doses of WP (80 mg/m2) alone or in combination with bevacizumab until disease progression or unacceptable toxicity were included in the analysis. Progression-free survival was assessed according to the Response Evaluation Criteria in Solid Tumors version 1.1. Information about toxicity was gathered from medical reports and lab tests. Kaplan-Meier curves and Log-rank test were performed for survival estimates. Results: In our sample, the median age was 68 years (IQR: 60-75) and the median number of previous lines of systemic treatment was 3 (range 1-5). 40% of patients received WP in combination with bevacizumab. The disease control rate was 60.7% (42.9% partial response and 17.8% stable disease). In the overall analysis, the median progression-free survival (mPFS) was 5.0 months (95% CI: 2.0-7.1 months). The presence of ascites significantly shortened the mPFS compared to patients without it (1.1 vs 5.1 months, p &lt; 0.001). Even though the addition of bevacizumab to WP improved the mPFS, the difference was not statistically significant compared to WP alone (7.1 vs 4.06 months, p=0.30). Peripheral neuropathy was the most common adverse event (78% all grades, 18% grade 3). No grade 3 hematologic toxicity was registered. Treatment was discontinued in 6 patients (20%) – 4 due to peripheral neuropathy and two because of toxicoderma. Conclusions: In our sample, WP was an active and safe regimen in heavily pretreated platinum-resistant ovarian carcinoma. WP was well tolerated in elderly patients. The presence of ascites was associated to a shorter PFS in patients treated with WP compared to ascites-free patients.

Comparison of dose-dense vs. 3-weekly paclitaxel and carboplatin in the first-line treatment of ovarian cancer in a propensity score-matched cohort

BackgroundBenefit of carboplatin and dose-dense weekly paclitaxel (ddCT) in first line treatment of ovarian cancer patients has been different in Western and Asian studies. In the present study we compare progression-free survival (PFS) of ddCT to three-weekly carboplatin and paclitaxel (CT) in first-line treatment of ovarian carcinoma in a single institution in a Western population.Materials and methodsWe conducted a retrospective review of medical records from patients with ovarian carcinoma treated in a tertiary cancer center from 2007 to 2018. All patients treated with ddCT or CT in the first-line setting were included. Patients who received first-line bevacizumab were not included. PFS and overall survival (OS) were compared in a propensity score-matched cohort to address selection bias. Patients were matched according to age, ECOG performance status, CA 125, FIGO stage, residual disease, and histological subtype, in a 1:2 ratio.ResultsFive hundred eighty-eight patients were eligible for propensity score matching, the final cohort consisted of 69 patients treated with ddCT and 138 CT group. Baseline characteristics were well-balanced. After a median follow-up of 65.1 months, median PFS was 29.3 vs 20.0 months, favouring ddCT treatment (p = 0.035). In the multivariate cox regression ddCT showed a 18% lower risk of progression (HR 0.82, 95% CI 0.68–0.99, p = 0.04). Overall survival data is immature, but suggested better outcomes for ddCT (not reached versus 78.8 months; p = 0.07).ConclusionOur retrospective study has shown superior PFS of ddCT over CT regimen in first-line treatment of ovarian carcinoma in a Western population not treated with bevacizumab.