3rd Line Treatment Research Articles

Bi-weekly irinotecan is an effective and convenient regimen in the treatment of relapsed or refractory small cell lung cancer

BackgroundDespite initial dramatic responses, metastatic small cell lung cancer (SCLC) invariably recurs. Irinotecan is one of the active agents for patients with recurrent SCLC. In the second line, weekly or three-weekly irinotecan regimens have been adopted, however, the optimal dose and schedule is not defined. In our institution, we use a bi-weekly regimen of irinotecan. In this study, we aimed to investigate the safety and efficacy of the bi-weekly irinotecan in the second- or third-line treatment of SCLC patients.MethodsThe study population consisted of advanced stage SCLC patients who were followed at Hacettepe University Cancer Institute between January 2007 and March 2021 and received salvage irinotecan 180 mg/m2 every two weeks, following progression after platinum-etoposide treatment.ResultsOne hundred patients were included. At diagnosis, nineteen patients (19%) had limited stage and 81 patients (81%) had extensive stage SCLC. Objective response rates (ORR) were 44.6% and 46.2% for patients who received irinotecan treatment in second line, and in third line, respectively. Seventeen percent of all the patients had grade 3 and above adverse events during irinotecan treatment. In our study, 45.8% of patients were able to complete at least 6 cycles of irinotecan treatment and 69.8% were able to receive at least 3 cycles of irinotecan treatment without any dose interruption or reduction.ConclusionsIrinotecan 180 mg/m2 every two weeks appears to be safe and effective in the 2nd- and 3rd-line treatment of advanced stage SCLC. Bi-weekly administration allows G-CSF prophylaxis in between doses, leading to an uninterrupted administration.

35 Efficacy of treatments post-lenvatinib in patients with advanced renal cell carcinoma (aRCC)

Abstract Background Lenvatinib is a tyrosine kinase inhibitor (TKI) that targets both vascular endothelial growth factor (VEGF) receptor and fibroblast growth factor receptor. It has demonstrated efficacy both in the upfront and refractory disease settings. However, there is a lack of data surrounding the efficacy of TKIs post-lenvatinib exposure. In this study, we investigate the activity of therapies post-lenvatinib in patients with aRCC. Methods We conducted a retrospective analysis utilizing the International Metastatic Database Consortium (IMDC). Patients having received treatment post-lenvatinib exposure were eligible and divided into two cohort: patients post-1st line lenvatinib (2nd line cohort) and patients post-2nd line lenvatinib (3rd line cohort). The primary objective was objective response rate (ORR) and time to treatment failure (TTF). ORR was summarized with 95% two-sided exact binomial confidence interval. TTF was defined as time from treatment initiation to drug cessation for any reason censored at the date of last follow-up. Results Overall, 84 patients received 1st line lenvatinib of whom 43 (51%) remain on therapy, 20 (24%) received 2nd line treatment, and 21 (25%) received no subsequent treatment. The median duration of prior lenvatinib was 9.7 months. All patients received 1st line pembrolizumab + lenvatinib (ORR 50%, median TTF 19.7 months). Reason for lenvatinib discontinuation was progression (50%), progression + toxicity (20%), toxicity (15%), or other (15%). For the 2nd line cohort, median age was 61 years, most patients were male (85%), had prior nephrectomy (75%), clear cell histology (85%), and were IMDC intermediate/poor risk (55%). 2nd line therapy regimens included TKI monotherapy (80%), TKI-IO (5%), and other (15%). The median follow up from 2nd-line treatment initiation was 4.9 months. The ORR to 2nd line treatment was 5% (95% CI 0.2-25) and median TTF was 5.8 months (95% CI 1.9-14.9). Of 2nd line lenvatinib-exposed patients (n=84), 24 (29%) remain on treatment, 34 (40%) received 3rd line treatment, and 26 (31%) did not receive additional therapy. The median duration of prior lenvatinib was 5.9 months. Most patients received 2nd line everolimus + lenvatinib (97%) (ORR 31%, median TTF 9.2 months). Reason for lenvatinib discontinuation was progression (59%), progression + toxicity (9%), toxicity (12%), or other (21%). For the 3rd line cohort, median age was 67 years, most patients were male (68%), had prior nephrectomy (88%), clear cell histology (68%), and were IMDC intermediate/poor risk (77%). 3rd line treatments included TKI alone (50%), IO-TKI (38%), and other (12%). The median follow up from 3rd-line treatment initiation was 14.9 months. The ORR to 3rd line treatment was 12% (95% CI 3.3-27) and median TTF was 2.8 months (95% CI 1.9-7.4). Conclusions In this analysis, we demonstrate modest activity of TKI-based therapy post-lenvatinib exposure. Our study highlights the need for improved treatment options for patients progressing on lenvatinib-based therapies.

Efficacy of post-lenvatinib treatments in patients (pts) with advanced renal cell carcinoma (aRCC).

4538 Background: Lenvatinib is a tyrosine kinase inhibitor (TKI) that targets both vascular endothelial growth factor (VEGF) receptor and fibroblast growth factor receptor. It has demonstrated efficacy both in the upfront and refractory disease settings. However, there is a lack of data surrounding the efficacy of TKIs post-lenvatinib exposure. In this study, we investigate the activity of post-lenvatinib therapies in pts with aRCC. Methods: We conducted a retrospective analysis utilizing the International Metastatic Database Consortium (IMDC). Pts having received treatment post lenvatinib exposure were eligible and divided into two cohort: pts post-1st line lenvatinib (2nd line cohort) and pts post-2nd line lenvatinib (3rd line cohort). The primary objective was objective response rate (ORR) and time to treatment failure (TTF). ORR was summarized with 95% two-sided exact binomial confidence interval. TTF was defined as time from treatment initiation to drug cessation for any reason censored at the date of last follow-up. Results: Overall, 84 pts received 1st line lenvatinib of whom 43 (51%) remain on therapy, 20 (24%) received 2nd line treatment, and 21 (25%) received no subsequent treatment. All pts received 1st line pembrolizumab + lenvatinib (ORR 50%, median TTF 9.7 months). Reason for lenvatinib discontinuation was progression (50%), progression + toxicity (20%), toxicity (15%), or other (15%). For the 2nd line cohort, median age was 61 years, most pts were male (85%), had prior nephrectomy (75%), clear cell histology (85%), and were IMDC intermediate/poor risk (55%). 2nd line therapy regimens included TKI monotherapy (80%), TKI-IO (5%), and other (15%). The ORR to 2nd line treatment was 5% (95% CI 0.2-25) and median TTF was 5.8 months (95% CI 1.9-14.9). Of 2nd line lenvatinib-exposed pts (n=84), 24 (29%) remain on treatment, 34 (40%) received 3rd line treatment, and 26 (31%) did not receive additional therapy. Most pts received 2nd line everolimus + lenvatinib (97%) (ORR 39%, median TTF 5.9 months). Reason for lenvatinib discontinuation was progression (59%), progression + toxicity (9%), toxicity (12%), or other (21%). For the 3rd line cohort, median age was 67 years, most pts were male (68%), had prior nephrectomy (88%), clear cell histology (68%), and were IMDC intermediate/poor risk (77%). 3rd line treatments included TKI alone (50%), IO-TKI (38%), and other (12%). The ORR to 3rd line treatment was 12% (95% CI 3.3-27) and median TTF was 2.8 months (95% CI 1.9-7.4). Conclusions: In this analysis, we demonstrate modest activity of TKI-based therapy post-lenvatinib exposure. Our study highlights the need for improved treatment options for pts progressing on lenvatinib-based therapies.

Prevalence of recreational and medical cannabis products in Veterans and their interactions with cancer directed pharmacological treatment.

3089 Background: There is proliferation of literature about the medical uses of cannabis products in patients with malignancies. However, research is lacking as to how cannabis use is affecting the efficacy and toxicity of anti-neoplastic regimens It is known that cannabis is metabolized by the cytochrome p450 pathway, the same as many anti-neoplastic agents and thus there are concerns for potential interactions. Methods: We report an observational study to identify cannabis users in veterans receiving anti-neoplastic therapy in the Memphis VA health system, and to then analyzed for potential interactions between cannabis product and the antineoplastic agent/s they were receiving. Data was collected via voluntary surveys. We then reviewed their charts, recorded the anti- neoplastic medications they were receiving, and evaluated for potential interactions with cannabis, based on a literature review of potential interactions. Results: In this study, 132 veterans agreed to participate. 50 of them acknowledged recent use of cannabis products within the last 90 days. Thus, the prevalence of cannabis use amongst those who participated is 37.87%. Demographically, 10% of the cannabis users were female, and 90% were male, with the majority aged 60-65 (range 46-85). Predominantly, patients inhaled cannabis once daily (38%) as opposed to using a different formulation. The patients who admitted cannabis use were primarily on chemotherapy (42%), while 38% were on immunotherapy, 24% were on targeted therapy and 20% were on endocrine therapy. Some were on multiple drugs. Based on this data and a literature search for interactions, we found that a significant number of the patients in our Veteran’s oncology clinic have a potential increase in toxicity or decreased efficacy from their ant-neoplastic therapy due to CYP interactions with cannabis use. Conclusions: In this exploratory study, we discovered a notable prevalence of patients concurrently using cannabis products while on anti-neoplastic treatment. Given that many anti-neoplastic agents undergo metabolism via the CYP450 pathway, our data suggest that a moderate number of patients in our clinic risk less than optimal outcomes due to concurrent cannabis and anti-neoplastic therapy. To delve deeper, we intend to conduct a follow-up study, focusing on specific adverse effects, hospitalizations, and the subsequent need for 2nd and 3rd line treatments in patients using cannabis. A much larger multi-institutional study should be considered to provide statistically relevant data on true outcomes. [Table: see text]

A propensity score–matched comparison of fruquintinib (FRU) versus FRU combined with PD-1 inhibitors for microsatellite stability (MSS) metastatic colorectal cancer: Real-world data.

e15564 Background: FRU has been approved for previously treated metastatic colorectal cancer (mCRC) in China and the United States, moreover it has shown synergistic effects in combination with immunotherapy in MSS CRC through immunomodulation of the tumor microenvironment. However, comparing the efficacy of FRU monotherapy (FM) and FRU combined with PD-1 inhibitors (FP) directly was rarely reported due to baseline differences in patient characteristics. To address this, we utilized the propensity score matching (PSM) to enhance the accuracy of efficacy prediction by matching relevant baseline features between the two groups. Methods: Our real-world observational study retrospectively included MSS CRC patients who have received 3rd line and above treatments from June 2019 to July 2022, and patients diagnosed with mCRC were eligible, and all patients received at least 2 cycles of FM or FP. As a result, 16 patients in the FM group and 51 patients in the FP group were enrolled. Utilizing stable LASSO (Least Absolute Shrinkage and Selection Operator) regression, we identified key clinical features relevant to outcomes for PSM. These included liver metastasis, lung metastasis, and prior chemotherapy with VEGF inhibitors. Based on these selected features, we conducted a 1:2 nearest neighbor matching algorithm to align the patients from the two groups more accurately for comparative analysis and subsequent survival analysis. The primary endpoint was progression-free survival (PFS). Results: The PSM process resulted in a matched cohort comprising 16 patients from the FM group and 32 patients from the FP group, totaling 48 patients in the analysis. The baseline characteristics of the included population were shown in Table 1. With a median follow-up of 22.87 months (95% CI: 17.00-26.07months), the median PFS in the FP group (13.27 months, 95% CI: 9.97-15.03 months) exhibited a noticeable extension compared to the FM group (4.30 months, 95% CI: 2.83-13.60 months). Additionally, the median overall survival (OS) in the FM group was 16.93 months (95% CI: 11.70-NA), and in the FP group, it was 21.30 months (95% CI: 13.67-NA). Conclusions: The FP group showed a significant increase in PFS compared to FM and PSM increased the comparability of real-world efficacy in MSS mCRC patients receiving FRU and FRU combined with PD-1 inhibitors. Further increasing the sample size may yield more valuable results. [Table: see text]

Treatment rationale and protocol design: an investigator-initiated phase II study of combination treatment of nivolumab and TM5614, a PAI-1 inhibitor for previously treated patients with non-small cell lung cancer.

There is no established standard 3rd line treatment for patients with advanced non-small cell lung cancer (NSCLC). Although cytotoxic chemotherapeutic agents that are not used as 1st or 2nd line treatment are administrated as 3rd line treatment, their anti-tumor efficacy is insufficient. Anti-programmed death ligand-1 (PD-L1)/programmed death-1 (PD1) treatment is more effective and less toxic than chemotherapy in anti-PD-L1/PD-1 treatment-naïve patients with NSCLC. Therefore, anti-PD-L1/PD-1 therapy is considered an appropriate 3rd line treatment. However, the anti-tumor efficacy is limited in patients previously treated with anti-PD-L1/PD-1 antibody. Today, new drugs are needed to increase the efficacy of anti-PD-L1/PD-1 antibodies. This open-label, single-arm, investigator-initiated phase II study is designed to evaluate combination treatment of nivolumab and TM5614, a plasminogen activator inhibitor (PAI-1) inhibitor as 3rd or more line treatment in NSCLC patients who underwent standard treatment. The primary endpoint is the objective response rate and the secondary endpoints are progression-free survival (PFS), overall survival (OS), duration of response (DOR) and safety. Recruitment began in September 2023 and is expected to continue for approximately three years. Currently, there is no standard 3rd line treatment for advanced NSCLC, and we hope that the findings of this study will facilitate more effective treatments in this setting. Ethics and dissemination: the study protocol conformed to the ethical principles outlined in the Declaration of Helsinki. All patients will provide written informed consent prior to enrollment. Results will be published in a peer-reviewed publication. This study is registered to Japan Registry of Clinical Trials with number: jRCT2061230039 (19/July/2023).

Abstract PO1-19-08: Phase I trial of pegylated liposomal doxorubicin chemotherapy in combination with CD40 agonist and Flt3 ligand in metastatic triple-negative breast cancer

Abstract Background: Only a subset of patients with metastatic triple-negative breast cancers (TNBC) demonstrate response to FDA approved PD-1 immune checkpoint blockade (ICB), and few have durable responses. Data suggests that breast cancers have defects in antigen presentation and that antigen presenting cells especially the cDC1 subtype of dendritic cells (DCs) are required for response to ICB. CD40 agonists activate antigen presenting cells including DCs and B cells and repolarize macrophages to an anti-tumor phenotype. Flt3 ligand is a growth factor that increases differentiation and expansion of DCs. We recently demonstrated in pre-clinical TNBC models that the combination of liposomal doxorubicin chemotherapy, a CD40 agonist, and a Flt3 ligand improves outcomes compared to alternate combinations. Methods: This is a single arm phase I pilot study of liposomal doxorubicin, CDX-1140 (CD40 agonist monoclonal antibody), and CDX-301 (recombinant Flt3 ligand) combination therapy in patients with metastatic or unresectable locally advanced metastatic TNBC. Patients will be randomized to 3 lead-in arms (triplet therapy, doublet immunotherapy only, or liposomal doxorubicin only) for one cycle prior to receiving triplet therapy with tissue biopsies done before and after the lead-in treatment. CDX-301 will be given for only two cycles; liposomal-doxorubicin and CDX-1140 will be continued until disease progression or clinically limiting toxicities. Primary endpoint is determination of a recommended phase II dose based on treatment-related adverse events and dose-limiting toxicities. Secondary endpoints include anti-tumor immune response after triplet therapy, after immunotherapy alone, and after liposomal doxorubicin alone; median progression-free survival, overall response rate, duration of response, and clinical benefit rate. Key eligibility criteria are unresectable stage III or stage IV TNBC (ER ≤10%, PR ≤10%, HER2/neu negative), 1st to 3rd line treatment for metastatic disease (1st line patients need to be PD-L1 negative by 22C3 assay), measurable disease by RECIST 1.1 criteria, consent for pre-treatment and on-treatment biopsies of amenable soft tissue tumor lesions, no prior treatment with an anti-CD40 antibody or a Flt3 ligand, no anthracycline treatment in the metastatic setting, no prior progression while on anthracycline-based therapy or within 6 months of completing neoadjuvant chemotherapy, and no history of non-infectious pneumonitis or current pneumonitis. This trial will enroll up to 45 patients across multiple sites (NCT05029999) and is currently open at University of Texas Southwestern Medical Center, Texas Oncology, University of Chicago, University of Texas San Antonio, Sarah Cannon Research Institute, and Johns Hopkins. Citation Format: Sangeetha Reddy, Joyce O'Shaughnessy, Navid Sadeghi, Samira Syed, Cesar Santa-Maria, Virginia Kaklamani, Nan Chen, Denise Yardley, Yisheng Fang, Isaac Chan, Nisha Unni, Sarah Kashanian, Namrata Peswani, Shahbano Shakeel, Meredith Carter, Kelly Kyle, Farjana Fattah, Chul Ahn, Ina Patel, Joshua Gruber, Dawn Klemow, Glenda Delgado, Nicole Sinclair, Michael Yellin, Heather McArthur, Rita Nanda, Suzanne Conzen, Carlos Arteaga. Phase I trial of pegylated liposomal doxorubicin chemotherapy in combination with CD40 agonist and Flt3 ligand in metastatic 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 PO1-19-08.

The Efficacy and Safety of Inetetamab and Pyrotinib in Combination with Vinorelbine for Second-line Therapy and Beyond in HER2-positive Metastatic Breast Cancer: A Single-institution Clinical Experience.

This study aimed to observe the efficacy and safety of inetetamab and pyrotinib in combination with vinorelbine in second-line therapy and beyond in HER2-positive metastatic breast cancer (MBC). Patients with HER2-positive MBC admitted to our hospital from January 2016 to December 2021 were selected. For patients who could not receive antibody‒drug conjugates (ADCs) during second-line (2nd-line) or third-line and beyond (≥ 3rd-line) anti-HER2 therapy, inetetamab + pyrotinib + vinorelbine was used for treatment until unacceptable adverse events occurred or the disease progressed, as evaluated by the Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 every 2 cycles. The progression-free survival (PFS), objective response rate (ORR), clinical benefit rate (CBR), and adverse reactions were recorded. Multivariate Cox regression analysis was performed to explore the prognostic factors influencing the curative effect. Overall, 52 patients were included; 13 patients received 2nd-line treatment, and 39 patients received ≥ 3rd-line treatment. The median PFS (mPFS) for all patients treated with inetetamab + pyrotinib + vinorelbine was 7 months. The mPFS of the 2nd-line subgroup was significantly better than that of the ≥ 3rd-line subgroup (17 vs. 5 months, P = 0.001). The mPFS of the subgroups that received trastuzumab (H) or trastuzumab and pertuzumab (HP) only was significantly better than that of the H or HP and tyrosine kinase inhibitor (TKI) subgroups (8 vs. 5 months, P = 0.030). The mPFS of the HER2 resistance subgroup was better than that of the HER2 refractoriness subgroup (14 vs. 7 months, P = 0.025). Cox regression analysis showed that the treatment line (2nd-line more so than ≥ 3rd-line) was an independent prognostic factor for PFS. In addition, the ORR and CBR of 2nd-line patients were significantly higher than those of ≥ 3rd-line patients (69.2% vs. 30.8% and 92.3% vs. 64.1%, respectively). The most common hematological toxicities were leukopenia and neutropenia, and the most common nonhematological toxicity was diarrhea. Inetetamab and pyrotinib in combination with vinorelbine have good efficacy in ≥ 2nd-line treatment of HER2-positive MBC with controllable toxicity, and the combination is a new treatment option, especially for patients who cannot use ADCs in 2nd-line treatment.

Résistance aux anti-EGFR via l’acquisition successive et cumulée de deux nouvelles addictions oncogénique BRAF et ALK

Targeted therapies are the standard first-line treatment for metastatic lung adenocarcinoma with certain molecular abnormalities. These abnormalities are particularly common in Southeast Asia and French Polynesia. A 51-year-old Tahitian female non-smoker was diagnosed in 2018with stage IV lung adenocarcinoma harboring a p.L858R EGFR mutation. She received gefitinib as first-line treatment. Due to locoregional progression and the presence of a resistance mutation (p.T790M of EFGR), she received osimertinib as second-line treatment, after which chemotherapy was proposed as 3rd-line treatment. An additional biopsy detected not only the previously known EGFR mutation, but also a BRAF p.V600E mutation. Following disease progression during chemotherapy, the patient received targeted therapies combining dabrafenib, trametinib and osimertinib. Due to a dissociated response after four months of treatment, a 5th line of paclitaxel bevacizumab was initiated. Subsequent to additional progression and given the ALK rearrangement shown on the re-biopsy, 6th-line treatment with alectinib was proposed. As the response was once again dissociated, a final line was proposed before stopping active treatments due to their toxicity and overall deterioration in the patient's state of health. This exceptional case is characterized by resistance to anti-EGFR through the successive and cumulative acquisition of two new oncogene addictions. The authors underline the importance of re-biopsy at each progression, leading (if at all feasible) to yet around round of targeted therapy.

Abstract 3827: Optimizing the treatment schedule of radiotherapy combined with VEGFR-TKIs and PD-(L) 1 inhibitors in metastatic colorectal cancer

Abstract Background: The oral vascular endothelial growth factor receptor (VEGFR) inhibitor fruquintinib, an innovative Chinese drug, has recently been approved by the U.S. Food and Drug Administration (FDA) for third-line treatment of metastatic colorectal cancer (mCRC) in adults. This study aims to investigate the efficacy and safety of radiotherapy (RT) combined with VEGFR-TKIs (such as fruquintinib) and PD-(L) 1 inhibitors in mCRC, and explore optimal sequence of RT with the systemic regimen. Methods: This retrospective study enrolled eligible patients with MSS/pMMR mCRC who had received RT in combination with anti-angiogenic drugs (Fruquintinib or Regorafenib) and immunotherapy (IT) between April 2018 and September 2023. Data on treatment response, progression-free survival (PFS), overall survival (OS), and adverse events were collected. Results: A total of 42 pts were analyzed. For Fru + IT + RT (n = 33) and Reg + IT + RT (n = 9), ORR were 21.2% (7/33) and 11.1% (1/9); DCR were 81.8% (27/33) and 88.9% (8/9), respectively. Median PFS were 6.4 mo and 5.0 mo (P=0.856) while median OS were 17.2 mo and 7.2 mo (P=0.578), respectively. In-depth analysis of Fru + IT + RT treated population, the PFS and OS of 3rd-line treatment were superior to later (≥ 4th) -line treatment (median: 6.7 vs 4.2 mo, P=0.02) and (median: 17.5 vs 8.9 mo, P=0.27), seemingly. Additionally, RT before initiation of Fru + IT demonstrated superior PFS compared to simultaneous/sequential RT with Fru + IT (median 7.1 vs 6.1 vs. 3.2 mo, p<0.001). Simultaneously, pts with interval time ≤1 month, received numerically benefit compared to interval time >1 month between RT and FRU+IT (mPFS: 6.2 vs. 3.8 mo, P=0.16; mOS: not reached vs. 7.65 mo, P=0.08). Further subgroup analysis revealed that men, age ≤56 years, ECOG PS score of 1, primary focal resection, recurrent metastatic disease, liver/pulmonary metastases, and metastatic involvement of organs ≥2, were more favorably treated with Fru for prolonged OS. Intriguingly, the 3rd-line treatment of Fru exhibited a tendency to prolong OS compared to Reg. Cox multivariate regression analysis suggested that the cycle of Fru/Reg combined with PD-1 inhibitor treatment was a common independent influencing factor for PFS and OS. Safety was consistent with previous reports, and the incidence of AE appeared to be lower in Fru + IT + RT than in Reg + IT + RT. Conclusion: In pts receiving RT of localized lesions, the addition of Fru combined with PD-1 inhibitor could prolong the pts' OS more than Reg plus PD-1 inhibitor. And radiotherapy sequential Fru + IT (interval time ≤1 mo) treatment is expected to be the optimal strategy for MSS/pMMR mCRC. Citation Format: Zhenyu Lin, Menglan Zhai, Tao Zhang. Optimizing the treatment schedule of radiotherapy combined with VEGFR-TKIs and PD-(L) 1 inhibitors in metastatic colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3827.

A multicenter, randomized phase 2 study to establish combinations of CBP501, cisplatin and nivolumab for ≥3rd-line treatment of patients with advanced pancreatic adenocarcinoma

BackgroundThere is no standard of care for ≥ 3rd-line treatment of metastatic pancreatic adenocarcinoma (PDAC). CBP501 is a novel calmodulin-binding peptide that has been shown to enhance the influx of platinum agents into tumor cells and tumor immunogenicity. This study aimed to (1) confirm efficacy of CBP501/cisplatin/nivolumab for metastatic PDAC observed in a previous phase 1 study, (2) identify combinations that yield 35% 3-month progression-free survival rate (3MPFS) and (3) define the contribution of CBP501 to the effects of combination therapy. MethodsCBP501 16 or 25 mg/m2 (CBP(16) or CBP(25)) was combined with 60 mg/m2 cisplatin (CDDP) and 240 mg nivolumab (nivo), administered at 3-week intervals. Patients were randomized 1:1:1:1 to (1) CBP(25)/CDDP/nivo, (2) CBP(16)/CDDP/nivo, (3) CBP(25)/CDDP and (4) CDDP/nivo, with randomization stratified by ECOG PS and liver metastases. A Fleming two-stage design was used, yielding a one-sided type I error rate of 2.5% and 80% power when the true 3MPFS is 35%. ResultsAmong 36 patients, 3MPFS was 44.4% in arms 1 and 2, 11.1% in arm 3% and 33.3% in arm 4. Two patients achieved a partial response in arm 1 (ORR 22.2%; none in other arms). Median PFS and OS were 2.4, 2.1, 1.5 and 1.5 months and 6.3, 5.3, 3.7 and 4.9 months, respectively. Overall, all treatment combinations were well tolerated. Most treatment-related adverse events were grade 1–2. ConclusionsThe combination CBP(25)/(16)/CDDP/nivo demonstrated promising signs of efficacy and a manageable safety profile for the treatment of advanced PDAC. Clinical trial registrationNCT04953962

Acceptability of the Delegation of Tasks by PLHIV for the Treatment of Hepatitis C by General Physicians in Public Health Facilities in the Centre Region of Cameroon in 2022

Introduction: Viral Hepatitis C is a public health problem that affects approximately 58 million people worldwide. In 2021, its prevalence in Cameroon was 1.1% in the general population and some small biased studies indicate a range of 0 to 7.2% in the Cameroonian population infected with HIV. Methods: The general objective of this study was to evaluate the acceptability of task delegation for the treatment of Hepatitis C within HIV care services by general practitioners in public health facilities in the region. of the center involved in the DEHEP-C project in 2022. This was a cross-sectional study of HIV patients cared for in 05 public health facilities in the said region comprising two components, one descriptive and the other analytical. The results were presented with a 95% confidence interval, odds ratios (crude and adjusted) and significance with value P˂0.05. Results: 510 patients were included, the general satisfaction of PLHIV with the services offered by the FOSAs in the study was 75%. The acceptability of the delegation of tasks for the treatment of Hepatitis C within HIV care services by general practitioners by the respondents was 89%. Factors such as residing in a rural area (aOR = 1.63 95% CI = 1.40 – 3.78 ; p<0.01 ), being a regular patient in a 4th category FOSA ( aOR = 1.59 95% CI = 1.43 – 3.47 ; p<0.01 ), following 3rd line treatment (aOR = 0.27 95% CI = 0.10 – 0.69; p<0.01 ) turned out to be significant factors of the acceptability of task delegation. Conclusion: The majority of PLHIV interviewed during this study were in favor of the delegation of tasks for the treatment of Hepatitis C by general practitioners in patients infected with HIV within the CTA or UPEC of the Central region.

Real-World Results of Cabozantinib Given as Alternative Schedule in Metastatic Renal Cell Carcinoma

BackgroundThe multikinase-inhibitor Cabozantinib is a widely used treatment strategy in metastatic renal cell carcinoma (mRCC), either in combination with the programmed cell death protein-1 (PD-1) inhibitor nivolumab or as monotherapy. Cabozantinib is given continuously at a dose of 60 mg once daily when used as a single agent and at 40 mg when combined with nivolumab. Treatment-related adverse events (TRAE's) were shown to occur frequently. ObjectiveWe aimed to assess the safety and efficacy of cabozantinib in patients with mRCC. Patients were treated in various lines. Furthermore, we analyzed the impact of an alternative treatment schedule in patients not able to maintain continuous dosing. PatientsThis is a single center retrospective study from the Medical University of Vienna. Outcome Measurements and Statistical AnalysisOverall response rates (ORR), progression free survival (PFS) and overall survival (OS) were evaluated for the entire cohort, by treatment line and by treatment schedule. ResultsBetween January 2014 until April 2021, 71 patients received cabozantinib. Sixty-seven patients were eligible for full evaluation. By IMDC criteria, 32.4%, 59.2%, and 8.5% were classified as favorable, intermediate and poor risk respectively. Cabozantinib was offered as a 2nd-line or 3rd-line treatment in 38.0% and 32.4% of patients, respectively. An alternative treatment schedule was offered in 39.1% of patients. Objective responses were found in 43.3% (CR 6%) of patients and the median PFS was 10.8 months (95% CI: 5.5-16.2). When compared to continuous dosing, an alternative treatment schedule was associated with longer PFS (12.2 months (95% CI: 0-25.5) vs. 6.1 months (95% CI: 0.37-11.8) (P = .014, HR 0.46 (95% CI: 0.24-0.86), respectively) and a lower frequency and severity of TRAE's. ConclusionsSafety and efficacy of cabozantinib in real world is comparable to what has been observed in the pivotal trials, irrespective of the treatment line. An alternative schedule may further improve efficacy and safety.

Effcacy and toxicity of regorafenib compared to reintrodaction of chemotherapy in metastatic colon cancer: retrospective multicenter study

The objective of the study is to compare the effectiveness of various systemic therapies in the 3rd and subsequent lines of therapy of metastatic colon cancer. Material and Methods. Retrospective multicenter study collected data from 2 clinics of the Russian Federation. We considered overall survival (OS) as the main criterion of effectiveness. Progression-free survival (PFS) was the additional criterion. We performed a single- and multifactorial analysis of the effect of various parameters on PFS. To evaluate the effectiveness of regorafenib and the reintroduction of previously effective drugs, we should prove the equivalence of reintroduction of the 3rd line chemotherapy (CT) and targeted therapy to regorafenib on the 6-month overall survival, provided that the equivalence boundaries would be between 0.8 and 1.25. To reach the 0.05 probability of type I error and the 80 % study power, 178 patients (89 in each group) should be included in the study. Results. The database identifed 215 patients with morphologically confrmed metastatic colon cancer who received two or more lines of antitumor drug therapy from 2010 to 2021. We selected 132 patients with the history of regorafenib therapy and 83 patients with the reintroduction of a previously used chemotherapy regimen as 3rd line treatment. The median OS in the reintroduction and regorafenib groups did not differ (HR, 1.01; 95 % CI, 0.7–1.45; p=0.920); 6-month OS were 74 and 70 %, respectively. Progression-free survival was signifcantly higher in the reintroduction group (HR, 1.94; 95 % CI, 1.3–2.7; p<0.001). Multivariate analysis showed that the reintroduction of previous treatment regimens kept its independent positive effect on PFS (HR, 1.9; 95 % CI, 1.3–2.8; p<0.001). In our study, toxicity on the 3rd line of CT developed in 117 (54.4 %) of 215 patients and signifcantly more frequent in the regorafenib group: 67.4 % (89/132) vs 33.7 % (28/83) in the group with repeated administration of previously effective regimens (p<0.001). Conclusion. Regorafenib and reintroduction of the previous treatment in the 3rd line did not differ in overall survival. Progression-free survival was signifcantly higher in the reintroduction group as the 3rd line of treatment, with signifcantly lower toxicity.

Efficacy of Empagliflozin as Add-on Therapy in Patients with Uncontrolled Type 2 Diabetes Mellitus

Background: Metformin is recommended as first-line pharmacotherapy for patients with type 2 Diabetes Mellitus (T2DM) who fail to achieve glycemic control through lifestyle modification. Metformin initially lowers blood glucose, but as diabetes progresses, it alone frequently fails to maintain glycemic control, and additional therapies are required. Empagliflozin is a potent and selective sodium-glucose co-transporter 2 (SGLT2) inhibitor that is effective in reducing blood sugar levels as monotherapy or add-on to existing therapy with significant improvements in glycemic control and weight.
 Materials & Methods: This quasi-experimental study was conducted in the Department of Pharmacology and Therapeutics in collaboration with Rajshahi Diabetic Association General Hospital, Rajshahi, for one year from January 2021 to December 2021 on 50 uncontrolled T2DM patients (glycosylated hemoglobin, HbA1c > 7.0 to ≤ 10.5%) for more than 12 weeks. The investigating drug, empagliflozin 10 mg (1 tablet) as a once-daily dose, was added to the ongoing treatment of each patient as 3rd line treatment and was followed up at 6 and 12 weeks.
 Results: The mean FBS at baseline was 10.8 mmol/L, which declined to 8.5 mmol/L at six weeks and then to 7.2 mmol/L after 12 weeks of intervention with Empagliflozin as add-on therapy in patients with uncontrolled T2DM. The overall reduction of FBS from baseline to 12 weeks of intervention was statistically significant (p < 0.001). Simultaneously the mean HbA1c also reduced from 9.4% to 7.7% after six weeks and to 7.1% after 12 weeks of intervention (p < 0.001). The mean systolic and diastolic blood pressures decreased from 129 mmHg to below 120 mmHg (p < 0.001) and 82.3 mmHg to below 80 mmHg (p = 0.029), respectively, after three months of intervention.
 Conclusion: Empagliflozin as add-on therapy responded well in patients with uncontrolled T2DM (previously treated with metformin combined with either sulfonylurea or DPP-4 inhibitors and/or supplemented by insulin) in achieving glycemic control. 
 TAJ 2022; 36: No-1: 89-95

Comparison of treatment discontinuation rates between CDK4/6 inhibitors.

2 Background: Abemaciclib and Palbociclib are both CDK4/6 inhibitors and its combination use with hormone drugs prolonged progression-free survival in estrogen receptor positive metastatic breast cancer. Both are not yet directly compared in terms of efficacy, adverse events, and discontinuation rates due to the adverse events. MonarchE trial evaluated adverse events of Abemaciclib as follows; 81.3% had diarrhea and 41.3% had neutropenia, whereas PALOMA-3 trial showed 92% of neutropenia (74% had Grade3 neutropenia) in patients receiving Palbociclib. Of the patients who received CDK4/6 inhibitors in our institutions, we compared the difference of rates in adverse events, and we discussed the importance of acknowledging the risks between the two drugs. Methods: We reviewed a total of 169 patients comprising 53 with Abemaciclib and 116 with Palbociclib from 2017 to 2023 at two institutions as 1st – 3rd line treatments. The year of prescription, treatment line, age and the adverse event which led to treatment discontinuation was analyzed. Results: All patients were women, and the median age was 57 (29-84). The patients who received treatment as 1st, 2nd, 3rd lines were 98, 49, and 22, respectively. Twenty-six patients received cytotoxic chemotherapy before CDK4/6 inhibitors. Patients diagnosed as de-novo stage IV patients were 108, while 61 had recurrent tumors. Treatment discontinuation due to adverse events of CDK4/6 inhibitors were 41 (24%) in which 14 (8.3%) had diarrhea and 20 (12%) had neutropenia. We conducted a multivariate analysis setting the endpoint as any adverse events resulting to treatment discontinuation. Abemaciclib (HR=1.20 p=0.01), the first prescription date (2017-19 vs 2020-23, HR:0.84 p=0.02), and patients with metastatic breast cancer at first diagnosis (HR:1.15 p=0.039) significantly affected adverse events leading to treatment discontinuation. Patients receiving Abemaciclib discontinuedecause of diarrhea more than patients receiving Palbociclib (p<0.001 HR:1.28), whereas patients receiving Palbociclib discontinued treatment because of neutropenia more than patients receiving Abemaciclib (HR=1.13 p=0.036). Conclusions: The type of CDK4/6 inhibitor, de-novo Stage IV or recurrent breast cancer, and the year of treatment initiation led to differences in safety of CDK4/6 inhibitor treatment. Abemaciclib leads to treatment discontinuation more than Palbociclib with the most reported adverse event; diarrhea. In addition, the risk of adverse events differs from the year of treatment initiation, which suggests that management of adverse events is improving over time. Thus, it is crucial to accomplish the management of adverse events when starting Abemaciclib which has higher treatment discontinuation rates due to adverse events.

A disease registry study to prospectively observe treatment patterns and outcomes in patients with HER2+ unresectable locally advanced or metastatic breast cancer (aBC): Interim results of the ESTHER study (NCT02393924).

e13039 Background: Over the last decade the standard-of-care treatment for patients with HER2+ aBC has included anti-HER2 therapies often combined with chemotherapy. These approaches have shown efficacy in clinical trials which have recruited patients in restricted populations defined by lines of therapy and previous treatments. There are few data regarding the long-term outcomes of patients treated with these regimens, including those with brain metastases. We conducted a prospective, multicentre non-interventional study to observe anti-cancer treatment regimens and clinical outcomes in patients with HER2 positive aBC. Methods: Adult patients diagnosed with HER2-positive aBC within the last 6 months were included. No specific treatment approach or course was mandated by the protocol. Source data was taken from the patient’s chart and other medical records, then reported by means of an electronic data collection system. Data regarding treatment received, efficacy (progression-free and overall survival (PFS), response rates (RR) and development of CNS metastases) and safety (including cardiac toxicity) were captured. Results: Between February 2015 and April 2018, 311 eligible patients were recruited with median age 57 years (24-96). At diagnosis of aBC the most common distant metastatic sites were bone (n = 145;47%), liver (n=117;38%), lung (n=100;32%) and brain (n=21;7%). First line treatment was with pertuzumab (P)/trastuzumab(T)/chemotherapy (n=212;68%), T/chemotherapy (n=45;14%), other T combinations without P (n=19;6%), Trastuzumab Emtansine regimens without T or P (n=16;5%) (19; 5% other combinations). Patients’ status as of cut-off date for this analysis (28th Feb 2022, median follow-up 44.1 months) is shown. The median PFS of patients treated in the 1st, 2nd and 3rd lines was 26.7 months, 10.7 months and 8.6 months. At the time of this analysis an additional 60 patients (19%) had developed brain metastases during first line. The number of patients starting 2nd, 3rd and 4th line treatment with brain metastases were 28 (22%), 17 (40%), 7 (37%) respectively. Conclusions: In routine clinical practice, as reflected by this registry, at least 40% of patients who initiate first line therapy for advanced breast cancer do not proceed to 3rd line therapy, and brain metastases become increasingly common. These findings have implications for selection of optimal 2nd and 3rd line treatment. Clinical trial information: ISRCTN02393924 . [Table: see text]

17th International Conference on Malignant Lymphoma, Palazzo dei Congressi, Lugano, Switzerland, 13 - 17 June, 2023.

Introduction: Allogeneic stem cell transplantation (alloSCT) was the only curative option for younger patients (pts) with relapsed/ refractory (r/ r) LBCL (DLBCL, tFL, PMBCL). Anti-CD19 CAR T-cells (CART) entered the clinical arena around 5 years ago now being considered standard of care for such patients. As >50% of LBCL pts progress or relapse after CART treatment we were interested in identifying prognostic factors for both modalities and their relative role in the treatment of advanced r/r LBCL. Methods: Pts registered with the EBMT database from 1/2016 to 5/2021 having received either a first alloSCT or commercially available CART therapy (Yescarta® or Kymriah ®) as ≥3rd therapy of LBCL were analyzed. To correct for imbalances in patient characteristics we did propensity score analyses considering only pts with complete information on IPI including LDH at the time of cell therapy. We performed multivariate analyses in patients with either low- or high-risk r/r LBCL according to LDH level at cell therapy in pts treated with alloSCT or CART. Results: We identified 515 pts with full information on IPI at cell therapy (212 alloSCT and 303 CART). Patient groups differed significantly in median age, IPI score, and disease status at cell therapy. Median follow up was 46.3 months after alloSCT and 22.1 months after CART treatment. In univariate analysis, type of cell therapy, disease status, and IPI at cell therapy had a significant impact on OS. Amongst IPI risk factors LDH, performance status, and number of extranodal sites had a significant impact on OS, PFS an RI. At 24 months, OS was 41% after allo SCT and 49% after CART. In a propensity score analysis using all IPI factors as covariates, CART was superior to alloSCT in terms of OS (HR 0.62, 95% CI: 45–0.84, p = 0.0193) but not PFS, RI or NRM. In multivariate analysis patients with IPI (o-2) low risk at cell therapy show better OS (HR 0.81, 95% CI 0.59–1.1, p < 0.0001) and PFS (HR 0.62, CI: 0.46–0.83, p = 0.00145), comparable RI and lower NRM (HR 0.21 CI: 0.11–0.42, p = 0.00001) with CART compared to allo SCT. In IPI (3–5) high-risk patients, CART showed significantly higher RI (HR 1.45, CI: 1.03–2.04, p = 0.03549) but lower NRM (HR 0.21, CI: 0.11–0.42), p = 0.00001) compared to allo SCT. OS and PFS did not significantly differ. Refractory disease was an independent adverse prognostic factor for OS (HR 1.74, CI: 1.3–2.33, p = 0.0002), PFS (HR 1.61 CI: 1.23–2.1, p = 0.0006) and RI (HR 1.79 CI: 1.29–2.49, p = 0.0006) but not for NRM. Results at 2 years are given in Table 1. Conclusion: IPI assessed at cell therapy is of prognostic impact for both CART and allo SCT. Overall, pts given CART for ≥3rd line treatment of DLBCL showed better OS than pts treated with alloSCT. In patients with high intermediate/high IPI results of CART must be improved and allogeneic SCT remains a valuable treatment strategy due to its high anti-lymphoma activity. Keyword: Cellular therapies Conflicts of interests pertinent to the abstract. B. Glass Consultant or advisory role: Kite, BMS, Novartis, Milteneyi, Roche, Janssen, Jazz, Abbvie Honoraria: Kite, BMS, Novartis, Milteneyi, Roche, Janssen, Jazz, Abbvie Research funding: Roche, Riemser A. Sureda Consultant or advisory role: Takeda, MSD, BMS, Novartis, Janssen, Roche, Sanofi, Gilead P. Dreger Consultant or advisory role: Kite, Novartis P. Corradini Honoraria: Abbvie, Amgen, Celgene, Giled, Incyte, Janssen, Takeda, R. Ram Honoraria: Novartis, Gilead, Takeda, BMS G. Wulf Consultant or advisory role: Gilead, Novartis A. M. García-Sancho Consultant or advisory role: Roche, BMS, Kyowa Kirin, Clinigen, Eusa Pharma, Novartis, Kite Gilead, Servier, Incyte, Lilly, Takeda, ADC Therapeutics America, Miltenyi, Kern M. Stelljes Consultant or advisory role: Medac, Pfizer, Jazz, Novartis, MSD, Amgen, BMS, Kite D. Blaise Consultant or advisory role: Jazz E. Forcade Consultant or advisory role: Gilead, Jazz, Novartis, GSK, Sanofi, MSD I. Hilgendorf Consultant or advisory role: Novartis, Abbvie J. A. Perez-Simon Consultant or advisory role: Novartis, Janssen, Gilead, Jazz, Alexion, Abbvie, Pfizer W. Bethge Consultant or advisory role: Gilead, Novartis, Miltenyi, Janssen, Celgene N. Schmitz Consultant or advisory role: Allogene Stock ownership: BMS Honoraria: Allogene Research funding: Janssen, Roche Educational grants: Allogene, Milteneyi

Use of clinical pathways to identify patients with cancer who may benefit from serious illness conversations.

12027 Background: Treatment pathways are widely used to provide decision support and encourage guideline adherence. Pathways data may be used to identify patients for targeted interventions to improve cancer care. For example, pathways data may enable the identification of patients with poor prognoses for whom serious illness conversations (SICs) should be prioritized to ensure goal-concordant care. Methods: For patients starting new therapies at Dana-Farber, oncologists select a node in clinical pathways to indicate the line of treatment. Subspecialty oncologists identified “poor prognosis” nodes in pathways, defined as therapies for patients with expected survivals of &lt; 12 months and for whom an SIC would be appropriate (e.g., 3rd-line treatment for metastatic colon cancer). Pathway node navigations for patients with metastatic solid tumor malignancies with poor prognosis nodes (n = 21 disease pathways) were combined with electronic medical record data to identify SIC documentation in an advance care planning module within 6 months of pathway navigation and patients’ dates of death if present. For each node, we calculated the median overall survival (OS), the proportion of patients with an SIC, and the proportion of patients who died before reaching the next node. Results: There were 10,132 navigations for 7,031 patients (median age 67 years, 52% female, 86% White) between 8/16/2019 and 1/4/2023. With each treatment line, patients’ median OS decreased and SIC rates increased (examples for 3 diseases in Table). Among patients who reached poor prognosis nodes, the median OS was 4.9 months, mean SIC rate was 43.8%, and 60.2% of patients died without reaching a subsequent node. For nodes immediately prior to poor prognosis nodes, the median OS was 7.1 months, the mean SIC rate was 25.2%, and 31.3% of patients died without reaching the next node. 46.3% of patients died without reaching a poor prognosis node. The proportion of patients having an SIC at death was 40.9% among all decedents, 50.8% for decedents reaching a poor prognosis node, and 29.3% for decedents who do not reach a poor prognosis node. Conclusions: Clinical pathways can be used as a scalable method to identify patients with metastatic solid tumors and poor prognoses. In our study, only half of patients who reached a poor prognosis node had an SIC before death and nearly half of decedents never reached a poor prognosis node, underscoring the importance of identifying this population to improve end-of-life care. A clinical trial using pathways to identify and deliver interventions to increase SICs is ongoing. [Table: see text]

Real-world treatment patterns and outcomes of abemaciclib for the treatment of HR + , HER2- metastatic breast cancer patients in Japan

IntroductionThis study described, in routine clinical practice in Japan, the patient characteristics, treatment patterns, and outcomes of female patients with HR + /HER2- metastatic breast cancer (MBC) who started abemaciclib treatment.MethodsClinical charts were reviewed for patients starting abemaciclib in 12/2018–08/2021 with a minimum of 3 months follow-up data post-abemaciclib initiation regardless of abemaciclib discontinuation. Patient characteristics, treatment patterns, and tumor response were descriptively summarized. Kaplan–Meier curves estimated progression-free survival (PFS).Results200 patients from 14 institutions were included. At abemaciclib initiation, median age was 59 years, and the Eastern Cooperative Oncology Group performance status score was 0/1/2 for 102/68/5 patients (58.3/38.9/2.9%), respectively. Most had an abemaciclib starting dose of 150 mg (92.5%). The percentage of patients receiving abemaciclib as 1st, 2nd, or 3rd line treatment was 31.5%, 25.8%, and 25.2%, respectively. The most frequent endocrine therapy drugs used with abemaciclib were fulvestrant (59%) and aromatase inhibitors (40%). Evaluation of tumor response was available for 171 patients, 30.4% of whom had complete/partial response. Median PFS was 13.0 months (95% CI 10.1–15.8 months).ConclusionsIn a routine clinical practice setting in Japan, patients with HR + , HER2- MBC appear to benefit from abemaciclib treatment in terms of treatment response and median PFS, with the results broadly reflecting the evidence demonstrated in clinical trials.