Third-line Setting Research Articles

Association of early tumor shrinkage with survival in patients with HER2-positive advanced gastric cancer treated with trastuzumab deruxtecan.

360 Background: Trastuzumab deruxtecan (T-DXd), an antibody-drug conjugate composed of an anti-human epidermal growth factor receptor 2 (HER2) antibody and a cytotoxic topoisomerase I inhibitor, has been approved as third or later-line treatment for unresectable HER2-positive advanced gastric cancer (AGC) based on the results of phase II DESTINY-Gastric 01 trial. However, there are few studies on real-world clinical outcomes and clinicopathological factors associated with efficacy of T-DXd in patients with HER2-positive AGC. Methods: This single-center retrospective study enrolled patients with AGC treated with T-DXd as third- or later-line chemotherapy between March 2018 and December 2023. Early tumor shrinkage (ETS) was defined as the relative change in the sum of longest diameters of RECIST target lesions at 8 ± 2 weeks compared with baseline. Prognostic outcomes were assessed using the log-rank test and Cox proportional hazards regression model. Results: A total of 57 patients were enrolled. The median age was 66 years (range, 31–82); 68% were male; 79% had HER2 3+; 23% had pulmonary metastasis; 67% were treated with T-DXd in the third-line setting. At a median follow-up of 27.6 months, the median progression-free survival (PFS) was 4.5 months (95% confidence interval [CI], 3.8–5.5), and the median overall survival (OS) was 7.3 months (95% CI, 4.9–9.4). Among 40 patients with target lesions, the overall response rate was 35.0% and the disease control rate was 90.0%. Patients with ETS had notably longer PFS (median PFS (months) 8.6 vs 4.1, P < 0.01) and OS (median OS (months) 9.1 vs 6.1, P < 0.01) than those without ETS. In multivariate analysis, ETS was associated with significantly longer PFS (hazard ratio [HR], 0.23; 95% CI, 0.08–0.63; P = 0.004) and OS (HR, 0.27; 95% CI, 0.12–0.65; P = 0.004), whereas pulmonary metastasis was associated with significantly shorter OS (HR 2.46, 95% CI, 1.07–5.65; P = 0.03). Conclusions: This study showed that achieving an ETS was significantly associated with a favorable prognosis in patients with HER2-positive AGC treated with T-DXd.

Comparative efficacy of TAS-102 and chemotherapy rechallenge in the third-line setting and beyond in patients with advanced colorectal cancer: A retrospective study.

78 Background: The optimal approach to third line therapy for patients with metastatic colorectal cancer remains a subject of debate. Options include Trifluridine/Tipiracil (TAS-102), TAS-102 with bevacizumab, regorafenib, chemotherapy rechallenge with or without an anti-EGFR agent, or fruquintinib. This study aims to evaluate the efficacy of standard of care TAS-102, TAS-102 with bevacizumab, or regorafenib versus chemotherapy rechallenge in patients with metastatic colorectal cancer in the third line setting and beyond. Methods: We conducted a retrospective analysis of patients with metastatic colorectal cancer who received either TAS-102 with or without bevacizumab, regorafenib or chemotherapy rechallenge with or without an anti-EGFR agent between 2018 and 2023, at the Ministry of National Guard for Health Affairs in Riyadh, Saudi Arabia. Patients received such agents in the third line setting and beyond. Results: A total of 75 patients were included in this study, with 39 patients receiving TAS-102 with or without bevacizumab, or regorafenib, and 36 receiving chemotherapy rechallenge. The median patient age was 58 years (range 28-81), with the majority being males at 55%. Among the chemotherapy rechallenge group, 31% were treated with cetuximab and 6% had panitumumab rechallenge, some of which were guided by cell free DNA liquid biopsy testing. In the other group, 66% received regorafenib, 26% TAS-102 alone, and 8% TAS-102 with bevacizumab. At the time of analysis, 56% of patients had passed away. Median overall survival for patients who received TAS-102 with our without bevacizumab, and regorafenib in the third line setting was found to be 13.1 months. Whereas for patients who received chemotherapy rechallenge, their median overall survival was 19.5 months. Conclusions: Patients with metastatic colorectal cancer who received chemotherapy rechallenge in the third line setting survived longer compared with patients who received TAS-102 with or without bevacizumab, or regorafenib.

Trifluridine/tipiracil regimen in combination with bevacizumab for metastatic colorectal cancer in the third line: an expert opinion.

The prolongation of survival along with the preservation of quality of life, possibly avoiding harmful cumulative toxicities, is the primary therapeutic aim for patients with metastatic colorectal cancer (mCRC) in the third-line setting. Several therapeutic options are now available, although some differences across countries in drug approval and the optimal therapeutic sequencing associated with each peculiar patient subgroup represent a clinical challenge for oncologists. Among various options, the SUNLIGHT trial showed how the combination of trifluridine/tipiracil (FTD/TPI) with bevacizumab is effective with an easily manageable toxicity profile compared to FTD/TPI alone. Of note, the efficacy is confirmed independently from KRAS mutational status and also for patients who had breaks in anti-vascular endothelial growth factor (anti-VEGF) therapy. Herein, we describe the current state of the art in the landscape of treatments after the second progression in mCRC. Based on a critical review of the literature aimed to guide clinicians in their daily decision-making, we point out that the combination of FTD/TPI with bevacizumab produces a clinical benefit in unselected mCRC patients. Therefore, the FTD/TPI plus bevacizumab regimen can represent a new standard of care for the treatment of patients with refractory mCRC who have progressed after two lines of therapy.

Real-world experience with TTFields in glioma patients with emphasis on therapy usage.

Tumor Treating Fields (TTFields) has emerged as a significant adjunctive component in the treatment of high-grade gliomas following the EF-14 trial in 2017. The incorporation of TTFields, alongside cyclic temozolomide therapy, has demonstrated improved patient outcomes when the usage exceeds 18 h per day (75% usage). Post-hoc analysis of the EF-14 trial has demonstrated that therapy usage exceeding 90% is associated with an additional benefit, while rates above 50% have also proven effective in literature. Given the cost-intensive nature and mild- to- moderate constraints associated with the therapy, our objective is to generate real-world data on therapy usage through a retrospective analysis at a high-throughput academic center. Between June 2015 and February 2022, a total of 113 high-grade glioma patients received TTFields therapy. Eight patients discontinued TTFields therapy within 2 months with less than 50% usage and were excluded from further analysis. For the remaining patients, the median age was 51 years (range: 20-76 years) and the mean preoperative Karnofsky index was 80%-90%. Most of the patients (75.2%) initiated therapy concurrently with first-line treatment, of whom 27.6% started TTFields therapy concomitant to the first cycle of temozolomide. 15.2% started TTFields therapy in the second-line and 9.5% in the third-line setting. The study cohort had an average therapy duration of 9.3 months with 3.2 break days per month. The mean therapy usage was 65.5% (SD 17.6%). Usage was highest during the first 3 months, with rates of 77.7%, 72.3%, and 71.6%, and then dropped to around 60% in the following 6 months. Linear regression found no predictors of usage, such as age, timing of therapy initiation, and duration or gender. 55% of patients continued TTFields beyond the first recurrence. Interestingly, no drop in usage rates was observed before tumor recurrence was communicated. However, after diagnosis, patients exhibited a significant drop in usage to an average of 52.3%. This high-volume, real-world TTFields usage data reveal that the extent of usage falls short of the intended 75%. It highlights the importance of monitoring and promoting adherence to maximize its potential benefits in managing high-grade glioma patients. Furthermore, strategies to expedite therapy initiation and improve long-term adherence are warranted.

Updates on Chimeric Antigen Receptor T-Cells in Large B-Cell Lymphoma.

CD19-targeting chimeric antigen receptor (CAR) T-cells have changed the treatment paradigm of patients with large B-cell lymphoma (LBCL). Three CAR T-cells were approved by the Food and Drug Administration (FDA) for patients with relapsed and/or refractory (R/R) LBCL in the third-line setting: tisagenlecleucel (tisa-cel), axicabtagene ciloleucel (axi-cel), and lisocabtagene maraleucel (liso-cel), with an ORR ranging from 58% to 82%. More recently, axi-cel and liso-cel were approved as second-line treatments for patients with R/R disease up to 12 months after the completion of first-line chemo-immunotherapy. The safety profile was acceptable with cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome being the two most frequent acute adverse events. Potential long-term toxicities of CD19-targeting CAR T-cells have also been described. Overall, 30% to 40% of patients are cured with a single infusion of CAR T-cells. However, 60% to 70% of patients relapse after being treated with CAR T-cells and have a dismal prognosis. The advent of bispecific antibodies (BsAb) offers an additional treatment modality for patients with R/R LBCL. The aim of this review is to describe the clinical efficacy of the three CAR T-cells, as well as their safety profile. We also compare these three CAR T-cells in terms of their efficacy and safety profile as well as evaluating the place of CAR T-cells and BsAb in the treatment arsenal of patients with R/R LBCL.

Real-World Study of EGFR-TKI Rechallenge With Another TKI After First-Line Osimertinib Discontinuation in Patients With EGFR-Mutated Non-Small Cell Lung Cancer: A Subset Analysis of the Reiwa Study.

First-line osimertinib is widely used to treat patients with epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancers (NSCLC). In clinical practice, rechallenge therapy with another EGFR-tyrosine kinase inhibitor (TKI) is often performed after first-line TKI discontinuation owing to resistance or toxicity; however, the efficacy and toxicity of EGFR-TKI rechallenge after first-line osimertinib have not been adequately investigated. This study aimed to examine the efficacy and safety of EGFR-TKI rechallenge with another TKI. This multicenter prospective observational study enrolled patients with EGFR-mutated NSCLC who received first-line osimertinib and another EGFR-TKI as second- or third-line treatment between September 2018 and August 2020. Fifty-three patients received rechallenge with another EGFR-TKI in the second-line (n = 38, 71.7%) or third-line (n = 15, 28.3%) setting. The primary reason for first-line osimertinib discontinuation was toxicity in 32 (60.4%, 17 patients with pneumonitis) and disease progression in 20 (37.7%) patients. The most common rechallenge EGFR-TKI was afatinib (n = 24, 45.3%), followed by gefitinib (n = 16, 30.2%) and erlotinib (n = 8, 15.1%). The real-world time to treatment failure (rwTTF) was 7.3 months. The rwTTF for the toxicity discontinuation and progressive disease discontinuation groups was 9.3 months and 5.1 months, respectively, (HR 1.61, p = 0.119). EGFR-TKI rechallenge was discontinued due to toxicity in nine patients (17.0%), but no patient developed pneumonitis. EGFR-TKI rechallenge with another TKI is well tolerated in patients with EGFR-mutated NSCLC. Thus, it may be a useful treatment option after first-line osimertinib failure, especially after osimertinib discontinuation due to toxicity.

A real-world comparison of commercial-use axicabtagene ciloleucel and lisocabtagene maraleucel in large B-cell lymphoma

Lisocabtagene maraleucel (liso-cel) and axicabtagene ciloleucel (axi-cel) are anti-CD19 chimeric antigen receptor (CAR) T-cell therapies approved for relapsed and refractory large B-cell lymphoma (LBCL); however, there is currently no published data on liso-cel outside of clinical trials nor any data comparing these therapies. In this retrospective analysis, we reviewed patients with LBCL receiving liso-cel or axi-cel at a single institution in the third-line setting. From June 2021 to September 2022, a total of 50 patients received axi-cel and 37 liso-cel. Baseline patient characteristics were similar, aside from older age in liso-cel recipients. The median time from leukapheresis to CAR T-cell infusion was significantly longer for liso-cel (41days) than axi-cel (30days). Complete response rates were not significantly differentbetween axi-cel (72%) and liso-cel (62%). At a median follow-up of 11months, progression-free survival (PFS) was not significantly different between axi-cel and liso-cel cohorts, with 12-month PFS of 59% and 44%, respectively. However, on a propensity score analysis, aninferior PFS was observed with liso-cel (hazard ratio, 2.95; 95% confidence interval , 1.14-7.60). The rates of cytokine release syndrome, immune effector cell-associated neurotoxicity syndrome, and prolonged neutropenia were higher with axi-cel than liso-cel. Overall, direct comparison of axi-cel and liso-cel cohorts shows similar key outcomes including response rate and PFS, but prolonged wait times for liso-cel may have resulted in biased selection of patients with more favorable characteristics for liso-cel. When accounting for these higher-risk characteristics, an inferior PFS is observed with liso-cel compared with axi-cel. These findings warrant further evaluation in a multicenter setting.

Moving T-Cell Therapies into the Standard of Care for Patients with Relapsed or Refractory Follicular Lymphoma: A Review.

Patients with follicular lymphoma, an indolent form of non-Hodgkin lymphoma, typically experience multiple relapses over their disease course. Periods of remission become progressively shorter with worse clinical outcomes after each subsequent line of therapy. Currently, no clear standard of care/preferred treatment approach exists for patients with relapsed or refractory follicular lymphoma. As novel agents continue to emerge for treatment in the third-line setting, guidance is needed for selecting the most appropriate therapy for each patient. Several classes of targeted therapeutic agents, including monoclonal antibodies, phosphoinositide 3-kinase inhibitors, enhancer of zeste homolog 2 inhibitors, chimeric antigen receptor (CAR) T-cell therapies, and bispecific antibodies, have been approved by regulatory authorities based on clinical benefit in patients with relapsed or refractory follicular lymphoma. Additionally, antibody-drug conjugates and other immunocellular therapies are being evaluated in this setting. Effective integration of CAR-T cell therapy into the treatment paradigm after two or more prior therapies requires appropriate patient selection based on transformation status following a rebiopsy; a risk evaluation based on age, fitness, and remission length; and eligibility for CAR-T cell therapy. Consideration of important logistical factors (e.g., proximity to the treatment center and caregiver support during key periods of CAR-T cell therapy) is also critical. Overall, an individualized treatment plan that considers patient-related factors (e.g., age, disease status, tumor burden, comorbidities) and prior treatment types is recommended for patients with relapsed or refractory follicular lymphoma. Future analyses of real-world data and a better understanding of mechanisms of relapse are needed to further refine patient selection and identify optimal sequencing of therapies in this setting.

Epcoritamab monotherapy in patients with relapsed or refractory follicular lymphoma (EPCORE NHL-1): a phase 2 cohort of a single-arm, multicentre study

A standard of care and optimal duration of therapy have not been established for patients with multiply relapsed or refractory follicular lymphoma. The aim of this study was to evaluate epcoritamab, a novel CD3 × CD20 bispecific antibody, in the third-line and later setting of follicular lymphoma. EPCORE NHL-1 is a multicohort, single-arm, phase 1-2 trial conducted at 88 sites across 15 countries. Here, we report the primary analysis of patients with relapsed or refractory follicular lymphoma in the phase 2 part of the trial, which included the pivotal (dose expansion) cohort and the cycle 1 optimisation cohort. Eligible patients were aged 18 years or older, had relapsed or refractory CD20+ follicular lymphoma (grade 1-3A), an Eastern Cooperative Oncology Group performance status of up to 2, and had received at least two previous lines of therapy (including an anti-CD20 monoclonal antibody and an alkylating agent or lenalidomide). Patients were treated with subcutaneous epcoritamab 48 mg in 28-day cycles: weekly in cycles 1-3, biweekly in cycles 4-9, and every 4 weeks until disease progression or unacceptable toxicity. To mitigate the risk and severity of cytokine release syndrome, in the pivotal cohort, cycle 1 consisted of a step-up dosing regimen of a 0·16-mg priming dose on day 1 and a 0·80-mg intermediate dose on day 8, followed by subsequent 48-mg full doses and prophylactic prednisolone 100 mg; in the cycle 1 optimisation cohort, a second intermediate dose of 3 mg on day 15, adequate hydration, and prophylactic dexamethasone 15 mg were evaluated during cycle 1 to further reduce risk and severity of cytokine release syndrome. Primary endpoints were independently reviewed overall response rate for the pivotal cohort and the proportion of patients with grade 2 or worse and any-grade cytokine release syndrome for the cycle 1 optimisation cohort. Analyses were done in all enrolled patients who had received at least one dose of epcoritamab. This study is registered with ClinicalTrials.gov, NCT03625037, and is ongoing. Between June 19, 2020, and April 21, 2023, 128 patients (median age 65 years [IQR 55-72]; 49 [38%] female and 79 [62%] male) were enrolled and treated in the pivotal cohort (median follow-up 17·4 months [IQR 9·1-20·9]). The overall response rate was 82·0% (105 of 128 patients; 95% CI 74·3-88·3), with a complete response rate of 62·5% (80 of 128; 95% CI 53·5-70·9). The most common grade 3-4 treatment-emergent adverse event was neutropenia in 32 (25%) of 128 patients. Grade 1-2 cytokine release syndrome was reported in 83 (65%) of 128 patients; grade 3 cytokine release syndrome was reported in two (2%). Immune effector cell-associated neurotoxicity syndrome was reported in eight (6%) of 128 patients (five [4%] grade 1; three [2%] grade 2). Between Oct 25, 2022, and Jan 8, 2024, 86 patients (median age 64 years [55-71]; 37 [43%] female and 49 [57%] male) were enrolled and treated in the cycle 1 optimisation cohort. The incidence of cytokine release syndrome was 49% (42 of 86 patients; eight [9%] grade 2; none of grade 3 or worse), with no reported immune effector cell-associated neurotoxicity syndrome. Epcoritamab monotherapy showed clinically meaningful activity in patients with multiply relapsed or refractory follicular lymphoma, and had a manageable safety profile. Genmab and AbbVie.

High-dose chemotherapy and peripheral blood stem cell transplantation as salvage therapy in primary mediastinal nonseminomatous germ cell tumors: The Indiana University experience.

Patients with relapsed primary mediastinal nonseminomatous germ cell tumor have low cure rates with salvage chemotherapy or surgery. The authors report survival outcomes of patients who received high-dose chemotherapy (HDCT) and peripheral blood stem cell transplantation (PBSCT) at Indiana University. The prospectively maintained Indiana University germ cell tumor database identified 32 patients with primary mediastinal nonseminomatous germ cell tumor who progressed after first-line cisplatin-based combination chemotherapy and received HDCT and PBSCT between 2006 and 2021. Therapy included two consecutive courses of HDCT consisting of 700 mg/m2 carboplatin and 750 mg/m2 etoposide, each for 3 consecutive days, and each followed by PBSCT. A second course was not given if the patient experienced progressive disease or prohibitive toxicity. Progression-free survival and overall survival were analyzed using the Kaplan-Meier method. Medians with 95% confidence intervals were also calculated along with 2-year probabilities. The median age at HDCT was 30 years (range, 18-61 years). With a median follow-up of 4.7 years (range, 1-14 years), the 2-year progression-free survival rate was 31% (95% confidence interval, 16%-47%), and the 2-year overall survival rate was 35% (95% confidence interval, 19%-52%). At last follow-up, nine patients (28%) remained without evidence of disease, including two platinum-refractory patients and two patients who were receiving HDCT as third-line therapy. There were three treatment-related deaths. Salvage HDCT and PBSCT is an active combination in patients who have relapsed primary mediastinal nonseminomatous germ cell tumor with curative potential and prolonged survival, including in platinum-refractory and third-line settings. The authors recommend this approach for initial salvage chemotherapy in this patient population.

Treatment patterns and clinical outcomes in patients with metastatic triple-negative breast cancer: a large-scale data analysis using the Japanese claims database

PurposeThis study evaluated treatment patterns and clinical outcomes among patients with metastatic triple-negative breast cancer (mTNBC) in real-world clinical settings in Japan.MethodsThe treatment patterns, time to next treatment or death (TTNTD), time to treatment discontinuation, adverse events of interest, and medical costs of treating patients with mTNBC in first-, second-, and third-line settings were investigated using data of patients meeting the inclusion criteria between January 2017 and March 2022 in a Japanese medical claims database. The treatment regimens for mTNBC were defined according to the Japanese Breast Cancer Society Clinical Practice Guidelines.ResultsIn this study, 2236 patients with mTNBC (median age 66.0 years; 99.8% female) were included in the first-line cohort. Of these, 46.6% and 20.8% were included in the second- and third-line cohorts, respectively. The two most frequently used treatments were capecitabine (19.1%) and S-1 (tegafur–gimeracil–oteracil) (14.5%) in the first-line cohort, eribulin (18.3%) and bevacizumab/paclitaxel (14.4%) in the second-line cohort, and eribulin (19.4%) and bevacizumab/paclitaxel (17.5%) in the third-line cohort. The TTNTD shortened as the line of therapy progressed (median 8.0, 6.5, and 5.2 months for the first-, second-, and third-line treatments, respectively). Nausea/vomiting and neutropenia/leukopenia occurred in 62.8% and 18.3% of all patients, respectively. The medical total costs per day were 6.7, 10.2, and 12.9 thousand yen during the first-/second-/third-line treatments, respectively.ConclusionThis study provides insight into current treatment patterns for mTNBC in Japan. The cost–benefit balance worsens with later-line treatment and a high unmet need for mTNBC drug treatment remains.

Abstract PO2-10-08: Contemporary HER2-Positive MBC Treatment Recommendations Among Community Healthcare Professionals: Analysis of an Online Interactive Decision Support Tool

Abstract Background: The management of HER2-positive (HER2+) metastatic breast cancer (MBC) has continued to evolve, with multiple FDA approvals of novel HER2-targeted agents since late 2019. Considering the growing HER2+ MBC treatment armamentarium, we sought to identify current practice patterns among community healthcare professionals (HCPs) for HER2+ MBC by comparing HCP and key opinion leader (KOL) treatment recommendations using an online decision support tool. Methods: An online decision support tool was developed with input from 5 KOLs to provide therapy recommendations for 630 HER2+ MBC patient case scenarios based on conventional considerations including distribution of metastatic disease, treatment history, duration of response, and specific comorbidities. HCP tool users entered specific patient criteria to define a case along with their intended management for each case. The tool then showed 5 KOL recommendations for the user-entered patient case, and the users were asked to indicate if the expert recommendations confirmed or changed their intended approach. An analysis of expert recommendations and user-selected therapy was performed. Results: Between November 2022 and July 2023, 313 patient cases were entered by 242 participating HCPs. HCP and KOL treatment recommendations were frequently discordant (Table). For patients with de novo HER2+ MBC (n = 55), there was strong concordance (63%; P = .0001) between HCP and KOL recommendations. However, weak treatment selection concordance (53%; P < .0001) was observed for patients with disease progression after standard neoadjuvant/adjuvant therapy with chemotherapy plus HER2-targeted agents (n = 57). In the second-line setting, 43% concordance was observed for patients with non‒central nervous system (CNS) disease progression without CNS progression after first-line therapy with THP (n = 67; P < .0001), whereas 61% concordance was observed for patients with non-CNS and CNS disease progression after first-line therapy with THP (n = 61; P < .0001). In the third-line setting, 31% concordance was observed for patients with non-CNS disease progression without CNS progression (n = 32; P < .0001), and 47% concordance was observed for patients with non-CNS and CNS disease progression (n = 19; P = .0009). For HCPs whose treatment plan did not match KOL recommendations in these scenarios, 62% indicated that KOL recommendations confirmed or changed their intended therapy, but 19% indicated that there were barriers to implementing those recommendations. Conclusions: These data suggest ongoing challenges to optimally incorporate novel HER2-targeted therapies in the care of patients with HER2+ MBC, particularly in the second line and beyond, but an online tool providing KOL advice on specific patient scenarios confirmed or changed the clinical approach for a majority of HCPs. Thus, continued development of resources for HCPs, including online decision support tools, may be increasingly important given the rapidly evolving treatment landscape. Table. Summary of Treatment Choices by KOLs or HCPs for Select Patient Scenarios Citation Format: Kristen Rosenthal, Sara Hurvitz, Komal Jhaveri, Heather McArthur, Sara Tolaney, Timothy Quill. Contemporary HER2-Positive MBC Treatment Recommendations Among Community Healthcare Professionals: Analysis of an Online Interactive Decision Support Tool [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 PO2-10-08.

Abstract PO2-17-01: Impact of the introduction of CDK4/6 inhibitors on treatment duration in patients with HR+, HER2– advanced breast cancer: Final analysis of TreatER+ight, a Canadian prospective, real-world, observational study

Abstract Background: Cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) in combination with endocrine therapy (ET) are the established first-line targeted therapy (TT) for patients with hormone receptor-positive (HR+), human epidermal growth factor receptor-2-negative (HER2–) advanced breast cancer (ABC). TreatER+ight, the first prospective, real-world study evaluating the treatment patterns, safety and effectiveness of ET alone or ET + TT in Canadian patients with HR+, HER2– ABC (2016 to 2020) recorded ET as the standard of care (SOC) in the first interim analysis report. However, treatment with CDK4/6i combined with ET have rapidly evolved as the SOC in the metastatic setting. Methods: This prospective, multicenter, observational study (NCT02753686) enrolled patients with HR+, HER2‒ ABC with or without prior exposure to ET and up to one line of prior CT in the advanced setting. The patients were enrolled by the line of their therapy (first-line, second-line or third-line) and grouped into 2 cohorts (ET and ET + TT). Duration of therapy, and overall survival (OS) are estimated using Kaplan–Meier method. Here, we report the final outcome with CDK4/6i treatment evolution with sequencing strategy and duration in routine clinical practice. Results: At data cutoff (December 1, 2022), a total of 439 enrolled patients (ET, n=104; ET + TT, n=335) from 25 centers in Canada, constituted the full analysis set. The median age (range) was 71.5 (37.0–96.0) years in ET cohort and 65.0 (23.0-87.0) years in ET + TT cohort. About 84.6% and 66.4% were postmenopausal patients in the ET and ET + TT cohorts, respectively. Patients with ECOG PS scores 0 to 1 composed of 82.0% and 93.5% in the ET and ET + TT cohorts, respectively. In the overall population, ET alone and ET + CDK4/6i were the most common treatment received by patients in first-line (43.5% and 43.3%) and second-line (36.3% and 24.6%) treatment settings. In third-line treatment setting, CT was the most common treatment received by patients (38.4%). Conclusions: Data from final analysis of TreatER+ight have further confirmed the evolution to primary use of CDK4/6i-based combination therapy in the first-line setting for Canadian patients with HR+, HER2– ABC. Additional details on duration of therapy by CDK4/6i agents, overall survival data and age subgroup analysis will be presented at SABCS 2023 Table 1_Baseline characteristics, treatment patterns, and duration of treatment Citation Format: Catherine Doyle, Ana Elisa Lohmann, Nayyer Iqbal, Jan-Willem Henning, Swati Kulkarni, Nadia Califaretti, John Hilton, Cristiano Ferrario, Nathaniel Bouganim, Mihaela Mates, Stephanie Guillemette, Ricardo Leite, Stephen Chia. Impact of the introduction of CDK4/6 inhibitors on treatment duration in patients with HR+, HER2– advanced breast cancer: Final analysis of TreatER+ight, a Canadian prospective, real-world, observational study [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 PO2-17-01.

Abstract PS12-08: MORPHEUS Hormone Receptor-Positive Breast Cancer: interim analysis of a Phase Ib/II, study of fulvestrant ± atezolizumab and abemaciclib triplet treatment in patients metastatic disease

Abstract BACKGROUND Endocrine therapy (ET) is the mainstay of treatment for metastatic hormone receptor-positive breast cancer (HR+ BC). ET resistance and disease progression are expected, thus novel therapies, like cancer immunotherapy, are needed. Prior data suggest that abemaciclib (abema), a cyclin-dependent kinase 4/6 (CDK4/6) inhibitor, has immunomodulatory activity. In the MORPHEUS HR+ BC study (NCT03280563), atezolizumab (atezo; anti–programmed death-ligand 1 [PD-L1]) was tested in combination with fulvestrant (FUL), with and without abema, in patients (pts) with HR+ metastatic BC. We present 24-week interim analyses. METHODS Pts with measurable disease progression during first- or second-line therapy for metastatic or inoperable locally advanced HR+ BC and prior treatment with a CDK4/6 inhibitor were randomized to receive FUL (control) or FUL + atezo (1200 mg intravenous every 3 weeks) or FUL + atezo + abema (150 mg twice a day); prior FUL was not permitted. Pts were treated until loss of clinical benefit or unacceptable toxicity. Primary endpoints were objective response rate (ORR) per Response Evaluation Criteria in Solid Tumours (RECIST) v1.1 and safety. Progression-free survival (PFS) was a secondary endpoint. Baseline tumor samples were analyzed for PD-L1 expression (SP263), CD8 T cell infiltration, and gene expression by RNAseq. RESULTS As of Dec 2022, 40, 31, and 25 pts (38, 30, and 20 evaluable pts) were randomized to atezo + abema + FUL, atezo + FUL, and FUL, respectively. Pts were followed for ≥ 24 weeks. Demographics were similar among the groups, with most pts receiving prior palbociclib (palbo) as part of their only prior metastatic therapy. Details and best confirmed ORRs are shown in the table. Median PFS was 6.34 months (95% confidence interval [CI] 5.52, 16.03) in the atezo + abema + FUL arm, 3.15 months (95% CI 1.51, 7.79) in the atezo + FUL arm, and 1.95 months (95% CI 1.45, 4.93) in the FUL arm. The hazard ratio of atezo + abema + FUL vs FUL was 0.43 (95% CI 0.24, 0.78). Safety data are shown in the table. Mild/moderate (grade 1/2) interstitial lung disease (ILD)/pneumonitis (7.7%) was observed in the atezo + abema + FUL arm. At baseline, tumors exhibited low prevalence of PD-L1 (median immune cells: 0.5%, tumor cells: 0%) and CD8 infiltration (12% inflamed phenotype), which did not associate with response in any arm. RNAseq analysis indicated that response to atezo + abema + FUL was strongly associated with low baseline expression levels of proliferation and metabolism signatures and trended with high expression of some immune signatures. CONCLUSIONS The triplet therapy of atezo + abema + FUL showed improved ORR and PFS compared with FUL monotherapy in the second- or third-line setting post-CDK4/6 inhibitor. This combination of atezo + abema + FUL was tolerable, with no unexpected safety signals, including no high-grade ILD/pneumonitis. Efficacy and safety Data are number of patients (%), unless otherwise specified. * Patient was treated in the second line and incorrectly included in this group. Abema, abemaciclib; AE, adverse event; ALT, alanine aminotransferase; AST, aspartate aminotransferase; atezo, atezolizumab; CDK4/6, cyclin-dependent kinase 4/6; CI, confidence interval; ful, fulvestrant; irAE, immune-related adverse event; L, line; ORR, objective response rate; PFS, progression-free survival; TRAE, treatment-related adverse event. Citation Format: Kyung Hae Jung, Seock-Ah Im, Denise Yardley, Sara Hurvitz, Keun Seok Lee, Amir Sonnenblick, Shlomit Shachar, Antoinette Tan, Elizabeth Comen, Einav Gal-Yam, Adam Brufsky, Hope Rugo, Jing Zhu, Kelly DuPree, Vanessa Breton, Fiona Young, Richard Schwab, Edward Cha, Melinda Telli. MORPHEUS Hormone Receptor-Positive Breast Cancer: interim analysis of a Phase Ib/II, study of fulvestrant ± atezolizumab and abemaciclib triplet treatment in patients metastatic disease [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 PS12-08.

Chemotherapy re-use versus anti-angiogenic monotherapy as the third-line treatment of patients with metastatic colorectal cancer: a real-world cohort study

BackgroundThere are various recommendations for third-line treatment in mCRC, however, there is no consensus on who is more suitable for particular strategy. Chemotherapy re-use in third-line setting is a common option in clinical practice. This study aimed to investigate the efficacy of third-line chemotherapy re-use by the comparison with that of anti-angiogenic monotherapy, and further find the population more suitable for third-line chemotherapy.MethodsUsing electronic medical records of patients with mCRC, a retrospective cohort study was conducted. A total of 143 patients receiving chemotherapy and 40 patients receiving anti-angiogenic monotherapy in third-line setting as control group were retrospectively collected. Baseline characteristics were analyzed using the χ² test or the Fisher’s exact test. ROC curve and surv_cutpoint function of ‘survminer’ package in R software were used to calculate the cut-off value. Survival curves were plotted with the Kaplan-Meier method and were compared using the log-rank test. The Cox proportional hazard regression model was used to analyze the potential risk factors.ResultsA total of 143 patients receiving chemotherapy and 40 patients receiving anti-angiogenic monotherapy in third-line setting were retrospectively collected. Chemotherapy rechallenge was recorded in 93 patients (93/143, 65.0%), and the remaining patients chose new chemotherapeutic drugs that had not been previously used, including irinotecan-based (22/50), oxaliplatin-based (9/50), raltitrexed (9/50), gemcitabine (5/50) and other agents (5/50). The ORR and DCR of third-line chemotherapy reached 8.8%, 61.3%, respectively (anti-angiogenic monotherapy group: ORR 2.6%, DCR 47.4%). The mPFS and mOS of patients receiving chemotherapy were 4.9 and 12.0 m, respectively (anti-angiogenic monotherapy group: mPFS 2.7 m, mOS 5.2 m). Subgroup analyses found that patients with RAS/RAF mutation, longer PFS (greater than 10.6 m) in front-line treatment or larger tumor burden had better prognosis with third-line chemotherapy rather than anti-angiogenic monotherapy.ConclusionsThird-line chemotherapy re-use was effective in mCRC. Those with more aggressive characteristics (RAS/RAF mutant, larger tumor burden) or better efficacy of previous chemotherapy (longer PFS) were more appropriate for third-line chemotherapy, rather than anti-angiogenic monotherapy.

Abstract A081: Real-world treatment patterns and clinical outcomes in patients with HER2+ metastatic breast cancer receiving systemic therapy in Ontario, Canada

Abstract Background: Real-world data on treatment patterns and prevalence of brain metastases in patients with HER2+ metastatic breast cancer (mBC) are limited. This study described treatment patterns and clinical outcomes among patients with HER2+ mBC in Canada. Methods: This was a retrospective chart review of adult patients diagnosed with de-novo or recurrent HER2+ mBC between Jan 1, 2014 and Mar 1, 2021 (prior to wide availability of new treatments) at Sunnybrook Research Institute and Sinai Health, two large BC treatment centres in Canada. Data on patient characteristics and treatment regimens were extracted. Treatment patterns, time to next treatment (TTNT; as a proxy for progression-free survival), and presence of brain metastases were assessed in the first-line (1L), second-line (2L), and third-line (3L) settings. TTNT analyses used Kaplan-Meier methodology to account for censoring. Results: Of 121 patients with HER2+ mBC, the median (IQR) age was 54.0 (17.0) years. 38.0% of patients had de-novo disease and 62.0% had recurrent mBC; 12 (9.9%) had brain metastases at the time of mBC diagnosis. Systemic therapies generally aligned with Canadian funded regimens for 1L (101 of 121 patients [83.5%] received trastuzumab + pertuzumab ± chemotherapy ± subsequent endocrine therapy; 8/121 [6.6%] received endocrine therapy only) and 2L (50/68 [73.5%] received T-DM1 ± endocrine therapy; 9/68 [13.2%] received endocrine therapy only). However, treatment patterns were heterogeneous in the 3L setting (14/46 [30.4%] received anti-HER2 TKI + chemotherapy ± trastuzumab; 10/46 [21.7%] received endocrine therapy only; 10/46 [21.7%] received chemotherapy). Median (95% CI) TTNT in months was 21.4 (16.1, 27.2) in 1L, 11.0 (8.5, 16.5) in 2L, and 8.7 (5.4, 15.6) in 3L. Median (IQR) follow-up was 29.9 (25.2) months. In total, 57 patients (47.1%) were diagnosed with brain metastases during the study period (17 pre-1L, 24 post-1L/pre-2L, 6 post-2L/pre-3L) and of these, 73.7% received radiation therapy. Conclusions: In patients with HER2+ mBC in Canada, 3L treatment patterns are heterogeneous, median TTNT is <1 year, and almost half develop brain metastases. These data from two large treating centres in Ontario suggest a high unmet need for more effective treatment regimens in later lines of therapy, particularly 3L, for patients with HER2+ mBC. Citation Format: Katarzyna J Jerzak, Ruth Moulson, Ling-I Hsu, Chris Lenhu, Dhivo Krishnathasan, Jessica Weiss, Christine Brezden-Masley. Real-world treatment patterns and clinical outcomes in patients with HER2+ metastatic breast cancer receiving systemic therapy in Ontario, Canada [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Breast Cancer Research; 2023 Oct 19-22; San Diego, California. Philadelphia (PA): AACR; Cancer Res 2024;84(3 Suppl_1):Abstract nr A081.

A nationwide analysis of the treatment patterns, survival, and medical costs in Korean patients with relapsed or refractory diffuse large B-cell lymphoma.

Approximately one-third of patients with diffuse large B-cell lymphoma (DLBCL) are refractory to treatment or experience relapse after initial therapy. Unfortunately, treatment options for older patients and those who experience relapse or become refractory to hematopoietic stem cell transplantation (HSCT) are limited. This nationwide population-based study aimed to identify treatment patterns, survival times, and treatment costs in patients with relapsed/refractory DLBCL (R/R DLBCL). Between 2011 and 2020, data on patients with R/R DLBCL were retrieved from the Korean Health Insurance Review & Assessment Service, encompassing the entire population. We identified the treatment patterns for each treatment line using a Sankey diagram and calculated the median time to the subsequent treatment in line. Median overall and progression-free survival times were estimated using the Kaplan-Meier survival curves. Finally, the medical costs incurred during DLBCL treatment were calculated for each treatment line and the costs related to HSCT were summarized at the episode level. A total of 864 patients with R/R DLBCL who received second-line treatment were identified, and a regimen of ifosfamide, carboplatin, and etoposide (ICE) was administered the most. Among them, 353 were refractory or relapsed cases that were treated with third-line treatments. The median times for second-line to third-line, third-line to fourth-line, fourth-line to fifth-line, and fifth-line to sixth-line treatment failures gradually decreased (3.93, 2.86, 1.81, and 1.38 months, respectively). The median overall survival time was 8.90 and 4.73 months following the second-line and third-line treatments, respectively. In the third-line treatment setting, the patients did not show a significant difference in survival time after HSCT. The median medical cost was $39,491 across all treatment lines including the cost of HSCT which was $22,054. The treatment patterns in patients with R/R DLBCL, especially at third-line treatments and thereafter, were complicated, and their prognosis was poor despite the high medical costs. Novel and effective treatment options are expected to improve the prognosis and alleviate the economic burden of patients with R/R DLBCL.

Comparing the efficacy of regorafenib and 5-fluorouracil-based rechallenge chemotherapy in the third-line treatment of metastatic colorectal cancer

BackgroundThe optimal treatment for metastatic colorectal cancer (mCRC) after the second line is still controversial. Regorafenib has been the standard of care in this setting as it improved overall survival (OS) compared to placebo. In real-world practice chemotherapy rechallenge is also a preferred option even though supporting evidence is not enough. We aim to compare the efficacy of regorafenib and 5-fluorouracil-based (5-FU) rechallenge treatment in the third line setting of mCRC.MethodsIn this retrospective multi-institutional trial, mCRC patients from 21 oncology centers who progressed after 2 lines of chemotherapy were analyzed. Patients who were treated with regorafenib or rechallenge therapy in the third-line setting were eligible. Rechallenge chemotherapy was identified as the re-use of the 5-FU based regimen which was administered in one of the previous treatment lines. OS, disease control rate (DCR), progression free survival (PFS) and toxicity were analyzed.ResultsThree hundred ninety-four mCRC patients were included in the study. 128 (32.5%) were in the rechallenge, and 266 (67.5%) were in the regorafenib group. Median PFS was 5.82 months in rechallenge and 4 months in regorafenib arms (hazard ratio:1.45,95% CI, p = 0.167). DCR was higher in the rechallenge group than regorafenib (77% vs 49.5%, respectively, p = < 0.001). Median OS after the third-line treatment was 11.99 (95% CI, 9.49–14.49) and 8.08 months (95% CI, 6.88–9.29) for rechallenge and regorafenib groups, respectively (hazard ratio:1.51, 95% CI, p < 0.001). More adverse effects and discontinuation were seen with regorafenib treatment.ConclusionOur study revealed that higher disease control and OS rates were achieved with rechallenge treatment compared to regorafenib, especially in patients who achieved disease control in one of the first two lines of therapy.

Efficacy and safety of immune checkpoint inhibitors in heavily pretreated patients with microsatellite stable metastatic colorectal cancer: a real-world retrospective study.

Immune checkpoint inhibitor (ICI) has changed the situation of anti-tumor therapy. Several phase I/II clinical trials explored ICI-based combinations in microsatellite stable (MSS) metastatic colorectal cancer (mCRC) with mixed outcomes. However, real-world data regarding ICI-based combinations in this population is lacking. This retrospective study aimed to evaluate the efficacy and safety of ICI in MSS mCRC patients in third-line or above setting. A total of 143 eligible patients who received third-line or above ICI monotherapy or ICI-based combinations at the Cancer Center of Renmin Hospital of Wuhan University from June 2019 to April 2024 were included in this study. The primary endpoints were real-world median progression-free survival (PFS) and overall survival (OS), and the secondary endpoints included objective response rate (ORR), disease control rate (DCR), safety and prognostic analyses. Results showed that the median PFS was 4.6 months, and the median OS was 11.8 months, with an ORR of 11.2% and a DCR of 72.7%. ICI plus small molecule tyrosine kinase inhibitors have become the most popular combination for MSS mCRC patients at third-line or above setting with a median PFS of 4.4 months and OS of 10.1 months. The subgroup of patients with liver metastasis had worse clinical outcomes and liver metastasis was an independent prognostic factor for PFS (HR = 2.35, 95% CI, 1.54-3.59; P = 0.000) and OS (HR = 1.77, 95% CI, 1.06-2.96; P = 0.030). Forty-eight patients received cross-line ICI and obtained significantly improved OS (15.8 months vs 10.2 months; HR = 0.59, 95% CI, 0.38-0.89; P = 0.017). No new safety concerns were detected. Grade 3/4 treatment-related adverse events were generally controllable, with an incidence of 39.9%. To conclude, ICI-based combinations provide survival benefits for these heavily pretreated MSS mCRC patients with manageable safety, which is worthy of further study.

An iodine‑labelled Antibody–drug conjugate PET probe for noninvasive monitoring of Nectin-4 expression in urothelial carcinoma

Some kinds of antibody-drug conjugate (ADC) with high affinity to Nectin-4 have demonstrated breakthrough progress in the third-line setting for bladder cancer. However, many patients are still difficult to benefit from treatment based on the heterogeneity of tumour. As the most advanced auxiliary treatment technology, treatment visualization can most intuitively predict the effectiveness of drug treatment, and timely detect the occurrence of drug resistance. Among them, nuclear medicine molecular probes play an important role in this field. 124/125I-EV was prepared by labelling Enfortumad Vedetin (EV), an ADC drugs widely used in clinic targeted Nectin-4, with Na124/125I using N-bromine succinimide as oxidant. The radiochemical purity was analyzed via radio-TLC and bioactivity was measured by enzyme-linked immunosorbent assay. Cell uptake assay and small-animal PET imaging were performed to verified the specificity and targeting. 124/125I-EV was prepared with high labeling yield and radiochemical purity. ELISA assays demonstrated that 124I-EV maintained the same high bioactivity as EV with significantly higher uptake in SW780 cells (Nectin-4 positive, 4.05±0.32%IA/5×105 cells at 8h) than that in T24 cells (Nectin-4 negative, 1.34±0.18%IA/5×105 cells, p<0.001). In PET imaging, 124I-EV had a significantly higher accumulation in SW780 tumour than that in T24 tumour and the uptake in SW780 tumour could be specifically blocked when co-injected with cold EV. The signal-to-noise ratio at the tumour site gradually increased with time, and peaked at 72h. 124I-EV was successfully prepared with high specificity and binding affinity of Nectin-4. This radioactive probe completely simulates the internal circulation of ADC drugs and tumour uptake and retention, which will greatly improve the clinical application of ADC therapy.