Estimated Median Progression-free Survival Research Articles

Anlotinib plus TQB2450, a PD-L1 Antibody, in Patients with Advanced Alveolar Soft Part Sarcoma: a single-arm, phase 2 trial.

Alveolar soft part sarcoma (ASPS) is an ultra-rare soft-tissue sarcoma with a high rate of metastasis and no established treatment. This study aimed to explore the efficacy and safety of anlotinib (a tyrosine-kinase inhibitor) and TQB2450 (a PD-L1 inhibitor) in ASPS patients. This single-arm, phase 2 study evaluated the efficacy of TQB2450, an anti-programmed death ligand 1 (PD-L1) agent, combined with anlotinib, a TKI, in adults with advanced ASPS. TQB2450 was given intravenously (1,200 mg) on day 1, and anlotinib (12 mg/day) was taken orally from day 1 to day 14 every 3 weeks. The primary endpoint was overall response rate, with secondary endpoints including duration of response (DOR), progression-free survival (PFS), and overall survival (OS). Lymphocyte infiltration and tertiary lymphoid structure (TLS) were also analyzed as potential prognostic biomarkers. The study enrolled 29 patients, with 28 evaluable (one withdrew due to acute pancreatitis). An objective response was achieved in 82.1% of patients, including 4 complete and 19 partial responses. The median time to response was 2.8 months, and the DOR was not reached, with an estimated median PFS of 35.2 months. Grade 3-4 treatment-related adverse events occurred in 44.8% of patients, with no study-related deaths. Responders had a higher proportion of TLS area, density, and CD20-positive immune cells. The combination of anlotinib and TQB2450 is effective and tolerable in ASPS patients. TLS may serve as a prognostic biomarker, meriting further investigation.

Southwest Oncology Group S0826: A phase 2 trial of SCH 727965 (NSC 727135, dinaciclib) in patients with stage IV melanoma.

Cell cycle inhibition is an established therapeutic approach for some cancers. A multicenter, single-arm, phase 2 trial (ClinicalTrials.gov identifier NCT00937937) of the cyclin-dependent kinase inhibitor SCH 727965 (NSC 747135; dinaciclib) was conducted in patients with metastatic melanoma to determine its clinical activity. Patients with metastatic melanoma of cutaneous or mucosal origin were eligible if they had zero to one previous treatments, a Zubrod performance status of 0-1, and adequate organ function. SCH 727965 50 mg/m2 was given intravenously every 3 weeks until progression. Co-primary end points were 1-year overall survival (OS) and 6-month progression-free survival (PFS). Seventy-two patients were enrolled from July 1, 2009, to November 1, 2010, at 24 institutions. Sixty-eight percent of patients had M1c disease, and 43% had elevated lactate dehydrogenase levels. Twenty-eight patients (39%) experienced grade 4 adverse events, including 20 cases of neutropenia. Sixty-seven patients were evaluable for response. There was a response in zero of 67 patients (95% confidence interval [CI], 0%-5%), and stable disease was observed in 21%. The estimated median PFS was 1.4 months (95% CI, 1.4-1.5 months), and the 6-month PFS rate was 6% (2%-13%). The median OS was 8.2 months (95% CI, 5.5-10.5 months), and the 1-year OS rate was 38% (95% CI, 26%-49%). This multicenter, US National Cancer Institute Cancer Therapy Evaluation Program-sponsored trial of SCH 727965 was conducted at a time when the current generation of effective therapies for melanoma were not available. Although the null hypothesis of 1-year OS was rejected, the minimal PFS impact and substantive toxicity indicated that this regimen lacks justification for further investigation as a single agent.

Risk of Tumor Progression after Microsurgery for Parasellar Meningioma Invading the Cavernous Sinus.

Parasellar meningiomas, which may invade the cavernous sinus, pose a significant challenge to neurosurgeons due to the high risk of postoperative neurological deficits associated with aggressive resection of the intracavernous part of the tumour. Therefore, subtotal tumour removal followed by observation or radiotherapy for the residual meningioma in the cavernous sinus is recommended. This retrospective study aimed to identify prognostic factors influencing recurrence and progression-free survival (PFS) in parasellar meningiomas invading the cavernous sinus after incomplete surgical treatment. This study included adult patients diagnosed with benign parasellar meningioma (WHO Grade I) invading the cavernous sinus, treated at our institution between 2006 and 2020, and with a postsurgical follow-up of at least 3 years. Surgical treatment involved near-total resection (NTR) with an intracavernous residual tumour or subtotal resection (STR) with additional extracavernous tumour left in place. Kaplan-Meier analysis estimated PFS rates, and Cox regression tested survival time differences between groups. Among the 32 patients, the estimated median PFS was 11 years. Radiotherapy improved 5-year PFS only in patients with STR (p = 0.003). The univariate analysis identified preoperative tumour size, low preoperative Karnofsky Performance Score (KPS), and marked brain oedema as significant factors affecting meningioma progression after surgery. The multivariate analysis confirmed tumour size as an independent factor for progression (p = 0.012). For patients with parasellar meningioma invading the cavernous sinus, extracavernous tumour removal followed by close radiological surveillance of the residual intracavernous meningioma is a safe and appropriate strategy. When an extracavernous tumour component is left, adjuvant stereotactic radiotherapy or radiosurgery is recommended to control tumour growth.

Retro TIMing: A multicentric retrospective analysis of immunotherapy timing in metastatic melanoma.

9542 Background: Immune checkpoint inhibitors (ICI) targeting programmed cell death protein 1 (PD-1) and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) are now the standard of care in the treatment of metastatic melanoma (mM). The interplay between cancer cells and tumor microenvironment cells (e.g. immune cells) impacts cancer cell survival, local invasion, and metastatic dissemination. Chrono-immunotherapy is an emerging field as circadian oscillations are observed in the immune landscape (e.g immune cell numbers) as well as in the expression of immunotherapy targets (e.g. PD-1). Recently, a growing body of evidence suggests the outcome can be influenced by the time of the day when immunotherapy is administered (morning versus in the afternoon). This work aims to evaluate the impact of immunotherapy with ICIs administration timing on the overall survival (OS) and progression-free survival (PFS) of patients with mM. Methods: Multicentric, retrospective cohort study of mM patients under immunotherapy (ipilimumab/nivolumab, nivolumab, or pembrolizumab) with PS 0-1, between July 2016 and June 2023. Clinical, demographic characteristics, and time of treatment administration were obtained from medical records. Patients were distributed in two groups: those who received less than 75% of infusions after 2pm (morning group), and those who received at least 75% of infusions after 2pm (afternoon group). OS and PFS were calculated with Kaplan-Meier method and tested using a Cox regression model, with a 95% confidence interval. Results: We identified 168 patients from the 7 Oncology Centers included. The majority were men (n=100, 59.5%), with a median age of 69 years old, and 22% of the patients (n=37) were included in the afternoon group. No significant demographic or tumor burden differences were found between the morning and afternoon groups. The median follow-up time was 29 months, the estimated median PFS was 11.8 months (CI 95%, 8.0 - 14.6) and median OS was 31.4 months (CI 95%, 20.6 - NR). Patients in the afternoon group presented with shorter OS compared with those in the morning group (14.4 vs 37.6 months; HR 1.94 [CI 95% 1.16 to 3.23]; p 0,014). No statistically significant differences were observed in PFS. Subgroup analysis showed an increased detriment of performing ICIs infusions in the afternoon in women (OS 8.7 (4.2, 21.2) versus 30.9 months (18.9, NR), p=0.002; afternoon versus morning) and those older than 65 years old (OS 14.2 months (4.7, 31.4) versus 24.2 months (18.3, NR), p=0.002); afternoon versus morning). Conclusions: This work provides valuable insights into the potential role of the circadian timing of immunotherapy treatments for mM, suggesting patients may benefit from having ICIs infusion in the morning. Prospective randomized studies with a translational approach are needed to validate and fully understand the underlying mechanisms at play in circadian timing efficacy.

The efficacy and safety of dalpiciclib, a cyclin-dependent kinase 4/6 inhibitor, in patients with advanced head and neck mucosal melanoma harboring CDK4 amplification

BackgroundMucosal melanoma (MM) is a rare but devastating subtype of melanoma. Our previous studies have demonstrated robust anti-tumor effects of cyclin-dependent kinase 4/6 (CDK 4/6) inhibitors in head and neck MM (HNMM) patient-derived xenograft models with CDK4 amplification. Herein, we aimed to investigate the efficacy and safety of dalpiciclib (SHR6390), a CDK4/6 inhibitor, in HNMM patients harboring CDK4 amplification.MethodsThe anti-tumor efficacy of dalpiciclib was assessed by HNMM patient-derived xenograft (PDX) models and patient-derived tumor cells (PDC) in vivo and in vitro. Immunohistochemical analyses and western blot were then performed to assess the markers of cell proliferation and CDK4/6 signaling pathway. For the clinical trial, advanced recurrent and/or metastatic HNMM patients with CDK4 amplification were treated with dalpiciclib 125 mg once daily for 21 consecutive days in 28-day cycles. The primary endpoint was disease control rate (DCR). Secondary endpoints included safety, objective response rate (ORR), progression-free survival (PFS), and overall survival (OS).ResultsDalpiciclib profoundly suppressed growth of HNMM-PDX and PDC with CDK4 amplification, whereas it showed relatively weak suppression in those with CDK4 wild type compared with vehicle. And dalpiciclib resulted in a remarkable reduction in the expression levels of Ki-67 and phosphorylated Rb compared with control group. In the clinical trial, a total of 17 patients were enrolled, and 16 patients were evaluable. The ORR was 6.3%, and the DCR was 81.3%. The estimated median PFS was 9.9 months (95% CI, 4.8-NA), and the median OS was not reached. The rate of OS at 12 months and 24 months was 68.8% (95% CI, 0.494–0.957) and 51.6% (95% CI, 0.307–0.866), respectively. The most frequent adverse events were neutrophil count decrease, white blood cell count decrease, and fatigue.ConclusionsDalpiciclib was well-tolerated and displayed a durable benefit for HNMM patients with CDK4 amplification in this study. Further studies on CDK4 inhibitors and its combination strategy for MM are worth further exploration.Trial registrationChiCTR2000031608.

Safety and Efficacy of the Combination Lurbinectedin plus Doxorubicin from a Phase 1b Trial in Patients with Advanced/Metastatic Soft-Tissue Sarcoma.

While cytotoxic chemotherapy is the standard first-line treatment for patients with metastatic soft-tissue sarcoma (STS), clinical outcomes remain suboptimal. Our prior study showed lurbinectedin plus doxorubicin is well tolerated with promising clinical activity in STS. We designed this phase 1b trial to optimize dosing as the basis for a randomized trial in leiomyosarcoma and to further explore the safety profile and efficacy signal. Patients had advanced/metastatic STS and no prior anthracycline/lurbinectedin/trabectedin. Escalation followed a 3 + 3 design with 3-week cycles: lurbinectedin (3.2 mg/m2 day 1) and two doxorubicin levels (DL1, 25 mg/m2 day 1; DL2, 25 mg/m2 days 1 and 8). The primary objectives were to identify the maximum tolerated dose and recommended dose for subsequent randomized trials. Ten patients were enrolled in a 6-month period. The most common treatment-emergent adverse events were grade (G) 2 fatigue and nausea, and G2 cytopenias with no febrile neutropenia events. There were two dose-limiting toxicities (DLTs) at DL2 [day 8 (G2 alanine aminotransferase [ALT]/aspartate aminotransferase increase, G3 neutropenia)], and one DLT in DL1 (G3 ALT increase). These were reversible and all patients continued the study. DL1 was chosen for further study. At the time of data cutoff, the estimated median progression-free survival is 16.5 months [95% confidence interval (CI), 6.0-ND]. The objective response rate was 60% (6/10 confirmed partial responses). In this phase 1b study, the recommended dose is lurbinectedin 3.2 mg/m2 in combination with doxorubicin 25 mg/m2 every 3 weeks. The study combination was well tolerated and demonstrated intriguing clinical activity.

Cytoreductive nephrectomy in the era of immune checkpoint inhibitors: a US Food and Drug Administration pooled analysis.

This pooled analysis of patient-level data from trials evaluated the clinical outcomes of patients with metastatic renal cell carcinoma with or without cytoreductive nephrectomy before a combination of immune checkpoint inhibitor and antiangiogenic therapy. Data from 5 trials of immune checkpoint inhibitors plus antiangiogenic therapy were pooled. Only patients with stage 4 disease at initial diagnosis were included to ensure that nephrectomy was performed for cytoreductive purposes and not to previously treat an earlier stage of disease. The effect of cytoreductive nephrectomy before immune checkpoint inhibitor therapy on outcomes was evaluated using the Kaplan-Meier method and a Cox proportional hazards regression model, adjusted for age, sex, risk group, performance status, and the presence of sarcomatoid differentiation. A total of 981 patients were included. The estimated median progression-free survival with and without nephrectomy was 15 and 11 months, respectively; the adjusted hazard ratio was 0.71 (95% confidence interval = 0.59 to 0.85). The estimated median overall survival with and without nephrectomy was 46 and 28 months, respectively; the adjusted hazard ratio was 0.63 (95% confidence interval = 0.51 to 0.77). Objective response was 60% of patients with vs 46% of patients without cytoreductive nephrectomy. Patients with metastatic renal cell carcinoma who undergo cytoreductive nephrectomy before immune checkpoint inhibitor plus antiangiogenic therapy had improved outcomes compared with patients without cytoreductive nephrectomy. Selection factors for cytoreductive nephrectomy may be prognostic and could not be fully controlled for in this retrospective analysis. Prospective determination of and stratification by prior cytoreductive nephrectomy may be considered when designing clinical trials to assess the impact of this factor on prognosis.

Treatment Outcomes of Stereotactic Ablative Body Radiotherapy on Extra-cranial Oligometastatic and Oligoprogressive Breast Cancer: Mature Results from a Single Institution Experience

AimsEvidence shows stereotactic ablative body radiotherapy (SABR) is used as a non-invasive ablative therapy in the treatment of multisite oligometastatic (OM) and oligoprogressive (OP) diseases originating from metastatic breast cancer. This study aims to report the treatment outcomes and to investigate what factors that are prognostic in terms of local control, progression-free survival (PFS) and overall survival (OS) in patients receiving SABR for extracranial OM and OP diseases originating from metastatic breast cancer. Materials and methodsA retrospective review on treatment records of patients with OM and OP from metastatic breast cancer who underwent SABR at a single was carried out. SABR was performed with daily image-guided radiotherapy (IGRT) using a dedicated robotic SABR machine. Local control, PFS and OS were calculated using Kaplan-Meier statistics and the post-treatment toxicity data was scored following the CTCAE v4.0 protocol. Univariate and multivariate Cox regression tests were used in the subgroup analysis of prognostic factors on PFS and OS including patients’ age, types of follow-up imaging (staging CT only vs whole-body MR/PET), metastases status (OM vs OP), primary breast cancer tumour grade, hormone receptors (ER/PR/HER2) status, change of systemic treatments at SABR, number of metastases, SABR treatment sites and doses. Results56 metastatic breast cancer patients (38 patients with OM and 18 patients with OP) were involved in this retrospective review. The median follow-up was 35.6 months (range 4.0–132.9 months). The estimated local control at 1 , 2 and 5 years were 90.9%, 88.7% and 88.7%, respectively. The estimated median PFS was 19.2 months (95%CI 10.3–28.1 months); the PFS at 1, 2 and 5 years were 63.3%, 44.4% and 33.2%. The estimated OS at 1, 2 and 5 years were 98.0%, 91.9% and 74.3%, respectively with the estimated median OS of 105.1 months (95%CI 51.5–158.7 months). The vast majority of patients tolerated the treatment well with the commonest acute side effects as grade 1 fatigue. There were no statistically significant factors found in OS regression analysis. The types of follow-up imaging, metastases status, oestrogen receptor status, and number of metastases for SABR were statistically significant factors (p < 0.05) in the multivariate Cox regression analysis on PFS. ConclusionThere are limited studies published on the efficacy and post-treatment toxicities of metastatic breast cancer OM and OP SABR with adequate length of follow-up. This study confirmed that SABR was a safe, non-invasive treatment option for patients with extracranial OM and OP diseases originated from primary breast cancer in terms of the acceptable post-treatment toxicities.

Early clearance of hairy cell leukaemia in the bone marrow after first-line treatment with cladribine predicts a favourable outcome.

First-line purine nucleoside analogues (PNAs) in hairy cell leukaemia (HCL) allow deep and long-lasting responses. We retrospectively analysed 53 HCL patients treated frontline with cladribine and assessed for response at 2 and 6 months after treatment to evaluate the kinetics of response. The estimated median progression-free survival was significantly different according to the degree of residual HCL infiltrate detected by immunohistochemistry at the bone marrow biopsy at 2 months (≤5% vs. >5%, 247 vs. 132 months, respectively, p = 0.033), but not at 6 months (p = 0.79). Our data suggest a favourable prognostic impact of early marrow HCL clearance in patients treated with cladribine.

A Retrospective Chart Review of Treatment Patterns and Overall Survival among a Cohort of Patients with Relapsed/Refractory Mycosis Fungoides in France, Germany, Italy, Spain and the United Kingdom

(1) Background: Most patients with mycosis fungoides (MF), a form of cutaneous T-cell lymphoma (CTCL), develop relapsed/refractory (R/R) disease following front-line systemic therapy. This report describes treatment patterns and outcomes from the subpopulation with R/R MF. (2) Methods: This observational, retrospective, cohort study analyzed patient records (1984–2016) from 27 clinical sites in Europe. Outcomes included treatments received, response to first-, second- and third-line treatment, overall survival (OS) and progression-free survival (PFS). (3) Results: Of 104 patients with MF, 100 received second-line and 61 received third-line therapy. The median (range) times from the start of first-line therapy to the first R/R MF and from the first to the second R/R MF were 11.2 (0.3–166.5) and 13.5 (0.0–174.6) months, respectively. Second-and third-line treatment options varied and comprised systemic therapies (85% and 79% of patients, respectively), radiotherapy (32% and 34%, respectively) and topical therapies (48% and 36%, respectively). The median (95% confidence interval [CI]) OS from the diagnosis of the first R/R MF was 11.5 (6.5–not reached [NR]) years and was higher with non-chemotherapy (NR) versus chemotherapy (6.5 years); the estimated median PFS (95% CI) from the time of the first R/R MF was 1.3 (1.0–2.1) years. (4) Conclusions: High rates of R/R disease were observed after second- and third-line treatments in this real-world cohort, with longer median OS in patients receiving non-chemotherapy treatment versus chemotherapy. Following the standard management of MF and using recently approved targeted therapies can help improve patient outcomes in advanced-stage MF.

Outcomes of Salvage VDT-PACE-like Regimens in Relapsed-Refractory Multiple Myeloma: 10-Year Experience of a Large Academic Institution

Introduction: Rapidly evolving therapies for multiple myeloma (MM) have drastically changed the treatment landscape over the last decade. Despite the introduction of novel agents into clinical practice, MM remains challenging to treat in the setting of aggressive relapse and/or multi-refractory disease, accompanied by high tumor burden and extramedullary sites. Intensive chemotherapy with VDT-PACE (bortezomib, dexamethasone, thalidomide, cisplatin, doxorubicin, cyclophosphamide, etoposide)-like regimens may be used for a limited number of cycles as a bridging regimen to quickly achieve cytoreduction. This study aimed to evaluate outcomes of patients treated with VDT-PACE-like regimens (VPRs) for relapsed-refractory MM (RRMM) at our center. Methods: We retrospectively analyzed medical records of patients with RRMM who were treated with VPRs at our institution between 1/1/2013 and 6/1/2023. Responses including complete response (CR), very good partial response (VGPR), partial response (PR) and minimal response (MR) were measured according to the International Myeloma Working Group (IMWG) criteria. Baseline characteristics were outlined by descriptive analysis. Kaplan-Meier method was used for progression free survival (PFS), and overall survival (OS) calculations. Patients were censored in PFS analysis if they started another therapy before progression. Results: A total of 93 patients with RRMM were included in this analysis. Median age was 59 (range 42-84) years, 41% were female and 82% were White. The median number of prior lines of therapy was 6 (range 1-17) and median percentage of bone marrow plasma cells prior to VPRs initiation was 70%. Of the entire cohort, 60% of patients had high risk cytogenetics and 27% had plasma cell leukemia; other baseline patient and disease characteristics are summarized in Table 1. Patients received a median of 1 cycle (range 1-4) of VPRs; 37% received &amp;gt;2 cycles of treatment. After completion of cycle 1, VGPR or better, PR, and MR were achieved in 25 (27%), 30 (32%) and 11 (12%) patients, respectively. The estimated median PFS was 4 months (95% Cl, 2.8 - not reached [NR]) and the estimated median OS was 7 months (95% Cl, 5-8) from VPRs initiation (Figure 1). Among the 72 patients who received further treatment post VPRs completion, 19% underwent autologous hematopoietic cell transplant (AHCT), 70% were switched to another plasma cell-directed therapy, and 11% received chimeric antigen receptor T (CAR T)-cell therapy as the next line of therapy. The remaining 21 patients were transitioned to hospice immediately following VPRs, or died prior to receiving next line of therapy due to disease progression. Thirty-eight patients (41%) were readmitted after cycle 1 due to complications; median number of readmissions was 1 (range 1-4), and median cumulative duration of inpatient hospital stay was 7.5 (range 1-42) days. Severe neutropenia (defined as neutrophilic count &amp;lt;500 x10 9/L) and severe thrombocytopenia (defined as platelet count &amp;lt;25 x10 9/L) were seen in 57 (61%) and 43 (46%) patients, respectively after cycle 1, and 28 (30%) patients developed neutropenic fever. Conclusion: VPRs are feasible salvage treatment options in RRMM patients with aggressive and multi agent-refractory disease. Most patients responded to VPRs bridge therapy and were able to transition to autologous hematopoietic cell transplant, CAR T-cell therapy or other less toxic plasma-cell directed regimens. Despite that, the median overall survival of the entire cohort was short indicating that VPRs might not be able to reverse the poor prognosis of highly aggressive RRMM disease.

A Cohort Study of the Antitumor Efficacy and Toxicity Profile of Alpelisib for Metastatic or Locally Advanced HR+, HER2− Breast Cancer: A Single-Institution Experience

Introduction: Alpelisib is approved in combination with endocrine therapy (ET) to treat patients with hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2−) progressive metastatic breast cancer (MBC). The SOLAR-1 trial demonstrated the efficacy of this oral agent and showed that, while alpelisib improves outcomes compared to placebo, it is also associated with clinically relevant adverse events (AEs). There is a pressing need for improved knowledge on the effectiveness and tolerability of this agent in real-world patient populations. Methods: We conducted a retrospective cohort study of patients with HR+, HER2− MBC treated with alpelisib and ET. We assessed the safety, tolerability, and effectiveness of alpelisib in a real-world population. Deidentified patient-, tumor-, and outcome-related data, including AEs, were collected and summarized. Kaplan-Meier methods were applied for survival analyses, and stratified analyses of interest were conducted. A p value <0.05 was considered statistically significant. Results: A total of 76 women treated with alpelisib + ET were included in our cohort. Most had been previously treated with cyclin-dependent kinase (CDK) 4/6 inhibitors and chemotherapy for MBC. The estimated median progression-free survival was 5.2 months (95% CI, 4.1–8.0). The median overall survival was longer among patients without prior everolimus therapy (hazard ratio, 4.28 [95% CI, 1.64–11.16]; p = 0.0012), and no significant outcome differences were observed between patients treated with different starting doses of alpelisib. Approximately 31.6% of patients permanently discontinued alpelisib due to AEs, and 32.9% had at least one dose reduction. The most common grade 3/4 AEs were hyperglycemia (21%), fatigue (13.2%), and diarrhea (10.5%). Conclusions: For progressive HR+, HER2− MBC, alpelisib + ET showed effectiveness in a real-world patient population that was comparable to published clinical trial data, regardless of starting dose. However, the effectiveness of alpelisib following previous everolimus exposure may be limited and, hence, should be a consideration to decide sequencing of therapy in these patients. Patients treated with alpelisib are at risk for clinically relevant AEs and require close monitoring.

Outcomes of Patients with Relapsed/Refractory Multiple Myeloma Who Received at Least 2 BCMA-Directed Therapies

Introduction:In recent years, many B-cell maturation antigen (BCMA) directed therapies (BDT) have demonstrated clinical response in heavily treated relapsed/refractory multiple myeloma (RRMM). These therapies include antibody-drug conjugates (ADC), chimeric antigen receptors (CAR-T), T-cell engaging bispecific antibodies (BsAb), and BCMA monoclonal antibodies (MoAb). BDT represents a breakthrough in the treatment of heavily treated RRMM. While these agents have led to deep responses and remissions, they have not been curative and many patients are exposed to more than one BDT. Optimal sequencing of BDT and outcomes in patients who received 2 or more BDT is not well understood. Our study aims to address these questions in this population. Methods: A retrospective review of 39 patients with RRMM that received 2 or more types of BDTs at the University of Kansas Medical Center, in collaboration with the U.S Myeloma Innovations Research Collaborative (USMIRC), as of 7/10/2023 was completed. Responses to therapy including overall response rate (ORR), complete response or better (&amp;gt;CR), and very good partial response (VGPR) were evaluated using the International Myeloma Working Group (IMWG) criteria. The Kaplan-Meier method was used for progression free survival (PFS) and overall survival (OS) assessments. OS was calculated from exposure of 1 st BDT till the last office visit/death. Regression models for univariate and multivariate analysis were performed. Results: Patients were previously treated with a median of 7 (4-12) prior lines of therapy before 2 nd BDT; 75% were Caucasians, 69% had IgG isotype, 74% had high-risk cytogenetics, and 51% had extramedullary disease (EMD). All patients were triple-class exposed, 95% were triple-class refractory, 82% were penta-class exposed and 74% were penta-class refractory, only 15% received 3 different types of BDTs. Median time between relapse after 1 st BDT to initiation of 2 nd BDT was 4 (0.5-33) months. Baseline characteristics are summarized in Table 1. Median follow-up was 19.4 (11.5-NR) months for the entire cohort. The most common first BDT were CAR-T and ADC (n=15, 38% and n=12, 31%), respectively. Whilethe most common second BDT were BsAb and CAR-T (n=17, 44% and n=13, 33%), respectively. The ORR after 1 st BDT and 2 nd BDT was 54% and 54%, respectively. The responses after 1 st BDT and 2 nd BDT were found to be deep (41% ≥VGPR, 36% ≥CR) and (44% ≥VGPR; 23% ≥CR), respectively. Detailed responses for the groups of interest are reported separately in Figure 1. The estimated median PFS for 1 st BDT was 5.8 months (95% CI 2.8-9.5) while for 2 nd BDT it was 5.2 months (95% CI 1.77-NA). Median OS from exposure to 1 st BDT was 19.5 months (95% CI 16.7-NA). At the time of data cut-off, 51% of patients had died with 90% of deaths were due to disease progression. Conclusions: This is one of the first reports on outcomes with second BDT in RRMM. Despite a heavily pre-treated patient population, 2 nd treatment with a BDT resulted in deep and durable responses, similar to treatment with 1 st BDT. Progression free survival was similar with 1 st and 2 nd BDT exposure. While our study is limited by a small population, our results support the use of a different type of BDT at progression even if previously exposed to a BCMA targeting agent. Further studies are needed to provide more guidance on appropriate sequencing of BDTs.

Camrelizumab Plus Apatinib and Temozolomide as First-Line Treatment in Patients With Advanced Acral Melanoma

Acral melanoma, known for low tumor mutation burden, responds poorly to immunotherapy. A standard therapy is still lacking. To investigate the activity and safety of camrelizumab (an anti-programmed cell death-1 antibody) plus apatinib (a vascular endothelial growth factor receptor 2 inhibitor) and temozolomide as first-line treatment in patients with advanced acral melanoma. In this single-arm, single-center, phase 2 nonrandomized clinical trial, patients with treatment-naive unresectable stage III or IV acral melanoma were enrolled at Peking University Cancer Hospital and Institute between June 4, 2020, and August 24, 2021. The data cutoff date was April 10, 2022. Patients received 4-week cycles of intravenous camrelizumab, 200 mg, every 2 weeks; oral apatinib 250 mg, once daily; and intravenous temozolomide, 200 mg/m2, once daily on days 1 to 5 until disease progression or unacceptable toxic effects. The primary end point was objective response rate as assessed by investigators according to the Response Evaluation Criteria In Solid Tumors (version 1.1). Secondary end points included progression-free survival, time to response, duration of response, disease control rate, overall survival, and safety. A total of 50 patients (32 men [64%]; median age, 57 years [IQR, 52-62 years]) were enrolled and received treatment. The median follow-up duration was 13.4 months (IQR, 9.6-16.2 months). The objective response rate was 64.0% (32 of 50; 95% CI, 49.2%-77.1%). The median time to response and duration of response were 2.7 months (IQR, 0.9-2.9 months) and 17.5 months (95% CI, 12.0 to not reached), respectively. The disease control rate was 88.0% (44 of 50; 95% CI, 75.7%-95.5%). The estimated median progression-free survival was 18.4 months (95% CI, 10.6 to not reached). The median overall survival was not reached. The most common grade 3 or 4 treatment-related adverse events were increased gamma-glutamyltransferase levels (15 [30%]), decreased neutrophil count (11 [22%]), increased conjugated bilirubin levels (10 [20%]), and increased aspartate aminotransferase levels (10 [20%]). No treatment-related deaths occurred. The findings of this nonrandomized clinical trial suggest that camrelizumab plus apatinib and temozolomide may be a potential first-line treatment option for patients with advanced acral melanoma, which warrants further validation in a randomized clinical trial. ClinicalTrials.gov Identifier: NCT04397770.

Cemiplimab in first line treatment for locally advanced and metastatic skin squamous cell carcinoma in Slovenia.

e21531 Background: Cemiplimab is a first PD1 inhibitor for treatment of locally advanced cutaneous squamous cell carcinoma (laSCC) and metastatic SCC (mSCC). The purpose of this study is to report outcomes of patients with SCC, treated with cemiplimab in routine clinical practice in Slovenia in twenty-month period. Methods: In this retrospective cohort study we analyzed medical records of patients with laSCC and mSCC inappropriate for surgery or radiotherapy treated with cemiplimab in first line between May 2020 and November 2022. The baseline characteristics, outcomes, immune related adverse events (irAE). Results: 28 patients were included, 24 with laSCC and 4 with mSCC, with a median age of 76.1 years. Of them, 18 % (5 patients) a concomitant autoimmune disease. The estimated median progression-free survival (PFS) was 4.4 months (95% CI: 1.5–7.3). The median overall survival (OS) was 7.3 months (95% CI: 4.6–9.9). Among 27 treated patients with an evaluable response, 3 (11 %) achieved complete response, 5 (19 %) achieved partial response, 6 (22 %) had stable disease and 13 (48 %) patients experienced a progressive disease. The overall response rate (ORR) was 30 %, and the disease control rate (DCR) was 52 %. A quarter of all patients had at least one immune related adverse events (irAEs). Only one patient had grade 3 event, there were no grade 4 and no fatal events. Higher response rate was achieved in patients with irAE – ORR was 43 % and DCR was 71 %. Seven patients are still on cemiplimab. Conclusions: Cemiplimab has shown meaningful efficacy with DCR of 52 % in patients with laSCC and mSCC in Slovenia. Patients developing irAE had higher response rate.

Safety and efficacy of CRISPR-based non-viral PD1 locus specifically integrated anti-CD19 CAR-T cells in patients with relapsed or refractory Non-Hodgkin's lymphoma: a first-in-human phase I study.

Thus far, all approved chimeric antigen receptor (CAR)-T products are manufactured using modified viruses, which increases the risk of tumorigenesis, costs and production time. We aimed to evaluate the safety and efficacy of a kind of virus-free CAR-T cells (PD1-19bbz), in which an anti-CD19 CAR sequence is specifically integrated at the PD1 locus using clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9, in adults with relapsed/refractory (r/r) B cell non-Hodgkin's lymphoma (B-NHL). This single-arm phase I dose-escalation clinical trial evaluated PD1-19bbz in adult patients with r/r B-NHL from May 3rd 2020 to August 10th 2021. The patients were recruited and treated at the First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China. Patients underwent leukapheresis and lymphodepleting chemotherapy before PD1-19bbz infusion. After the dose-escalation phase including three cohorts: 2×106/kg, 4×106/kg, 6×106/kg with three patients at each dose level, the optimal biological dose was determined to be 2×106/kg, which was then applied to an extended cohort of nine patients. The primary endpoint was the incidence of dose-limiting toxicities (DLT). The secondary endpoint was the response and survival. This trial was registered at www.clinicaltrials.gov as #NCT04213469. Twenty-one patients received PD1-19bbz infusion. Among all treated patients, 19 (90%) patients were diagnosed with stage III or IV disease. Meanwhile, 19 (90%) were stratified as intermediate risk or worse. Of note, four participants had >50% programmed death ligand-1 (PD-L1) expression in pre-treatment tumour sample, including two with extremely high levels (∼80%). There was no DLT identified. Fourteen patients had low-grade (1-2) cytokine release syndrome and two patients received tocilizumab. Four patients experienced immune effector cell-associated neurotoxicity syndrome of grade 1-2. The most common adverse events were hematologic toxicities, including anaemia (n=6), lymphocyte count decreased (n=19), neutrophil count decreased (n=17), white blood cell count decreased (n=10), and platelet count decreased (n=2). All patients had objective response and 18 patients reached complete response. At a median follow-up of 19.2 months, nine patients remained in remission, and the estimated median progression-free survival duration was 19.5 months (95% confidence interval: 9.9-infinity), with the median overall survival not reached. In this first-in-human study of non-viral specifically integrated CAR-T products, PD1-19bbz exhibited promising efficacy with a manageable toxicity profile. A phase I/II trial of PD1-19bbz in a larger patient cohort is underway. National Key R&D Program of China, National Natural Science Foundation of China, Key Project of Science and Technology Department of Zhejiang Province, Shanghai Zhangjiang National Independent Innovation Demonstration Area, Key Projects of Special Development Funds.

Radiofrequency and microwave ablation controls hepatic oligoprogression of advanced gastroenteropancreatic neuroendocrine tumors.

In progression of multifocal liver metastases of gastroenteropancreatic neuroendocrine tumors (GEP-NET) escalation of systemic therapy is indicated. The aim of this retrospective study was to investigate the potential of local thermal ablation in hepatic oligoprogression and otherwise stable disease in GEP-NET. Patients with hepatic oligoprogression and otherwise stable disease, who underwent radiofrequency ablation (RFA) or microwave ablation (MWA) for local control, were included in the study. Thermal ablation was performed while maintaining the ongoing systemic therapy or without addition of a systemic therapy. The effectiveness of this therapeutic approach was evaluated by determination of local treatment success, improvement of progression-free survival (PFS) and the safety. Seventeen thermal ablation procedures were performed in 13 patients with well differentiated NET including seven ileum NET, four pancreatic NET, one appendix NET and one rectum NET. RFA and MWA of liver metastases were well tolerated without major complications. Thermal ablation resulted in an estimated median PFS of 62.6 weeks (mean 50.5 weeks; range 10.1-78.9 weeks) per procedure. In four patients, two ablation procedures were performed throughout the course of their disease resulting in an estimated median PFS of 69.1 weeks (mean 71.6 weeks; range 10.1-123.1 weeks) per patient. Start or change of systemic therapy could be delayed up to 123.1 weeks by using thermal ablations for isolated progression of single liver metastases. 88% of thermal ablations prolonged PFS. Thermal ablation of liver metastases in a non-curative intent has the potential to provide focal growth control and to prolong PFS in GEP-NET patients with hepatic oligoprogression.

Biomarkers for Outcome in Metastatic Melanoma in First Line Treatment with Immune Checkpoint Inhibitors.

A high proportion of metastatic melanoma patients do not respond to immune checkpoint inhibitors (ICI), and until now, no validated biomarkers for response and survival have been known. We performed a retrospective analysis of outcomes in patients with metastatic melanoma treated with first-line ICI at the Institute of Oncology Ljubljana from January 2018 to December 2020. The immune-related adverse events (irAEs) and serum immune-inflammation parameters (neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (LR), systemic immune-inflammation index (SII) and pan-immune-inflammation value (PIV)) were analyzed as potential biomarkers for response and survival. Survival rates were calculated using the Kaplan-Meier method and then compared with the log-rank test. Multivariate regression Cox analysis was used to determine independent prognostic factors for progression-free survival (PFS) and overall survival (OS). Median follow-up was 22.5 months. The estimated median progression-free survival (PFS) was 15 months (95% CI 3.3-26.2). The two-year survival rate (OS) was 66.6%. Among 129 treated patients, 24 (18.6%) achieved complete response, 28 (21.7%) achieved partial response, 26 (20.2%) had stable disease and 51 (39.5%) patients experienced a progressive disease. There was a higher response rate in patients with irAEs (p < 0.001) and high NLR before the second cycle of ICI (p = 0.052). Independent prognostic factors for PFS were irAE (HR 0.41 (95% CI 0.23-0.71)), SII before the first cycle of ICI (HR 1.94 (95% CI 1.09-3.45)) and PLR before the second cycle of ICI (HR 1.71 (95% CI 1.03-2.83)). The only independent prognostic factor for OS was SII before the first cycle of ICI (HR 2.60 (95% CI 0.91-7.50)). Patients with high pre-treatment levels of SII had a higher risk of progression and death; however, patients with irAEs in the high-SII group might respond well to ICI. Patients who develop irAEs and have high NLRs before the second ICI application have higher rates of CR and PR, which implicates their use as early biomarkers for responsiveness to ICI.

Abstract P3-01-04: A real-world evidence study of everolimus plus endocrine therapy beyond CDK4/6 inhibitors for HR+/HER2- advanced breast cancer

Abstract Introduction Since the approval a decade ago of everolimus in combination with endocrine therapy (ET), the treatment landscape of metastatic breast cancer (mBC) has changed dramatically. Endocrine monotherapy after progression to CDK4/6 inhibitors has shown a limited progression-free survival (PFS) below 3 months. Evidence of the efficacy of everolimus plus ET after CDK4/6 inhibitors is scarce. Methods We performed a retrospective observational study of patients with mBC treated with everolimus between September 2011 and April 2022 in 4 Spanish hospitals. Clinical and demographic data were collected from medical records. Our main objective was to estimate the median progression-free survival (mPFS) for everolimus + ET in patients previously treated with a CDK4/6 inhibitor. We also collected the adverse events (AE) related to everolimus. Quantitative variables were summarized with medians (range), and qualitative variables with proportions. We used the Kaplan-Meier method for survival estimates. Results We identified a total of 297 mBC patients treated with everolimus plus ET. The median follow-up time was 20 months (interquartile range: 1 – 97 months). In this cohort, the median age at diagnosis was 49 years (26 – 84 years). At the moment of starting everolimus, the median number of previous lines of treatment was 2 (0 – 12), 22% of patients were ‘de novo’ metastatic, 67% presented visceral involvement, 40% had received previous chemotherapy for advanced disease, and 51% (n=152) had received a previous CDK4/6 inhibitor. The ET combined with everolimus was exemestane (77%), fulvestrant (18%), and tamoxifen (5%). 45% of patients were alive at data cut-off. In patients previously treated with a CDK4/6 inhibitor, the estimated median PFS (mPFS) was 5.9 months (95%CI: 5.0 – 7.8 months). In patients without visceral involvement (n=52), mPFS was 7.2 months (95%CI: 5.5 – 11.0 months), and 5.6 months (95%CI: 3.9 – 7.8 months) in the presence of visceral metastasis (n=100). In patients without previous chemotherapy in the metastatic setting (n=109), mPFS was 7.2 months (95%CI: 5.9 – 8.4 months), and 4.6 months (95%CI: 3.1 – 5.7 months) for patients who had received previous chemotherapy (n=43). For patients without a previous CDK4/6 inhibitor (n=145), the median PFS was 8.3 months (95%CI: 6.4 – 10.3 months). Everolimus starting doses were 10 mg (83%), 5 mg (15%), and 7.5 mg (2%). Dexamethasone mouthwash was used by 44% of patients. The most frequent AE were mucositis (51%; 3% grade 3), anemia (41%; 3% grade 3), hyperglycemia (34%; 2% grade 3), rash (28%; 2% grade 3), neumonitis (21%; 2% grade 3), and diarrhea (17%; 1% grade 3). There were no grade 4-5 adverse events. Dose reduction was made in 35% of patients, and in 16% of patients the treatment was discontinued due to toxicity. Conclusions In our cohort, the use of everolimus plus ET in mBC patients previously treated with a CDK4/6 inhibitor showed a clinically significant benefit in terms of PFS, especially in patients without visceral metastasis, and no previous chemotherapy for advanced disease. In this real-world study, the toxicity profile of everolimus was manageable. Citation Format: Rodrigo Sánchez-Bayona, Manuel Alva, Alfonso López de sa, Yolanda Jerez Gilarranz, Ana Sánchez de torre, Pablo Tolosa, Alicia de luna, Sara López-Tarruella, Laura Lema, Fernando Moreno, Isabel Echavarria, Ainhoa Madariaga, Javier Benítez, Blanca Herrero, Macarena Rey, Justo Ortega, Salvador Gámez, Andrea Modrego, Rocío Martín Lozano, Luis Figuero-Pérez, Roberto Jiménez, Marta González Sevilla, Irene González, Marianela Bringas Beranek, María de toro, Tatiana Massarrah, María del Monte-Millán, Marina Pinardo, Luis Manso, Coralia Bueno-Muiño, José Ángel García-Sáenz, Miguel Martín, Eva Ciruelos. A real-world evidence study of everolimus plus endocrine therapy beyond CDK4/6 inhibitors for HR+/HER2- advanced breast cancer. [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P3-01-04.

Survival benefit and biomarker analysis of pyrotinib or pyrotinib plus capecitabine for patients with HER2-positive metastatic breast cancer: a pooled analysis of two phase I studies

BackgroundPyrotinib, a novel irreversible tyrosine kinase inhibitor (TKI), has demonstrated promising antitumor activity to improve the overall response rate and progression-free survival (PFS) in patients with HER2-positive metastatic breast cancer (MBC). However, the survival data of pyrotinib or pyrotinib plus capecitabine in HER2-positive MBC remains scarce. Thus, we summarized the updated individual patient data from the phase I trials of pyrotinib or pyrotinib plus capecitabine, to provide a cumulative assessment on long-term outcomes and associated biomarker analysis of irreversible TKIs in HER2-positive MBC patients.MethodsWe performed a pooled analysis of the phase I trials for pyrotinib or pyrotinib plus capecitabine based on the updated survival data from individual patients. Next-generation sequencing was performed on circulating tumor DNA for predictive biomarkers.ResultsA total of 66 patients were enrolled, including 38 patients from the phase Ib trial for pyrotinib and 28 patients from the phase Ic trial for pyrotinib plus capecitabine. The median follow-up duration was 84.2 months (95% CI: 74.7–93.7 months). The estimated median PFS in the entire cohort was 9.2 months (95% CI: 5.4–12.9 months) and median OS was 31.0 months (95% CI: 16.5–45.5 months). The median PFS was 8.2 months in the pyrotinib monotherapy cohort and 22.1 months in the pyrotinib plus capecitabine group, while the median OS was 27.1 months in the pyrotinib monotherapy group and 37.4 months in the pyrotinib plus capecitabine group. Biomarker analysis suggested that the patients harbored concomitant mutations from multiple pathways in HER2-related signaling network (HER2 bypass signaling pathways, PI3K/Akt/mTOR pathway and TP53) were observed with significantly poorer PFS and OS when compared to those with none or one genetic alteration (median PFS, 7.3 vs. 26.1 months, P = 0.003; median OS, 25.1 vs. 48.0 months, P = 0.013).ConclusionsThe updated survival results based on individual patient data from the phase I trials of pyrotinib-based regimen revealed promising PFS and OS in HER2-positive MBC. Concomitant mutations from multiple pathways in HER2-related signaling network may be a potential efficacy and prognosis biomarker for pyrotinib in HER2-positive MBC.Trial registrationClinicalTrials.gov. (NCT01937689, NCT02361112).