First-Line Treatment Of Cancer Research Articles

Pegylated liposomal doxorubicin and carboplatin versus paclitaxel and carboplatin as first-line treatment for Chinese patients with ovarian cancer: A multi-center, randomized, open-label trial.

5556 Background: Paclitaxel combined with carboplatin is a standard first-line chemotherapy regimen for ovarian cancer. This study was designed to evaluate the efficacy and safety of pegylated liposomal doxorubicin (PLD) plus carboplatin (CD) compared with paclitaxel plus carboplatin (CP) as first-line treatment for epithelial ovarian cancer (EOC). Methods: Patients with stage IC to IV EOC, fallopian tube cancer, or primary peritoneal cancer were eligible for enrolment in this open-label, randomized controlled trial at 20 centers in China. Patients were randomly assigned 1:1 to CD group (carboplatin area under the curve [AUC] 5 plus PLD 30 mg/m2) or CP group (carboplatin AUC 5 plus paclitaxel 175 mg/m2) every 3 weeks for 3-6 cycles. The primary end point was progression free survival (PFS); secondary end points were overall survival (OS), objective response rate (ORR), disease control rate (DCR) and safety. Results: Between March, 2019 to December, 2021, 395 patients were enrolled, of whom 391 patients were analyzed (195 assigned to CD, 196 to CP). Baseline characteristics were balanced between the two treatment groups. The median follow-up was 21.6 months for the CD group and 22.5 months for the CP group. There was no significant difference in PFS between the two arms (P=0.516); the median PFS was 28.1 months and 30.1 months in the CD and CP arms, respectively. OS data were immature at data cutoff, with a total of 26 deaths in the two treatment groups. In patients with at least one measurable lesion at baseline, ORR was 65.5% in the CD arm and 66.2% in the CP arm (P= 0.941); DCR was 74.1% and 73.8% in the CD and CP arms, respectively (P= 0.971). Among patients who were evaluable by GCIG CA125 criteria, CA125 response was obtained in 86.0% and 88.5% of patients in the CD and CP arms, respectively (P=0.560). More frequent grade 1 to 3 alopecia (32.1% vs 12.3%) and neurotoxicity (20.4% vs 0%) were observed in the CP arm; more hand-foot syndrome (grade 1 to 3, 10.8% vs 2.6%), and oral mucositis (grade 1-3, 12.8% vs 5.1%) in the CD arm. Conclusions: The efficacy of CD regimen is comparable to that of CP, with less alopecia and neurotoxicity. CD may be an alternative first-line treatment for EOC. However, survival data are not yet mature, and longer follow-up is needed. Clinical trial information: NCT03794778 .

The prognostic impact of NKA dynamics in first-line treatment of metastatic colorectal cancer.

e15514 Background: Metastatic colorectal cancer (mCRC) remains a therapeutic challenge and new markers hold high priority. Natural Killer (NK) cells are immune cells with potent antitumor properties. The association between neoplastic development and level of effector functions of this cell type is well known. Moreover, it is recognized that NK cells are subject to tumor-mediated immune suppression. The present study aimed at elucidating a potential relationship between NK cell activity (NKA) and response to folinic acid, 5-fluorouracil, oxaliplatin, and irinotecan (FOLFOXIRI) in mCRC. Methods: NKA was analyzed in patients enrolled in a randomized trial of mCRC receiving FOLFOXIRI and either tocotrienol or placebo as first-line treatment. Blood (1 mL) was sampled into NK Vue tubes at baseline and before treatment cycles 2-3, placed at 37°C for 24 hours, and after incubation, the level of interferon-γ (IFNγ) in the plasma was a surrogate measure for NKA. A cutoff of 250 pg/mL IFNγ distinguished normal and low NKA. The endpoints were response rate (RR), progression-free survival (PFS), and overall survival (OS). Results: A total of 70 patients were enrolled in the randomized clinical trial. The results showed that tocotrienol had no effect on either RR (p = 0.62), PFS (p = 0.52), or OS (p = 0.80). Patients were classified into two groups according to the dynamics of NKA measured at the available time points. Patients that dropped from a normal to a low level of NKA in samples taken between baseline and before cycle 3 and patients with continuous low NKA (IFNγ < 250 pg/mL) were categorized as NKA-low. The NKA-high group included patients that increased from an abnormal to a normal level of NKA and patients that remained within the normal range (IFNγ > 250pg/mL) in all available samples. The RR in the two groups were 38% (8/21) and 69% (24/35), respectively (p = 0.0496). The median PFS was 186 days (95% confidence interval (CI) 136-225 days, n = 23) for the NKA-low group and 252 days (95% CI 223-305 days, n = 37) for NKA-high (p = 0.0005). The hazard ratio (HR) was 2.65 (95% CI 1.28-5.50). After adjusting for age, performance status (PS), and tumor location, NKA remained an independent prognostic factor for PFS (HR = 3.32, 95% CI 1.67-6.61, p = 0.001). Median OS was 408 days (95% CI 219-679 days, n = 23) and 1051 days (95% CI 645-1225 days, n = 37), respectively (p = 0.0034). For OS, the NKA-low group also showed a poor prognosis, HR 2.23 (95% CI 1.17-4.25). NKA dynamics remained an independent prognostic marker for OS after adjusting for age, PS, and tumor location (HR = 2.74, 95% CI 1.50-5.03, p = 0.001). Conclusions: The results suggest that NKA dynamics within the first two cycles of treatment may hold relevant prognostic information in first-line treatment of mCRC. The possible causative relationship between NKA and treatment effect needs further elucidation, but calls for experimental trials combining chemotherapy with NK cell therapy in mCRC.

Real world clinical outcomes of patients with HER2 positive metastatic breast cancer with central nervous system involvement treated with modern regimens.

e13040 Background: In 25-55% of Human epidermal growth factor receptor type 2 (HER2+) metastatic breast cancer (MBC) patients, central nervous system metastases will occur. Herein we describe treatment patterns and clinical outcomes in a modern series of patients with HER2+ MBC with brain metastases in a population based cohort of Maccabi Healthcare Services in Israel. Methods: Patients aged ≥18 years, who initiated first-line treatment for metastatic HER2 positive breast cancer between 1st January 2013 until 30th June 2021 and received brain surgery and/or irradiation were identified and followed until December 2021. The index date was fixed as the first day of first-line treatment. Time on treatment (ToT, as a surrogate for progression-free survival) and overall survival (OS) were determined. Results: A total of 61 patients with HER2+ MBC and brain metastases were identified. Median theoretical follow-up time was 6.2 years. The cohort consisted of 98.4% females, median age 50 years (IQR: 44-63), tumors were invasive ductal in 85% and in 57% were hormone receptor positive; ECOG performance status was 0-1 in 51% and missing in 32%. All patients initiated tratuzumab-pertuzumab-chemotherapy (TPC) combination, and second-line treatment was started in 72% during study follow up. Median ToT for first and second-line treatments were 16.9 months (95% CI: 13.9-27.7) and 7.92 months (5.6-10.9), respectively. In 15 patients (25%) brain metastases were diagnosed prior to TPC or within 6 months of treatment initiation, in 25 patients (41%) while on TPC treatment, and in 21 (34%) at later periods. Median OS was 45.5 months (35.4-71.2) from initiation of first-line treatment, and 36.3 months when brain metastases occurred upfront, 59.1 months when diagnosed while on TPC, and 40.8 months when diagnosed later. Median OS from brain metastases diagnosis was 25.1 months (17.0-34.6). Conclusions: We provide ToT (as surrogate for PFS) and OS on HER2+ MBC patients with brain metastases treated with upfront TPC in first line setting and mostly TDM1 in second line setting in a real-world setting. Outcome with newer anti-HER2 directed regimens for patients with brain metastases should consider clinical findings in this relatively modern series. [Table: see text]

Patient-reported outcomes (PROs) among men receiving talazoparib (TALA) + enzalutamide (ENZA) vs placebo (PBO) + ENZA as first-line (1L) treatment for metastatic castration-resistant prostate cancer (mCRPC): Results from a phase 3 study (TALAPRO-2).

5013 Background: TALAPRO-2 (NCT03395197) showed statistically significant improvement in radiographic progression free survival with TALA + ENZA (n=402) vs PBO + ENZA (n=403) (HR=0.63 95% CI 0.51-0.78; P<0.001) in men receiving 1L treatment for mCRPC. Here we report PRO endpoints from TALAPRO-2. Methods: PROs were assessed at day 1 (baseline) and at scheduled visits until radiographic progression (every 4 weeks until week 53, and then every 8 weeks) using the EORTC QLQ-C30 and its prostate cancer module, QLQ-PR25. Prespecified PRO analyses included overall mean change from baseline (per longitudinal repeated measures mixed-effects model) and time to definitive clinically meaningful (≥10-point change) deterioration (TTD). Between-arm comparisons of TTD were made using a stratified log-rank test and a Cox proportional hazards model. Results: Of the 805 men randomized and treated, 793 had a baseline score followed by at least 1 post-baseline score; TALA + ENZA (n=395), PBO + ENZA (n=398). Although the treatment effect on global health status (GHS)/quality of life (QoL) significantly favored PBO + ENZA, the predefined threshold of clinical meaningfulness was not met; moreover, no significant differences between the arms were observed in any functioning scales. A significantly longer TTD in GHS/QoL was observed for TALA + ENZA; HR=0.780 (95% CI: 0.62, 0.99), P=0.038; median: 30.8 months vs 25.0 months. A numerical greater delay in TTD in urinary symptoms was longer for TALA + ENZA; HR=0.759 (95% CI: 0.543, 1.061), P=0.105; median not reached vs 35.9 months. Additional PRO results will be presented. Conclusions: Compared with PBO + ENZA, in the TALA + ENZA arm there was 1) a modest deterioration disfavoring GHS/QoL (deterioration was not clinically meaningful based on the predefined threshold), and 2) a maintenance in all functioning scales. TTD in GHS/QoL was significantly longer with TALA + ENZA vs PBO + ENZA, reflecting improved disease control. These results complement the benefit-risk assessment of TALAPRO-2. Clinical trial information: NCT03395197 . [Table: see text]

Reconsidering the cutoff between sensitive and refractory relapses in extensive-stage small cell lung cancer in the era of immunotherapy.

8576 Background: The use of platinum-based doublet chemotherapy combined with immune checkpoint inhibitors (ICIs) has demonstrated promising outcomes in the first-line treatment of extensive-stage small cell lung cancer (ES-SCLC). Relapsed SCLC has been classified into "sensitive" or "refractory" relapse types according to cutoff values (60 or 90 days) of duration from the last chemotherapy administration to disease progression. However, it is unclear whether these cutoff values can be applied to ICI combination therapy. Methods: We retrospectively analyzed a multicenter database of ES-SCLC patients who received second-line therapy after the platinum-etoposide plus ICI (atezolizumab or durvalumab). An optimal cutoff value for the platinum-free interval (PFI) was selected, which minimized the two-sided p-value and maximized hazard ratio (HR) regarding relapse type (sensitive or refractory according to a cutoff value) calculated from a multivariable Cox regression model for overall survival (OS) including performance status (PS) and sex as covariates. The internal validity of the selected cutoff value was assessed via two-fold cross-validation (CV) manner. Results: A total of 101 patients (61 deaths) from 10 hospitals were included in the study. The median follow-up period was 21.1 months. The optimal cutoff value was 75 days (p=0.0002), and when applying this cutoff value, median OS was 15.9 and 5.0 months of sensitive- (n=51) and refractory- (n=50) relapsed patients, and the HR calculated from a two-fold CV was 3.13 (95% confidence interval [CI], 1.66 to 5.90). Additionally, traditional cutoff values of 60 and 90 days also predicted prognosis better, but cutoff values of 110 days or longer did not (Table). Conclusions: Even in the era of combined immunotherapy in ES-SCLC patients, the threshold days for classifying as sensitive- or refractory- relapse did not exhibit a significant change compared to the pre-immunotherapy era. Although further validation studies with a larger sample size would be needed, relapse type classification using the selected cutoff value of 75 days is worth considering as a new prognostic factor for relapsed ES-SCLC patients. [Table: see text]

Safety and efficacy of QL1706 plus carboplatin/etoposide (EC) as first-line (1L) treatment for extensive-stage small-cell lung cancer (ES-SCLC): The results from a phase II single-arm study.

8525 Background: Although the combination of PD-L1 inhibitor and platinum-etoposide chemotherapy has been the preferred 1L treatment for patients (pts) with ES-SCLC, the clinical benefit of the addition of PD-L1 inhibitor was still modest. QL1706 is a novel bifunctional antibody, containing a mixture of anti-PD-1 IgG4 and anti-CTLA-4 IgG1 antibodies produced by MabPair. In phase I trials, QL1706 monotherapy has shown promising antitumor efficacy in nasopharynx cancer and cervical cancer, as well as other advanced solid tumors including SCLC (to be published). This study aims to assess the safety and efficacy of QL1706 plus EC in treatment-naïve ES-SCLC. Methods: In this phase II, open-label, single-arm, multi-center study, eligible pts (18-75 years, ECOG 0-1) received 4-6 cycles of QL1706 (5mg/kg, IV, Q3W) plus EC (etoposide, 100 mg/m2, D1-3, Q3W; carboplatin, AUC = 5, D1, Q3W), followed by the maintenance therapy of QL1706 until disease progression, intolerable toxicity or other discontinuation events defined in the study protocol. Tumor imaging was performed every 6 weeks for the first year and every 9 weeks thereafter. The primary endpoint is safety. Results: From Apr 18, 2022 to Jul 27, 2022, a total of 40 pts were enrolled with a median age of 58.5 years (range, 38−73). 87.5% pts were men, 80% were smokers and 90% had ECOG PS of 1. As of data cutoff (Jan 16, 2023), the median QL1706-treatment duration was 5.9 (range, 0.7−8.9) mo. Twenty pts remained on treatment and 20 pts discontinued due to progressive disease (16, 40.0%) or patient decision (4, 10.0%). Thirty two (80.0%) pts had at least one TRAE (QL1706-related). Fifteen (37.5%) pts experienced grade 3-4 TRAEs, including neutropenia (8, 20%), thrombocytopenia (4, 10%), anemia (3, 7.5%), WBC count decreased (2, 5.0%), AST increased (2, 5.0%), ALT increased (1, 2.5%), gamma-GT increased (1, 2.5%), rash (1, 2.5%), and diarrhea (1, 2.5%). No grade 5 TRAE occurred. No AE led to discontinuation of any treatment. Of the 39 pts who had at least 1 post-baseline tumor assessment, 37 achieved PR (35 confirmed and 2 unconfirmed) and 1 achieved SD. Thus, the confirmed ORR was 89.7% (95% CI, 75.8%−97.1%), and the DCR was 97.4% (95% CI, 86.5−99.9%) (per RECIST v1.1). The mDoR was 4.5 (95% CI, 4.2−not evaluable) mo, with the longest response duration more than 7.2 mo and ongoing. The mPFS was 5.7 (95% CI, 5.4−7.1) mo, together with 3 mo- and 6 mo-PFS rates of 94.8 (95% CI, 80.8−98.7%) and 44.7% (95% CI, 27.3−60.6%), respectively. With a median follow-up time for OS of 6.2 mo, the mOS has not been reached. Conclusions: QL1706 plus EC chemotherapy showed tolerable safety profile and promising efficacy as first-line treatment for pts with ES-SCLC. These data support further clinical development of QL1706 in ES-SCLC. Clinical trial information: NCT05309629 .

Real world outcomes of trilaciclib in ES-SCLC.

e20637 Background: Carboplatin, etoposide, and atezolizumab (PEA) is the most widely used combination for first-line treatment of extensive-stage small cell lung cancer (ES-SCLC). Chemotherapy-induced myelosuppression is a common sequalae that is traditionally managed with lineage-specific supportive care modalities. Studies that evaluated trilaciclib versus placebo in combination with chemotherapy demonstrated statistically significant improvements in the duration of severe neutropenia (SN), defined as ANC < 500 cells/µL, in cycle 1 and incidence of SN as a result of its transient myeloprotective effects. There remains considerable controversy in the adoption of trilaciclib as a supportive medication in clinical practice. The objective of this quality assessment study was to assess utility of trilaciclib in real-world ES-SCLC patients. Methods: This was a single center study with quasi-experimental design comparing patients with confirmed ES-SCLC who received trilaciclib + PEA (PEAT) from April 2021 to July 2022 versus those who received PEA without trilaciclib (PEA) from February 2020 to February 2021. Patients with limited-stage SCLC, prior treatment with immunotherapies, carboplatin dose AUC < 3.5 with cycle 1, and active clinical trial enrollment were excluded. The primary endpoint evaluated was incidence of SN after cycle 1 and during treatment period. Additional measures related to myelopreservation and patient outcomes were assessed as secondary endpoints. Demographic data was analyzed using descriptive statistics. Dichotomous and continuous variables were compared by Mann-Whitney U or one-sided Fisher’s exact test. Progression-free survival (PFS) and overall survival (OS) were evaluated by Kaplan-Meier (KM) estimate. Results: 34 patients received PEAT and 44 patients received PEA. Demographic and baseline clinical characteristics were similar between both cohorts except for older median age of patients (69 years old vs 64 years old) and higher proportion of male patients (65% vs 39%) in the trilaciclib cohort. Even though there was a numerically lower rate of SN (3%) and hospitalization due to febrile neutropenia (FN) or infection (6%) in the PEAT versus the PEA (18%;11%) cohort, statistical significance was not met (p = 0.07;p = 0.065). Likewise, incidence of FN, platelet transfusion requirements, all-cause chemotherapy reductions, and treatment delays were not statistically different. However, the PEAT cohort as compared to PEA experienced a statistically significant reduction in red blood cell transfusion requirements (3% vs 23%; p = 0.02) and grade 3-4 anemia (6% vs 25%; p = 0.03). PFS and OS between the two cohorts were not statistically different. Conclusions: Based on this single center retrospective study, use of trilaciclib appears to confer improvement in the safety profile of PEA without negatively impacting survival outcomes. Therefore, results of this study support the integration of trilaciclib with PEA for ES-SCLC.

FUTURE-SUPER: A randomized, subtyping-based umbrella phase II trial for first-line treatment of metastatic triple-negative breast cancer.

3011 Background: Triple-negative breast cancers (TNBCs) are heterogeneous in molecular drivers and immune traits. Our previous studies classified TNBCs into four subtypes (luminal androgen receptor, LAR; immunomodulatory, IM; basal-like immune-suppressed, BLIS; and mesenchymal-like, MES). The subtyping-based treatment strategy was proved clinically feasible, with promising efficacy (Cell Res 2021, NCT03805399) in patients with heavily pretreated metastatic TNBC (mTNBC). Here, we conducted FUTURE-SUPER, a multi-cohort, randomized trial to further evaluate the efficacy of subtyping-based therapy in the first-line treatment of mTNBC. Methods: Patients with untreated locally recurrent inoperable or mTNBC were enrolled. After categorization into 5 cohorts according to TNBC subtypes and genomic biomarkers, patients were randomly assigned (in a 1:1 ratio) to receive nab-paclitaxel (control group) or nab-paclitaxel plus subtyping-based treatment (subtyping-based group): pyrotinib (LAR-HER2 mut), everolimus (LAR- PI3K/AKTmut), camrelizumab and famitinib (IM), bevacizumab (BLIS/MES- PI3K/AKT WT), everolimus (MES- PI3K/AKT mut). The primary endpoint was progression-free survival (PFS). Secondary endpoints included PFS in each subtyping-based cohort, objective response rate (ORR), overall survival (OS) and safety. Results: Between July 29, 2020, and October 17, 2022, 139 patients were enrolled and randomly assigned. With a median follow-up of 18.5 mo (range, 3.5 to 30.3), 101 (72.7%) events of disease progression or death occurred. Median PFS was significantly longer in the subtyping-based group than in the control (11.3 mo vs 5.8 mo; hazard ratio [HR], 0.38; 95% confidence interval [CI], 0.25 to 0.57; P<0.0001). Greater magnitude of PFS benefits were seen for the IM (median, 15.1 mo vs 6.5 mo; HR 0.37; 95% CI, 0.19 to 0.73), BLIS (median, 9.4 mo vs 3.9 mo; HR 0.41; 95% CI, 0.16 to 0.56) and LAR- PI3K/AKT mut (median, 19.1 mo vs 8.4 mo; HR 0.42; 95% CI, 0.12 to 1.53) subtypes. The ORR (measurable-disease population) was higher in the subtyping-based group than in the control group (80.0% [48/60] vs. 44.8% [26/58]; odds ratio, 0.20; 95% CI, 0.09 to 0.46). OS data were not mature. Most adverse events were of grade 1 or 2. Grade 3 and 4 toxicities were as expected, with neutropenia more frequently reported in the subtyping-based group (56.5% vs 26.1%). No treatment-related deaths were recorded. Further high-throughput biomarker analyses are ongoing. Conclusions: Subtyping-based precision treatment significantly prolonged PFS versus nab-paclitaxel in the first-line treatment of advanced TNBC, with manageable toxicities. Our findings highlight the profound clinical benefits with treatment optimization according to molecular/immunological subtypes in TNBC, outlining a direction for further exploration. Clinical trial information: NCT04395989 .

Combination of eribulin with trastuzumab and pertuzumab for HER2 positive advanced or recurrent breast cancer: JBCRGM03.

e13031 Background: Pertuzumab (P) was an effective first-line treatment for HER2 positive metastatic breast cancer (MBC) in the CLEOPATRA study, improving both overall and progression-free survival (PFS). However, it is challenging to provide intravenous docetaxel to MBC patients over long term at a dosage of 75 mg/m2 every three weeks. Eribulin (E) is a well tolerated cytotoxic agent. In a multicenter, open-label phase II research (UMIN000012232), we have shown the effectiveness and safety of E combined with trastuzumab (T) with P as first- and second-line treatment for metastatic or advanced BC. Methods: The study included HER2 positive MBC patients with no or one previous treatment, including advanced or recurrent chemotherapy. All patients were administered with T and taxane as perioperative or first-line chemotherapy. E (1.4 mg/m2) along with T (8 mg/kg loading dosage > 6 mg/kg), and P (840 mg loading dose > 420 mg) was administered intravenously on days 1 and 8 of a 21-day cycle, once every three weeks. The primary end point was PFS and the secondary endpoints were the response rate (RR) based on RECIST ver1.1. Overall patient survival effectiveness following P administration, E compliance, and success of follow-up therapies were observed. Results: A total of 50 patients were enrolled, with 49 of them qualifying for the safety analysis. However, the full analysis set (FAS) consisted of 46 individuals. The average patient age was 56 years old (range 23–70), and 9 (18%) and 40 (82%) patients received care in first- and second-line settings, respectively. The median PFS for patients who received main therapy was 20.5 months, whereas the median PFS for patients who received subsequent treatment was 8.6 months. Thirty-five patients (76.1%) were able to receive concomitant E until the end of protocol treatment. The overall RR was 56.5% among the 46 patients in the FAS. Nine patients (19.5%) responded completely, whereas 17 patients (37.0%) responded partially. There were 13 cases of stable disease (28.2%), six cases of progressing disease (13.0%), and one case was not evaluable (1.2%). The median survival of the primary treatment population was not reached; however, the median survival of the secondary treatment population was 42.4 months. Twenty three patients received T-DM1 as a follow-up treatment, 13 patients received TP plus chemotherapy, and five patients received additional therapies. The average duration of treatment with T-DM1 as a consequent therapy was approximately four months, whereas the average duration of treatment with HP plus chemotherapy was 11 months. Conclusions: For HER2positive MBC, E in combination with T plus P was well tolerated and may be an alternative to docetaxel-based combination therapy. Results from the JBCRG M06 trial research, which compares taxanes combination with T plus P with E combined with T plus P in first-line therapy, are still pending. Clinical trial information: UMIN000012232 .

A multicenter phase I/II trial of induction chemotherapy followed by camrelizumab, apatinib, plus chemotherapy as first-line treatment for extensive-stage small-cell lung cancer.

8590 Background: Extensive-stage small-cell lung cancer (ES-SCLC) is a highly aggressive tumor with poor prognosis and limited treatment options. It is necessary to explore new first-line therapeutic strategies to improve patients’ outcomes. This study aimed to assess the safety and efficacy of induction chemotherapy followed by camrelizumab, apatinib plus chemotherapy as first-line treatment in patients with ES-SCLC. Methods: Patients (pts) aged 18-75 years with histopathologically confirmed ES-SCLC and ECOG performance score of 0-1 who did not receive systemic treatment were prospectively enrolled to this study. After two 21-day cycles of induction chemotherapy (etoposide 100 mg/m2 on days 1-3 and carboplatin AUC 5 mg/mL/min on day 1 [EC]), pts received camrelizumab (200 mg, q3w) plus apatinib (250 mg, qd) and EC for 2-4 cycles, then followed by camrelizumab and apatinib as maintenance treatment until disease progression/unacceptable toxicity/up to two years. The primary endpoint was safety. Secondary endpoints were objective response rate (ORR), PFS and OS. Targeted sequencing and whole transcriptome sequencing (WTS) were performed for pts who had sufficient tissue samples. Results: From Jan 28, 2021 to Aug 20, 2022, 40 eligible pts were enrolled. At the data cut-off (Jan 21, 2023), the median follow-up time was 13.6 months. Grade 3/4 treatment-related adverse events (TRAEs) were reported in 72.5% (29/40) of pts. The most common grade 3/4 TRAEs were decreased neutrophil count (35.0%, 14/40), anemia (15.0%, 6/40), decreased platelet count (12.5%, 5/40), increased serum alanine aminotransferase (12.5%, 5/40), and hyponatremia (12.5%, 5/40). Hemoptysis was observed in 15.0% of (6/40) pts, all of whom were grade 1-2. No treatment-related deaths occurred. Efficacy was evaluated in 36 pts who received two cycles of induction therapy and had at least one post-treatment efficacy evaluation. The ORR after two cycles of induction chemotherapy was 66.7% (24/36). The overall ORR and disease control rate reached 88.9% (32/36) and 97.2% (35/36), respectively. The median PFS was 7.4 months (95% CI: 6.5-8.3). The 1-year OS rate was 63.4%. Thirty and 20 pts underwent targeted sequencing and WTS, respectively. Pts with high tumor mutational burden level (TMB ≥ 7.0, p < 0.001), high homologous recombination deficiency score (HRD ≥ 34.0, p = 0.012), and altered RB1 (p < 0.001) presented a longer PFS, respectively. WTS suggested that high expression of cancer-associated fibroblast signature was associated with a shorter PFS (p = 0.001). Conclusions: Induction chemotherapy followed by camrelizumab, apatinib plus EC and then maintenance therapy showed acceptable safety and encouraging efficacy, and might be a promising regimen as first-line treatment in ES-SCLC. TMB, HRD and RB1 might be predictive biomarkers of response to the regimen. Clinical trial information: NCT05001412 .

EE303 Cost-Effectiveness Analysis of Pd-L1 Testing Associated with Pembrolizumab for First-Line Treatment of Advanced NSCLC in China

To assess the cost-effectiveness of PD-L1 testing associated with Pembrolizumab for first-line treatment of advanced non-small cell lung cancer (NSCLC) from the perspective of the Chinese healthcare system.

A pilot study of anlotinib with third-generation epidermal growth factor receptor tyrosine kinase inhibitors in untreated EGFR-mutant patients with advanced non-small cell lung cancer.

In recent years, osimertinib, a third-generation epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI), has been recommended as a first-line treatment for EGFR-mutant advanced non-small cell lung cancer (NSCLC). A phase III study (AENEAS) to assess the efficacy and safety of aumolertinib, another third-generation EGFR-TKI, vs. gefitinib as a first-line treatment in patients with locally advanced or metastatic NSCLC harboring EGFR mutations has also achieved positive results. Despite the improvements in progression-free survival (PFS) and overall survival (OS) of third- vs. first-generation EGFR-TKIs, combined treatment strategies to postpone drug resistance and further prolong survival benefits remain to be explored. We conducted a nonrandomized phase II trial (ChiCTR2000035140) of an oral multitarget antiangiogenic TKI (anlotinib) with third-generation EGFR-TKIs (osimertinib or aumolertinib) in untreated patients with EGFR mutation and advanced NSCLC. Anlotinib and the third-generation EGFR-TKIs were orally administrated (anlotinib at a dose of 12 mg once every other day and osimertinib at 80 mg once daily or aumolertinib at 110 mg once daily). The primary end point of the study was the objective response rate (ORR). Secondary endpoints included the disease control rate (DCR), OS, PFS, and safety of the combined treatment. Enrollment was ceased due to treatment-related adverse events (trAEs) after 11 of 35 planned patients were treated. Among these 11 patients, two were lost to follow-up, and the treatment of five of the remaining nine patients was discontinued due to trAEs, including stomachache, rash, hyponatremia, pulmonary embolism, and interstitial pneumonia. AEs of grade 3 or worse were observed in five patients, but no treatment-related death occurred in these patients. Combining anlotinib and third-generation EGFR-TKIs in untreated EGFR-mutant patients with advanced NSCLC demonstrated significantly increased toxicity, suggesting that the combined treatment strategy was an inappropriate therapeutic choice in this setting.

Penpulimab plus platinum-based chemotherapy combined with anlotinib in first-line treatment for persistent, recurrent, or metastatic cervical cancer: A single-arm, open-label phase Ⅱ study (ALTN-AK105-II-06).

e17512 Background: Penpulimab is a novel human immunoglobulin G1 (IgG1) anti-programmed cell death-1 (PD-1) antibody. Anlotinib is a novel oral multi-target tyrosine kinase inhibitor and primary targeted to VEGFR, FGFR, PDGFR and c-Kit. ALTN-AK105-II-06 (ChiCTR2200062897) is a single-arm, open phase Ⅱ clinical trial aimed to assess the effiacy and safety of penpulimab plus chemotherapy combined with anlotinib as fist-line therapy for persistent, recurrent, or metastatic cervical cancer. Methods: Eligible adults with persistent, recurrent, or metastatic cervical cancer not previously treated with systemic chemotherapy and not amenable curative treatment, with CPS more than 1% PD-L1 expression, and ECOG 0-1 were considered eligible for enrolment. Patients received 2 cycles of penpulimab 200mg Q3W + chemotherapy (paclitaxel 175 mg/m2 + cisplatin 50 mg/m2 or carboplatin AUC 5) + anlotinib 10mg, following with penpulimab and anlotinib for maintenance therapy. Patients were treated on continuous 3 weeks of penpulimab for up to 2 years, until disease progression, or unacceptable toxicities. The primary endpoint was objective response rate (ORR). Secondary endpoints included progression-free survival (PFS), disease control rate (DCR), duration of response (DoR), overall survival (OS), 6-month PFS, safety and quality of life. Results: From Sep 2022 to Feb 2023, 9 patients were recruited with a median age of 56.4 years (range: 45-66), FIGO histopathological stage IIB (33.3%), III (44.5%) and IV (22.2%) were enrolled. 22.2% patients had ECOG PS 0. At data cutoff date (Feb 02, 2023), 8 patients had at least one post treatment anti-tumor assessment. 1 (12.5%) patient achieved CR, 6 (75%) patients achieved PR and 1 (12.5%) patient NE. The ORR was 87.5%. Median PFS and OS were not reached. Grade ≥3 TRAEs incidence was 44.44%. The most common grade ≥3 TRAEs were hypertension (22.22%), leukopenia (11.11%), neutropenia (11.11%) and hypertriglyceridemia (11.11%). Conclusions: This chemo-less therapy of only 2 cycles of chemotherapy combined with penpulimab + anlotinib in first-line treatment, maintaining with penpulimab and anlotinib showed promising efficacy with a favourable toxicity profile for patients with persistent, recurrent, or metastatic cervical cancer. We will report more data in the future. Clinical trial information: ChiCTR2200062897 .

Oxaliplatin related lncRNAs prognostic models predict the prognosis of patients given oxaliplatin-based chemotherapy

BackgroundOxaliplatin-based chemotherapy is the first-line treatment for colorectal cancer (CRC). Long noncoding RNAs (lncRNAs) have been implicated in chemotherapy sensitivity. This study aimed to identify lncRNAs related to oxaliplatin sensitivity and predict the prognosis of CRC patients underwent oxaliplatin-based chemotherapy.MethodsData from the Genomics of Drug Sensitivity in Cancer (GDSC) was used to screen for lncRNAs related to oxaliplatin sensitivity. Four machine learning algorithms (LASSO, Decision tree, Random-forest, and support vector machine) were applied to identify the key lncRNAs. A predictive model for oxaliplatin sensitivity and a prognostic model based on key lncRNAs were established. The published datasets, and cell experiments were used to verify the predictive value.ResultsA total of 805 tumor cell lines from GDSC were divided into oxaliplatin sensitive (top 1/3) and resistant (bottom 1/3) groups based on their IC50 values, and 113 lncRNAs, which were differentially expressed between the two groups, were selected and incorporated into four machine learning algorithms, and seven key lncRNAs were identified. The predictive model exhibited good predictions for oxaliplatin sensitivity. The prognostic model exhibited high performance in patients with CRC who underwent oxaliplatin-based chemotherapies. Four lncRNAs, including C20orf197, UCA1, MIR17HG, and MIR22HG, displayed consistent responses to oxaliplatin treatment in the validation analysis.ConclusionCertain lncRNAs were associated with oxaliplatin sensitivity and predicted the response to oxaliplatin treatment. The prognostic models established based on the key lncRNAs could predict the prognosis of patients given oxaliplatin-based chemotherapy.

Bevacizumab loaded CalliSpheres® bronchial arterial chemoembolization combined with immunotherapy and targeted therapy for advanced lung adenocarcinoma.

Background: As a new drug delivery and embolization system, drug-eluted bronchial artery chemoembolization (DEB-BACE) can not only embolize the tumor blood supply artery but also load chemotherapy drugs and slowly release them into the local environment. Bevacizumab (BEV) combined with chemotherapy drugs has attained significant achievements in the first-line treatment of advanced non-squamous non-small cell lung cancer (NSCLC). The role of BEV-loaded DEB-BACE combined with immunotherapy and targeted therapy in patients with lung adenocarcinoma (LUAD) is unclear. This study was designed to evaluate the efficacy and safety of bevacizumab-loaded CalliSpheres® bronchial arterial chemoembolization combined with immunotherapy and targeted therapy in patients with lung adenocarcinoma. Methods: Nine patients with LUAD who received BEV-loaded CalliSpheres® BACE combined with immunotherapy and targeted therapy from 1 Jan 2021 to Dec 2021 were included in this study. The primary endpoint was the disease control rate (DCR) and the objective response rate (ORR). The secondary endpoints were the overall survival rates (OS) at 6months and 12months. The tumor response was evaluated according to the mRECIST standard. Safety was assessed by the occurrences of adverse events and the severity of the adverse events. Results: All patients received CalliSpheres® BACE loaded with BEV (200mg) in combination with immunotherapy and targeted therapy. A total of nine patients received the BACE procedures 20 times, four of them received a third session of BACE, three underwent a second session of DEB-BACE, and two underwent one cycle of DEB-BACE. Partial response and stable disease were found in seven (77.8%), and two (22.2%) patients, respectively, 1month after the last multimodal treatment. The ORR at 1, 3, 6, and 12months was 77.8%, 66.7%, 44.4%, and 33.3%, respectively, while the DCR was 100%, 77.8%, 44.4%, and 33.3%, respectively. The OS rates at 6-and 12-month were 77.8% and 66.7%, respectively. There were no serious adverse events. Conclusion: BEV-loaded CalliSpheres® transcatheter bronchial arterial chemoembolization combined with immunotherapy and targeted therapy is a promising and well-tolerated treatment for patients with lung adenocarcinoma.

Docetaxel plus S-1 versus docetaxel plus capecitabine as first-line treatment for advanced breast cancer patients: a prospective randomized phase II study

BackgroundThis study was conducted to evaluate the efficacy and safety of docetaxel/S-1 (TS) compared with docetaxel/capecitabine (TX) as a first-line treatment for advanced breast cancer. MethodsPatients with advanced metastatic breast cancer were randomly divided into the TS group (n = 54) and the TX group (n = 57) for first-line chemotherapy from August 2015 to April 2019 (ClinicalTrials.org registration no. NCT02947061). Following the completion of combination therapy, patients without progression received S-1 or capecitabine maintenance treatment. The primary end point was progression-free survival (PFS). ResultsAmong 111 enrolled patients, the median PFS did not differ significantly between the TS group and the TX group (TS vs. TX, 9.0 vs. 7.4 months, P = 0.365, 95% confidence interval [CI]: 0.50–1.11, hazard ratio [HR]: 0.75). There was also no statistically significant difference in median overall survival (OS) between the two groups (TS vs. TX, 40.2 vs. 41.3 months, P = 0.976). In addition, visceral metastasis and metastasis sites, such as the liver or lung, did not lead to a significant effect on PFS and OS. The two regimens showed no significant difference in adverse events, except hand-foot syndrome, which predominated in the TX group (38.6% vs. 7.4%, P = 0.001), and diarrhea (24.1% vs. 3.6%, P = 0.003) and elevation of aspartate aminotransferase (AST)/alanine aminotransferase (ALT) levels (14.8% vs. 3.5%, P = 0.049), which were more frequent in the TS group. ConclusionsThe TS and TX regimens demonstrated similar efficacy and safety for the first-line treatment of advanced breast cancer. The TS regimen had fewer cases of severe hand-foot syndrome than the TX regimen, representing an effective alternative option to the TX regimen. Further studies are warranted to define the efficacy and safety of this strategy in real-world settings.

Tislelizumab plus chemotherapy as first-line treatment for recurrent or metastatic nasopharyngeal cancer: A multicenter phase 3 trial (RATIONALE-309)

Checkpoint inhibitors are effective in recurrent/metastatic nasopharyngeal cancer (R/M NPC). RATIONALE-309 (NCT03924986) randomized 263 treatment-naive R/M NPC patients to tislelizumab or placebo every 3weeks (Q3W), plus chemotherapy (Q3W for 4-6 cycles). At interim analysis, progression-free survival (PFS) was significantly longer with tislelizumab-chemotherapy versus placebo-chemotherapy (hazard ratio: 0.52; 95% confidence interval: 0.38, 0.73; p<0.0001). PFS benefit for tislelizumab-chemotherapy versus placebo-chemotherapy was observed regardless of programmed death-ligand 1 expression. PFS after next line of treatment and overall survival showed favorable trends for tislelizumab-chemotherapy versus placebo-chemotherapy. The safety profile was similar between arms. Gene expression profiling (GEP) identified immunologically "hot" tumors, and showed an activated dendritic cell (DC) signature was associated with tislelizumab-chemotherapy PFS benefit. Our results support that tislelizumab-chemotherapy should be considered as first-line treatment for R/M NPC, and GEP and activated DC signature results may help identify patients who might benefit most from immunochemotherapy treatment. VIDEO ABSTRACT.

Cost-Effectiveness Analysis of Monoclonal Antibodies Associated With Chemotherapy in First-Line Treatment of Metastatic Colorectal Cancer

ObjectivesThis study aimed to evaluate the cost-effectiveness of anti–epidermal growth factor receptor (cetuximab and panitumumab) or anti–vascular endothelial growth factor (bevacizumab) monoclonal antibodies associated with conventional chemotherapy (CT) (fluorouracil and leucovorin with irinotecan) as a first-line treatment for unresectable metastatic colorectal cancer. MethodsA partitioned survival analysis model was adopted to simulate direct health costs and benefits comparing therapeutic options in a 10 years’ time horizon. Model data were extracted from the literature and costs were obtained from Brazilian official government databases. The analysis considered the perspective of the Brazilian Public Health System; costs were measured in local currency (BRL) and benefits in quality-adjusted life-years (QALY). A 5% discount rate was applied to costs and benefits. Alternative willingness-to-pay scenarios, varying from 3 to 5 times the cost-effectiveness threshold established in Brazil, were estimated. The results were presented incremental cost-effectiveness ratio (ICER), and both deterministic and probabilistic sensitivity analyses were performed. ResultsThe most cost-effective choice would be the association of CT with panitumumab, with an ICER of $58 330.15/QALY compared with isolated CT. The second-best option was CT with bevacizumab and panitumumab, with an ICER of $71 195.40/QALY compared with panitumumab alone. Although having higher costs, the second-best option was the most effective. Both strategies were cost-effective in part of the Monte Carlo iterations, considering the 3× threshold. ConclusionsThe therapeutic option CT + panitumumab + bevacizumab represents the most significant effectiveness gain in our study. It is the second-lowest cost-effectiveness, and this option includes monoclonal antibodies association for patients with and without KRAS mutation.

Sociodemographic disparities in targeted therapy in ovarian cancer in a national sample.

The treatment landscape for ovarian cancer has changed in recent years with the introduction of targeted therapies to treat patients with advanced disease. We investigated patient demographic and clinical factors associated with use of targeted therapies as a part of the first-line treatment for ovarian cancer. This study included patients diagnosed with stage I-IV ovarian cancer between 2012 and 2019 from the National Cancer Database. Information on demographic and clinical characteristics were collected and described using frequency and percent across receipt of targeted therapy. Logistic regression was used to compute the odds ratios (ORs) and 95% confidence intervals (CI) associating patient demographic and clinical factors with receipt of targeted therapy. Among 99,286 ovarian cancer patients (mean age 62 years), 4.1% received targeted therapy. The rate of targeted therapy receipt across racial and ethnic groups over the study period was fairly similar; however, non-Hispanic Black women were less likely to receive targeted therapy than their non-Hispanic White counterparts (OR=0.87, 95% CI: 0.76-1.00). Patients who received neoadjuvant chemotherapy were more likely to receive targeted therapy than those who received adjuvant chemotherapy (OR=1.26; 95% CI: 1.15-1.38). Moreover, among patients who received targeted therapy, 28% received neoadjuvant targeted therapy, with non-Hispanic Black women being most likely to receive neoadjuvant targeted therapy (34%) compared with other racial and ethnic groups. We observed differences in receipt of targeted therapy by factors such as age at diagnosis, stage, and comorbidities present at diagnosis, as well as factors related to healthcare access-including neighborhood education level and health insurance status. Approximately 28% of patients received targeted therapy in the neoadjuvant setting, which could negatively impact treatment outcomes and survival due to the increased risk of complications associated with targeted therapies that may delay or prevent surgery. These results warrant further evaluation in a cohort of patients with more comprehensive treatment information.

Quality of life with cemiplimab plus chemotherapy for first-line treatment of advanced non-small cell lung cancer: Patient-reported outcomes from phase 3 EMPOWER-Lung 3.

EMPOWER-Lung 3, a randomized 2:1 phase 3 trial, showed clinically meaningful and statistically significant overall survival improvement with cemiplimabplusplatinum-doublet chemotherapy versus placebopluschemotherapy for first-line treatment of advanced non-small cell lung cancer. This study evaluated patient-reported outcomes (PROs). PROs were assessed at day 1 (baseline), the start of each treatment cycle (every 3weeks) for the first six doses, and then at start of every three cycles, using the European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life-Core 30 (QLQ-C30) and Quality of Life-Lung Cancer Module (QLQ-LC13) questionnaires. Prespecified analyses included a longitudinal mixed-effect model comparing treatment arms and a time to definitive clinically meaningful deterioration (TTD) analysis performed for global health status/quality of life (GHS/QoL) and all scales from the questionnaires. Between-arm TTD comparisons were made using a stratified log-rank test and proportional hazards model. A total of 312 patients were assigned to receive cemiplimabplusplatinum-doublet chemotherapy and 154 to receive placebopluschemotherapy; 391 (83.9%) were male and the median age was 63.0years (range, 25-84). For pain symptoms (EORTC QLQ-C30), a statistically significant overall improvement from baseline (-4.98, 95% confidence interval [CI] -8.36 to -1.60, p=.004) and a statistically significant delayin TTD (hazard ratio, 0.39; 95% CI, 0.26-0.60, p<.0001) favoring cemiplimabpluschemotherapy were observed. Statistically significant delays in TTD, all favoring cemiplimabpluschemotherapy, were also observed in functioning and symptom scales. A significant overall improvement from baseline in GHS/QoL was seen for cemiplimabpluschemotherapy compared with nonsignificant overall change from baseline for placebopluschemotherapy (1.69, 95% CI, 0.20-3.19 vs. 1.08, 95% CI, -1.34 to 3.51; between arms, p=.673). No analyses yielded statistically significant PRO resultsfavoring placebopluschemotherapy for any QLQ-C30 or QLQ-LC13 scale. Cemiplimabpluschemotherapy resulted in significant overall improvement in pain symptoms and delayed TTD in cancer-related and lung cancer-specific symptoms and functions.