Prior Platinum-based Chemotherapy Research Articles

A brief report on stable disease among amivantamab-treated patients with post-platinum epidermal growth factor receptor exon 20 insertion–mutated non-small cell lung cancer: A response-based analysis from the CHRYSALIS study

BackgroundAmivantamab, an EGFR-MET bispecific antibody, is the first approved targeted therapy for patients with EGFR Ex20ins NSCLC after prior platinum-based chemotherapy—a population with historically poor outcomes before amivantamab approval. As antitumor activity in single-arm studies typically focuses on responders, the evaluation of outcomes in patients with stable disease (SD) as best response is of clinical interest. Patients and methodsAmong 114 patients with post-platinum EGFR Ex20ins NSCLC in CHRYSALIS (NCT02609776; data cutoff: March 30, 2021), response was assessed by blinded independent central review via RECIST v1.1. Patients alive and receiving therapy at 12 weeks were grouped by response at this landmark: partial or complete response (PR+), SD, or progressive disease (PD). Progression-free survival (PFS) and overall survival (OS) by response cohort were determined using the Kaplan-Meier method; hazard ratios (HRs) and 95% confidence intervals (CIs) between response cohorts were calculated using Cox proportional hazards regression. ResultsAmong patients alive and receiving therapy at 12 weeks (n=107), 42 (39%) had PR+, 52 (49%) had SD, and 13 (12%) had PD. Among patients with PR+ and SD, median PFS was 12.2 and 7.0 months, respectively. A corresponding improvement in OS was observed in patients achieving PR+ (median: not reached; HR vs PD=0.21 [95% CI: 0.08–0.54]) and SD (median: 23.0 months; HR vs PD=0.33 [95% CI: 0.14–0.77]), relative to those with PD (median: 14.0 months). ConclusionSD was observed in 49% of patients receiving amivantamab, with corresponding increases in OS that dramatically improved the prognoses of this patient population.

Dose-expansion part of a phase 1b global study of E7386 in combination with lenvatinib (LEN) in patients (pts) with hepatocellular carcinoma (HCC) and other solid tumors including endometrial cancer (EC).

TPS3169 Background: E7386, a first-in-class anticancer agent, inhibits protein-protein interaction between β-catenin and the CREB-binding protein, thus modulating Wnt/β-catenin signaling. E7386 is being tested in combination with LEN in the open-label global phase 1b Study 102. The dose-escalation part of Study 102 determined the recommended dose of E7386 + LEN in pts with HCC and other solid tumors. Here we describe the ongoing dose-expansion part in pts with HCC or EC. Methods: Eligible pts ≥18 years old should have an ECOG PS of 0-1 and a confirmed diagnosis of advanced, unresectable, or recurrent solid tumor. Pts with HCC will have a Child-Pugh score of A and a categorization of BCLC Stage B (not amenable to locoregional therapy or refractory to locoregional therapy, and not amenable to a curative treatment) or Stage C. Pts with HCC should also have received 1 prior immuno-oncology (IO)-based regimen and have progressed on/after prior treatment with IO therapy. If ineligible for IO therapy, pts should not have received prior systemic therapy; pts who previously received LEN are ineligible. In the EC subpart, pts should have disease progression after receiving prior platinum-based chemotherapy (PBT) and an IO-based therapy for EC. Pts may have received 1 additional line of PBT if given in the neoadjuvant/adjuvant setting, but not exceeding 3 lines of therapies. Pts with EC who are ineligible for IO therapy may have received only 1 prior systemic therapy including PBT. Pts who have received prior LEN therapy will be eligible if they meet protocol-specified criteria. Pts with HCC (n≈60) will be randomized in a 2:1 ratio into 1 of 2 treatment arms and will receive either the combination E7386 + LEN or LEN monotherapy in 28-day cycles. E7386 will be administered at 100 mg BID in the combination arm and LEN will be administered QD at 8 mg (if body weight <60 kg) or 12 mg (if body weight ≥60 kg) in both arms. Pts with HCC will be stratified by geographical region (Western Europe and North America vs Japan vs other countries). Pts with EC (n≈30) will receive only the combination E7386 120 mg BID + LEN 14 mg QD. The expansion part of Study 102 aims to assess safety and tolerability (primary endpoints), and pharmacokinetics and preliminary efficacy (secondary endpoints), of E7386 in combination with LEN for pts with HCC and EC. Efficacy of LEN monotherapy will be assessed for HCC (secondary endpoint). Tumors will be assessed by investigator per RECIST v1.1 every 8 weeks from the date of the first dose. Adverse events will be monitored and recorded for up to 30 days after the last dose or until initiation of a new anticancer therapy, whichever occurs first. Study sites will include the United States, France, Republic of Korea, Japan, and Taiwan. As of February 5, 2024, 46 pts with HCC and 16 pts with EC have enrolled. Clinical trial information: NCT04008797 .

A phase 1/2 study of ubamatamab (REGN4018), a MUC16×CD3 bispecific antibody, administered alone or in combination with cemiplimab (anti–PD-1) in patients with recurrent ovarian cancer or MUC16+ endometrial cancer.

TPS5632 Background: Mucin 16 (MUC16) is a cell surface glycoprotein that is overexpressed in ovarian cancer (OC) and endometrial cancer (EC). Ubamatamab is a MUC16 × cluster of differentiation 3 (MUC16×CD3) bispecific antibody that bridges MUC16 on tumor cells and CD3 on T cells to promote T-cell–mediated cytotoxicity. Cemiplimab, a monoclonal antibody targeting the programmed cell death-1 (PD-1) receptor, enhanced MUC16×CD3 activity in preclinical models. In Phase 1 of this first-in-human study (NCT03564340), ubamatamab alone and in combination with cemiplimab demonstrated an acceptable safety profile, durable clinical activity across a range of doses, and linear pharmacokinetics (PK) in patients (pts) with recurrent OC (Liu et al. IGCS 2023. Plenary 03). Phase 2 will assess the efficacy of ubamatamab alone and in combination with cemiplimab in pts with recurrent OC. Ubamatamab will also be evaluated for recurrent advanced or metastatic EC that is MUC16+. Methods: For individuals with recurrent OC, elevated serum cancer antigen (CA)-125 ≥2× the upper limit of normal, and up to four prior lines of cytotoxic therapy, weekly dosing of ubamatamab alone or in combination with cemiplimab will be evaluated in monotherapy and combination therapy expansion cohorts. A Phase 2 cohort will also be randomized 1:1:1 to receive ubamatamab 250 mg IV Q3W or 800 mg IV Q3W or ubamatamab 250 mg IV Q3W + cemiplimab 350 mg IV Q3W. For the EC cohort (≥25% of tumor cells MUC16+, as assessed by immunohistochemistry [IHC]) pts with advanced or metastatic EC that has progressed or is recurrent after prior anti–PD-1 therapy and prior platinum-based chemotherapy will be enrolled. The initial EC cohort will receive ubamatamab 250 mg IV Q3W. Based upon observed safety and activity, additional cohorts may be enrolled to receive ubamatamab 800 mg IV Q3W and/or ubamatamab 250 mg IV Q3W + cemiplimab 350 mg IV Q3W. To limit the risk of cytokine release syndrome, all pts will receive ubamatamab once-weekly step-up dosing prior to addition of cemiplimab and/or Q3W dosing. Expansion cohorts will use a Simon 2-stage study design, with an interim analysis after the first 20 pts. Any treatment arm with ≥3 objective responses may be expanded to 50 pts. In Phase 2, the primary endpoint will be the objective response rate for each arm (RECIST v1.1). Secondary endpoints include duration of response and progression-free survival, safety, PK, and change from baseline in quality of life. Exploratory objectives include clinical correlation with serum CA-125, MUC16 IHC, and immune markers. The study is currently enrolling to these OC and EC expansion cohorts. Clinical trial information: NCT03564340 .

Overall survival in patients with BRCA-mutated platinum-sensitive relapsed ovarian cancer (PSROC) treated with olaparib maintenance: Real-world data of the C-PATROL study.

e17542 Background: Maintenance monotherapy with PARP-inhibitor (PARPi), olaparib has previously shown good effectiveness and tolerability in total population of patients with PSROC who were in response to platinum-based chemotherapy (PBC) in the C-PATROL study. Here we present the overall survival (OS) data in different subgroups. Methods: The prospective German non-interventional study C-PATROL (NCT02503436) captured routine clinical data of olaparib maintenance according to label in patients with BRCA-mutated PSROC treated with PBC. The primary endpoint was PFS, relevant secondary endpoints included OS and safety. Data were analyzed by descriptive statistics. Results: Between 10/2015 and 10/2019, 277 patients were enrolled. The ITT set (study selection criteria fulfilled) comprised 267 patients (median age: 60 yrs; ECOG ≤1: 93%; ≥2 relapses: 32%; ≥3 prior PBC: 29%). Median follow-up was 23.5 months (range 0.0–80.5) and median olaparib treatment duration was 13.6 months (0.1–80.9). 10% of patients received olaparib for ≥ 5 years and 8% of patients received further PARPi also as subsequent treatment. Median OS was 35.4 months (95% CI 29.2–49.9). The longest median OS was observed in patients with a complete debulking after the surgery at current relapse, a complete response (CR) to the current PBC and a BRCA2 mutation. Adverse events (AEs) were consistent with the known tolerability profile of olaparib (safety set: n=274; any AE: 95%, AE of CTCAE grade ≥ 3: 40%, olaparib discontinuation due to AE: 11%; most common AE any CTCAE: nausea (46%), fatigue (39%), anaemia (31%), and vomiting (17%); most common AE CTCAE grade ≥ 3: anaemia (14%)). Conclusions: Olaparib is effective and safe in the real-world setting. In olaparib-treated patients with BRCA-mutated PSROC longer OS was observed mainly with respect to resection status after debulking surgery at current relapse, to tumor burden at the therapy start and BRCA mutation type. Our data underline the role of cytoreduction and platinum response in the context of PARPi maintenance therapy. Clinical trial information: NCT02503436 . [Table: see text]

Post-marketing safety evaluation of lurbinectedin: a pharmacovigilance analysis based on the FAERS database.

Background: On 15 June 2020, the United States Food and Drug Administration (FDA) approved lurbinectedin for treating adult patients with metastatic small-cell lung cancer whose disease has progressed despite prior platinum-based chemotherapy. Following its market approval, safety data on lurbinectedin in large populations is currently lacking. Therefore, this study aims to evaluate adverse events (AEs) associated with lurbinectedin using the FDA's Adverse Event Reporting System (FAERS)database. Methods: Data concerning lurbinectedin from the FAERS database were extracted for the period from June 2020 to September 2023. Four disproportionality analysis algorithms were utilized to assess potential AEs linked to lurbinectedin: reporting odds ratio (ROR), proportional reporting ratio, disproportionate multi-item gamma Poisson shrinker, and Bayesian confidence propagation neural network. These algorithms were applied to quantify signals of lurbinectedin-related AEs. Result: A total of 5,801,535 AE reports were retrieved from the FAERS database, with 511 related to lurbinectedin. These lurbinectedin-induced AEs were observed in 23 system organ classes (SOCs). After simultaneously applying the four algorithms, 47 lurbinectedin-induced AE signals were detected in 23 SOCs. At the SOC level, blood and lymphatic system disorders (ROR, 6.70; 95% confidence interval [CI]: 5.47-8.22) were the only SOC that met all four algorithms. Lurbinectedin's most frequent adverse event was death (ROR: 6.11%, 95% CI: 4.86-7.68), while extravasation exhibited the strongest signal intensity in the ROR algorithm (ROR: 326.37%, 95% CI: 191.66-555.75). Notably, we identified a novel signals: tumor lysis syndrome (ROR: 63.22%, 95% CI: 33.87-117.99). The mean time of onset of AEs was 66 days, the median time of onset was 25days (interquartile range: 8-64days), and most AEs occurred within the first month of lurbinectedin treatment. Conclusion: Our study provided a comprehensive evaluation of lurbinectedin's safety profile in the post-marketing setting. In addition to the adverse events consistent with the existing clinical trials and labeling information, we have also identified an unreported signal related to tumor lysis syndrome. This finding will better guide the clinical practice of lurbinectedin and provide valuable evidence for future research.

Translational insights and overall survival in the U31402-A-U102 study of patritumab deruxtecan (HER3-DXd) in EGFR-mutated NSCLC

Human epidermal growth factor receptor 3 (HER3) is broadly expressed in non-small-cell lung cancer (NSCLC) and is the target of patritumab deruxtecan (HER3-DXd), an antibody-drug conjugate consisting of a HER3 antibody attached to a topoisomerase I inhibitor payload via a tetrapeptide-based cleavable linker. U31402-A-U102 is an ongoing phase I study of HER3-DXd in patients with advanced NSCLC. Patients with epidermal growth factor receptor (EGFR)-mutated NSCLC that progressed after EGFR tyrosine kinase inhibitor (TKI) and platinum-based chemotherapy (PBC) who received HER3-DXd 5.6 mg/kg intravenously once every 3 weeks had a confirmed objective response rate (cORR) of 39%. We present median overall survival (OS) with extended follow-up in a larger population of patients with EGFR-mutated NSCLC and an exploratory analysis in those with acquired genomic alterations potentially associated with resistance to HER3-DXd. Safety was assessed in patients with EGFR-mutated NSCLC previously treated with EGFR TKI who received HER3-DXd 5.6 mg/kg; efficacy was assessed in those who also had prior PBC. In the safety population (N= 102), median treatment duration was 5.5 (range 0.7-27.5) months. Grade ≥3 adverse events occurred in 76.5% of patients; the overall safety profile was consistent with previous reports. In 78/102 patients who had prior third-generation EGFR TKI and PBC, cORR by blinded independent central review (as per RECIST v1.1) was 41.0% [95% confidence interval (CI) 30.0% to 52.7%], median progression-free survival was 6.4 (95% CI 4.4-10.8) months, and median OS was 16.2 (95% CI 11.2-21.9) months. Patients had diverse mechanisms of EGFR TKI resistance at baseline. At tumor progression, acquired mutations in ERBB3 and TOP1 that might confer resistance to HER3-DXd were identified. In patients with EGFR-mutated NSCLC after EGFR TKI and PBC, HER3-DXd treatment was associated with a clinically meaningful OS. The tumor biomarker characterization comprised the first description of potential mechanisms of resistance to HER3-DXd therapy.

Datopotamab deruxtecan in locally advanced/metastatic urothelial cancer: Preliminary results from the phase 1 TROPION-PanTumor01 study.

603 Background: Datopotamab deruxtecan (Dato-DXd) is an antibody-drug conjugate consisting of a humanized anti-TROP2 IgG1 monoclonal antibody covalently linked to a highly potent topoisomerase I inhibitor payload via a plasma-stable, tumor-selective, tetrapeptide-based cleavable linker. Dato-DXd has shown encouraging antitumor activity and a manageable safety profile in patients (pts) with solid tumors. We report preliminary results in pts with advanced/metastatic (a/m) urothelial cancer from the ongoing phase 1 TROPION-PanTumor01 study (NCT03401385). Methods: Pts with unresectable a/m urothelial cancer treated with ≥1 prior line of therapy received intravenous Dato-DXd 6 mg/kg Q3W. Primary study objectives were safety and tolerability. Secondary endpoints were objective response rate (ORR; complete response [CR] + partial response [PR]), and disease control rate (DCR; CR + PR + stable disease) per RECIST 1.1 by BICR. This is the first data disclosure from this cohort in an ongoing expansion cohort study. Results: At data cutoff (May 18, 2023), 18 pts had received Dato-DXd. Median follow-up was 9.1 (range 5–17) months; 6 (33.3%) pts were receiving ongoing treatment. Median age was 63.5 (range 46–79) yrs. Pts were heavily pretreated, 15 (83.3%) had received ≥3 prior regimens. All pts received prior immunotherapy, 17 (94.4%) prior platinum-based chemotherapy, and 4 (22.2%) prior taxanes. Treatment-emergent adverse events (TEAEs) occurred in 100% (any grade [gr]) and 44.4% (gr ≥3) of pts, and drug-related TEAEs occurred in 94.4% (any gr) and 16.7% (gr ≥3) of pts. No drug-related serious AEs were reported, and no TEAEs associated with death were observed. Any gr TEAEs associated with reduction, interruption, and discontinuation of treatment were reported in 11.1%, 33.3%, and 5.6% of pts, respectively (Table). Adjudicated drug-related interstitial lung disease (gr 2) occurred in 1 (5.6%) pt. Confirmed ORR was 27.8% (95% CI 9.7–53.5); 1 pt achieved a CR and 4 achieved a PR. DCR was 77.8% (95% CI 52.4–93.6). Clinical evaluation of this cohort is ongoing and updated results will be presented. Conclusions: In heavily pretreated pts with a/m urothelial cancer, Dato-DXd demonstrated a tolerable and manageable safety profile with encouraging antitumor activity. Dato-DXd is being evaluated in pts with urothelial cancer as part of the phase 1/2 TROPION-PanTumor02 (NCT05460273) and the phase 2 TROPION-PanTumor03 (NCT05489211) studies. Clinical trial information: NCT03401385 . [Table: see text]

Abstract C114: Dose escalation results from a first-in-human, phase I/II study of GB263T, a novel EGFR/cMET/cMET trispecific antibody, in patients with advanced EGFR-mutated (EGFRm) non-small cell lung cancer (NSCLC)

Abstract Background: GB263T, a novel trispecific antibody directed against EGFR and cMET, adopts the design of two humanized VHH antibodies that recognize two different cMET epitopes, in which a conformational change induced by the first VHH binding exposes the second epitope for the second VHH to bind. Sequential binding of the two VHH antibodies to cMET increases tumor specificity, which results in widening of the safety window. In vitro studies show that GB263T induces better antigen-antibody molecular endocytosis, more completely blocks the signal transduction pathway, and has better ADCC activity compared to a benchmark. In addition, GB263T has demonstrated promising pre-clinical activity in models with various EGFR/cMET alterations, including those with high medical need. Here, we report updated dose escalation results of the first-in-human phase I/II study of GB263T in patients (pts) with advanced EGFRm NSCLC (NCT05332574). Methods: This multicenter (China and Australia), phase I/II study was conducted using an accelerated titration method followed by a traditional 3+3 design for dose escalation. Pts with EGFRm NSCLC with prior EGFR TKI and platinum-based chemotherapy were enrolled. GB263T was given at 140-1680 mg (5 dose cohorts) IV weekly for the first two 28-day cycles and biweekly thereafter. Objectives were to evaluate the safety and tolerability, determine the maximum tolerated dose (MTD) and the recommended Phase 2 dose (RP2D), assess the pharmacokinetics, immunogenicity, and preliminary efficacy of GB263T. Results: As of July 5, 2023, 13 pts were treated: 140mg (n=1), 420mg (n=1), 840mg (n=3), 1260mg (n=3), 1680mg (n=5). The enrolment of the 1680mg cohort is ongoing. All pts had received previous third-generation EGFR-TKI and platinum-based chemotherapy. Median number of prior lines of systemic therapy was 3 (range 1-7). One patient at 1680mg experienced DLT (grade 3 oral mucositis, which has resolved after symptomatic treatment). The most common treatment-related adverse events (TRAEs) were rash (61.5%), infusion related reaction (38.5%), fatigue (30.8%) and myalgia (23.1%), and all are mild (grade 1/2). Only one patient developed ≥grade 3 TRAE (grade 3 oral mucositis). There were no treatment-related discontinuations. Among 10 response-evaluable pts, two achieved partial response (PR) and four achieved stable disease (SD) with tumor shrinkage observed in 3/4 SD pts. The disease control rate (DCR) is 60%. The objective response rate (ORR) at the therapeutic dose range (1260-1680mg) is 40% (2/5). Two PR pts and 2/4 SD pts remained on treatment at data cutoff. Conclusions: Results to date demonstrate a good safety profile with promising efficacy at the therapeutic dose range (1260-1680mg). Continued dose escalation and clinical investigation of GB263T is ongoing.Clinical trial information: NCT05332574. Research Sponsor: Genor Biopharma Co. Ltd. Citation Format: Jin-Ji Yang, Nick Pavlakis, Fan Xie, Tong Li, Yi-Long Wu. Dose escalation results from a first-in-human, phase I/II study of GB263T, a novel EGFR/cMET/cMET trispecific antibody, in patients with advanced EGFR-mutated (EGFRm) non-small cell lung cancer (NSCLC) [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr C114.

Identification, Monitoring and Reversibility of PARP Inhibitor Associated Clonal Haematopoiesis and Myelodysplastic Syndrome: A Case Series

Background: Poly ADP ribose polymerase inhibitors (PARPi) are widely used as maintenance treatment for ovarian cancer (OC) after response to platinum chemotherapy in the first line setting and recurrent disease. Their use has significantly improved outcomes, particularly in patients with BRCA mutations in whom first-line PARPi maintenance therapy increases progression-free survival from 13.8 to 56.0 months (Hazard Ratio, 0.33; 95% CI, 0.25-0.43). However, a recent meta-analysis of clinical trial adverse events and pharmacovigilance data showed that PARPi therapy significantly increases the risk of therapy related myeloid neoplasms (tMN), myelodysplastic syndrome (MDS) and acute myeloid leukaemia with poor outcomes. Platinum based chemotherapy is the mainstay of OC treatment and is associated with clonal haematopoiesis (CH) with mutations in DNA damage response genes. CH is recognised as a premalignant myeloid state but real world data on clonal dynamics during PARPi therapy are lacking. We present a case series of OC patients receiving PARPi-therapy referred for haematological review for beyond-expected HT or unexplained full blood count (FBC) abnormalities with serial FBC and myeloid next generation sequencing (mNGS) clonal monitoring in relation to PARPi therapy. Methods: Seven patients with stage III/IV high-grade OC were referred to haematology at the discretion of the treating oncologist between February 2017 and May 2022 (mean age (SD): 68 (7.0) years, median PARPi duration: 18 months (range: 4-86)). All patients had received prior platinum-based chemotherapy and were screened with mNGS in peripheral blood (PB) or bone marrow aspirate and trephine (BMAT) at initial assessment. Results: Reasons for referral are detailed in Table 1 and include two patients with isolated elevated nucleated red blood cell (NRBC) counts. Six patients had clonal pathology (CP), five of whom had single-nucleotide variants typical of platinum-exposure defined by the involved gene or platinum-associated mutational signatures. Clinical details including BRCA-status, haematological diagnosis and mNGS results are detailed in Table 1. PARPi-therapy was discontinued in four patients with CP, with resolution or improvement of FBC and m-NGS abnormalities (variant allele frequencies (VAFs) and/or copy number variations (CNVs)) in three patients. These findings were most marked in Patient 1, referred with grade 3 thrombocytopenia and transfusion dependence and in whom PARPi cessation resulted in transfusion independence and resolution of morphological and cytogenetic abnormalities (clinical course including BMAT results and haematological parameters illustrated in Figure 1), and Patient 3, who demonstrated selective regression of a TP53 mutated clone on PARPi cessation. Two patients with germline BRCA mutations continued PARPi therapy with 3 monthly PB mNGS monitoring after discussion at multidisciplinary team meetings. Conclusions: We show using sequential molecular and haematological monitoring before and after PARPi cessation that morphological, FBC and clonal abnormalities can be reversed on PARPi discontinuation, potentially mitigating the risk of life-threatening tMNs in some patients. We also highlight that, in addition to cytopenias, persistently elevated NRBCs may be an indicator of clinically relevant CP not well described in pharmacovigilance data based on common terminology criteria for adverse events criteria. Large scale prospective data on clonal dynamics in PARPi therapy are needed to inform mNGS screening and tMN risk stratification as scoring systems based on age associated clonal haematopoiesis of indeterminate potential may not be applicable. Until these data are available we demonstrate the value in MDT discussion and serial PB mNGS monitoring in formulating case-by-case therapeutic decisions regarding CP and PARPi therapy, particularly patients with high risk BRCA mutated OC.

Evaluating niraparib versus active symptom control in patients with previously treated mesothelioma (NERO): a study protocol for a multicentre, randomised, two-arm, open-label phase II trial in UK secondary care centres

BackgroundMalignant mesothelioma is a rapidly lethal cancer that has been increasing at an epidemic rate over the last three decades. Targeted therapies for mesothelioma have been lacking. A previous study...

AK112, a novel PD-1/VEGF bispecific antibody, in combination with chemotherapy in patients with advanced non-small cell lung cancer (NSCLC): an open-label, multicenter, phase II trial

Inhibiting vascular endothelial growth factor (VEGF) function can improve the efficacy of immunotherapy by modulating the tumor immune microenvironment. AK112 is the first-in-class humanized IgG1 bispecific antibody targeting programmed death-1 (PD-1) and VEGF. This study aimed to evaluate the efficacy and safety of AK112 combined with chemotherapy in patients with advanced non-small cell lung cancer (NSCLC). This open-label, multicenter, phase II clinical trial was conducted in 11 hospitals in China. Eligible participants were adults aged 18-75 years with locally advanced or metastatic NSCLC, an Eastern Cooperative Oncology Group performance status of 0 or 1, at least one measurable lesion, and an estimated life expectancy of at least 3 months. The participants were categorized into three cohorts based on prior therapy and functional genomic alterations. Patients in cohort 1 were previously untreated advanced NSCLC, had no epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK) gene modifications, and received AK112 combined with pemetrexed (500mg/m2) for non-squamous (non-sq)-NSCLC or paclitaxel (175mg/m2) for sq-NSCLC plus carboplatin (area under the curve of 5mg/mL per min) for four cycles, followed by AK112 with pemetrexed for non-sq-NSCLC and AK112 alone for sq-NSCLC as maintenance therapy. The participants in cohort 2 had advanced NSCLC with EGFR-sensitive mutations, failed previous EGFR-tyrosine kinase inhibitor (TKI) therapy, and received pemetrexed plus AK112 and carboplatin for four cycles, followed by pemetrexed plus AK112 as maintenance therapy. The participants in cohort 3 had advanced NSCLC who failed systemic platinum-based chemotherapy and anti-PD-1/programmed death-ligand 1 (PD-L1) treatments and received AK112 plus docetaxel (75mg/m2). Two dosages of AK112 (10 or 20mg/kg) were examined in each cohort, and the drug was administered intravenously on day 1 of each 3-week treatment cycle. The primary endpoints were the investigator-assessed objective response rate (ORR) and safety. This study was registered with ClinicalTrials.gov (NCT04736823). Eighty-three patients were enrolled from February 2021 to August 2022 and received the study treatment. Cohorts 1, 2, and 3 had 44, 19, and 20 patients, respectively. The confirmed ORR was 53.5% (23/43) [95% CI, 36.9-67.1], 68.4% (13/19) [95% CI, 43.4-87.4], and 40.0% (8/20) [95% CI, 19.1-63.9] in cohorts 1, 2, and 3, respectively. In cohort 1, the median PFS was not reached, and the 12-month PFS rate was 59.1%. In cohorts 2 and 3, the median PFS were 8.5 [95% CI, 5.5-NE] and 7.5 [95% CI, 2.3-NE] months, and the 12-month PFS rates were 35.5% and 44.5%, respectively. The most common grade ≥3 treatment-related adverse events were decreased white blood cell count [7 (8.4%)], neutropenia [5 (6.0%)], thrombocytopenia [2 (2.4%)], anemia [4 (4.8%)], and myelosuppression [2 (2.4%)]. AK112 plus platinum-doublet showed promising antitumor activity and safety not only in first-line treatment of advanced NSCLC patients without driver mutation but also in patients with EGFR-functional mutation who failed previous EGFR-TKI therapy and advanced NSCLC patients who failed prior systemic platinum-based chemotherapy and PD-1/PD-L1 inhibitor treatments, suggesting a valuable potential new treatment option for this patient population. Akeso Biopharma, Inc., Zhongshan, China, and National Natural Science Foundation of China.

Platinum resistance and sensitivity in recurrent/metastatic head and neck squamous cell carcinoma

ObjectiveFor patients with recurrent/metastatic head and neck squamous cell carcinoma (R/MHNSCC), platinum-free interval (PFI)-based differences in the effectiveness of rechallenge with platinum-based chemotherapy (PBCT) remain unknown. We aimed to evaluate the difference in platinum sensitivity based on PFI in R/MHNSCC. MethodsWe retrospectively examined 80 patients with R/MHNSCC who underwent PBCT between 2001 and 2020. Treatment efficacy was compared between patients with prior PBCT for treatment of recurrence/metastasis or concurrent chemoradiotherapy during radical treatment (rechallenge group) and those without (control group). Patients with prior PBCT (rechallenge group) were stratified by PFI. PFI was defined as the period from the last dosing date with the previous platinum agent to rechallenge with PBCT. ResultsOf 80 patients, 55 had been with prior PBCT (rechallenge group) and 25 had been without prior PBCT (control group).The rechallenge group was divided into three groups: PFI <6 months (10), PFI 6-11 months (17), and PFI ≥12 months (28). The PFI <6-month group had shorter overall survival (p=0.047, the log-rank test) and lower disease control rate (p=0.02, Fisher's exact test) than the control group. The PFI 6–11- and ≥12-month group outcomes did not significantly differ from those of the control group. ConclusionsPatients with PFI <6 months tend to have a poorer prognosis after rechallenge with PBCT than patients without prior PBCT, suggesting that PFI 6 months may be considered as a threshold of platinum resistance and rechallenge with PBCT may be a valid option in PFI ≥6 months.

Efficacy and safety of pralsetinib in patients with advanced RET fusion-positive non-small cell lung cancer.

Pralsetinib is a potent, selective RET inhibitor targeting oncogenic RET alterations. As part of the global, phase 1/2 ARROW trial (NCT03037385), the efficacy and safety of pralsetinib in Chinese patients with advanced RET fusion-positive non-small cell lung cancer (NSCLC) were evaluated. Adult patients with advanced, RET fusion-positive NSCLC with or without prior platinum-based chemotherapy were enrolled into two cohorts receiving 400-mg once-daily oral pralsetinib. Primary end points were objective response rates assessed by blinded independent central review and safety. Of 68 patients enrolled, 37 had received prior platinum-based chemotherapy (48.6% with ≥3 prior systemic regimens) and 31 were treatment-naïve. As of March 4, 2022 (data cutoff), of the patients with measurable lesions at baseline, a confirmed objective response was observed in 22 (66.7%; 95% confidence interval [CI], 48.2-82.0) of 33 pretreated patients, including 1 (3.0%) complete response and 21 (63.6%) partial responses; and in 25 (83.3%; 95% CI, 65.3-94.4) of 30 treatment-naïve patients, including two (6.7%) complete responses and 23 (76.7%) partial responses. Median progression-free survival was 11.7months (95% CI, 8.7-not estimable) in pretreated patients and 12.7months (95% CI, 8.9-not estimable) in treatment-naïve patients. The most common grade 3/4 treatment-related adverse events in 68 patients were anemia (35.3%) and decreased neutrophil count (33.8%). Eight (11.8%) patients discontinued pralsetinib because of treatment-related adverse events. Pralsetinib showed robust and durable clinical activity with a well-tolerated safety profile in Chinese patients with RET fusion-positive NSCLC. NCT03037385.

Emerging phase 1 data of BLU-451 in advanced NSCLC with EGFR exon 20 insertions.

9064 Background: In patients (pts) with NSCLC harboring EGFR exon 20 insertions (ex20ins), treatment options are limited, with platinum-based chemotherapy with/without programmed death-ligand 1 inhibitors being the standard of care in first line, and recent accelerated approvals of mobocertinib and amivantamab in the USA for second-line treatment. These second-line therapies have overall response rates of 28% and 40%, respectively, limited CNS activity, and are associated with AEs such as severe gastrointestinal AEs and edema. BLU-451 is an investigational, CNS-penetrant, potent, selective, and wild-type sparing EGFR tyrosine kinase inhibitor that is under investigation in the ongoing phase 1/2 CONCERTO trial (NCT05241873), including in pts with ex20ins. Methods: In phase 1 dose escalation using a 3+3 design, BLU-451 monotherapy was administered orally QD or BID and given in continuous 21-day cycles. The primary objectives include maximum tolerated dose (MTD) and/or recommended phase 2 dose (RP2D) determinations and safety. Key secondary objectives include antitumor activity, PK, and pharmacodynamics. Pts with EGFR ex20ins–positive NSCLC after prior platinum-based chemotherapy were enrolled. Prior ex20ins–targeted therapy and asymptomatic CNS disease were permitted. Tumor response was assessed per RECIST v1.1. Serial blood samples for analysis of BLU-451 PK and circulating tumor DNA (ctDNA) were collected. Results: As of Jan 20, 2023, 28 pts have been enrolled and dosed in 5 cohorts (100 mg–400 mg QD and 200 mg BID), including 19 (68%) pts with exon 20 insertions. The median number of prior systemic lines of therapy was 2.5 (range, 1–10), and 19/28 (68%) pts had prior ex20ins-targeted agents. The most common AEs were diarrhea (21%), cough (18%), fatigue (14%), pruritis (14%) and rash (14%); all were Grade 1 or 2. There were no dose-limiting toxicities. Partial responses, including a disappearance of a CNS target lesion, were seen, and early evidence of on-target activity with ctDNA reductions was observed. Conclusions: As of the data cutoff, BLU-451 monotherapy was generally well tolerated, with early evidence of clinical activity in heavily pretreated pts with EGFR ex20ins–positive NSCLC. Early data at initial dose levels consisted of tumor reduction including responses, CNS activity, and ctDNA responses. The dose escalation is ongoing to determine the MTD and/or RP2D. Clinical trial information: NCT05241873 .

Long-term survival outcomes and immune checkpoint inhibitor (ICI) retreatment in patients with advanced cervical cancer who received camrelizumab plus apatinib in the CLAP study.

e17513 Background: Camrelizumab (a programmed death 1 [PD-1] inhibitor) plus apatinib (a vascular endothelial growth factor receptor 2 [VEGFR2] inhibitor) showed promising efficacy and safety profiles in patient with advanced cervical cancer in the CLAP study (NCT03816553). Herein we present updated efficacy and safety data with more than 24 months of additional follow-up, and outcomes for patients retreated with ICIs following disease progression. Methods: In this single-arm phase 2 trial, 45 patients received camrelizumab (200 mg intravenously, q2w) and apatinib (250 mg orally, qd) on a 4-week cycle until disease progression, unacceptable toxicity, withdrawal of consent, or up to 2 years. For patients who completed 2 years treatment and were considered to benefit from continuing treatment, a one-year extension treatment would be provided if the patients agreed. Results: At the data cutoff (August 31, 2022), the median duration of follow-up was 11.9 (range, 1.0–43.9) months. Nine (20.0%) patients completed 2-year treatment (eight entered the one-year extension treatment, of which five completed and three discontinued due to disease progression) and 36 (80.0%) discontinued treatment (24 [53.3%] disease progression, 4 [8.9%] adverse events, 5 [11.1%] patient refusal, and 3 [6.7%] withdrawal of consent). The median duration of treatment was 6 (range, 0.9–37.4) months. The confirmed objective response rate was 55.6% (95% CI: 40.0, 70.4) that was unchanged from previous report, including two (4.4%) complete response (CR) and 23 (51.1%) partial response (PR). The median duration of response was 16.6 (95% CI, 5.6–29.9) months among 25 responders. Median progression-free survival (PFS) was 8.9 (95% CI, 5.6–18.1) months; the 12-month PFS rate was 40.7% (95% CI, 25.2–55.6). The median overall survival (OS) was 15.9 (95% CI, 9.3–36.9) months; the 24-month OS rate was 46.4% (95% CI, 30.1–61.1). Age &gt; 50, programmed death-ligand 1 (PD-L1) combined positive score (CPS) ≥ 1, CPS ≥ 10, TMB-high, and PIK3CA mutation were associated with longer OS. Seven patients were retreated with the same or other ICIs after disease progression. All of them showed initial response (one CR and 6 PR) to study treatment, then had progressive disease (PD) and discontinued treatment. Of the seven patients, six achieved stable disease and one had PD following ICIs retreatment. Four patients died and three were alive at the data cutoff. Two patients received ICIs retreatment for more than 20 months, one of which was still on ICIs retreatment. No new safety signals were identified with additional 24-month follow-up. Conclusions: This long-term follow-up data demonstrate sustained and durable efficacy of camrelizumab plus apatinib, with no new safety signals, in patients with advanced cervical cancer who progressed after prior platinum-based chemotherapy. Clinical trial information: NCT03816553 .

Bemcentinib and pembrolizumab in patients with relapsed mesothelioma: MIST3, a phase IIa trial with cellular and molecular correlates of efficacy.

8511 Background: AXL receptor tyrosine kinase is a key facilitator of immune escape and drug resistance, conferring a more aggressive phenotype. Targeting the PD1-PDL1 axis has demonstrated significant efficacy in patients with relapsed malignant mesothelioma (MM), however, responses are only observed in a fraction of patients. Preclinical studies suggest that dual PD1 and AXL inhibition is synergistic. We developed a multi-centre, molecularly stratified phase IIa trial to evaluate the efficacy of AXL/PD-1 inhibition with bemcentinib (Bem)/pembrolizumab (Pem) and to uncover cellular and molecular determinants of efficacy as arm 3 of the Mesothelioma Stratified Therapy umbrella trial (NCT03654833, MiST3). Methods: Patients with pleural mesothelioma were enrolled. Key inclusion factors were ECOG performance status (PS) 0-1, prior platinum-based chemotherapy (maximum of 2 prior lines allowed), evidence of disease progression with measurable disease by CT (Modified RECIST 1.1), and adequate haematological/organ function. All patients received 200mg Pem IV q3W in combination with Bem, loading dose 400mg PO for the first 3 days and then 200mg od q3w. Primary endpoint was disease control rate at 12 weeks (DCR12w). Secondary endpoints: DCR at 24 weeks (DCR24w), best objective response rate (ORR) and toxicity (NCI CTCAE 4.03). Pre-treatment fresh biopsy was required to enable multiplex immunofluorescence, whole exome and RNA transcriptome sequencing. Gut microbiome 16s RNA sequencing also was undertaken at baseline (n=21). Results: Between September 2020 and March 2022, 26 patients with MM started treatment and received at least one dose of Pem Bem. Median age was 72.5 (range, 55-85) years, 88% were male 12% were female, Histology: 88% epithelioid, 8% Biphasic, 4% Sarcomatoid, ECOG PS1 77%, &gt; 1 prior systemic therapy 35%. The median cycles of Pem Bem was 4 (IQR, 2-11). The DCR12w was 46.2% (12/26) (90% confidence limit (CI), 29.2% –63.4 %;), ORR was 15.4% (95%CI, 4.4- 34.9%; all PR)) with stable disease in 57.7% (36.9 – 76.6%); DCR24w was 38.5% (10/26) (95%CI, 20.2% – 59.4%). Adverse events (any cause): ≥ grade 3 toxicities affected 38% of pts and there were no treatment-related deaths. The most frequent adverse events recorded were fatigue in 12/26 (46%) patients and nausea in 11/26 (42%) patients. Conclusions: MiST3 met its primary endpoint and warrants further evaluation. Analysis of the cellular and molecular correlates of response are ongoing and will be presented. Clinical trial information: NCT03654833 .

Preliminary dose escalation results from a first-in-human, phase I/II study of GB263T, a novel EGFR/cMET/cMET trispecific antibody, in patients with advanced EGFR-mutated (EGFRm) non-small cell lung cancer (NSCLC).

e21085 Background: GB263T, a novel trispecific antibody directed against EGFR and cMET, adopts the design of two humanized VHH antibodies that recognize two different cMET epitopes, in which a conformational change induced by the first VHH binding exposes the second epitope for the second VHH to bind. Sequential binding of the two VHH antibodies to cMET increases tumor specificity, which results in widening of the safety window. In vitro studies show that GB263T induces better antigen-antibody molecular endocytosis, more completely blocks the signal transduction pathway, and has better ADCC activity compared to a benchmark. In addition, GB263T has demonstrated promising pre-clinical activity in models with various EGFR/cMET alterations. Here, we report the preliminary dose escalation results of the first-in-human phase I/II study of GB263T in patients (pts) with advanced EGFRm NSCLC (NCT05332574). Methods: This multicenter (China and Australia), phase I/II study was conducted using an accelerated titration method followed by a traditional 3+3 design for dose escalation. Pts with EGFRm NSCLC with prior EGFR TKI and platinum-based chemotherapy were enrolled. GB263T was given at 140-1680 mg (5 dose cohorts) IV weekly for the first two 28-day cycles and biweekly thereafter. Objectives were to evaluate the safety and tolerability, determine the maximum tolerated dose (MTD) and the recommended Phase 2 dose (RP2D), and assess the pharmacokinetics, immunogenicity, and preliminary efficacy of GB263T. Results: As of Feb 7, 2023, 6 pts were treated: 140mg (n = 1), 420mg (n = 1), 840mg (n = 3), 1260mg (n = 1). The enrolment of the 1260mg cohort is ongoing. All pts had received previous third-generation EGFR-TKI and platinum-based chemotherapy. Medium treatment duration was 49.5 days (range 2-113). No DLTs were observed. Five (83.3%) pts experienced treatment-related AEs (TRAEs), and all TRAEs were mild (grade 1/2): infusion related reaction (n = 3, 50%), rash (n = 2, 33%), mouth ulcer (n = 1, 17%), fatigue (n = 1, 17%), GGT increased (n = 1, 17%), ALP increased (n = 1, 17%) and direct bilirubin increased (n = 1, 17%). There were no treatment-related discontinuations. Among five response-evaluable pts, three (60%) achieved stable disease (SD). Tumor shrinkage was observed in all three SD pts, with a maximum reduction of 17% in the target lesion. All three SD pts remained on treatment at data cutoff. Conclusions: Results to date demonstrate a favorable safety profile with early signal of clinical activity. Continued dose escalation and clinical investigation of GB263T is ongoing. Updated data will be presented. Clinical trial information: NCT05332574 .

Evaluating the efficacy and safety of pembrolizumab monotherapy or in combination with standard chemotherapy in the first-line treatment of locally recurrent head and neck squamous cell carcinoma in different TP53 and PI3K statuses.

e18014 Background: Pembrolizumab (pembro)-based therapy is currently widely used in recurrent/metastatic head and neck squamous-cell carcinoma (R/M HNSCC). The study will explore the association between different TP53 and PI3K statuses and survival in locally recurrent HNSCC. Methods: This is a prospective, single-center study analyzing patients with locally recurrent HNSCC and prior platinum-based chemotherapy for at least 6 months without progression. Patients received pembro monotherapy (200mg) or pembro plus standard chemotherapy (PF, TP, P, G, GP; paclitaxel 175mg/m2, cisplatin 100 mg/m2, 5-fluorouracil 1000 mg/m2 per day for 4 consecutive days, Gemcitabine 1000mg/m2 day 1 and day 8) every 21-day for 6 cycles and followed by pembro maintenance therapy until progression or unacceptable toxicity or 35 cycles, whichever occurred first. Patient’s response to the therapy was evaluated using RECIST 1.1. Primary endpoint was PFSITT,PFSTP53mut,PFSTP53wt, PFSPI3Kmut/amp and PFSPI3Kwt. Secondary endpoint was ORR, DCR and OS of ITT patients and combination group. Results: From January 8, 2020 until September 20 2022, 20 patients were enrolled. Median age was 56 (range 47-73). Baseline HPV positive (1,5%), HPV negative (12,60%) and HPV unknow (7,35%). TP53mut (9,45%) and TP53wt (7,35%), TP53 unknow (4,20%). PI3Kmut/amp (2,10%) and PI3Kwt (11,55%), PI3K unknow (7,35%). CPS≥20 (3,15%), CPS 1-19 (9,45%), CPS unknow (8,40%). Primary region showed that 1 patients (5%) in the oral cavity, 2 (10%) in the oropharynx, 7 patients (35%) in the larynx, 4 (20%) in the hypopharynx, 2 (10%) in the sins, 1 (5%) in the epithelial-myoepithelial and 3 (15%) in the unknown primary site. There were 16 patients (80%) with only local recurrent disease, 4 (20%) with local disease combined with distant diseases at enrollment. Median follow-up was 2 years. Adverse reactions are overall controllable (Table), but who one died with grade 4 cardiotoxicity The mPFSITT was 4.9 months, PFSmono was 4 months and PFScombination was 4.93 months (p=0.89). The mPFSITT+TP53mut was 5.1 months, mPFSITT+TP53wt was 4.6 months (p=0.63). mPFSITT+PI3Kmut/amp was 7.2 months and mPFSITT+PI3Kwt was 4.6 months. The ORRITT was 73.7% (14/19) and no complete response was achieved. The ORRcombination was 66.7% (10/15). The DCRITT and DCRcombination were all 100% . (Not included 1 died). The median OS was not reached. Conclusions: This study proves that pembro alone and combined with standard chemotherapy has good efficacy and safety in locally recurrent HNSCC, and the statuses of TP53 and PI3K may be an important factor for the prognosis of immunotherapy. Acknowledgement: Thanks MSD China Medical Affair oncology team for giving scientific support. Clinical trial information: ChiCTR2100046731 . [Table: see text]

RAMP 202: A phase 2 study of avutometinib (VS-6766) ± defactinib, in patients with advanced KRAS G12V mutant non–small cell lung cancer (NSCLC).

9100 Background: KRAS mutations (mt) occur in ~30% of lung adenocarcinomas, among which G12C is most common (40%), followed by G12V (22%) and G12D (16%). Approved treatments for advanced KRAS mt NSCLC (excluding G12C) are limited to chemotherapy and immune checkpoint inhibitors (ICIs). Avutometinib is a novel small molecule RAF/MEK clamp. Focal adhesion kinase (FAK) activation is a resistance mechanism to RAF/MEK inhibition. Defactinib, a small molecule FAK inhibitor, has shown synergistic antitumor activity with avutometinib in preclinical models. In prior studies, avutometinib ± defactinib has shown responses in patients (pts) with KRAS mt NSCLC, including KRAS G12V. Methods: RAMP 202 is a randomized, phase 2, adaptive, multicenter, open-label study evaluating the efficacy and safety of avutometinib ± defactinib in previously-treated KRAS mt NSCLC (NCT04620330). Key inclusion criteria include histologically confirmed NSCLC with known KRAS mt and ≥1 prior systemic therapy (platinum-based and immune checkpoint inhibitor or appropriate therapy for activating mutation). Part A evaluated the optimal regimen, either 4.0 mg avutometinib orally (PO), twice weekly, 3 weeks on, 1 week off (mono) or 3.2 mg avutometinib PO twice weekly + 200 mg defactinib PO twice per day, 3 weeks on, 1 week off (combo) in pts with KRAS G12V mt NSCLC. Primary endpoint was confirmed objective response rate (ORR) by blinded independent central review. The optimal regimen determined in Part A would subsequently be assessed for efficacy in Part B. Exploratory assessment of ORR is also planned in KRAS-other (non-G12V) NSCLC. Results: Of 35 pts with KRAS G12V enrolled to Part A, 16 pts received mono, and 19 received combo. Patients received up to 5 lines of prior systemic therapy (median 2), including prior platinum-based chemotherapy, ICIs, and bevacizumab. No confirmed responses were seen in the mono group. In the combo group, 2 pts (11%) experienced a confirmed partial response. The duration of each response was 7.9 and 8.5 months, with both ongoing at data cut. The majority of treatment-related adverse events (TRAEs, any grade) (N = 72) were mild to moderate. The most common Grade ≥3 TRAEs included blood CPK increase (11.1%), diarrhea (5.6%), anemia (5.6%), and rash (1.4%). Most AEs were manageable/reversible. Conclusions: In this heavily pretreated population of patients with KRAS G12V mt NSCLC, limited clinical activity was observed with combination therapy. While no new safety signals were identified, criteria to proceed to part B were not met, and further evaluation of avutometinib ± defactinib in KRAS G12V mt NSCLC will not be pursued. Additional trials evaluating rational avutometinib combinations (sotorasib, adagrasib, everolimus) are ongoing in patients with KRAS mt NSCLC. Clinical trial information: NCT04620330 .

Adjuvant treatment for resectable non-small cell lung cancer

Background: Low-dose chest computed tomography is being increasingly used to screen for lung cancer, and the proportion of early diagnoses of patients with lung cancer in potentially resectable stages is increasing. After complete resection, reducing the possibility of postoperative relapse is of the utmost priority. In this review, recent updates in adjuvant treatment for resectable non-small cell lung cancer (NSCLC) were briefly explained.Current Concepts: Even though platinum-based adjuvant chemotherapy was traditionally used, there was only a small increase in overall survival and a 15% decrease in relapse.Discussion and Conclusion: With the advent of immunotherapy and epidermal growth factor receptor tyrosine kinase inhibitors, the landscape of adjuvant treatment for completely resectable NSCLC is rapidly changing. The ADAURA study showed that adjuvant osimertinib, regardless of prior platinum-based postoperative chemotherapy, significantly extended disease-free progression survival in epidermal growth factor receptor mutation-positive patients with resectable NSCLC. The IMpower010 study showed that postoperative atezolizumab can be an option in patients without targetable mutations for reducing the possibility of postoperative relapse. Postoperative radiotherapy can be beneficial for patients with lymph node metastases (N2).