bluuebunny/crossref_metadata_2025 huggingface dataset:
A phase 1, multicenter, open-label, dose-escalation and dose-expansion study to evaluate the safety, tolerability, pharmacokinetics (PK), and efficacy of HS-10382 (TERN-701) in patients (pts) with chronic myeloid leukemia (CML).
Authors: Li Weiming , Xu Na , Xu Zhongyuan , Zhang Yanli , Li Junmin , Zhu Huanling , Zheng Li , Yan Xiaojing , Du Xin , Wei Hongying , Huang Qiqi , Wei Jiawei , Hu Yu
Published: June 2023

TPS7081

Background: There is a need for new treatment options for pts with CML who are intolerant/resistant to currently available BCR-ABL1 ATP-binding site targeted tyrosine kinase inhibitors (TKIs). HS-10382 (TERN-701) is a potent, oral small molecule allosteric inhibitor of BCR-ABL. By binding to the myristoyl site of the BCR-ABL1 protein, HS-10382 (TERN-701) locks BCR-ABL1 into an inactive conformation. This results in a mutation-driven resistance profile different from that of ATP-binding site TKIs, providing potential for both monotherapy and combination therapy with ATP-binding site TKIs. In preliminary nonclinical assays, HS-10382 (TERN-701) was highly potent against wild type BCR-ABL1 as well as most common mutations acquired by pts treated with second generation active site TKIs. This ongoing first-in-human phase 1 study is evaluating HS-10382 (TERN-701) in pts with CML. Methods: Eligible adult CML chronic phase (CP) or advanced phase (AP) pts who are resistant or intolerant to prior BCR-ABL-1 TKI therapy are enrolled in an open-label Phase 1 study to evaluate the safety, tolerability, PK and efficacy of HS-10382 (TERN-701). This study is being conducted in two parts: Part 1 dose escalation utilizing a rolling six design and Part 2 dose expansion. In the dose escalation stage, CML-CP/AP pts who are resistant or intolerant to prior BCR-ABL-1 therapy are being enrolled to determine the maximum tolerated dose (MTD) or maximum applicable dose. Doses selected from the escalation part will be evaluated in the expansion stage in CML-CP pts who are resistant or intolerant to prior BCR-ABL-1 TKI therapy and have no T315I mutation. All pts will be carefully followed for adverse events for the duration of study treatment and for 28 days after the last dose of study drug. Pts will be permitted to continue therapy with assessments for progression if the study drug is well-tolerated and the pt has no objective evidence of disease progression. This study is ongoing (enrollment underway for Part 1, dose 3 as of February 2023) with 7 participating study sites in China. Clinical trial information: NCT05367700 .
Phase 1 study to determine the safety and efficacy of onvansertib, a novel, oral, PLK1 inhibitor in patients with proliferative chronic myelomonocytic leukemia relapsed/refractory or intolerant to available therapies.
Authors: McCullough Kristen , Mangaonkar Abhishek A , Burgess Ashya R. , Al-Kali Aref , Alkhateeb Hassan B. , Begna Kebede , Gangat Naseema , Geyer Susan Michelle , Hogan William J. , Litzow Mark Robert , Reichard Kaaren , Saliba Antoine N , Shah Mithun Vinod , Wolanskyj-Spinner Alexandra P. , Patnaik Mrinal Mahesh
Published: June 2023

TPS7089

Background: Chronic myelomonocytic leukemia (CMML) is a myelodysplastic/myeloproliferative overlap neoplasm (MDS/MPN) that can be further divided into MD (WBC < 13 x 109/L) and MP (≥13 x 109/L) subtypes. MP-CMML is enriched in RAS pathway mutations ( NRAS, CBL, KRAS, PTPN11 and NF1), has a shorter median survival (19 vs 36 months), has a higher rate of acute myeloid leukemia (AML) transformation (40% vs 10%) and has a unique transcriptomic and epigenetic composition. These RAS pathway mutations promote selective PLK1 overexpression, a mitotic checkpoint kinase. Given the relative inefficacy of hypomethylating agents (HMA) in MP-CMML and previously demonstrated in vitro and in vivo efficacy data for PLK1 inhibition on MP-CMML with RAS pathway mutations, we designed a phase 1 clinical trial testing the safety of onvansertib, a novel, orally bioavailable, PLK1 inhibitor in relapsed/refractory MP-CMML. Methods: This is an investigator-initiated, prospective, open-label, phase I study of onvansertib in MP-CMML relapsed/refractory (RR) or intolerant to existing therapies including HMA and hydroxyurea. The primary endpoint is characterization of safety. Secondary endpoints include efficacy as defined by the 2015 MDS/MPN International Working Group criteria, volumetric spleen response and symptom response via assessment with MPN-SAF-TSS. Inclusion criteria include MP-CMML RR following hydroxyurea or at least 4-cycles of HMA or intolerance of treatment with either, platelets ≥ 20,000/m3 and Cockcroft-Gault creatinine clearance ≥ 60 mL/min/m2. Hydroxyurea may continue for the first 28 days on study. Onvansertib will be given orally on days 1 through 21 of a 28-day cycle with a Bayesian optimal interval design to assess the safety and recommended phase II dose. Exploratory end points include targeting efficacy, impact of PLK1 and KMT2A expression and interactions with ASXL1 and TET2 mutations. Twenty-five patients will be enrolled at Mayo Clinic in Minnesota, with enrollment open since November 2022. Clinical trial information: NCT05549661 .
BRUIN CLL-314: A phase 3, open-label, randomized study of pirtobrutinib versus ibrutinib in patients with chronic lymphocytic leukemia/small lymphocytic lymphoma.
Authors: Woyach Jennifer Ann , Coombs Catherine Callaghan , Lewis Katharine L. , Escalon Maricer P. , Ceccarelli Matteo , Bian Yuanyuan Faith , Wierda William G.
Published: June 2023

TPS7584

Background: Covalent (c) Bruton tyrosine kinase inhibitors (BTKi) have transformed the management of chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), but these agents are not curative. cBTKi share pharmacologic liabilities such as low oral bioavailability and a short half-life that may lead to suboptimal BTK target coverage, especially in rapidly proliferating tumors with high BTK protein turnover, such as accelerating CLL/SLL, which can manifest as acquired resistance to cBTKi. Novel therapeutic agents addressing both intolerance and resistance while also improving efficacy are needed. Pirtobrutinib, a highly selective, non-covalent (reversible) BTKi, inhibits both wildtype and C481-mutant BTK with equal low nM potency and has favorable oral pharmacology that enables continuous BTK inhibition throughout the dosing interval regardless of intrinsic rate of BTK turnover. In the phase 1/2 BRUIN study, pirtobrutinib demonstrated promising durable overall response rates (ORR) and was well tolerated in patients with CLL/SLL irrespective of prior therapy (including cBTKi), number of prior lines of therapy, BTK C481 mutation status, or reason for prior cBTKi discontinuation. The objective of this study is to compare efficacy and tolerability of pirtobrutinib versus ibrutinib in patients with CLL/SLL. Methods: BRUIN CLL-314 (NCT05254743) is a global, phase 3, open-label, randomized study comparing pirtobrutinib with ibrutinib. Approximately 650 BTKi-naïve patients, either treatment-naïve (up to 30%) or previously treated with other non-BTKi agents, will be randomized 1:1 to receive daily 200 mg pirtobrutinib once daily or 420 mg ibrutinib as continuous monotherapy. Randomization will be stratified by del(17p) status (yes/no) and number of prior lines of therapy (0 vs 1 vs ≥2). Enrollment for this study is ongoing. Adults with CLL/SLL who require therapy per iwCLL 2018 criteria are eligible. Key exclusion criteria include prior exposure to any BTKi, use of some concomitant therapies including anticoagulants, such as warfarin and other vitamin K antagonists, significant cardiovascular disease, active infections, and other clinically significant conditions. The primary objective is to establish non-inferiority of pirtobrutinib versus ibrutinib by comparing the ORR per iwCLL guidelines assessed by an independent review committee. Superiority of pirtobrutinib versus ibrutinib in progression-free survival is a key secondary outcome. Other endpoints include duration of response, overall survival, time-to-next treatment, tolerability, and patient-reported outcomes. Trial efficacy and safety will be monitored by an independent data monitoring committee. Clinical trial information: NCT05254743 .
MajesTEC-9: A randomized phase 3 study of teclistamab versus pomalidomide, bortezomib, and dexamethasone or carfilzomib and dexamethasone in patients with relapsed/refractory multiple myeloma.
Authors: Touzeau Cyrille , Hungria Vania TM , Bhutani Divaya , Landgren Ola , Vieyra Diego , Guo Yue , Verona Raluca , Miao Xin , Qi Mia , Watkins Latisha , Shah Priya , Chastain Katherine , Qi Ming , Quach Hang
Published: June 2023

TPS8067

Background: Despite the advance in therapeutic options for patients with relapsed/refractory multiple myeloma (RRMM) over recent years, there remains a significant unmet medical need for new, well-tolerated therapies in earlier lines for patients who have previously received an anti-CD38 monoclonal antibody and lenalidomide. Teclistamab is the first B-cell maturation antigen (BCMA)-directed bispecific antibody approved for the treatment of triple class-exposed RRMM. Teclistamab redirects CD3+ T cells to mediate T-cell activation and subsequent lysis of BCMA-expressing myeloma cells. MajesTEC-9 (NCT05572515) is a phase 3, randomized, open-label, multicenter study comparing teclistamab with investigator’s choice of pomalidomide, bortezomib, and dexamethasone (PVd) or carfilzomib and dexamethasone (Kd) in patients with RRMM. Methods: Patients aged ≥18 years with RRMM (International Myeloma Working Group [IMWG] criteria) must have evidence of progressive disease or failure to achieve a response to last line of therapy and an Eastern Cooperative Oncology Group performance status score of 0–2. All patients must have received 1–3 prior lines of therapy, including ≥2 consecutive cycles of an anti-CD38 monoclonal antibody and ≥2 consecutive cycles of lenalidomide. Those treated with prior BCMA-directed therapy will be excluded. Approximately 590 patients will be randomized 1:1 to receive either teclistamab (28-day cycles) or PVd (21-day cycles) or Kd (28-day cycles). Stratification factors include investigator’s choice of PVd or Kd, stage of disease, number of prior lines of therapy, and anti-CD38 monoclonal antibody refractory status. Treatment will continue until disease progression, death, intolerance, withdrawal of consent, or end of study, whichever occurs first. The primary endpoint is progression-free survival (IMWG 2016 criteria); secondary endpoints include overall response rate, duration of response, and overall survival. Adverse events (AEs) will be graded by Common Terminology Criteria for AEs v5.0; cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome will be graded by American Society for Transplantation and Cellular Therapy criteria. The study opened in January 2023 and enrollment is ongoing. Clinical trial information: NCT05572515 .
A phase I-III platform study evaluating the safety and efficacy of multiple therapies in patients with biomarker-defined locally advanced, unresectable stage III non–small-cell lung cancer (NSCLC).
Authors: Paz-Ares Luis G. , Gay Carl Michael , Zhou Caicun , Kato Terufumi , Corrales Luis , Redhead Karl , Rahman Ahmadur , Bradley Denise , Theogaraj Elizabeth , Hutchinson Katherine E. , Shagan Sarah M. , Solomon Benjamin J.
Published: June 2023

TPS8605

Background: Durvalumab following chemoradiation (CRT) is a standard of care for unresectable stage III NSCLC, but there remains an unmet need for improved therapeutic options among patients with driver-mutated tumors that are unresponsive to immunotherapy. As targeting of specific driver mutations (e.g. ALK, RET, ROS1) has proven effective in the metastatic setting, it is hypothesized that outcomes could also be improved for patients with driver-mutated stage III NSCLC. Methods: BO42777 (NCT05170204) is a phase I–III platform study evaluating the safety and efficacy of multiple targeted therapies versus durvalumab following CRT in patients with locally advanced, unresectable stage III NSCLC. Biomarker eligibility is determined via local tissue testing or central testing within the BX43361 master screening study (NCT05419375). Biomarker-eligible patients are enrolled into the relevant cohort and randomized 1:1 to receive durvalumab or targeted therapy (alectinib [ ALK+], entrectinib [ ROS1+], or pralsetinib [ RET fusion+]). New cohorts may be added in the future. Key inclusion criteria: locally advanced, unresectable stage III NSCLC, age ≥18 years, ≥2 prior cycles of concurrent or sequential CRT (cCRT or sCRT), and ECOG PS 0–2. Patients are stratified based on staging (IIIA vs IIIB or IIIC), CRT type (cCRT vs sCRT), and PD-L1 status (tumor cell score < 1% vs ≥1% vs unknown) and will receive investigational treatment for three years or durvalumab for one year, until progression or maximum duration of treatment, unacceptable toxicity, consent withdrawal, or death. Primary endpoint: progression-free survival (RECIST v1.1) by blinded independent central review. Key secondary endpoints: distant metastasis-free survival, time to CNS progression, objective response rate, duration of response, overall survival, and safety (adverse events). Time to confirmed deterioration and patient-reported outcomes will be assessed through questionnaires. Tumor response will be assessed by CT/MRI imaging at regular intervals. Enrolment is ongoing (target of 320 patients) across 200 sites in 11 countries. As of 7 February 2023, five patients have been randomized. This trial in progress was previously presented at ELCC, Luis Paz-Ares et al. (#744), and reused with permission. Clinical trial information: NCT05170204 .
A randomized, double blinded, multicenter phase 3 study of platinum-based chemotherapy with or without QL1706 as adjuvant therapy in completely resected stage II-IIIb NSCLC.
Authors: Zhu Yuming , Jiang Tao , Fang Lianghua , Zhang Tao , Kang Xiaoyan , Zhou Caicun
Published: June 2023

TPS8606

Background: Adjuvant atezolizumab is approved for PD-L1 positive stage II-IIIA NSCLC in USA and China. To date, there are few clinical studies on dual immune checkpoint inhibitors in adjuvant settings of NSCLC. QL1706, a MabPair product, is a novel bifunctional antibody containing a mixture of anti-PD-1 IgG4 and anti-CTLA-4 IgG1 antibodies. QL1706 monotherapy has demonstrated good safety and promising antitumor activity in advanced solid tumors in a phase Ia/Ib study with 518 patients, including 146 NSCLC patients. Meanwhile, in NSCLC patients with negative oncogene drivers, QL1706 plus 2 cycles of chemotherapy as first line treatment resulted in an ORR of 58.6% (17/29) and the mPFS was 6.97 months. Furthermore, in the EGFR mutant NSCLC patients who previously were treated with EGFR-TKI, QL1706 plus platinum-based chemotherapy and bevacizumab showed promising efficacy with an ORR of 64.5% (20/31). This study is designed to investigate the efficacy and safety of QL1706 or placebo plus platinum doublet chemotherapy as adjuvant treatment in stage II-IIIB NSCLC. Methods: In this phase Ⅲ, randomized, double-blind, placebo-controlled, multicenter study, 632 eligible pts, who is completely resected stage Ⅱ-ⅢB NSCLC (AJCC 8th) with negative EGFR, ALK etc, will be enrolled. Pts will be randomized 1:1 to receive QL1706 (5 mg/kg) or placebo plus chemotherapy, administered every 3 weeks (Q3W). The regimen of vinorelbine/paclitaxel plus cisplatin/carboplatin is chosen for squamous NSCLC, while pemetrexed/vinorelbine plus cisplatin/carboplatin for non-squamous NSCLC. Randomization will be stratified by PD-L1 TPS (ie, < 1%, ≥1%), disease stage (stage II, III) and predominant tumor histology (ie, squamous vs non-squamous). The primary endpoint is disease-free survival (DFS) per investigators in PD-L1 TPS ≥1% pts and in all randomized pts, which will be tested hierarchically. An interim analysis is to occur when about 70% DFS events achieved in pts with PD-L1≥1%. Enrollment began in Nov, 2022. ClinicalTrials.gov NCT05487391. Clinical trial information: NCT05487391 .
A phase III study of lurbinectedin alone or in combination with irinotecan vs investigator's choice (topotecan or irinotecan) in patients with relapsed small cell lung cancer (SCLC; LAGOON trial).
Authors: Besse Benjamin , Paz-Ares Luis G. , Peters Solange , Cappuzzo Federico , Reck Martin , Calles Antonio , Califano Raffaele , Lopez-Vilariño Jose Antonio , Veramendi Susie , Kahatt Carmen Maria , Zeaiter Ali Hassan , Sands Jacob
Published: June 2023

TPS8613

Background: Lurbinectedin is a novel synthetic chemical entity that acts as an inhibitor of oncogenic transcription and is active in tumors addicted to transcription. A phase II Basket trial (NCT02454972) in patients with small cell lung cancer (SCLC) treated with lurbinectedin in the second-line setting showed overall response rate (ORR) of 35.2% and median duration of response (DoR) of 5.3 months, with durable responses (43.0% ≥ 6 months). Based on these results, lurbinectedin was granted accelerated approval by the US FDA. An ongoing phase I/II trial (NCT02611024) is evaluating the lurbinectedin/irinotecan combination. Preliminary results showed ORR of 62% and median DoR of 5.7 months (2020 World Conference on Lung Cancer) warranting expansion to 100 patients. These results have supported the conduction of a phase III trial (LAGOON - NCT05153239). Methods: LAGOON is a randomized phase III clinical trial evaluating two experimental arms (lurbinectedin alone, 3.2 mg/m2 D1 q3wk, or lurbinectedin 2 mg/m2 D1 plus irinotecan D1, D8 q3wk) versus Investigator’s Choice (topotecan D1-5 q3wk or irinotecan D1 q3wk according to label) as control arm in relapsed SCLC patients. Approximately 705 patients will be enrolled. Central randomization will be implemented (1:1:1 ratio). Stratification will be done according to chemotherapy-free interval (CTFI) after first line (sensitive vs. resistant); prior anti-PD-(L)1; baseline central nervous system (CNS) involvement; lactate dehydrogenase value, and Investigator’s preference for the Control Arm. Main inclusion criteria include age ≥ 18 years, confirmed SCLC diagnosis, one prior line of platinum-containing chemotherapy with/without anti-PD-(L)1, and CTFI ≥ 30 days. Patients with CNS metastases can participate if pretreated and radiologically stable for at least 4 weeks. Main exclusion criteria include platinum-naïve patients, patients pretreated with more than one prior chemotherapy regimen (including platinum re-challenge), and prior treatment with lurbinectedin, trabectedin, PM14, or topoisomerase I inhibitors. An Independent Data Monitoring Committee will oversee the conduct of the study. An Independent Review Committee will provide the patient’s response at each tumor assessment endpoint to determine the best patient’s response and the date of objective response or progression/censoring according to RECIST v.1.1. Clinical trial information: NCT05153239 .
Phase II study of hemithoracic intensity-modulated pleural radiation therapy (IMPRINT) for patients with pleural metastases from thymic malignancies.
Authors: Rimner Andreas , Huang James , Pagano Andrew , Ginsberg Michelle S. , Chang Jason C. , Riely Gregory J. , Simone Charles B. , Gomez Daniel Richard , Shepherd Annemarie
Published: June 2023

TPS8616

Background: Pleural metastases are common sites for recurrence and progression in patients with thymic malignancies. The management of pleural metastases typically involves surgical resection with or without neoadjuvant or adjuvant systemic therapy. After surgical resection of pleural metastases, the 5-year progression-free survival (PFS) rate is about 29-45%. While radiation therapy (RT) is standardly used in the management of locally-advanced thymic malignancies, the role of RT in patients with pleural metastases in unclear. Intensity-modulated pleural radiation therapy (IMPRINT) is a RT technique currently being used to treat malignant pleural mesothelioma (MPM) patients with 2 intact lungs at centers that specialize in MPM treatment. This IMPRINT technique can potentially be extrapolated to thymic patients with pleural metastases. Because the risk of toxicity is of greater concern for thymic patients given their overall relatively favorable prognosis, the rate of toxicity, particularly radiation pneumonitis, needs to be established in the thymic patient population. Methods: This is a single-arm, single institution Phase II study of hemithoracic IMPRINT for patients with pleural metastases from thymic malignancies. The primary endpoint of this study is grade 3 or higher radiation pneumonitis within 4 months of completing RT. Secondary endpoints include any toxicity, progression-free survival, patterns of failure and overall survival. Patients must have a pathologically confirmed diagnosis of a thymic malignancy with radiologic or pathologic evidence of pleural metastases. Thymoma or thymic carcinoma are allowed. Patients may have de novo stage IVA disease or recurrent disease in the pleura. There must be no evidence of extrathoracic metastatic disease or contralateral pleural/pericardial disease. Surgical resection of the pleural nodules (ex: pleurectomy/decortication, debulking/metastasectomy) are allowed. Extrapleural pneumonectomy is not allowed. Patients are excluded if they have undergone prior thoracic radiation therapy preventing hemithoracic pleural IMRT, whereas prior thymic bed radiation and/or prior pleural SBRT are allowed. RT will be administered to the ipsilateral pleura to 50.4 Gy in 28 fractions. An optional dose-painting boost to gross disease up to 60 Gy while respecting normal tissue constraints is allowed. Patients can be treated with photon or proton therapy. Simulation, contouring and RT planning guidelines have been developed. Patients will be followed per protocol at regular intervals for at least 12 months following RT. The expected accrual is 36 patients over 4 years. Further information can be found on clinicaltrials.gov (NCT05354570). Clinical trial information: NCT05354570 .
Circulating tumor DNA to guide furmonertinib monotherapy or combination therapy in advanced EGFR mutant non-small cell lung cancer (NSCLC): A randomized, open-label, multicenter study (FOCUS-C).
Authors: Fang Wenfeng , Jia Jun , Jiang Guanming , Dong Xiaofang , ShangGuan Zongxiao , Han Zhengxiang , Shen Hong , Zhang Li
Published: June 2023

TPS9150

Background: Detection of EGFR ctDNA after several weeks EGFR-TKIs treatment was an effective method to identify prognosis of advanced EGFR mutant NSCLC patients. Patients with uncleared EGFR ctDNA had shorter progression-free survival (PFS) ( Mack PC et al; CCR 2022). However, whether they can benefit from EGFR-TKI combination therapy has not been reported. Furmonertinib (AST2818), a potent, orally bioavailable, highly brain penetrant, third generation EGFR-TKI with unique chemical structure designed to improve potency and specificity, showed superior efficacy compared with gefitinib as first-line therapy in EGFR mutant NSCLC along with an acceptable safety profile without new signals ( Shi, YK et al.; Lancet Respir Med 2022). We hypothesized that monitoring clearance of EGFR ctDNA in blood could rationally guide subsequent monotherapy or combination therapy with furmonertinib and will improve outcomes in patients with uncleared EGFR ctDNA. Methods: The FOCUS-C study is a multicenter, open-label, randomized study. Patients who are aged 18 years or older and have histologically confirmed, locally advanced or metastatic, stage IIIB, IIIC, or IV unresectable NSCLC with EGFR exon 19 deletions (19Del) or exon 21 Leu858Arg mutation (L858R) on tissue biopsy and plasma will be treated with furmonertinib. Eligible patients with uncleared EGFR 19Del or L858R ctDNA after 3 weeks furmonertinib treatment will be stratified according to EGFR mutation (19Del or L858R), central nervous system metastases (with or without) and detectable accompanying gene aberrances in plasma (with or without) and randomly assigned (2: 2: 1) to receive furmonertinib or furmonertinib plus chemotherapy (pemetrexed and carboplatin for 4 cycles followed by maintenance pemetrexed) or furmonertinib plus chemotherapy plus bevacizumab (pemetrexed, carboplatin and bevacizumab for 4 cycles followed by maintenance pemetrexed and bevacizumab) in 21-day cycles until disease progression, the occurrence of intolerable toxicities, withdrawal of consent, or other discontinuation reasons judged by the investigators. The primary endpoint is PFS between furmoneritnib plus chemotherapy versus furmonertinib alone. Secondary endpoints include PFS, objective response rate, duration of response, disease control rate, overall survival and safety. Several exploratory endpoints will also be evaluated based on ctDNA detection by next-generation sequencing (Genecast, Wuxi, China). The study is enrolling. 34 patients had been enrolled till 2nd Feb 2023. Clinical trial information: NCT05334277 .
LUNG-IST-127: A pilot phase II study of maintenance cabozantinib plus pembrolizumab for patients with metastatic squamous non-small cell lung cancer (sqNSCLC) with disease control following induction therapy.
Authors: Nguyen Ryan Huu-Tuan , Notardonato Lucia , Hulbert Alicia , Mallisetty Apurva , Weinberg Frank , Rubinstein Israel , Juson Irene , Chan Cindy , Liu Li C. , Chen Zhengjia , Feldman Lawrence Eric
Published: June 2023

TPS9151

Background: First-line combination chemotherapy with pembrolizumab followed by maintenance pembrolizumab is the standard of care treatment for patients with metastatic sqNSCLC. This was established by the phase III KEYNOTE-407 trial, which demonstrated a median progression-free survival (PFS) of 6.4 months in the experimental arm. Despite these advances, there remains a need to continue to improve upon survival outcomes for these patients. Cabozantinib is a small-molecule inhibitor of multiple tyrosine kinsases including MET, VEGFRs, AXL, RET, and ROS, which are receptors involved in tumor cell-proliferation, angiogenesis, and immune cell regulation. Preclinical studies have demonstrated the ability of cabozantinib to modulate both adaptive and innate immune cells and to exhibit synergistic activity when used in combination with immune checkpoint inhibitors. We hypothesize that cabozantinib in combination with pembrolizumab in the maintenance phase of first-line treatment of metastatic sqNSCLC will prolong median PFS with a tolerable toxicity profile. Methods: LUNG-IST 127 is a pilot phase II, single-arm clinical trial of maintenance cabozantinib in combination with pembrolizumab for patients with metastatic sqNSCLC who achieved disease control following standard 1L induction therapy with chemotherapy and pembrolizumab. Thirty-six patients will be enrolled at 2 US sites to receive first-line induction therapy with carboplatin, nab-paclitaxel or paclitaxel, and pembrolizumab for four cycles. After induction therapy, those who have achieved disease control based on re-staging imaging will continue onto maintenance therapy with cabozantinib 40mg PO daily in combination with pembrolizumab 200mg IV every 3 weeks. The primary endpoint is PFS estimated by Kaplan-Meier methods with associated 95% confidence intervals. Based on an exploratory power analysis using an elevated one-sided alpha level of 0.40, we hypothesize that the proposed therapy will prolong median PFS from 6.4 to 9 months. Key secondary endpoints include overall survival (OS), overall response rate (ORR), and characterizing the safety and tolerability of cabozantinib in combination with pembrolizumab. Quality of life will also be measured with the EORTC QLQ-C30. Correlative endpoints include characterizing cfDNA from biofluids and assessing the change in circulating immune cells in different phases of treatment in association with PFS and OS. This trial would be the first to address whether there is clinical benefit in utilizing combination cabozantinib and pembrolizumab in the maintenance phase of treatment in metastatic sqNSCLC. Clinical trial information: NCT05613413 .
Osimertinib then chemotherapy in EGFR-mutated lung cancer with osimertinib third-line rechallenge (OCELOT).
Authors: Breadner Daniel Adam , Vincent Mark David , Liu Geoffrey , Rothenstein Jeffrey , Menjak Ines B. , Cheema Parneet Kaur , Juergens Rosalyn A. , Mithoowani Hamid , Bains Puneet , Wang Ying , Wheatley-Price Paul
Published: June 2023

TPS9160

Background: The results of the FLAURA study established osimertinib as the new first-line standard of care for patients with the two ‘common’ types of epidermal growth factor receptor mutation-positive (EGFR+) advanced non-small-cell lung cancer (aNSCLC). Second-line (2L) treatment is typically platinum pemetrexed chemotherapy and the standard third-line (3L) treatment is docetaxel throughout much of the globe, which has a modest response rate of 7 – 15%. Previously, when first generation (1G) EGFR tyrosine kinase inhibitor (TKIs) were standard of care in the first-line setting, a number of prospective and retrospective studies examined 3L rechallenge with the same 1G EGFR TKI following 2L chemotherapy, with varying levels of success. Osimertinib is a well-tolerated EGFR TKI which is active against the T790M resistance mutation, which would have limited the efficacy of rechallenge with 1G EGFR TKIs. Methods: This is a multicentered international phase II investigator-initiated study of osimertinib in the 3L rechallenge of patients with EGFR+ aNSCLC, following 1L treatment with osimertinib and 2L therapy with platinum pemetrexed chemotherapy. A maximum of 255 patients will be enrolled. Patients with ‘common’ EGFR exon 19 deletions or L858R mutations will enroll at the start of 2L chemotherapy or 3L osimertinib rechallenge. The primary objective is 3L objective response rate (ORR) in the first 100 evaluable patients, according to RECIST 1.1. Secondary objectives include disease control rate (DCR), progression free survival (PFS), time to treatment failure, overall survival and toxicity for 3L osimertinib rechallenge. Exploratory objectives include assessment of osimertinib resistance based on serial ctDNA samples collected from all participants. The OCELOT study, NCT04335292, is actively enrolling participants. Clinical trial information: NCT04335292 .
Camrelizumab combined with anlotinib and nab-paclitaxel in patients with untreated advanced mucosal melanoma: A single-arm, multicenter, exploratory study.
Authors: Wu Di
Published: June 2023

TPS9593

Background: Anti-programed cell death-1 (PD-1) monotherapy is a part of the standard treatment for cutaneous melanoma, but its efficacy in mucosal melanoma is not ideal. In vivo studies have demonstrated that co-inhibition of the VEGF receptor (VEGFR) and PD-1 pathways increased T cell infiltration and suppressed tumor growth synergistically. Early phase trial data confirmed that PD-1 inhibitors combined with anti-angiogenic drugs showed efficacy in the treatment of advanced mucosal melanoma, but still did not meet clinical needs. Previous studies have shown that chemotherapy combined with anti-angiogenic drugs has significantly improved median PFS and median OS compared with chemotherapy alone, and has a certain effect as a salvage treatment for progression after PD-1 inhibitor treatment. In addition, previous retrospective analysis showed that PD-1 inhibitors combined with chemotherapy drugs such as nab-paclitaxel were superior to anti-PD-1 monotherapy in the treatment of advanced mucosal melanoma. In summary, the combination of anti-PD-1, anti-angiogenic drugs and chemotherapy may bring new hope for the treatment of advanced mucosal melanoma. Methods: This is a single-arm, multicenter, exploratory study to evaluate the efficacy and safety of camrelizumab combined with anlotinib and nab-paclitaxel as first-line therapy in patients with advanced mucosal melanoma. The trial is expected to enrol 66 patients. Key Inclusion Criteria are pts with confirmed recurrence, unresectable or metastatic mucosal melanoma after surgery (stage III/IV) and ECOG performance status of ≤1.Pts with previous adjuvant therapy or neoadjuvant therapy (except PD-1/PDL1 monoclonal antibody and VEGFR TKI) at least 4 weeks before the first administration of the study drug are allowed. Patients received intravenous camrelizumab (200 mg) on day 1, intravenous nab-paclitaxel (260mg/m2) on day 1, and oral anlotinib (8mg) on days 1-14 every 3 weeks. The primary endpoint is objective response rate (ORR). Secondary endpoints include disease control rate (DCR),progression-free survival (PFS), and 2-year overall survival (OS). Clinical trial information: NCT04979585 .
Phase Ib/II study of XmAb23104 (PD1 X ICOS) and XmAb22841 (CTLA-4 X LAG3) combination in metastatic melanoma refractory to prior immune checkpoint inhibitor therapy with and without CNS disease.
Authors: Jacob Saya , Daud Adil
Published: June 2023

TPS9595

Background: Immune checkpoint inhibitors (ICI) have greatly improved outcomes for patients by targeting programmed cell death protein 1 (PD1), cytotoxic T-lymphocyte–associated antigen 4 (CTLA4) and Lymphocyte Activation Gene-3 (LAG-3) to increase immune-mediated anti-tumor response. Despite these advances, ~50% of patients with metastatic melanoma do not respond to standard of care ICI. We strive to address this unmet clinical need through a Phase Ib/II, first-in-human, multi-center trial of two bispecific antibodies targeting four different immune checkpoints: XmAb23104 (PD1 X ICOS) and XmAb22841 (CTLA-4 X LAG3) in patients with melanoma refractory to ICI. This is the first trial of quadruple checkpoint inhibitor therapy. Furthermore, bispecific antibodies may allow simultaneous checkpoint blockade on the same cell and have been shown to heighten T cell activation in pre-clinical models. Two ongoing phase I trials of these bispecific antibodies with PD1 therapy have observed an immune related adverse event (irAE) rate of 20-24% with efficacy analysis ongoing (NCT03752398; NCT03849469). We postulate that treatment with XmAb23104 and XmAb22841 will enhance immune activation, overcome resistance, and improve disease control for patients refractory to traditional ICI. Methods: Eligible patients must have advanced/metastatic melanoma and have progressed on prior PD1/PD-L1 inhibitor or PD1/CTLA4 dual inhibition. Cutaneous, acral, mucosal and melanoma of unknown origin are allowed. Patient with CNS metastasis are allowed if these are asymptomatic and stable on MRI imaging obtained within 4 weeks of enrollment. Patients with prior unresolved irAE or irAE ≥ grade 3 are not allowed. XmAb23104 and XmAb22841 will be given on D1 and D15 of a 28-day cycle for 4 cycles, after which XmAb23104 (PD1 X ICOS) will be given alone for a total of 2 years. The phase I portion will be a dose escalation using standard 3+3 design of XmAb22841 (CTLA-4 X LAG3) with three dose levels (0.3 mg/kg, 1 mg/kg and 3 mg/kg). The dose of XmAb23104 (PD1 X ICOS) will remain at 10 mg/kg. These doses were selected based on results of prior early phase trials when these agents were combined with PD1. Once the P2RD of XmAb22841 (CTLA-4 X LAG3) is established, we will move on to dose escalation using a Simon’s 2-stage design. This portion will include two arms: Arm A consisting of 17 patients without CNS disease and Arm B consisting of 17 patients with CNS disease (total 34). Primary endpoints include dose limiting toxicities (DLT)/irAE and Objective Response Rate (ORR) at the time of best response by RECIST 1.1. Secondary endpoints include progression-free survival, overall survival, CNS response. At the time of this abstract submission, Cohort 1 of dose escalation has begun with the first few patients still within the DLT observation window. Clinical trial information: NCT05695898 .
Phase II study of niraparib in patients with advanced melanoma with genetic homologous recombination (HR) mutation/alteration.
Authors: Kim Kevin B.
Published: June 2023

TPS9596

Background: There are a limited number of therapeutic options available for metastatic melanoma patients progressing on the checkpoint inhibitor(s) and BRAF-targeting drugs. PARP inhibitors have been approved in the setting of BRCA1/2 germline mutations, and have demonstrated activity in the setting of HR deficiency in other cancers. Documentation of PARP inhibitors in melanoma would have clear clinical impact. We have previously shown that 21-34% of metastatic melanomas harbor at least 1 molecular aberration in the HR pathway, considered pathogenic, and likely leading to HR deficiency. Previously, we demonstrated dramatic regression of tumors harboring HR mutation(s) with PARP inhibitor treatment in a PDX model. These findings provide a strong rationale to evaluate the clinical efficacy of a PARP inhibitor in patients with advanced melanoma with HR deficiency. Methods: This is a single arm, open-label, multi-center phase II trial. The primary objective of the study is: To evaluate the clinical efficacy of niraparib in advanced melanoma patients with HR deficiency. The secondary objectives is to evaluate PFS, OS, and safety profile of niraparib. The key eligibility criteria: Advanced melanoma patients with mutation in any of the following: ARID1A/B, ARID2, ATM, ATR, ATRX, BARD1, BRCA1/2, BAP1, BRIP1, CHEK2, FANCD2, MRN11A, RAD50, RAD51, RAD54B, PALB2 (requires a genetic analysis result performed at any CLIA-certified laboratory) disease progression on PD1-antibody therapy and if BRAF mutant, BRAF/MEK inhibitors ≥ 18 years of age; ECOG PS ≤ 1; prior systemic cytotoxic therapy ≤1 regimen; no limit on number of prior immunotherapy or targeted therapy regimens. No symptomatic brain metastasis; active brain lesions ≥6 mm size, or requiring steroid treatment Patients will be treated with oral niraparib once daily (28-day cycle); the dose will be 300 mg (if weight ≥77 kg and platelet counts of ≥150,000 µL); otherwise 200 mg RECIST 1.1 will be used to evaluate clinical response every 8 weeks. Adverse events will be recorded according to CTCAE version 4.03. The primary study endpoint is overall response rate. Simon’s optimal 2-stage design is proposed. With significance level of5% and 80% power, our null hypothesis that the true response rate is 0.10 will be tested against a one-sided alternative: H0: p ≤ 10%, a response rate of no real interest VS H1: p ≥ 30%, a response rate that would be of considerable interest 10 patients will be analyzed for a response evaluation in the first stage of the study, and 19 in the second stage, for a total of 29 patients. If the response rate is 10% (1/10) or less at the end of the first stage, further accrual will be terminated. With 2 or more responses in the first stage, accrual will continue to a total of 29 patients for this cohort. The null hypothesis will be rejected if ≥6 responses are observed in a cohort of 29 subjects. Clinical trial information: NCT03925350 .
A pilot trial of autologous tumor infiltrating lymphocytes (lifileucel, LN-144) for patients with asymptomatic melanoma brain metastases.
Authors: Betof Warner Allison , Postow Michael A. , Panageas Katherine , Smithy James William , Schoenfeld Adam Jacob , Wolchok Jedd D. , Shoushtari Alexander Noor
Published: June 2023

TPS9606

Background: Melanoma brain metastases (MBM) are a leading cause of morbidity and mortality for patients with advanced melanoma. Modern systemic therapies are insufficient at controlling MBM, and median overall survival (OS) for pts with MBM is < 1 year. Adoptive T cell therapy using tumor infiltrating lymphocytes (TIL) has demonstrated efficacy in advanced melanoma. Lifileucel (LN-144), an autologous TIL product, was recently shown to be safe and effective for patient with PD-1 refractory melanoma. Patients with active MBM were excluded from lifileucel trials to date. Methods: This single-center pilot trial (NCT05640193) is enrolling up to 10 pts with asymptomatic MBM from non-uveal melanoma to receive lifileucel. Patients must have ≥1 intracranial lesion measuring 5-30mm visible on MRI to be used as a target lesion for modified (m)RECIST measurement, progression on prior anti-PD-1 therapy (with or without anti-CTLA-4), progression on targeted therapy if BRAF V600E/K-mutated), ECOG PS ≤1, ≥1 resectable lesion(s) (≥1.5 cm), recovered from prior surgery/anticancer treatment-related AEs (grade ≤1). Patients are not eligible if they have symptomatic MBM and/or require corticosteroids of ≥10 mg/day of prednisone or equivalent. Lifileucel is generated from resected tumor in a centralized GMP process. The regimen includes nonmyeloablative lymphodepletion, lifileucel infusion, and a short course of high-dose IL-2. The primary endpoint is feasibility, defined as ≥7/10 patients who undergo tumor harvest receiving lifileucel infusion. Secondary endpoints are safety, feasibility of manufacturing lifileucel in patients with MBM, and brain metastasis response rate (BMRR) per mRECIST 1.1. Exploratory endpoints include overall objective response rate by mRECIST 1.1, best extracranial response rate, intracranial progression-free survival (PFS), overall PFS, OS. Extensive correlative analyses of peripheral blood mononuclear cells, plasma, tumors, and cerebrospinal fluid are planned to better understand MBM growth, treatment resistance, and response of the central nervous system to lifileucel. Clinical trial information: NCT05640193 .
Phase II, Open-Label Study of Encorafenib Plus Binimetinib in Patients With BRAFV600-Mutant Metastatic Non–Small-Cell Lung Cancer
Authors: Riely Gregory J. , Smit Egbert F. , Ahn Myung-Ju , Felip Enriqueta , Ramalingam Suresh S. , Tsao Anne , Johnson Melissa , Gelsomino Francesco , Esper Raymond , Nadal Ernest , Offin Michael , Provencio Mariano , Clarke Jeffrey , Hussain Maen , Otterson Gregory A. , Dagogo-Jack Ibiayi , Goldman Jonathan W. , Morgensztern Daniel , Alcasid Ann , Usari Tiziana , Wissel Paul , Wilner Keith , Pathan Nuzhat , Tonkovyd Svitlana , Johnson Bruce E.
Published: June 2023

PURPOSE

The combination of encorafenib (BRAF inhibitor) plus binimetinib (MEK inhibitor) has demonstrated clinical efficacy with an acceptable safety profile in patients with BRAFV600E/K-mutant metastatic melanoma. We evaluated the efficacy and safety of encorafenib plus binimetinib in patients with BRAFV600E-mutant metastatic non–small-cell lung cancer (NSCLC).

METHODS

In this ongoing, open-label, single-arm, phase II study (ClinicalTrials.gov identifier: NCT03915951 ), patients with BRAFV600E-mutant metastatic NSCLC received oral encorafenib 450 mg once daily plus binimetinib 45 mg twice daily in 28-day cycles. The primary end point was confirmed objective response rate (ORR) by independent radiology review (IRR). Secondary end points included duration of response (DOR), disease control rate (DCR), progression-free survival (PFS), overall survival, time to response, and safety.

RESULTS

At data cutoff, 98 patients (59 treatment-naïve and 39 previously treated) with BRAFV600E-mutant metastatic NSCLC received encorafenib plus binimetinib. Median duration of treatment was 9.2 months with encorafenib and 8.4 months with binimetinib. ORR by IRR was 75% (95% CI, 62 to 85) in treatment-naïve and 46% (95% CI, 30 to 63) in previously treated patients; median DOR was not estimable (NE; 95% CI, 23.1 to NE) and 16.7 months (95% CI, 7.4 to NE), respectively. DCR after 24 weeks was 64% in treatment-naïve and 41% in previously treated patients. Median PFS was NE (95% CI, 15.7 to NE) in treatment-naïve and 9.3 months (95% CI, 6.2 to NE) in previously treated patients. The most frequent treatment-related adverse events (TRAEs) were nausea (50%), diarrhea (43%), and fatigue (32%). TRAEs led to dose reductions in 24 (24%) and permanent discontinuation of encorafenib plus binimetinib in 15 (15%) patients. One grade 5 TRAE of intracranial hemorrhage was reported. Interactive visualization of the data presented in this article is available at the PHAROS dashboard ( https://clinical-trials.dimensions.ai/pharos/ ).

CONCLUSION

For patients with treatment-naïve and previously treated BRAFV600E-mutant metastatic NSCLC, encorafenib plus binimetinib showed a meaningful clinical benefit with a safety profile consistent with that observed in the approved indication in melanoma.
Patient-Reported Outcomes During and After Treatment for Locally Advanced Rectal Cancer in the PROSPECT Trial (Alliance N1048)
Authors: Basch Ethan , Dueck Amylou C. , Mitchell Sandra A. , Mamon Harvey , Weiser Martin , Saltz Leonard , Gollub Marc , Rogak Lauren , Ginos Brenda , Mazza Gina L. , Colgrove Brian , Chang George , Minasian Lori , Denicoff Andrea , Thanarajasingam Gita , Musher Benjamin , George Thomas , Venook Alan , Farma Jeffrey , O'Reilly Eileen , Meyerhardt Jeffrey A. , Shi Qian , Schrag Deborah
Published: June 2023

PURPOSE

The standard of care for locally advanced rectal cancer in North America is neoadjuvant pelvic chemoradiation with fluorouracil (5FUCRT). Neoadjuvant chemotherapy with fluorouracil and oxaliplatin (FOLFOX) is an alternative that may spare patients the morbidity of radiation. Understanding the relative patient experiences with these options is necessary to inform treatment decisions.

METHODS

PROSPECT was a multicenter, unblinded, noninferiority, randomized trial of neoadjuvant FOLFOX versus 5FUCRT, which enrolled adults with rectal cancer clinically staged as T2N+, cT3N–, or cT3N+ who were candidates for sphincter-sparing surgery. Neoadjuvant FOLFOX was given in six cycles over 12 weeks, followed by surgery. Neoadjuvant 5FUCRT was delivered in 28 fractions over 5.5 weeks, followed by surgery. Adjuvant chemotherapy was suggested but not mandated in both groups. Enrolled patients were asked to provide patient-reported outcomes (PROs) at baseline, during neoadjuvant treatment, and at 12 months after surgery. PROs included 14 symptoms from the National Cancer Institute's Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE). Additional PRO instruments measured bowel, bladder, sexual function, and health-related quality of life (HRQL).

RESULTS

From June 2012 to December 2018, 1,194 patients were randomly assigned, 1,128 initiated treatment, and 940 contributed PRO-CTCAE data (493 FOLFOX; 447 5FUCRT). During neoadjuvant treatment, patients reported significantly lower rates of diarrhea and better overall bowel function with FOLFOX while anxiety, appetite loss, constipation, depression, dysphagia, dyspnea, edema, fatigue, mucositis, nausea, neuropathy, and vomiting were lower with 5FUCRT (all multiplicity adjusted P < .05). At 12 months after surgery, patients randomly assigned to FOLFOX reported significantly lower rates of fatigue and neuropathy and better sexual function versus 5FUCRT (all multiplicity adjusted P < .05). Neither bladder function nor HRQL differed between groups at any time point.

CONCLUSION

For patients with locally advanced rectal cancer choosing between neoadjuvant FOLFOX and 5FUCRT, the distinctive PRO profiles inform treatment selection and shared decision making.