Response Evaluation Criteria In Solid Tumors V1 Research Articles

Toripalimab Plus Bevacizumab as First-line Treatment for Advanced Hepatocellular Carcinoma: A Prospective, Multicenter, Single-Arm, Phase II Trial.

This phase II, multicenter, prospective, single-arm study aimed to evaluate the efficacy and safety of toripalimab plus bevacizumab in treating advanced hepatocellular carcinoma (HCC). Treatment-naïve patients with advanced HCC received toripalimab 240 mg plus bevacizumab 15 mg/kg every 3 weeks. Primary endpoints included safety and tolerability, and objective response rate (ORR) assessed by the investigator per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. Fifty-four patients were enrolled between Apr 17, 2020 and Dec 11, 2020. As assessed by the investigator according to RECIST v1.1, the ORR was 31.5% [95% confidence interval (CI), 19.5-45.6] and the lower bound of the 95% CI was above the pre-specified boundary of 10%. The independent review committee (IRC) assessed ORR according to modified RECIST (mRECIST) was 46.3% (95% CI, 32.6-60.4). The median progression-free survival were 8.5 months (95% CI, 5.5-11.0) and 9.8 months (95% CI, 5.6-not evaluable) assessed by the investigator according to RECIST v1.1 and IRC according to mRECIST criteria, respectively. The median overall survival (OS) was not reached, and the 12- and 24-month OS rates were 77.3% and 63.5%, respectively. Grade 3 or higher treatment-emergent adverse events (TEAEs) occurred in 27 patients (50.0%). The most common TEAEs were proteinuria (59.3%), hypertension (38.9%), aspartate aminotransferase increased (33.3%), amylase increased (29.6%), platelet count decreased (27.8%), and bilirubin increased (27.8%). Toripalimab plus bevacizumab showed a favorable efficacy and safety profile, supporting further studies of this combination regimen as a first-line treatment of advanced HCC.

Abstract CT277: BGB-LC-201 (NCT05635708): A phase 2, open-label, multi-arm study of tislelizumab (TIS; anti-PD-1) in combination with investigational agents +/- chemotherapy as first-line treatment for patients with locally advanced, unresectable, or metastatic non-small cell lung cancer (NSCLC)

Abstract Background: Prognosis for locally advanced, unresectable, or metastatic NSCLC remains poor despite advances in the use of immune checkpoint inhibitors (ICI) with or without histology-appropriate chemotherapy (chemo), partly due to innate or adaptive resistance to ICI. Combination therapies aim to overcome resistance to anti-programmed cell death protein-1 or programmed death-ligand-1 (PD-1/PD-L1) therapy and thus improve anticancer activity. This phase 2 study will determine whether adding investigational agents BGB-A445 (OX40 agonistic monoclonal antibody [mAb]), LBL-007 (anti-lymphocyte activation gene-3 mAb), or BGB-15025 (hematopoietic progenitor kinase 1 [HPK1] inhibitor) improves the therapeutic benefit of TIS (anti-PD-1 mAb) +/- chemo in patients with locally advanced, unresectable, or metastatic NSCLC. Methods: The umbrella design allows for the use of multiple investigational drugs, administered alone or in combination, in patients with untreated locally advanced, unresectable, or metastatic NSCLC without actionable driver mutations. Approximately 400 patients aged ≥18 years will be enrolled in 1 of 2 Substudies based on PD-L1 expression and randomized 2:1 to either the experimental or reference arm within each Substudy. Patients in Substudy 1 (PD-L1 ≥50%) will be randomized to receive either TIS (200 mg intravenously [IV] every 3 weeks [Q3W]) in combination with BGB-A445 (2400 mg IV Q3W), LBL-007 (600 mg IV Q3W), or BGB-15025 (experimental arms) or TIS monotherapy (reference arm). Those in Substudy 2 (PD-L1 <50%) will receive TIS + chemo in combination with BGB-A445 (2400 mg IV Q3W), LBL-007 (300 mg, 600 mg, or 1200 mg IV Q3W), or BGB-15025 (experimental arms) or TIS + chemo (reference arm). Patients will receive up to 36 cycles (each cycle lasting 3 weeks) or until disease progression, intolerable toxicity, or withdrawal of consent. The primary endpoint is investigator-assessed confirmed overall response rate per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1; secondary endpoints include investigator-assessed progression-free survival, duration of response, clinical benefit rate, disease control rate (per RECIST v1.1), pharmacokinetics, immunogenicity, and safety. Exploratory endpoints include overall survival, time to response, and relevant biomarker associations with response or resistance to study treatments. Enrollment is ongoing at 66 sites in China, Asia-Pacific, the United States, and the European Union. Citation Format: George Blumenschein, Benjamin Besse, Justin F. Gainor, DingZhi Huang, Steven Kao, Se-Hoon Lee, Luis Paz-Ares, Xin Chen, Wanyu He, Sridharan Gururangan, Kathy Zhang, Caicun Zhou. BGB-LC-201 (NCT05635708): A phase 2, open-label, multi-arm study of tislelizumab (TIS; anti-PD-1) in combination with investigational agents +/- chemotherapy as first-line treatment for patients with locally advanced, unresectable, or metastatic non-small cell lung cancer (NSCLC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT277.

Abstract CT274: BGB-A317-LBL-007-202: A phase 2, randomized, active-controlled, open-label study to evaluate the efficacy and safety of LBL-007 (anti-LAG-3) in combination with tislelizumab (TIS; anti-PD-1) plus chemotherapy (chemo) as first-line (1L) treatment in patients with unresectable locally advanced/metastatic esophageal squamous cell carcinoma (ESCC)

Abstract Background: ESCC is the predominant histological subtype of esophageal cancer, accounting for 85% of cases. Patients (pts) with locally advanced/metastatic ESCC have poor clinical outcomes, with a 5-year survival rate of 6.1% for pts with distant metastases. 1L treatment with programmed cell death protein-1 (PD-1) inhibitors + platinum-based chemo has become the new standard of care for metastatic ESCC, however, there is an unmet need for enhanced treatment efficacy and a prolonged life span. LBL-007 is a monoclonal antibody (mAb) against lymphocyte activation gene-3 (LAG-3), an immune checkpoint receptor that negatively regulates T-cell activity. TIS is an anti-PD-1 mAb that blocks the PD-1/programmed death-ligand 1 (PD-L1) immune checkpoint, resulting in T-cell activation. This study (NCT06010303) aims to evaluate the efficacy and safety of LBL-007 + TIS + chemo as a 1L treatment in pts with unresectable, locally advanced/metastatic ESCC. Methods: This phase 2 study will enroll approximately 116 pts with a pathologically confirmed diagnosis of unresectable, locally advanced/metastatic ESCC and no prior systemic therapy. Pts will be randomized 2:1 to either Arm A (LBL-007 600 mg intravenously [IV] every 3 weeks [Q3W] + TIS 200 mg IV Q3W + chemo doublet) or Arm B (TIS 200 mg IV Q3W + chemo doublet), stratified by PD-L1 expression (tumor area positivity score ≥10% or <10%). The chemo doublet will consist of either cisplatin (60-80 mg/m2 IV Q3W) + 5-fluorouracil (750-800 mg/m2 IV daily on Days 1-5 Q3W), or cisplatin + paclitaxel (175 mg/m2 IV Q3W), determined by the investigator before randomization. Treatments will be administered until disease progression, intolerable toxicity, or withdrawal for other reasons. The primary endpoint is the overall response rate, as assessed by the investigator per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. Secondary endpoints include progression-free survival, duration of response, and disease control rate (all by investigator per RECIST v1.1), and the incidence and severity of adverse events per National Cancer Institute-Common Terminology Criteria for Adverse Events v5.0. A safety monitoring committee is monitoring the safety of LBL-007 + TIS + chemo vs TIS + chemo. Exploratory endpoints include comparison of overall survival, assessment of predictive, prognostic, and pharmacodynamic biomarkers, pharmacokinetic evaluation of LBL-007 and TIS, and immunogenicity. The study is currently recruiting at approximately 46 sites across Asia, including Taiwan, mainland China, South Korea, and Thailand. Citation Format: Sook Ryun Park, Ming-Huang Chen, Arunee Dechaphunkul, Ningning Ding, Xiao Lin, Jinghui Zhang, Vivian Li, Qiao Li, Yi Ba. BGB-A317-LBL-007-202: A phase 2, randomized, active-controlled, open-label study to evaluate the efficacy and safety of LBL-007 (anti-LAG-3) in combination with tislelizumab (TIS; anti-PD-1) plus chemotherapy (chemo) as first-line (1L) treatment in patients with unresectable locally advanced/metastatic esophageal squamous cell carcinoma (ESCC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT274.

Abstract CT077: An open-label phase 1 study to investigate SGN-CEACAM5C in adults with advanced solid tumors (SGNCEA5C-001, Trial in Progress)

Abstract Background Patients (pts) with recurrent or metastatic solid tumors, including non-small cell lung cancer (NSCLC), small cell lung cancer (SCLC), colorectal cancer (CRC), gastric adenocarcinoma (GC), and pancreatic ductal adenocarcinoma (PDAC), have limited treatment options with short PFS and OS despite recent advances (Bordry 2021; Chakrabarti 2022; Merle 2022). Carcinoembryonic antigen-related cell adhesion molecule 5 (CEACAM5) is highly expressed across multiple solid tumors, such as CRC, GC, PDAC, and NSCLC. Restricted normal tissue expression and efficient lysosomal trafficking of CEACAM5 highlight its potential as an anticancer target. SGN-CEACAM5C is a novel investigational antibody-drug conjugate (ADC) directed to CEACAM5 composed of the humanized immunoglobulin G (IgG1) anti-CEACAM5 monoclonal antibody tusamitamab chemically conjugated to 8 molecules of the topoisomerase 1 inhibitor 7-aminomethyl-10,11-methylenedioxycamptothecin (AMDCPT). SGN-CEACAM5C selectively binds to CEACAM5 present on the cell surface and is internalized via the endo-lysosomal pathway, with subsequent release of the payload through enzymatic cleavage. Release of the cytotoxic payload induces DNA damage, cell cycle arrest in S phase, and apoptosis in tumor cells. In vitro bystander activity was observed against tumor cells without CEACAM5 surface expression. SGN-CEACAM5C is highly active in multiple patient-derived xenograft models, including CRC, GC, and NSCLC, across various levels of CEACAM5 expression (Baudat 2023; Baudat 2024). These preclinical findings justify evaluation of SGN-CEACAM5C in a clinical trial setting. Methods SGNCEA5C-001 (NCT06131840) is a phase 1, open-label, multicenter study designed to characterize the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and preliminary antitumor activity of SGN-CEACAM5C in adults with select advanced solid tumors. This study consists of dose escalation (Part A), dose and schedule optimization (Part B), and dose expansion (Part C). Eligible pts are adults ≥18 years of age with confirmed metastatic or unresectable solid tumor malignancy, measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1, an ECOG PS of 0-1, and 1 of the following tumor types: CRC, GC/gastroesophageal junction adenocarcinoma (GEJ), PDAC, NSCLC (squamous/non-squamous), or SCLC. Primary endpoints include incidence of AEs, laboratory abnormalities, dose modifications due to AEs, dose-limiting toxicities, and cumulative safety. Secondary endpoints include estimates of PK parameters, incidence of antidrug antibodies, objective response rate and best response per RECIST v1.1 by investigator, duration of response, PFS, and OS. Safety and antitumor activity endpoints will be summarized using descriptive statistics. Recruitment is ongoing for Part A in North America. Citation Format: Funda Meric-Bernstam, Cesar A. Perez, Nehal Lakhani, Meredith Pelster, Justin Call, Suzanne McGoldrick, Tianhua Wang, Brigitte Demers, Amita Patnaik. An open-label phase 1 study to investigate SGN-CEACAM5C in adults with advanced solid tumors (SGNCEA5C-001, Trial in Progress) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT077.

Abstract CT016: Immunomodulation of the tumor microenvironment of pancreatic ductal adenocarcinoma with histone deacetylase inhibition: Results of a phase 2 clinical trial of entinostat in combination with nivolumab

Abstract Background The tumor microenvironment (TME) of pancreatic ductal adenocarcinoma (PDA) is characterized by a paucity of cytotoxic tumor-infiltrating lymphocytes, an abundance of immune-suppressive cell populations, and a general resistance to immune checkpoint inhibitor (ICI) therapy. In preclinical models of PDA, the HDAC inhibitor entinostat modulated the transcriptional programming of myeloid cells, reducing their capacity for immunosuppression and sensitizing tumors to ICI therapy. Methods We conducted a single-center, open-label, Simon two-stage, phase II study of entinostat in combination with the PD1 inhibitor nivolumab in patients with advanced PDA. Patients received oral entinostat 5 mg once a week. After a 14-day lead-in with entinostat monotherapy, patients concurrently receive entinostat 5 mg orally once a week plus nivolumab 240 mg intravenously every 2 weeks. After 4 months, therapy was continued with entinostat 5 mg weekly plus nivolumab at a dose of 480 mg fixed dose every 4 weeks until the time of progression or unacceptable toxicities. The primary endpoint was the objective response rate by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. Peripheral immune profiles at baseline and on treatment were assessed by high-dimensional mass cytometry by time of flight (CyTOF) and by Luminex of chemokines in the plasma, and changes in the TME were performed on paired baseline and on treatment biopsies by multiplexed immunohistochemistry (mIHC), image cytometry-based quantification, and bulk RNA-seq analysis. Results From November 2017 to November 2020, 27 evaluable patients were enrolled. Three patients had a partial response (PR) by RECIST v1.1 criteria (objective response rate (ORR)) of 11%, 95% CI, 0.024-0.292), with a median duration of response of 10.2 months. Grade ≥3 treatment-related adverse events (TRAEs) were observed in 19 (63%) patients. The most common grade ≥3 TRAEs were decreased lymphocyte count, anemia hypoalbuminemia, and hyponatremia. Dendritic cell (DC) activation, maturation, migration, antigen processing, and presentation were increased in the periphery after entinostat treatment, consistent with HDAC inhibitor mediated myeloid reprogramming. Gene expression analysis of paired baseline and on treatment tumors demonstrated an enrichment in inflammatory response signaling pathways with combination treatment. Conclusions Entinostat and nivolumab demonstrated durable radiological responses in a subset of patients with PDA. Paired tissue and peripheral analysis showed immunomodulation of myeloid cell populations, consistent with the preclinical hypothesis supporting the trial. This study creates a roadmap for this strategy with future combinatorial therapeutic approaches to enhance the clinical benefit in PDA patients further. Citation Format: Marina Baretti, Ludmila Danilova, Jennifer N. Durham, Courtney B. Betts, Leslie Cope, Dimitrios N. Sidiropoulos, Joseph A. Tandurella, Soren Charmsaz, Nicole Gross, Alexei Hernandez, Won J. HO, Chris Thoburn, Rosalind Walker, James Leatherman Leatherman, Sarah Mitchell, Brian Christmas, Daria A. Gaykalova, Srinivasan Yegnasubramanian, Elana J. Fertig, Lisa M. Coussens, Mark Yarchoan, Elizabeth Jaffee, Nilofer S. Azad. Immunomodulation of the tumor microenvironment of pancreatic ductal adenocarcinoma with histone deacetylase inhibition: Results of a phase 2 clinical trial of entinostat in combination with nivolumab [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT016.

Abstract CT090: DAREON™-7: A phase 1, open-label, dose escalation and expansion cohort trial of the delta-like ligand (DLL3)-targeting T-cell engager BI 764532, plus first-line platinum-based chemotherapy in patients with DLL3-positive (+) neuroendocrine carcinomas

Abstract Background Neuroendocrine carcinomas (NECs) have limited treatment options. DLL3 is highly expressed in NECs and is a promising treatment target. In an ongoing phase 1 trial (NCT04429087), BI 764532, a DLL3/CD3 IgG-like T-cell engager, was tolerable with clinical activity in patients with DLL3-positive (+) tumors, including those with small cell lung cancer and other NECs. Purpose DAREON™-7 (NCT06132113), a phase 1, open-label, dose-escalation (Part A) and dose-expansion (Part B) trial, aims to determine the maximum tolerated dose (MTD), recommended dose for expansion (RDE)/recommended phase 2 dose (RP2D), and the safety and efficacy of BI 764532 + platinum and etoposide in patients with DLL3+ NEC. Experimental design Part A: ~25 patients will receive intravenous BI 764532 (target dose after step-in dosing) plus carboplatin/etoposide (CE) until intolerable toxicity, or progression per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1, or for a maximum of 36 months. BI 764532 dose escalation will be guided by a Bayesian logistic regression model with overdose control. Part B: 2 cohorts (~15 patients each) will receive BI 764532 at the RDE/RP2D + CE or cisplatin/etoposide (carboplatin/etoposide or cisplatin/etoposide are the most-used standard of care [SOC] regimens). Key inclusion criteria: patients must have no prior systemic treatment for DLL3+ locally advanced or metastatic NEC (extrapulmonary or unknown primary) or large cell NEC of the lung except for 1 cycle of standard platinum/etoposide regimen as first-line treatment prior to entering the treatment period of the trial; patients with localized NEC or resectable disease who received prior adjuvant therapy can participate in the trial if they experienced a treatment-free interval of >6 months prior to the diagnosis of metastatic disease; and patients must have at least 1 measurable lesion as defined per RECIST v1.1. Patients must be adequate candidates to receive platinum/etoposide as the SOC treatment. Primary endpoints: occurrence of dose-limiting toxicities (DLTs) in the MTD evaluation (Part A) and on-treatment (Part B) periods. Secondary endpoints: occurrence of DLTs and adverse events during the on-treatment period (Part B), and efficacy measured by objective response and duration of response (Part B). Enrollment is ongoing. Citation Format: Jaume Capdevila, Timon Vandamme, Patricia Niccoli, Saori Mishima, Ken Kato, Yiyuan Ma, Ping Sun, Lijiang Geng, Ulrich M. Lauer. DAREON™-7: A phase 1, open-label, dose escalation and expansion cohort trial of the delta-like ligand (DLL3)-targeting T-cell engager BI 764532, plus first-line platinum-based chemotherapy in patients with DLL3-positive (+) neuroendocrine carcinomas [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT090.

PANOVA-4 (EF-39): Pilot study of tumor treating fields (TTFields) therapy with atezolizumab, gemcitabine (GEM), and nab-paclitaxel (NabP) as first-line (1L) treatment for metastatic pancreatic ductal adenocarcinoma (mPDAC).

TPS718 Background: TTFields are electric fields that exert physical forces to disrupt cellular processes critical for cancer cell viability and tumor progression. TTFields therapy is noninvasive, locoregional, and is delivered via a portable electric field generator and skin-placed arrays. TTFields therapy has low risk of systemic toxicity and is approved for glioblastoma (and grade 4 glioma in Europe), and pleural mesothelioma. In vitro, TTFields (150 kHz) application decreased pancreatic cancer cell proliferation and clonogenicity; in vivo, TTFields concomitant with chemotherapy (chemo) had greater antitumor effect than chemo alone in orthotopic pancreatic tumors. Co-application of TTFields with immune checkpoint inhibitors (ICIs) significantly decreased tumor volume, increased tumor infiltration and IFN-γ production, and did not impede ICI-induced effector memory T-cell production versus in vivo controls. The pilot (phase 2) PANOVA clinical study (NCT01971281) showed safety and feasibility with TTFields therapy plus NabP and GEM in metastatic and locally advanced pancreatic adenocarcinoma (LAPC). The randomized, pivotal (phase 3) PANOVA-3 clinical study (NCT03377491), evaluating TTFields therapy with GEM and NabP in LAPC, is ongoing. Methods: PANOVA-4 (pilot, single-arm clinical study) assesses the safety and efficacy of TTFields therapy (NovoTTF-200T device) concomitant with atezolizumab, GEM, and NabP as 1L treatment for mPDAC. Eligible patients (pts) are ≥18 years of age and have a new mPDAC diagnosis, measurable abdominal disease per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1, Eastern Cooperative Oncology Group performance status (ECOG PS) 0–1, and no prior systemic PDAC therapy. Atezolizumab (1680 mg, IV infusion) is given before chemo on day 1 of each 28-d cycle, with NabP (125 mg/m2 IV) and GEM (1000 mg/m2 IV) given on days 1, 8, and 15. TTFields therapy (150 kHz) is delivered for ≥18 h/d until disease progression per RECIST v1.1 or loss of clinical benefit. Clinical follow-up occurs every 4 weeks (q4w) with CT scans q8w. Survival is assessed every 3 mo post last on-site visit. The primary endpoint is disease control rate (DCR). Secondary endpoints include overall survival (OS), progression-free survival (PFS), 1-year OS rate, objective response rate, PFS at 6 mo, duration of response, and safety. 76 pts are required to achieve 80% power (1-sided α level 0.05) to detect a 63% DCR vs historical 48% DCR in pts with mPDAC receiving 1L GEM and NabP. Clinical trial information: EUCTR2022-003157-55 .

Influence of Tumor Cavitation on Assessing the Clinical Benefit of Anti-PD1 or PD-L1 Inhibitors in Advanced Lung Squamous Cell Carcinoma

PurposeA considerable portion of lung squamous cell cancer (LUSC) displays radiographic signs of cavitation. The cavitation of lesions is not accounted for in the prevailing Evaluation Criteria of Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 or iRECIST in lung cancer. We hypothesized that cavitation might alter response assessment in these patients. Patients and MethodsWe performed a retrospective radiologic review of 785 patients with stage IV LUSC treated with PD-1/PD-L1 antibody combined with platinum-based doublet chemotherapy. 131 patients exhibited cavitation lesions pre- or after-treatment. Response was assessed by RECIST v1.1 and a modified Evaluation Criteria in Solid Tumors (mRECIST) guidelines in which the longest diameter of any cavity was subtracted from the overall longest diameter of that lesion to measure target lesions. The response rate and PFS and OS between mRECIST and RECIST v1.1 were compared. Survival curves of different response categories in each criterion were prepared using the method of Kaplan-Meier and log-rank tests. Weighted κ statistics were used to assess interobserver reproducibilities and to compare response rates. The chi-square test confirmed the relationship between PD-L1 expression and post-treatment cavitation. ResultsNotable cavitation of pulmonary lesions was seen in 16.7% of 785 patients treated with immunotherapy combined with platinum-based chemotherapy. Using the mRECIST for response assessment resulted in a higher response rate than RECIST v1.1 (66% vs. 57%). mRECIST might better identify patients with PFS and OS benefits who have cavitation. The chi-square test revealed a marginally significant difference between PD-L1 expression and tumor cavitation. Interobserver reproducibility of mRECIST for tumor cavitation evaluation was acceptable (the weighted k coefficients for mRECIST criteria was 0.821). ConclusionCavitation lesions at baseline and after checkpoint treatment are common in LUSC patients. mRECIST records a significantly higher response rate than RECIST for these LUSC patients. Response assessment might be improved by incorporating cavitation into volume assessment for target lesions. These results may inform further modifications to RECIST V1.1 to better reflect efficacy with immunotherapy.

Camrelizumab (a PD-1 inhibitor) plus apatinib (an VEGFR-2 inhibitor) and hepatic artery infusion chemotherapy for hepatocellular carcinoma in Barcelona Clinic Liver Cancer stage C (TRIPLET): a phase II study

Hepatic arterial infusion chemotherapy (HAIC) using a combination of oxaliplatin, fluorouracil, and leucovorin (FOLFOX) has shown promise for hepatocellular carcinoma (HCC) patients classified under Barcelona Clinic Liver Cancer (BCLC) stage C. In China, the combined therapy of camrelizumab and apatinib is now an approved first-line approach for inoperable HCC. This study (NCT04191889) evaluated the benefit of combining camrelizumab and apatinib with HAIC-FOLFOX for HCC patients in BCLC stage C. Eligible patients were given a maximum of six cycles of HAIC-FOLFOX, along with camrelizumab and apatinib, until either disease progression or intolerable toxicities emerged. The primary outcome measured was the objective response rate (ORR) based on the Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. Thirty-five patients were enrolled. Based on RECIST v1.1 criteria, the confirmed ORR stood at 77.1% (95% CI: 59.9% to 89.6%), with a disease control rate of 97.1% (95% CI: 85.1% to 99.9%). The median progression-free survival was 10.38 months (95% CI: 7.79 to 12.45). Patient quality of life had a transient deterioration within four cycles of treatment, and generally recovered thereafter. The most frequent grade ≥3 or above treatment-related adverse events included reduced lymphocyte count (37.1%) and diminished neutrophil count (34.3%). The combination of camrelizumab, apatinib, and HAIC demonstrated encouraging results and manageable safety concerns for HCC at BCLC stage C.

Real-world efficacy and safety of donafenib-based therapies in patients with unresectable hepatocellular carcinoma: A retrospective study.

e16169 Background: According to the results of phase III ZGDH3 study, donafenib has significantly improved overall survival (OS) versus sorafenib in first-line treatment for patients with unresectable hepatocellular carcinoma (uHCC). The present study aimed to evaluate the efficacy and safety of donafenib-based therapies in patients with uHCC regardless of first- or later-line systemic therapy. Methods: This single-center retrospective study involved 30 patients with histopathologically/cytologically or clinically confirmed uHCC at Sun Yat-sen Memorial Hospital, Sun Yat-sen University between August 2021 and February 2022. Eligible patients underwent donafenib-based therapies until disease progression, death, or unacceptable toxicity. The primary endpoint was progression-free survival (PFS) per the Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. Secondary endpoints included OS, objective response rate (ORR), disease control rate (DCR), and safety. Tumor response was determined according to the RECIST v1.1 and modified (m)RECIST. Results: Of these eligible 30 patients, the median age was 55 years (range, 27–73), 93% were male, 93% with HBV and 63% were BCLC C. Donafenib was commonly used as a monotherapy (17%) or in combination with immune checkpoint inhibitors (ICIs), transarterial therapy, both, or other treatments. Twenty (67%) patients underwent donafenib-based therapies as a first-line treatment, of which 15 (75%) underwent a triple combination of donafenib, ICIs, and transarterial therapy. By the cutoff date of January 2023, the median PFS and OS were not yet reached; the 6-month PFS and OS rates were 70.0% and 90.0%, respectively, and the 12-month PFS and OS rates were 66.5% and 86.5%, respectively. The ORR and DCR for all patients were 43.3% and 73.3%, respectively, based on both RECIST v1.1 (CR 4 [13.3%], PR 9 [30.0%], SD 9 [30.0%]) and mRECIST (CR 5 [16.7%], PR 8 [26.7%], SD 9 [30.0%]). Among the 20 patients who underwent donafenib-based first-line systemic therapy, the ORRs according to RECIST v1.1 and mRECIST were both 55.0%, and higher ORRs (73.3% per RECIST v1.1 and mRECIST) were observed in 15 patients who underwent donafenib, ICIs, and transarterial therapy. Overall, 15 (50.0%) patients had more than one treatment-related adverse event (TRAEs) and the most common AEs were hand-foot skin reaction (26.7%), rash (10.0%), and gingival bleeding (10.0%). Grade 3 AEs occurred in 16.7% of patients. No TRAE led to death in the study. Conclusions: This study indicated that donafenib-based therapies, particularly donafenib in combination with ICIs plus transarterial therapy, show promising antitumor activity in patients with uHCC, and no new safety signals were observed in real-world settings. Clinical trial information: ChiCTR2200063822 .

ENGOT-EN20/GOG-3083/xport-EC-042: A phase 3, randomized, placebo-controlled, double-blind, multicenter trial of selinexor in maintenance therapy after systemic therapy for patients with P53 wild-type, advanced or recurrent endometrial carcinoma.

TPS5627 Background: Patients (pts) with first-line metastatic or recurrent endometrial cancer (EC) have a poor prognosis. Selinexor is an oral XPO1 inhibitor, which leads to nuclear accumulation of tumor suppressor proteins, including p53. Selinexor is FDA-approved for use in multiple myeloma and diffuse large B-cell lymphoma, and has shown clinical activity in previously treated, advanced EC. Molecular characterization of EC is critical in directing treatment for advanced and recurrent disease. Of the EC molecular subtypes, TP53 wild type (wt) tumors represent 50% of advanced and recurrent tumors. A recent phase 3 study in maintenance after chemotherapy found that, despite the primary endpoint (PFS) not reaching statistical significance, prolonged PFS of oral once-weekly selinexor versus placebo (13.7 months and 3.7 months, respectively) was observed in a prespecified exploratory subgroup analysis of patients with advanced or recurrent TP53wt EC. Methods: XPORT-EC-042 (NCT05611931) is a Phase 3 randomized, double-blind, placebo-controlled study designed to evaluate the efficacy and safety of selinexor as maintenance therapy in pts with TP53wt advanced or recurrent EC, who have achieved a partial response or complete response per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 after completing at least 12 weeks of platinum combination chemotherapy ±immunotherapy for primary stage IV or recurrent disease. Eligible pts must be ≥18 years of age, have histologically confirmed EC, and TP53 wt disease based on NGS sequencing assessed by Foundation Medicine. Pts will be randomized 1:1 with either selinexor 60 mg or placebo once weekly in 28-day cycles until progressive disease, toxicity, or 3 years if in complete response. A total of 220 pts will be enrolled at sites across the United States, Canada, Europe, and Israel. The primary objective is to compare PFS in pts treated with selinexor compared to placebo based on RECIST v1.1 criteria as assessed by the Investigator. Key secondary objective is overall survival. Other secondary objectives are safety, time to first subsequent therapy, time to second subsequent therapy, time from randomization until the second progression event (PFS2), and PFS by a blinded independent central review. Patient enrollment is ongoing. Clinical trial information: NCT05611931 .

ARC-10: A phase 3 study to evaluate zimberelimab + domvanalimab versus pembrolizumab in front-line, PD-L1-high, locally advanced or metastatic non–small-cell lung cancer.

TPS9148 Background: Despite improvements in the management of locally advanced or metastatic non–small cell lung cancer (NSCLC) from programmed cell death/ligand protein 1 (PD-[L]1) inhibition, there remains an unmet need for improved treatment options. PD-L1 expression is a known biomarker of response to anti–PD-L1 therapies in metastatic NSCLC. The combination of PD-1 inhibition with inhibition of the immunosuppressive T cell Immunoglobulin and ITIM domain (TIGIT) pathway is associated with improved response and prolonged progression-free survival in patients with advanced NSCLC. Domvanalimab (dom) is an Fc-silent humanized IgG1 monoclonal antibody (mAb) that blocks TIGIT, thereby reducing immunosuppression of T/natural killer (NK) cells and promoting antitumor activity. Zimberelimab (zim) is an mAb that binds to PD-1 on T/NK cells, preventing PD-L1-mediated immunosuppressive effects and resulting in tumor cell death. This phase 3 study will investigate the efficacy and safety of combination therapy with dom + zim compared with pembrolizumab monotherapy in patients with PD-L1-high NSCLC. Methods: ARC-10 (NCT04736173) is a global, phase 3, randomized, multicenter, open-label study. Eligible patients are adults with histologically confirmed, treatment-naive, locally advanced or metastatic, squamous or non-squamous NSCLC with ≥1 measurable lesion(s) per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1, high expression of PD-L1 (tumor cells [TC] ≥50%), and an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. Patients must not have genomic tumor aberrations for which targeted therapies are approved and available (eg, EGFR, ALK, ROS, BRAF, NTRK). Approximately 600 patients will be randomized 1:1 to receive combination therapy with dom + zim (dom 1200 mg intravenous [IV] once every 3 weeks [Q3W] + zim 360 mg IV Q3W) or pembrolizumab monotherapy (200 mg IV Q3W) for 21-day cycles until disease progression, intolerance, or a maximum of 35 cycles. Randomization will be stratified by ECOG performance status (0 vs 1), geographical region (Asia vs non-Asia), and histology (squamous vs non-squamous). The primary efficacy endpoint is overall survival. Secondary efficacy endpoints include blinded independent central review of progression-free survival and confirmed overall response rate according to RECIST v1.1. Safety endpoints include the presence of treatment-emergent adverse events and laboratory parameters. Health-related quality of life will be assessed by measuring the time to first symptom deterioration in the NSCLC-Symptom Assessment Questionnaire total score. Study recruitment is planned in Asia, North and South America, Africa, and Europe. Clinical trial information: NCT04736173 .

Phase 2 clinical study evaluating the efficacy and safety of disitamab vedotin with or without pembrolizumab in patients with HER2-expressing urothelial carcinoma (RC48G001).

TPS594 Background: Urothelial carcinoma (UC) is the 10th most diagnosed cancer worldwide, and nearly 50% of patients cannot tolerate the current first-line (1L) standard of care. There is a need to improve outcomes in 1L and later lines of therapy. HER2 is overexpressed in UC and may be associated with poor outcomes. Despite this, no HER2-directed therapies are currently approved for UC. Disitamab vedotin (DV; RC48-ADC) is an investigational antibody-drug conjugate comprising a novel HER2-directed monoclonal antibody, disitamab, conjugated to monomethyl auristatin E (MMAE) via a protease-cleavable mc-vc linker. DV elicits antitumor activity through multimodal mechanisms of action including MMAE-mediated direct cytotoxicity, bystander effect, and immunogenic cell death. Methods: RC48G001 (NCT04879329) is a phase 2, multi-cohort, open-label, multicenter trial to evaluate DV in patients with HER2-expressing locally advanced/metastatic UC (LA/mUC). Patients are enrolled in 3 cohorts based on prior treatment and tumor HER2 expression by immunohistochemistry (IHC) and gene amplification (via in situ hybridization [ISH]), assessed centrally. Cohorts A and B are enrolling patients who have received prior systemic therapy (1 or 2 lines, including platinum-containing chemotherapy) and whose tumors are HER2-positive (IHC 3+, or 2+ and ISH-positive) or HER2-low (IHC 2+ and ISH-negative, or IHC 1+), respectively. Cohort C is enrolling 1L treatment-naive patients in the LA/mUC setting, whose tumors have HER2-positive or HER2-low expression. Cohorts A and B will evaluate DV as monotherapy (intravenous [IV] administration, once every 2 weeks [Q2W]). Cohort C will evaluate DV (IV, Q2W) +/– pembrolizumab (IV, Day 1 of each 6-week cycle). Patients in all cohorts must have measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 and an Eastern Cooperative Oncology Group Performance Status of 0–1 in Cohorts A and B, and 0–2 in Cohort C. The primary endpoint is confirmed objective response rate (cORR) per blinded independent central review (BICR). Secondary endpoints include cORR by investigator assessment, overall survival, duration of response, progression-free survival, disease control rate per RECIST v1.1 by BICR and investigator, safety, and pharmacokinetic parameters. Enrollment for all cohorts is ongoing in North America and Europe, and planned in Latin America, Asia-Pacific, and Israel. Clinical trial information: NCT04879329 .

Pembrolizumab plus Olaparib in Patients with Metastatic Castration-resistant Prostate Cancer: Long-term Results from the Phase 1b/2 KEYNOTE-365 Cohort A Study

BackgroundPembrolizumab and olaparib have shown single-agent activity in patients with previously treated metastatic castration-resistant prostate cancer (mCRPC). ObjectiveTo evaluate the efficacy and safety of pembrolizumab plus olaparib in mCRPC. Design, setting, and participantsCohort A of the phase 1b/2 KEYNOTE-365 study enrolled patients with molecularly unselected, docetaxel-pretreated mCRPC whose disease progressed within 6 mo of screening. InterventionPembrolizumab 200 mg intravenously every 3 wk plus olaparib 400-mg capsule or 300-mg tablet orally twice daily. Outcome measurements and statistical analysisThe primary endpoints were safety, confirmed prostate-specific antigen (PSA) response rate, and objective response rate (ORR) as per Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1, by blinded independent central review. The secondary endpoints included radiographic progression-free survival (rPFS) and overall survival (OS). Results and limitationsOf 104 enrolled patients, 102 were treated. The median age was 70 yr (interquartile range [IQR], 65–76), and 59 patients (58%) had measurable disease as per RECIST v1.1. The median time from the first dose to database cutoff was 24 mo (IQR, 22–47). The confirmed PSA response rate was 15%. The confirmed ORR was 8.5% (five partial responses) for patients with measurable disease. The median rPFS was 4.5 mo (95% confidence interval [CI], 4.0–6.5) and median OS was 14 mo (95% CI, 10.4–18.2). Clinical activity was consistent across the programmed death ligand 1 (PD-L1)-positive and homologous recombination repair mutation subgroups. Treatment-related adverse events (TRAEs) occurred in 93 patients (91%). Grade 3–5 TRAEs occurred in 49 patients (48%). Six deaths (5.9%) were due to adverse events; two (myocardial infarction and unknown cause) were attributed to treatment. Limitations of the study include the single-arm design. ConclusionsPembrolizumab plus olaparib had a safety profile consistent with the profiles of the individual agents and demonstrated antitumor activity in previously treated patients with molecularly unselected, docetaxel-pretreated mCRPC. Patient summaryPembrolizumab plus olaparib showed antitumor activity and expected safety in patients with metastatic castration-resistant prostate cancer.

The combination treatment strategy of lenvatinib for hepatocellular carcinoma: a real-world study.

Lenvatinib is recommended as a first-line therapy in unresectable hepatocellular carcinoma (HCC). Combination therapy with local therapy (LT) or PD-1/PD-L1 inhibitors (PI) might improve the antitumor effect of lenvatinib. The objective of this study was to investigate the antitumor effect of lenvatinib-based combination therapies. The study retrospectively analyzed 215 HCC patients who received lenvatinib therapy. The outcomes of patients treated with lenvatinib monotherapy as well as combination strategies were compared. Progression-free survival (PFS) by Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 was the primary endpoint, while PFS by mRECIST, overall survival (OS), objective response rate (ORR) and safety were the secondary endpoints. Propensity score matching (PSM) analysis was performed to overcome the bias of baseline characteristics. Compared with lenvatinib monotherapy, combination therapy prolonged PFS (by RECIST v1.1, 7.77 vs. 4.43months, P = 0.045; by mRECIST, 6.97 vs. 5.27months, P = 0.067). A higher ORR was also recorded in the combined-therapy group, according to both RECIST v1.1 (37 vs. 5%, P < 0.001) and mRECIST (53 vs. 11%, P < 0.001). Similar outcomes were obtained after PSM. Moreover, triple therapy (combined with both PI and LT) was significantly superior to dual therapy (combined with either PI or LT) in terms of better PFS according to RECIST v1.1 (8.90 vs. 6.43months, P = 0.023). However, adverse events occurred in more patients receiving combined therapy and triple therapy. No difference was observed in OS between groups. Combination therapies based on lenvatinib were associated with significantly better PFS and tumor response rates than lenvatinib monotherapy in HCC patients.

P-54 Phase 2a study of NT-I7, a long-acting interleukin-7, plus pembrolizumab: Cohort of subjects with checkpoint inhibitor-naïve advanced MSS-colorectal cancer

Checkpoint inhibitor (CPI) monotherapy is ineffective for microsatellite stable colorectal cancer (MSS-CRC). NT-I7 (efineptakin alfa) is a long-acting IL-7 that can increase T-cell infiltration in the tumor microenvironment (TME). We hypothesize that NT-I7 may create a favorable immune-reactive TME to enhance the efficacy of CPI when combined with pembrolizumab (pembro). This is an open-label, phase 2a study in subjects with relapsed/refractory (R/R) tumors, including CPI-naïve R/R MSS-CRC. Subjects were enrolled following Simon’s 2-stage minimax design; 17 were enrolled in the first stage, and 8 additional subjects were enrolled for the second stage. Subjects received the recommended-phase-2-dose of NT-I7 intramuscularly at 1200 μg/kg every 6 weeks (Q6W) plus pembro 200 mg intravenously Q3W. Preliminary anti-tumor activity based on Overall Response Rate (ORR) was assessed by Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 and iRECIST. Biomarker analyses in peripheral blood and tumor biopsy were performed. As of 14-Jan-2022, 28 subjects were enrolled in the CPI-naïve R/R MSS-CRC cohort. Median age was 56.0 years [37-81], with ECOG PS 0 (28.6%) and 1 (71.4%). Twenty-three (82%) subjects received ≥ 2 prior therapies. All subjects had metastatic or locally advanced disease at enrollment. The median duration of follow-up was 5.3 months. Among these 25 evaluable subjects ORR and disease control rate (DCR) was 4% (1/25 subjects) and 40% (10/25) per RECIST v1.1; 12% (3/25 subjects) and 44% (11/25) per iRECIST. In addition to 3 subjects with iPR, 11 subjects are still ongoing to follow up responders. Interestingly, in patients with rectal malignancy both ORR and DCR by iRECIST were 50% (2/4). The ORR and DCR by iRECIST were 25% (1/4) and 50% (2/4) in 2L; 17% (1/6) and 33% (2/6) in 3L; and 13% (1/8) and 50% (4/8) in 4L. Among subjects without/with ≥ 2 liver mets, the ORR was 33.3% (2/6) vs 5.3% (1/19); DCR was 83.3% (5/6) vs 31.6% (6/19) and PFS was 11.6 weeks vs 6.1 weeks. All subjects with responses continue on treatment. Treatment-related adverse events (trAEs) occurred in 27 (96.4%) subjects, 12 (42.8%) G1-2 events and 14 (50%) G3 events; 1 (3.6%) G4 and no G5 trAEs were reported. No subjects discontinued from the study due to trAE. One iPR subject with available biopsy data showed an enhanced T-cell infiltration in the TME at week 5. The chemotherapy-free combination of NT-I7 + pembro was well tolerated in heavily pretreated subjects with CPI-naïve R/R MSS-CRC. The encouraging antitumor activity showed that subjects without liver metastasis sites especially benefited from the combination of NT-I7 and pembro therapy. Biomarker analyses demonstrated improved peripheral and intratumoral T cell responses. Plan is to enroll 25 more patients to further evaluate efficacy of NT-I7 + pembro in CPI-naïve subjects with R/R MSS-CRC.

AcceleRET Lung: A phase 3 study of first-line pralsetinib in patients with RET fusion–positive advanced/metastatic NSCLC.

TPS9159 Background: RET gene fusions have been identified as oncogenic drivers in multiple tumor types, including 1–2% of non-small cell lung cancer (NSCLC). Pralsetinib is a potent, selective RET inhibitor, approved in the US and EU for the treatment of metastatic RET fusion–positive NSCLC based on the phase 1/2 ARROW study (NCT03037385). In the ARROW study (data cutoff: Nov 6, 2020), patients who initiated 400 mg once daily (QD) of pralsetinib after platinum-based chemotherapy achieved an overall response rate (ORR) of 62%, per independent central review. In the treatment-naïve group, the ORR was 79%. Most treatment-related adverse events were grade 1–2 across the entire safety population treated at 400 mg QD (n=471). AcceleRET Lung, an international, open-label, randomized, phase 3 study (NCT04222972), will evaluate the efficacy and safety of pralsetinib versus standard of care (SOC) for first-line treatment of advanced/metastatic RET fusion–positive NSCLC. Abstracts for this study were previously submitted to the European Lung Cancer Congress 2020, the American Society of Clinical Oncology 2020 annual meeting, and 2020 World Conference on Lung Cancer. Methods: Approximately 226 patients with metastatic RET fusion–positive NSCLC will be randomized 1:1 to oral pralsetinib (400 mg QD) or SOC (non-squamous histology: platinum/pemetrexed ± pembrolizumab followed by maintenance pemetrexed ± pembrolizumab [at investigator’s discretion]; squamous histology: platinum/gemcitabine or platinum + pembrolizumab + paclitaxel/nab-paclitaxel followed by maintenance pembrolizumab). Stratification factors include intended use of pembrolizumab, history of brain metastases, and Eastern Cooperative Oncology Group Performance Status. Key eligibility criteria include no prior systemic treatment for advanced/metastatic NSCLC; RET fusion–positive tumor by local or central assessment; no additional actionable oncogenic drivers; no prior selective RET inhibitor; measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. Patients with central nervous system metastases were permitted if asymptomatic and on a stable dose of corticosteroids. Cross-over to receive pralsetinib upon disease progression will be permitted for patients randomized to SOC. The primary endpoint is progression-free survival (blinded independent central review; RECIST v1.1). Secondary endpoints include ORR, overall survival, duration of response, disease control rate, clinical benefit rate, time to intracranial progression, intracranial ORR, safety/tolerability and quality of life evaluations. Identification of potential biomarkers of antineoplastic activity and resistance was an exploratory endpoint. Recruitment has begun with sites (active or planned) in North America, Central America, Europe and Asia. Clinical trial information: NCT04222972.

A Randomized, Double-Blind Noninferiority Study to Evaluate the Efficacy of the Cabozantinib Tablet at 60 mg Per Day Compared with the Cabozantinib Capsule at 140 mg Per Day in Patients with Progressive, Metastatic Medullary Thyroid Cancer.

Background:Cabozantinib inhibits pathways involved in medullary thyroid cancer (MTC). Cabozantinib is approved as 140 mg/day in capsules for MTC and 60 mg/day in tablets for other solid tumors. This study compared the two doses in progressive metastatic MTC.Methods:In this Phase 4, randomized, double-blind noninferiority (NI) trial (NCT01896479), patients with progressive metastatic MTC were randomized 1:1 to cabozantinib 60 mg/day tablet or 140 mg/day capsules. The primary end point was progression-free survival (PFS) by blinded independent radiology committee (BIRC) per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. NI would be concluded if the upper 95% confidence interval [CI] for the PFS hazard ratio (HR) was less than the NI margin, 1.58. The secondary end point was objective response rate (ORR) by BIRC per RECIST v1.1; additional end points included safety and pharmacokinetics.Results:At data cutoff (July 15, 2020), 247 patients were randomized to the 60 mg/day tablet arm (n = 123) and the 140 mg/day capsules arm (n = 124). NI was not met (median PFS 11.0 months vs. 13.9 months in the 60 and 140 mg/day arms [HR 1.24; CI 0.90–1.70; p = 0.19]). The ORR was 33% in both arms. Generally, adverse event (AE) incidence was lower in the 60 mg/day arm (Grade 3/4, 63% vs. 72%), as were dose reductions (69% vs. 81%) and treatment discontinuations due to AEs (23% vs. 36%). Initially, cabozantinib plasma concentrations were higher in the 140 mg/day arm but became similar between arms at later time points.Conclusions:PFS NI of the cabozantinib 60 mg/day tablet vs. 140 mg/day capsules was not met. The 60 mg/day tablet had the same ORR and lower rates of AEs.Clinical Trial Registry:ClinicalTrials.gov NCT01896479.

Implementing Real-World RECIST-based Tumor Response Assessment in Patients With Metastatic Non-small Cell Lung Cancer

BackgroundTo accelerate drug approvals while maintaining scientific rigor in the evaluation of a therapeutic's efficacy and safety, the United States Food and Drug Administration now considers real-world data (RWD) to support New Drug Applications and expanded indications. Response Evaluation Criteria in Solid Tumors (RECIST) are the gold standard in clinical trials, but the derivation of RECIST-based treatment response from RWD is unproven. This study investigated the feasibility of implementing RECIST criteria in RWD by comparing lung cancer response assessments from RECIST-based measurement of lesions on archived radiologic films with results from medical oncologist and radiologist narratives recorded in electronic health records (EHR). Materials and MethodsResponse to index treatment via different assessment approaches was compared among 30 metastatic non-small cell lung cancer (mNSCLC) patients receiving systemic treatment (index) after progression on a platinum or anti-PD(L)-1-containing regimen. Specifically, responses based on assessments documented in the medical oncologists’ narratives were compared to a radiologist's assessments of archived images using RECIST v1.1 criteria. Each patient's best overall response was characterized as complete or partial (CR/PR), stable disease (SD), progressive disease (PD), or not evaluable (NE). ResultsSimilar distributions of best overall response and substantial concordance (77%) between medical oncologist-reported and radiologist re-assessed responses were observed. There were no instances of CR/PR to PD or PD to CR/PR discordance. ConclusionsResults suggest that accurate treatment responses, similar to RECIST, may be derived using RWD. Further validation and improvement of real-world response assessment are needed to develop a scalable real-world approach for response assessment.

HER2CLIMB-04: Phase 2 open label trial of tucatinib plus trastuzumab deruxtecan in patients with HER2+ unresectable locally advanced or metastatic breast cancer with and without brain metastases (trial in progress).

TPS1097 Background: Tucatinib (TUC) is an oral, reversible, small molecule tyrosine kinase inhibitor highly selective for human epidermal growth factor receptor 2 (HER2) with minimal inhibition of human epidermal growth factor receptor (EGFR). In the pivotal, randomized HER2CLIMB trial (NCT02614794), the combination of TUC + trastuzumab (T) + capecitabine (C) demonstrated statistically significant and clinically meaningful improvements in progression free survival (PFS), overall survival (OS), and PFS in patients (pts) with brain metastases (BM), compared to T + C alone. These data supported regulatory approvals in the US and internationally for TUC in combination with T + C in pts with HER2+ metastatic breast cancer (MBC). Trastuzumab deruxtecan (T-DXd) is an antibody-drug conjugate of trastuzumab and a topoisomerase I inhibitor payload approved in the US for treatment of HER2+ MBC in pts who have received 2 or more prior anti-HER2 regimens in the metastatic setting. Approval was based on data from the single arm Destiny-Breast01 trial (NCT03248492) where treatment with T-DXd resulted in a confirmed objective response rate (cORR) of 61.4% (95% CI: 54.0, 68.5) in pts with HER2+ MBC who had prior ado-trastuzumab emtansine treatment. Despite these advances, HER2+ MBC remains incurable, and pts will eventually progress on currently available therapies. Combining TUC and T-DXd may result in further improvement on the efficacy seen with either agent alone. Methods: HER2CLIMB-04 (NCT04539938) is a single arm, open-label phase 2 trial evaluating safety and antitumor activity of TUC + T-DXd in pts with HER2+ unresectable locally-advanced or MBC who have received 2 or more prior HER2-based regimens in the metastatic setting. Pts with BM, including active BM, may be enrolled. Ten pts will be enrolled in the safety lead-in portion of the trial and followed for at least 1 cycle. If safety of the combination is acceptable, the trial will continue until approximately 60 response-evaluable pts have been enrolled, approximately evenly distributed between pts with and without BM. The primary endpoint is cORR by investigator (INV) per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. Secondary endpoints are PFS, duration of response (DOR), and disease control rate (DCR) by INV per RECIST v1.1, OS, and safety. Exploratory endpoints will include cORR, PFS, DOR, DCR by independent central review per RECIST v1.1, pharmacokinetic analyses, biomarker analyses, and changes in patient-reported outcomes using the European Quality of Life 5-Dimension 5-Level instrument. Enrollment began in late 2020 in the United States. Clinical trial information: NCT04539938 .