Investigation Of Choice Research Articles

Overall survival with camrelizumab plus famitinib versus camrelizumab alone and investigator's choice of chemotherapy for recurrent or metastatic cervical cancer

Overall survival with camrelizumab plus famitinib versus camrelizumab alone and investigator's choice of chemotherapy for recurrent or metastatic cervical cancer

Cisplatin- or Carboplatin-Based Chemotherapy Plus Pembrolizumab in Advanced Urothelial Cancer: Exploratory Analysis From the Phase 3 KEYNOTE-361 Study

IntroductionKEYNOTE-361 evaluated first-line pembrolizumab with and without platinum-based chemotherapy versus chemotherapy alone in advanced or metastatic urothelial carcinoma. The primary end points of progression-free survival (PFS) or overall survival (OS) were not met. Exploratory analysis of efficacy by platinum agent (cisplatin or carboplatin) is reported. Patients and MethodsEligible patients were randomly assigned 1:1:1 to receive pembrolizumab 200 mg intravenously every 3 weeks for ≤35 cycles with or without chemotherapy (gemcitabine with investigator's choice of either cisplatin or carboplatin) or chemotherapy alone. This exploratory subset analysis evaluated PFS and objective response rate (ORR) per RECIST v1.1 by blinded independent central review and OS for cisplatin- or carboplatin-based chemotherapy with versus without pembrolizumab for patients assigned to chemotherapy-containing arms of KEYNOTE-361. ResultsOf 1010 patients enrolled, 703 were assigned to receive a chemotherapy-containing regimen (n = 312 cisplatin based; n = 391 carboplatin based). Median follow-up was 31.3 months. For cisplatin-based arms, with versus without pembrolizumab, median OS was 20.1 versus 16.4 months (HR 0.88, 95% CI 0.67-1.15) and median PFS was 8.5 versus 7.1 months (HR 0.67, 0.51-0.89). ORR was 64.1% versus 48.7%, respectively. For carboplatin-based arms, with versus without pembrolizumab, median OS was 15.5 versus 12.3 months (HR 0.84, 95% CI 0.67-1.06) and median PFS was 8.0 versus 6.7 months (HR 0.86, 0.68-1.09). ORR was 47.2% versus 41.8%, respectively. Among patients in the cisplatin-based versus carboplatin-based chemotherapy alone arms, 55.8% versus 41.8% received a subsequent anti–programmed cell death protein 1/ligand 1 therapy. The addition of pembrolizumab did not significantly increase the incidence of adverse events reported. ConclusionResults suggest trends towards OS and PFS improvements with the addition of pembrolizumab to gemcitabine-platinum doublet over gemcitabine-platinum alone regardless of whether cisplatin or carboplatin was the chosen platinum agent. OS may have been influenced by active subsequent therapies. MicroAbstractUntil recently, the standard first-line treatment for advanced urothelial carcinoma included platinum-based chemotherapy containing either cisplatin or carboplatin. This exploratory analysis from the KEYNOTE-361 study describes efficacy outcomes with the addition of pembrolizumab to cisplatin- or carboplatin-based chemotherapy to determine if there are differences in clinical benefit between patients who received cisplatin-based versus carboplatin-based combination therapy.

A phase III, randomized trial evaluating avutometinib plus defactinib compared with investigator's choice of therapy among patients with recurrent low-grade serous ovarian cancer: GOG-3097/ENGOT-OV81/NCRI/RAMP 301

A phase III, randomized trial evaluating avutometinib plus defactinib compared with investigator's choice of therapy among patients with recurrent low-grade serous ovarian cancer: GOG-3097/ENGOT-OV81/NCRI/RAMP 301

Efficacy and safety of tisotumab vedotin versus investigator's choice of chemotherapy in second-line or third-line recurrent or metastatic cervical cancer (innovaTV 301/ENGOT-cx12/GOG-3057): A global, randomized, open-label, phase III study

Efficacy and safety of tisotumab vedotin versus investigator's choice of chemotherapy in second-line or third-line recurrent or metastatic cervical cancer (innovaTV 301/ENGOT-cx12/GOG-3057): A global, randomized, open-label, phase III study

REFRaME-O1/ENGOT-OV79/GOG-3086: A phase II/III, open-label study evaluating the efficacy and safety of luveltamab tazevibulin versus investigator's choice of chemotherapy in women with relapsed platinum-resistant epithelial ovarian cancer expressing folate receptor alpha

REFRaME-O1/ENGOT-OV79/GOG-3086: A phase II/III, open-label study evaluating the efficacy and safety of luveltamab tazevibulin versus investigator's choice of chemotherapy in women with relapsed platinum-resistant epithelial ovarian cancer expressing folate receptor alpha

Overall survival with camrelizumab plus famitinib versus camrelizumab alone and investigator's choice of chemotherapy for recurrent or metastatic cervical cancer

Overall survival with camrelizumab plus famitinib versus camrelizumab alone and investigator's choice of chemotherapy for recurrent or metastatic cervical cancer

Patient-reported outcome results from phase III MIRASOL trial of mirvetuximab soravtansine versus investigator's choice of chemotherapy in FRα-positive, platinum-resistant ovarian cancer

Patient-reported outcome results from phase III MIRASOL trial of mirvetuximab soravtansine versus investigator's choice of chemotherapy in FRα-positive, platinum-resistant ovarian cancer

Datopotamab Deruxtecan Versus Chemotherapy in Previously Treated Inoperable/Metastatic Hormone Receptor-Positive Human Epidermal Growth Factor Receptor 2-Negative Breast Cancer: Primary Results From TROPION-Breast01.

The global, phase 3, open-label, randomized TROPION-Breast01 study assessed the trophoblast cell surface antigen 2-directed antibody-drug conjugate datopotamab deruxtecan (Dato-DXd) versus investigator's choice of chemotherapy (ICC) in hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR+/HER2-) breast cancer. Adult patients with inoperable/metastatic HR+/HER2‒ breast cancer, who had disease progression on endocrine therapy, for whom endocrine therapy was unsuitable, and had received one to two previous lines of chemotherapy in the inoperable/metastatic setting, were randomly assigned 1:1 to Dato-DXd (6 mg/kg once every 3 weeks) or ICC (eribulin/vinorelbine/capecitabine/gemcitabine). Dual primary end points were progression-free survival (PFS) by blinded independent central review (BICR) and overall survival (OS). Patients were randomly assigned to Dato-DXd (n = 365) or ICC (n = 367). Dato-DXd significantly reduced the risk of progression or death versus ICC (PFS by BICR hazard ratio [HR], 0.63 [95% CI, 0.52 to 0.76]; P < .0001). Consistent PFS benefit was observed across subgroups. Although OS data were not mature, a trend favoring Dato-DXd was observed (HR, 0.84 [95% CI, 0.62 to 1.14]). The rate of grade ≥3 treatment-related adverse events (TRAEs) with Dato-DXd was lower than ICC (20.8% v 44.7%). The most common TRAEs (any grade; grade ≥3) were nausea (51.1%; 1.4%) and stomatitis (50%; 6.4%) with Dato-DXd and neutropenia (grouped term, 42.5%; 30.8%) with ICC. Patients receiving Dato-DXd had statistically significant and clinically meaningful improvement in PFS and a favorable and manageable safety profile, compared with ICC. Results support Dato-DXd as a novel treatment option for patients with inoperable/metastatic HR+/HER2‒ breast cancer who have received one to two previous lines of chemotherapy in this setting.

Cemiplimab monotherapy in Japanese patients with recurrent or metastatic cervical cancer.

In the phase 3 EMPOWER-Cervical 1/GOG-3016/ENGOT-cx9 study, cemiplimab significantly improved overall survival (OS) versus chemotherapy for patients with recurrent or metastatic cervical cancer who progressed after first-line platinum-based chemotherapy. We present a post hoc subgroup analysis of patients enrolled in Japan. Patients were enrolled regardless of programmed cell death-ligand 1 status and randomized 1:1 to cemiplimab 350 mg intravenously every 3 weeks or investigator's choice single-agent chemotherapy for up to 96 weeks. Primary endpoint was OS. Key secondary endpoints were progression-free survival (PFS) and objective response rate (ORR). Overall, 608 patients were randomized, of whom 56 (9.2%) were in Japan (cemiplimab, n = 29; chemotherapy, n = 27). The median (range) duration of follow-up was 13.6 (6.0-25.3) versus 18.2 (6.0-38.2) months for patients in Japan and for the overall population, respectively. Median OS (95% confidence interval [CI]) was 8.4 (7.0-not evaluable) and 9.4 (5.4-14.9) months for cemiplimab versus chemotherapy (hazard ratio [HR]: 0.86; 95% CI: 0.43-1.68). Median PFS (95% CI) was 4.0 (1.4-8.2) versus 3.7 (1.8-4.2) months with cemiplimab and chemotherapy (HR: 0.90; 95% CI: 0.50-1.61), respectively. ORR was 17.2% for cemiplimab and 7.4% for chemotherapy (odds ratio, 2.47; 95% CI, 0.44-13.99). Incidence of treatment-emergent adverse events at any grade was 79.3% for cemiplimab and 100% for chemotherapy. Grade ≥3 adverse events were 37.9% versus 66.7% with cemiplimab and chemotherapy, respectively. While acknowledging limitations inherent to a small subgroup analysis, the HR of 0.86 observed in Japanese patients suggests an emerging survival benefit despite a 4.6-month shorter median duration of follow-up versus the overall study population.

436TiP DYNASTY-Breast02: A phase III trial of BNT323/DB-1303 vs investigator's choice chemotherapy in HER2-low, hormone receptor positive, metastatic breast cancer

436TiP DYNASTY-Breast02: A phase III trial of BNT323/DB-1303 vs investigator's choice chemotherapy in HER2-low, hormone receptor positive, metastatic breast cancer

Pembrolizumab Plus Carboplatin and Paclitaxel as First-Line Therapy for Recurrent/Metastatic Head and Neck Squamous Cell Carcinoma (KEYNOTE-B10): A Single-Arm Phase IV Trial.

Standard-of-care first-line treatment for recurrent/metastatic head and neck squamous cell carcinoma (R/M HNSCC) is pembrolizumab plus platinum and fluorouracil (FU). However, FU is associated with potential challenges (continuous 4-day infusion, high administration costs, and cardiovascular and gastrointestinal toxicities), creating a clinical need for alternative chemotherapy combinations. We evaluated the efficacy and safety of first-line pembrolizumab plus carboplatin and paclitaxel for R/M HNSCC in the open-label, single-arm, phase IV KEYNOTE-B10 study (ClinicalTrials.gov identifier: NCT04489888). Eligible adults had previously untreated, histologically or cytologically confirmed R/M HNSCC regardless of PD-L1 status, measurable disease per RECIST v1.1 by blinded independent central review (BICR), and an Eastern Cooperative Oncology Group performance status of 0 or 1. Patients received pembrolizumab 200 mg intravenously once every 3 weeks for ≤35 cycles and carboplatin AUC 5 mg/mL/min intravenously once every 3 weeks for ≤6 cycles and investigator's choice of paclitaxel 100 mg/m2 on days 1 and 8 or 175 mg/m2 on day 1, intravenously once every 3 weeks. The primary end point was objective response rate per RECIST v1.1 by BICR. Between October 27, 2020, and April 29, 2022, 149 patients were screened and 101 received treatment. As of February 20, 2023, the median follow-up was 18.9 months (range, 9.1-27.0). At this final analysis, 49 (49%) of 101 patients had an objective response (95% CI, 38.4 to 58.7), including seven patients (7%) with a confirmed complete response. Of the 101 treated patients, grade 3-5 and serious treatment-related adverse events occurred in 76 (75%) and 27 (27%), respectively. There were no new safety signals. Pembrolizumab plus carboplatin and paclitaxel showed promising antitumor activity and a manageable safety profile in first-line R/M HNSCC, suggesting this combination may be an alternative option for this patient population.

Tebentafusp Induces a T-Cell–Driven Rash in Melanocyte-Bearing Skin as an Adverse Event Consistent with the Mechanism of Action

Tebentafusp is a gp100xCD3 bispecific ImmTAC designed to redirect polyclonal T cells against cells presenting the melanocyte lineage specific antigen gp100 on HLA-A*02:01. Skin-related adverse events, predominantly rash, are frequent and occur within a few hours after initial infusions, yet the mechanisms are unknown. Here we analysed clinical data from the randomised phase 3 trial (NCT03070392) of tebentafusp (n=252) versus investigator's choice (n=126). Translational analyses were performed on paired on-treatment skin samples from 19 patients collected in the phase 1 trial (NCT01211262). Our analyses showed that rash is a clinical manifestation of tebentafusp-induced recruitment of T cells to cutaneous melanocytes. Development of rash depended on baseline expression levels of gp100 and other melanin pathway genes in the skin. On treatment, melanocyte number was reduced and expression of melanocytic genes decreased, while gene expression related to immunity and cytokine signalling increased. When adjusted for baseline prognostic features, patients with rash within the first week of tebentafusp treatment had the same overall survival compared to patients without a rash in the phase 3 randomized trial IMCgp100-202 (HR 0.84; 95% CI 0.53-1.32). In summary, skin rash is an off-tumour, on-target effect of tebentafusp against gp100+ melanocytes, in line with the mechanism of action.

Bempegaldesleukin Plus Nivolumab Versus Sunitinib or Cabozantinib in Previously Untreated Advanced Clear Cell Renal Cell Carcinoma: A Phase III Randomized Study (PIVOT-09).

Bempegaldesleukin (BEMPEG) is a pegylated interleukin (IL)-2 cytokine prodrug engineered to provide controlled and sustained activation of the clinically validated IL-2 pathway, with the goal of preferentially activating and expanding effector CD8+ T cells and natural killer cells over immunosuppressive regulator T cells in the tumor microenvironment. The open-label, phase III randomized controlled PIVOT-09 trial investigated the efficacy and safety of BEMPEG plus nivolumab (NIVO) as first-line treatment for advanced/metastatic clear cell renal cell carcinoma (ccRCC) with intermediate-/poor-risk disease. Patients with previously untreated advanced/metastatic ccRCC were randomly assigned (1:1) to BEMPEG plus NIVO, or investigator's choice of tyrosine kinase inhibitor (TKI; sunitinib or cabozantinib). Coprimary end points were objective response rate (ORR) by blinded independent central review and overall survival (OS) in patients with International Metastatic RCC Database Consortium (IMDC) intermediate-/poor-risk disease. Overall, 623 patients were randomly assigned to BEMPEG plus NIVO (n = 311) or TKI (n = 312; sunitinib n = 225, cabozantinib n = 87), of whom 514 (82.5%) had IMDC intermediate-/poor-risk disease. In patients with IMDC intermediate-/poor-risk disease, ORR with BEMPEG plus NIVO versus TKI was 23.0% (95% CI, 18.0 to 28.7) versus 30.6% (95% CI, 25.1 to 36.6; difference, -7.7 [95% CI, -15.2 to -0.2]; P = .0489), and median OS was 29.0 months versus not estimable (hazard ratio, 0.82 [95% CI, 0.61 to 1.10]; P = .192), respectively. More frequent all-grade treatment-related adverse events (TRAEs) with BEMPEG plus NIVO versus TKI included pyrexia (32.6% v 2.0%) and pruritus (31.3% v 8.8%). Grade 3/4 TRAEs were less frequent with BEMPEG plus NIVO (25.8%) versus TKI (56.5%). First-line BEMPEG plus NIVO for advanced/metastatic ccRCC did not improve efficacy in patients with intermediate-/poor-risk disease but led to fewer grade 3/4 TRAEs versus TKI.

Lenvatinib Plus Pembrolizumab Versus Standard of Care for Previously Treated Metastatic Colorectal Cancer: Final Analysis of the Randomized, Open-Label, Phase III LEAP-017 Study.

Treatment options are limited for patients with previously treated metastatic colorectal cancer (mCRC). In the LEAP-017 study, we evaluate whether lenvatinib in combination with pembrolizumab improves outcomes compared with standard of care (SOC) in previously treated mismatch repair proficient or not microsatellite instability high (pMMR or not MSI-H) mCRC. In this international, multicenter, randomized, controlled, open-label, phase III study, eligible patients age 18 years and older with unresectable, pMMR or not MSI-H mCRC, that had progressed on or after, or could not tolerate, standard treatment, were randomly assigned 1:1 to lenvatinib 20 mg orally once daily plus pembrolizumab 400 mg intravenously once every 6 weeks or investigator's choice of regorafenib or trifluridine/tipiracil (SOC). Randomization was stratified by presence or absence of liver metastases. The primary end point was overall survival (OS). LEAP-017 is registered at ClinicalTrials.gov (NCT04776148), and has completed recruitment. Between April 8, 2021, and December 21, 2021, 480 patients were randomly assigned to lenvatinib plus pembrolizumab (n = 241) or SOC (n = 239). At final analysis (median follow-up of 18.6 months [IQR, 3.9]), median OS with lenvatinib plus pembrolizumab versus SOC was 9.8 versus 9.3 months (hazard ratio [HR], 0.83 [95% CI, 0.68 to 1.02]; P = .0379; prespecified threshold P = .0214). Grade ≥3 treatment-related adverse events occurred in 58.4% (lenvatinib plus pembrolizumab) versus 42.1% (SOC) of patients. Two participants died due to treatment-related adverse events, both in the lenvatinib plus pembrolizumab arm. In patients with pMMR or not MSI-H mCRC that had progressed on previous therapy, there was no statistically significant improvement in OS after lenvatinib plus pembrolizumab treatment versus SOC. No new safety signals were observed.

Efficacy and safety of fruquintinib plus investigator's choice of chemotherapy as second-line therapy in metastatic colorectal cancer: Updated results of a multicenter, single-arm, phase 2 trial.

3571 Background: Fruquintinib, a potent and highly selective vascular endothelial growth factor receptor (VEGFR) inhibitor, combined with investigator’s choice of chemotherapy as second-line therapy in patients (pts) with metastatic colorectal cancer (mCRC) showed promising efficacy in preliminary analysis (2023 ASCO Poster-3582) of the prospective, open-label, multicenter, single-arm phase 2 trial (ChiCTR2200059280). Here we reported the updated efficacy data. Methods: Pts with mCRC progressed after first-line prior systemic treatment were administered fruquintinib (5~3 mg, d1-21, q4w) and investigator’s choice of chemotherapy (fluorouracil ± irinotecan ± oxaliplatin, d1, q3w) for up to 8 cycles. Patients without disease progression (PD) were followed by fruquintinib maintenance until PD or unacceptable toxicities. The primary endpoint was progression-free survival (PFS). The secondary endpoints included objective response rate (ORR), disease control rate (DCR), duration of response (DoR), overall survival (OS) and safety. Results: From November 2021 to November 2023, 100 pts were enrolled. Median age was 63 years (IQR, 56.5-71) and 61.0% were male. The left colon cancer involved in 77.0% pts. All pts had MSS/pMMR phenotype and 37.0% had RAS/BRAF-mutated tumors. 9.0% received prior anti-EGFR and 55.0% received anti-VEGF therapy. Most common sites of metastatic disease were liver (57.0%) and lung (41.0%). As of January 20, 2024, with a median follow-up of 9.3 mo, the median PFS was 6.9 mo (95%CI, 5.2-8.6), median OS was 20.1 mo (95%CI, 13.7-26.3). ORR was 26.0% (95%CI, 17.9-36.2), DoR was 11.3 mo (95%CI, 8.6-14.0), and DCR was 83.3% (95%CI, 74.0-89.9) in 96 efficacy-evaluable pts. The incidence of adverse events was comparable to the known toxicities associated with fruquintinib and chemotherapy. No treatment-related deaths occurred. Grade 3/4 adverse effects occurred in 33 pts (33.0%), and most commonly were neutropenia (21.0%), leukopenia (14.0%), thrombocytopenia (6.0%), proteinuria (5.0%), hypothyroidism (3.0%), diarrhea (2.0%), hand-foot syndrome (2.0%) and hypertension (1.0%). Conclusions: Fruquintinib combined with investigator’s chemotherapy followed by fruquintinib maintenance as second-line therapy showed satisfactory anti-tumor activity, prolonged PFS and OS, and manageable safety profiles in pts with mCRC. Further analysis of all pts with long-term follow-up will be presented in the future. Clinical trial information: ChiCTR2200059280.

Efficacy and safety of luveltamab tazevibulin vs investigator’s choice of chemotherapy in patients with recurrent platinum-resistant ovarian cancer (PROC) expressing folate receptor alpha (FRα): The REFRaME-01 (GOG-3086, ENGOT-79ov, and APGOT-OV9) phase 2/3 study.

TPS5637 Background: The treatment of recurrent epithelial ovarian cancer remains a challenge, particularly for tumors with low to moderate expression levels of FRα. Luveltamab tazevibulin (luvelta) is an anti–FRα-targeting antibody-drug conjugate with a stable cleavable linker and a 3-aminophenyl hemiasterlin warhead (DAR=4), which induces cytotoxic and immunologic cell death. Luvelta was designed to treat multiple cancers with a broad range of FRα expression. Luvelta demonstrated preliminary antitumor activity in women with recurrent ovarian cancer, selected for FRα expression level of ≥25% at any intensity (tumor proportion score [TPS]). In PROC, this cutoff represents an estimated 80% of patients (pts). In a phase 1 study of luvelta in relapsed ovarian cancer, the overall response rate (ORR) was 37.5% with a median duration of response (DOR) of 5.5 months and a median progression-free survival (PFS) of 6.1 months. ORR was higher at 5.2 mg/kg compared with 4.3 mg/kg (43.8% vs 31.3%). The safety profile was manageable, with the most common grade ≥3 adverse events consisting of neutropenia, arthralgia, and anemia (Oaknin et al. J Clin Oncol 2023;41[16 suppl]:5508). These results support further investigation in pts with PROC whose tumors have a broad range of FRα expression. Herein, we describe a phase 2/3 pivotal study (REFRaME-01)of luvelta in this pt population. Methods: This randomized, global, open-label, 2-part phase 2/3 pivotal study has been designed to assess the efficacy and safety of luvelta vs investigator’s choice (IC) chemotherapy in pts with recurrent PROC expressing FRα (NCT05870748). Eligible pts are adults (≥18 years) with relapsed PROC, 1–3 prior lines of therapy (which must include bevacizumab), measurable disease, Eastern Cooperative Oncology Group performance status ≤1, and TPS for FRα expression ≥25% using Ventana validated IHC assay. Part 1 (phase 2) consists of a luvelta dose-optimization stage in which pts are randomized 1:1 to receive intravenous (IV) luvelta every 3 weeks (Q3W) at 4.3 mg/kg or IV luvelta Q3W at 5.2 mg/kg with prophylactic G-CSF for 2 cycles followed by 4.3 mg/kg luvelta from cycle 3 onward. Part 1 data will be used to select the optimal dosing regimen. In part 2 (phase 3) ~550 pts will be enrolled and randomized 1:1 to the optimal luvelta dosing regimen or IC chemotherapy (gemcitabine, paclitaxel, pegylated liposomal doxorubicin, or topotecan). Primary endpoints are PFS and ORR, with response evaluated per RECIST v1.1. Secondary endpoints include overall survival, DOR, safety, and quality of life. Clinical trial information: NCT05870748 .

Neoadjuvant pegylated liposomal doxorubicin-containing chemotherapy in combination with trastuzumab and pertuzumab in patients with HER2-positive early breast cancer: A randomized phase II study (METIS).

596 Background: In the neoadjuvant phase, anti-HER2 therapy is usually delayed when combined with anthracycline-containing chemotherapy regimens, since conventional anthracycline and anti-HER2 agents cannot be given simultaneously. Pegylated liposomal doxorubicin (PLD) is a modified form of doxorubicin that can lower the risk of heart damage while preserving its anticancer activity. In this study, we aimed to explore whether PLD could replace conventional anthracycline and be used earlier with anti-HER2 agents to enhance neoadjuvant efficacy without increasing cardiotoxicity. Methods: The METIS study was an investigator-initiated, multicenter, open-label, randomized, phase II study conducted at 11 centers in China. Patients aged 18 to 70 years old with previously untreated stage II–III histologically documented HER2-positive breast cancer were randomly assigned (1:1) to receive PLD-containing or epirubicin-containing neoadjuvant chemotherapy. The PLD-containing regimen consisted of 4 cycles of PLD (35 mg/m2) and cyclophosphamide (600 mg/m2) every 3 weeks, followed by 4 cycles of a taxane of the investigator's choice (docetaxel, paclitaxel, or nab-paclitaxel). The epirubicin-containing regimen consisted of 4 cycles of epirubicin (90 mg/m2) and cyclophosphamide (600 mg/m2) every 3 weeks, followed by 4 cycles of a taxane of the investigator's choice. Both regimens included trastuzumab (8 mg/kg loading dose, then 6 mg/kg maintenance dose) and pertuzumab (840 mg loading dose, then 420 mg maintenance dose) every 3 weeks. Trastuzumab and pertuzumab were given with all chemotherapy cycles in the PLD-containing group, and with the taxane cycles only in the epirubicin-containing group. The primary end point was investigator-assessed total pathological complete response (tpCR) rate in the intention-to-treat population. Results: From August 2019 to March 2023, 156 were enrolled and randomly assigned to receive PLD-containing (n=80) or epirubicin-containing (n=76) treatment. At date of data analysis, the median follow-up duration was 16.3 months. The PLD-containing treatment group had a higher rate of pathological complete response (67.5%, 95% CI 56.1-77.6) than the epirubicin-containing group (48.7%, 95% CI 37.0-60.4), with a rate difference of 18.8% (p=0.033). Only one patient in the epirubicin-containing group experienced a grade 3 decrease in left ventricular ejection fraction, while none did in the PLD-containing group. Other adverse events were similar in both groups. Conclusions: A combination of PLD and cyclophosphamide with trastuzumab and pertuzumab, followed by a taxane, trastuzumab, and pertuzumab, significantly increased the rate of tpCR without more cardiotoxicity in neoadjuvant treatment for early-stage HER2-positive breast cancer patients. Clinical trial information: NCT04172259 .

A phase III, open-label, multicenter, randomized controlled trial of tunlametinib versus investigator-selected chemotherapy in patients with advanced NRAS-mutant melanoma who had previously received immunotherapy.

TPS9606 Background: NRAS-mutant melanoma is an aggressive subtype with worse prognosis. However, no targeted therapy has been approved to date worldwide. Tunlametinib (HL-085) has showed an encouraging efficacy (confirmed ORR:34.8%, mPFS:4.2 months) with a manageable safety profile in phase II pivotal registrational study, which was published in ASCO 2023 annal meeting (NO.:9510). Here, we present the design of phase III randomized controlled study. Methods: This is a multicenter, two-arm, open-label, randomized controlled phase III confirmatory clinical trial to evaluate the efficacy and safety of tunlametinib in comparison with the combination chemotherapy of investigator's choice in advanced NRAS-mutant melanoma patients who had previously received immunotherapy. A total of 165 subjects from about 12 sites in China will be included and randomly assigned to the corresponding treatment group in 2:1 ratio. Two stratification factors before randomization: LDH level and whether have received chemotherapy. The key inclusion criteria included: a) Patients with unresectable stage III or metastatic IV melanoma confirmed by histology or cytology; b) History of immunotherapy failure or could not tolerate immunotherapy; c) Be able to provide NRAS mutation positive test report at baseline and provide sufficient histological specimens for NRAS mutation confirmation by central laboratory. Experimental group subjects will receive continuous administration of tunlametinib 12mg BID, 28 days per cycle. Control group subjects will receive one of the following regimens which according to investigator's choice (paclitaxel plus carboplatin, or temozolomide plus cisplatin, or dacarbazine plus cisplatin) , 28 days per cycle. The two groups will receive continuous therapy until disease progression or intolerable toxicity. The primary endpoint is progression-free survival which assessed by independent radiology review committee. Secondary endpoints included overall survival, objective response rate, disease control rate, duration of response, safety, pharmacokinetics and exposure-response. Exploratory endpoints are to evaluate quality of life between two groups and to development a companion diagnostic kit for NRAS gene mutations detection. This study is currently open for enrollment. Clinical trial information: NCT06008106 .

EFFECT-neo: A phase 3 study of pembrolizumab plus chemotherapy versus chemotherapy as neoadjuvant therapy in patients with resectable locally advanced head and neck squamous cell carcinoma.

TPS6123 Background: There is still a huge need for treatment of operable locally advanced head and neck squamous cell carcinoma (LA HNSCC). Multiple phase 2 studies have shown that PD-1 combined with chemotherapy has good short-term efficacy, especially the pathological complete response (pCR) rate exceeds 30%, which is also considered to be an important factor in the survival benefit that neoadjuvant immune therapy may bring. The randomized, open-label, phase 3 EFFECT-neo study (NCT06102395) will evaluate efficacy and safety of pembrolizumab plus chemotherapy versus chemotherapy as neoadjuvant therapy in patients with resectable LA HNSCC. Methods: Patients with untreated LA HNSCC who met the inclusion criteria will be randomly assigned 1:1 to two treatment arms. Experimental group will be given 2 cycles of pembrolizumab (200mg d1, Q3W) + chemotherapy (perfer TPF regimens) . Control group will undergo 2 cycles of chemotherapy. Both two arms should finish imaging evaluation, and If the result is CR after neoadjuvant treatment, radiotherapy (RT) (60-70Gy) ± chemotherapy (investigator's choice) will be given as adjuvant treatment; if the result are PR or SD, surgery (within 2 weeks) will be performed, and then RT ± chemotherapy will be given. If the imaging evaluation is PD, patients will be received standard treatment. Enrolled patients must closely monitor the adverse reactions of chemotherapy and record the time, grade, treatment measures, outcomes, etc. All patients will be reviewed every 3 months for 1 year; after 1 year, they were reviewed every 6 months for 3 years; patient recurrence and survival data were recorded. Eligibility criteria will include age ≥18 years; untreated with immunotherapy, resectable, stage III/IVB HNSCC (AJCC Cancer Staging Manual, 8th edition); ECOG performance status 0-2; and the investigators believe that patients can safely receive pembrolizumab combined with chemotherapy in neoadjuvant chemotherapy. Randomization treatment will continue until disease progression, unacceptable toxicity, or decision to withdraw. Primary end points is pCR, defined as the absence of residual invasive squamous cell carcinoma within the primary tumor specimen on resection/needle biopsy (Patients with CR imaging results will undergo multi-point biopsy). Secondary end points include objective response rate, 1-year and 2-year event-free survival rates, 2-year overall survival rate, functional preservation rate, safety and Karnofsky performance status. Recruitment is ongoing and will continue until 272 patients are enrolled. Clinical trial information: NCT06102395 .

Efficacy and safety of the vebreltinib in patients with previously treated, secondary glioblastoma/IDH mutant glioblastoma with PTPRZ1-METFUsion GENe (FUGEN): A randomised, multicentre, open-label, phase II/III trial.

2003 Background: Although gliomas with mutated IDH have an improved prognosis compared to gliomas with wild-type IDH, IDH-mutant gliomas carry a high risk of malignant transformation from low-grade gliomas into high-grade gliomas within 10 years, resulting in poor prognosis. However, effective targeted drugs for high-grade gliomas are still lacking. Here, we report data from the FUGEN study of Vebreltinib, the first completed phase II/III trial of sGBM / IDH mutant glioblastoma patients with previously treated, PTPRZ1-MET Fusion gene positive. Methods: In this open-label, phase II/III trial, we randomly assigned, in a 1:1 ratio, 84 patients with Histologically confirmed secondary GBM or IDH-mutant GBM to receive twice-daily oral vebreltinib in 300 mg dose or the investigator's choice of chemotherapy (temozolomide [100-150 mg/m2/day, 7days on followed by 7 days off ] or cis-platinum [80-100 mg/m2 for 3 days] combined with etoposide [100mg/m2/day for 3 days]) every 28 days. The primary endpoint was overall survival (OS), and the secondary endpoints were progression-free survival (PFS) and objective response rate (ORR). Results: 42 patients of the vebreltinib group and 39 patients of the chemotherapy group were included in the full analysis set. After a median follow-up of 4.44 months, the median OS in the vebreltinib group and chemotherapy group was 6.31 months (95% CI, 4.44-8.77) and 3.38 months (95% CI, 2.37-4.27), respectively. The HR for OS was 0.52 (90% CI, 0.32-0.85; P = 0.009). The median PFS in the vebreltinib group and chemotherapy group was 1.87 months (95% CI, 1.41-2.76) and 1.05 months (95% CI, 0.95-1.77), respectively. The HR for PFS was 0.54 (95% CI, 0.33-0.88; P = 0.014). No significant differences were observed in ORR (9.5% vs. 2.6%) for the vebreltinib group and chemotherapy group. Treatment-related adverse events of grade 3 or 4 were reported in 7% of the patients in the vebreltinib group, as compared with 12.2% of those in the chemotherapy group. No treatment-related deaths were observed. Conclusions: These results of the FUGEN trail support the use of vebreltinib as the first target therapy in patients with previously treated, PTPRZ1-MET fusion gene positive, secondary glioblastoma / IDH-mutant glioblastoma, and shed light on a novel therapeutic pathway in the landscape of IDH-mutant high-grade gliomas. Clinical Trials Information: NCT06105619 and ChiCTR2300077783 Research Funding:Beijing Pearl Biotechnology Co., Ltd. and Avistone Biotechnology Limited. Clinical trial information: NCT06105619 .