01/06/2024 Oncology Daily Report
Gynecological Cancers
In the BEATcc trial, an investigator-initiated, randomized, open-label, phase 3 trial, the efficacy of atezolizumab in combination with bevacizumab and chemotherapy was evaluated for patients with metastatic, persistent, or recurrent cervical cancer (1). The study enrolled 410 patients from 92 sites across Europe, Japan, and the USA. These patients had stage IVB cervical cancer, were previously untreated, and were not candidates for curative surgery or radiation. They were randomly assigned to receive either the standard therapy (cisplatin or carboplatin, paclitaxel, and bevacizumab) or the standard therapy plus atezolizumab. Treatment continued until disease progression, unacceptable toxicity, patient withdrawal, or death.
The study's dual primary endpoints were progression-free survival and overall survival, assessed in the intention-to-treat population. The results showed a median progression-free survival of 13.7 months with atezolizumab versus 10.4 months with standard therapy (HR=0.62; p<0.0001). The median overall survival was 32.1 months with atezolizumab compared to 22.8 months with standard therapy (HR 0.68; p=0.0046). Grade 3 or worse adverse events occurred in 79% of patients in the atezolizumab group and 75% in the standard therapy group, with increased occurrences of grade 1-2 diarrhea, arthralgia, pyrexia, and rash observed with atezolizumab. The study concluded that adding atezolizumab to the standard bevacizumab plus platinum regimen significantly improves survival outcomes and should be considered as a new first-line therapy option for this patient population.
A second study, titled "PAZEC: a Dutch Gynaecological Oncology Group open-label, multicenter, phase II study of pazopanib in metastatic and locally advanced hormone-resistant endometrial cancer," was a phase II, open-label trial (2). It focused on patients with histologically or cytologically confirmed endometrial cancer exhibiting documented progressive disease and a WHO performance status of ≤2. The intervention under investigation was pazopanib administered at a dosage of 800 mg daily until progression, unacceptable toxicity, or patient refusal. There was no mention of a control group in the provided text.
A total of 60 patients were included in the study, with a median age of 68 years, ranging from 53 to 85 years. The study aimed to assess pazopanib's effectiveness in achieving progression-free survival at 3 months as its primary endpoint. Secondary outcomes included overall response rate, progression-free survival, overall survival, and toxicity. The study achieved a 3-month progression-free survival rate of 63.3%, with median progression-free and overall survival times of 3.4 and 7.5 months, respectively. The overall response rate was 8.3%.
However, the study noted significant toxicity issues, with the most common severe adverse events being gastrointestinal toxicity, occurring in 21% of participants. This included two cases of gut perforation, one fatal gastrointestinal hemorrhage, one enterocutaneous fistula, and one fatal enterovaginal fistula. Most patients with severe gastrointestinal toxicity had extensive peritoneal disease. The study concluded that while pazopanib met its primary endpoint, the response rates were modest and severe gastrointestinal toxicity might correlate with previous treatments or disease sites, although a definite correlation was not established.
References
Oaknin A, Gladieff L, Martínez-García J, Villacampa G, Takekuma M, De Giorgi U, Lindemann K, Woelber L, Colombo N, Duska L, Leary A, Godoy-Ortiz A, Nishio S, Angelergues A, Rubio MJ, Fariñas-Madrid L, Yamaguchi S, Lorusso D, Ray-Coquard I, Manso L, Joly F, Alarcón J, Follana P, Romero I, Lebreton C, Pérez-Fidalgo JA, Yunokawa M, Dahlstrand H, D'Hondt V, Randall LM; ENGOT-Cx10–GEICO 68-C–JGOG1084–GOG-3030 Investigators. Atezolizumab plus bevacizumab and chemotherapy for metastatic, persistent, or recurrent cervical cancer (BEATcc): a randomised, open-label, phase 3 trial. Lancet. 2024 Jan 6;403(10421):31-43. doi: 10.1016/S0140-6736(23)02405-4. Epub 2023 Dec 1. PMID: 38048793.
Westermann A, Ottevanger P, Reyners A, Kroep JR, Van Oijen MGH, Lalisang R, Witteveen PO. PAZEC: a Dutch Gynaecological Oncology Group open-label, multicenter, phase II study of pazopanib in metastatic and locally advanced hormone-resistant endometrial cancer. Int J Gynecol Cancer. 2024 Jan 6:ijgc-2023-004781. doi: 10.1136/ijgc-2023-004781. Epub ahead of print. PMID: 38184318.
Pediatric Cancers
In a Phase I study, the safety and feasibility of nivolumab in combination with three different metronomic chemotherapy (MC) regimens were evaluated for children and adolescents with relapsing/refractory solid tumors (1). This multicenter study enrolled patients under 18 years, grouping them into three arms based on the MC regimen: cyclophosphamide and vinblastine (arm A), capecitabine (arm B), or a combination of cyclophosphamide, vinblastine, and capecitabine (arm C). The decision to open arm C was contingent on the safety assessment of arms A and B. The study's primary focus was on evaluating dose-limiting toxicities (DLTs) during the first two cycles of treatment.
The population under investigation included 16 patients, with a median age of 11.5 years and a history of extensive prior treatments. The distribution of patients was 3 in arm A, 6 in arm B, and 7 in arm C. The patients had undergone a median of 3.5 lines of systemic treatment before the study and most had received surgery and radiotherapy.
Results indicated a median of 2 treatment cycles per patient (ranging from 1 to 24 cycles), with arm C patients receiving a median of 4 cycles and a longer treatment duration of 95 days. Notably, no dose-limiting toxicities were observed. However, 50% of the patients experienced Grade 3 adverse events, and 6% encountered serious adverse events within the first two cycles. No Grade 4 adverse events were reported. The 6-month progression-free survival (PFS) and overall survival (OS) rates were 12% and 44%, respectively. Notably, prolonged stable disease was observed in patients with high-grade glioma and an atypical teratoid rhabdoid tumor.
The study concluded that the regimen in arm C was safe and a randomized Phase II trial is underway to further evaluate the efficacy of adding nivolumab to the triple MC regimen.
Reference
André N, Deley MCL, Léguillette C, Probst A, Willems L, Travers R, Aerts I, Faure-Conter C, Revond-Riviere G, Min V, Geoerger B, Chastagner P, Entz-Werlé N, Leblond P. METRO-PD1: Phase 1 study of nivolumab in combination with metronomic chemotherapy in children and adolescents with relapsing/refractory solid tumors. Eur J Cancer. 2024 Jan 6;198:113525. doi: 10.1016/j.ejca.2024.113525. Epub ahead of print. PMID: 38199147.
Multiple Myeloma
In an open-label, phase I study, researchers investigated the combination of metformin, a complex I inhibitor, and nelfinavir, a GLUT4 inhibitor, with bortezomib in patients with relapsed and refractory multiple myeloma (MM) (1). The study's population comprised nine patients with a median age of 65, who had previously undergone an average of seven prior lines of therapy. Employing a 3+3 dose escalation design, the trial aimed to determine the maximal tolerated dose of these drugs, assess their safety, and evaluate the overall response rate (ORR).
Initially, the first three patients received only metformin and nelfinavir. One of these patients showed minimal response, while the other two exhibited progressive disease. Subsequently, bortezomib was added to the treatment regimen for the next six patients. Among them, one achieved a partial response, one experienced stable disease, and the remaining either faced progressive disease or went off study for hospice care.
The study was concluded early due to limited therapeutic activity, with no ORR observed except for one patient who attained stable disease. This allowed the disease to stabilize until another novel therapy was available, highlighting the combination's potential in stabilizing disease in some cases. However, overall, the study yielded negative results regarding the efficacy of this drug combination in treating this challenging population of MM patients.'
Reference
Alodhaibi I, Ailawadhi S, Burbano GP, O'Brien PJ, Buadi FK, Hayman S, Kumar SK, Gonsalves WI. An Open-Label Phase I Study of Metformin and Nelfinavir in Combination With Bortezomib in Patients With Relapsed and Refractory Multiple Myeloma. Clin Lymphoma Myeloma Leuk. 2024 Jan 6:S2152-2650(24)00019-3. doi: 10.1016/j.clml.2024.01.002. Epub ahead of print. PMID: 38220589.
Prostate Cancer
The study in question is a safety analysis of the Phase 3 VISION trial, focusing on the use of [177Lu]Lu-PSMA-617 in patients with metastatic castration-resistant prostate cancer (1). This was an open-label, international, randomized trial. The intervention investigated was [177Lu]Lu-PSMA-617 combined with standard of care, compared to the standard of care alone as the control group. The study population consisted of patients with progressive PSMA-positive metastatic castration-resistant prostate cancer, who had previously received at least one androgen receptor pathway inhibitor and one or two taxane-containing regimens.
A total of 734 out of 831 patients received at least one dose of the study treatment. The 177Lu-PSMA-617 arm involved 529 patients, while the control arm included 205 patients. The median duration of treatment exposure varied, with the 177Lu-PSMA-617 arm having a longer median exposure than the control arm. Results showed that the incidence of treatment-emergent adverse events (TEAEs) was consistent across different cycles of 177Lu-PSMA-617 treatment, and there were no additional safety concerns for patients who received more than four cycles. The study concluded that longer exposure to 177Lu-PSMA-617 plus standard care was not associated with a higher toxicity risk. The findings supported a favorable benefit-risk profile for up to six cycles of 177Lu-PSMA-617 treatment in this setting.
Reference
Chi KN, Armstrong AJ, Krause BJ, Herrmann K, Rahbar K, de Bono JS, Adra N, Garje R, Michalski JM, Kempel MM, Fizazi K, Morris MJ, Sartor O, Brackman M, DeSilvio M, Wilke C, Holder G, Tagawa ST. Safety Analyses of the Phase 3 VISION Trial of [177Lu]Lu-PSMA-617 in Patients with Metastatic Castration-resistant Prostate Cancer. Eur Urol. 2024 Jan 6:S0302-2838(23)03297-9. doi: 10.1016/j.eururo.2023.12.004. Epub ahead of print. PMID: 38185538.
Advanced Malignant Tumors
In this phase I study, the safety, tolerability, pharmacokinetics, immunogenicity, and preliminary antitumor activity of TQB2450, a novel monoclonal antibody targeting programmed cell death ligand 1, were evaluated in patients with advanced malignant tumors. Administered intravenously every three weeks, the study included both a 3 + 3 dose-escalation phase ranging from 1-30 mg/kg and a specific dose-expansion phase at 1200 mg. The primary endpoints focused on the maximum tolerated dose (MTD), dose-limiting toxicity (DLT), and safety, while secondary endpoints included pharmacokinetics, immunogenicity, and the investigator-assessed response rate.
Between April 2018 and February 2020, 40 patients participated, with 22 in the dose-escalation phase and 18 in the dose-expansion phase. Notably, no DLTs were reported, and the MTD was not reached. Treatment-related adverse events of grade 3 or higher occurred in 27.50% of patients, including increased aspartate aminotransferase, leukopenia, and anemia, each affecting 5.00% of participants. Six patients experienced serious adverse events, with decompensated liver function being the most common (5.00%). However, no treatment-related deaths occurred. The study also found that the maximum serum concentration of TQB2450 increased proportionally with the dose. Anti-drug antibodies were detected in 31.58% of patients (12 out of 38).
The objective response rate, as assessed by investigators, was 5.00%, with a disease control rate of 52.50%, including 2 partial responses and 19 cases of stable disease. The median progression-free survival was 2.69 months, with a 95% confidence interval of 2.07-6.14 months. The conclusion drawn from this study is that TQB2450 has a manageable safety profile and shows early evidence of clinical activity in advanced malignant tumors, displaying favorable pharmacokinetics and immunogenicity profiles.
Reference
Xue J, Xue L, Tang W, Ge X, Zhao W, Li Q, Peng W, Dai C, Guo Y, Li J. TQB2450 in patients with advanced malignant tumors: results from a phase I dose-escalation and expansion study. Ther Adv Med Oncol. 2024 Jan 6;16:17588359231220516. doi: 10.1177/17588359231220516. PMID: 38188467; PMCID: PMC10771754.
Colorectal Liver Metastases
The study titled "TQB2450 in patients with advanced malignant tumors: results from a phase I dose-escalation and expansion study" was designed as a phase I open-label, single-arm dose-escalation and expansion study (1). The population under investigation comprised adult patients with advanced malignant tumors that were histologically or cytologically confirmed and had either progressed or developed intolerable toxicity to standard treatment.
The intervention under investigation was TQB2450, a novel monoclonal antibody targeting programmed cell death ligand 1 (PD-L1). This study involved intravenous administration of TQB2450 once every three weeks, with a dose range from 1 to 30 mg/kg during the dose-escalation phase and a specific dose of 1200 mg during the expansion phase.
A control group was not mentioned, as is typical for early-phase trials focusing on safety and preliminary efficacy.
A total of 40 patients were enrolled, with 22 in the dose-escalation phase and 18 in the dose-expansion phase. The study found that no dose-limiting toxicity was reported, and the maximum tolerated dose was not reached. Treatment-related adverse events of grade 3 or higher occurred in 27.5% of patients. The most common severe treatment-related adverse events included increased aspartate aminotransferase, leukopenia, and anemia, each occurring in 5% of patients. No treatment-related deaths were reported. The study demonstrated a manageable safety profile for TQB2450, with the investigator-assessed objective response rate being 5%, and the disease control rate was 52.5%. This included 2 partial responses and 19 stable diseases. The median progression-free survival was 2.69 months.
Reference
Coffman-D'Annibale K, Myojin Y, Monge C, Xie C, Hrones DM, Wood BJ, Levy EB, Kleiner D, Figg WD, Steinberg SM, Redd B, Greten TF. VB-111 (ofranergene obadenovec) in combination with nivolumab in patients with microsatellite stable colorectal liver metastases: a single center, single arm, phase II trial. J Immunother Cancer. 2024 Jan 6;12(1):e008079. doi: 10.1136/jitc-2023-008079. PMID: 38184304; PMCID: PMC10773432.