Oncology Daily Report: 01/08/2024
Carcinomas: Primary liver cancer with malignant ascites
The study presented is an exploratory clinical trial conducted on advanced primary liver cancer patients with malignant ascites (1). It was a single-arm, single-center, phase Ib trial designed to assess the safety and clinical efficacy of intraperitoneal anti-programmed cell death protein 1 (PD-1) antibody, specifically sintilimab, in this patient population.
The intervention under investigation involved administering sintilimab at a dosage of 100 mg intraperitoneally, combined with the best supportive care. This treatment was given on days 1, 8, and 15 in three cycles, each spanning four weeks. The course was repeated every 28 days until either intolerable toxicity was observed or the disease progressed. The primary objective of the study was to evaluate the safety of this treatment, while secondary objectives included assessing the objective response rate (ORR), ascites control rate (ACR), and overall survival (OS).
In this trial, a total of 21 patients were enrolled between February 2021 and November 2022, including 14 with hepatocellular carcinoma and 7 with cholangiocarcinoma. Of these, 12 patients experienced adverse events (AEs), with the most common grade 3 AEs being fatigue, rash, and abdominal pain. Notably, there were no AEs of grade 4 or higher reported in any of the patients.
The efficacy of the treatment was evaluated in terms of ORR, which was assessed in 13 patients. The results showed a partial response in 4 patients, stable disease in 7, and progressive disease in 2. There was a reduction in the median maximum diameter of the tumor post-treatment, but this change was not statistically significant. The objective remission rate of ascites was 43.75%. The median overall survival for all 21 patients was reported to be 17.6 weeks.
In conclusion, this phase Ib study demonstrated the safety of intraperitoneal anti-PD-1 antibody administration, with no unexpected safety concerns. However, the clinical efficacy, though promising, requires further validation through a larger, multicenter, prospective study.
References
Chen C, Li Z, Xiong X, Yao A, Wang S, Liu X, Liu X, Wang J. Intraperitoneal PD-1 monoclonal antibody for the treatment of advanced primary liver cancer with malignant ascites: a single-arm, single-center, phase Ib trial. ESMO Open. 2024 Jan 8;9(1):102206. doi: 10.1016/j.esmoop.2023.102206. Epub ahead of print. PMID: 38194882.
Carcinomas: Triple-negative breast cancer (TNBC)
This study, titled "Optimising first-line subtyping-based therapy in triple-negative breast cancer (FUTURE-SUPER): a multi-cohort, randomised, phase 2 trial," was designed to evaluate the efficacy and safety of subtyping-based therapy in the first-line treatment of triple-negative breast cancer (1). Conducted at the Fudan University Shanghai Cancer Center in Shanghai, China, the study was a phase 2, open-label, randomised, controlled trial.
The population under investigation comprised female participants aged between 18 and 70 years, all diagnosed with histologically confirmed, untreated metastatic or recurrent triple-negative breast cancer. Their Eastern Cooperative Oncology Group performance status ranged from 0 to 1. The study enrolled 139 participants, who were then categorized into five cohorts based on molecular subtype and genomic biomarkers. These participants were randomly assigned in a 1:1 ratio, with a block size of 4, and stratified by subtype.
The intervention groups received a subtyping-based regimen alongside nab-paclitaxel. This regimen varied depending on the subtype: pyrotinib for the LAR-HER2(mut) subtype, everolimus for the LAR-PI3K/AKT(mut) and MES-PI3K/AKT(mut) subtypes, camrelizumab and famitinib for the immunomodulatory subtype, and bevacizumab for the BLIS/MES-PI3K/AKT(WT) subtype. The control group received only nab-paclitaxel.
In total, 69 participants were assigned to the subtyping-based group, while 70 were in the control group. The primary endpoint of the study was the progression-free survival in the pooled subtyping-based group compared to the control group, assessed in the intention-to-treat population. Safety was also analyzed in all patients who received at least one dose of the study drug.
The results showed that the median progression-free survival was significantly longer in the subtyping-based group, with 11.3 months (95% CI 8.6-15.2), compared to 5.8 months (95% CI 4.0-6.7) in the control group. This difference represented a hazard ratio of 0.44 (95% CI 0.30-0.65; p<0.0001). Regarding safety, the most common grade 3-4 treatment-related adverse events included neutropenia, anaemia, and increased alanine aminotransferase. There were more treatment-related serious adverse events reported in the subtyping-based group (10% of 69 patients) compared to none in the control group, but no treatment-related deaths were reported in either group.
The study, registered with ClinicalTrials.gov (NCT04395989), suggests potential clinical benefits of using molecular subtype-based treatment optimization in patients with triple-negative breast cancer and underscores the need for further clinical investigation, including phase 3 randomised clinical trials. The study was funded by the National Natural Science Foundation of China, the Natural Science Foundation of Shanghai, the Shanghai Hospital Development Center, and Jiangsu Hengrui Pharmaceuticals.
Reference
Fan L, Wang ZH, Ma LX, Wu SY, Wu J, Yu KD, Sui XY, Xu Y, Liu XY, Chen L, Zhang WJ, Jin X, Xiao Q, Shui RH, Xiao Y, Wang H, Yang YS, Huang XY, Cao AY, Li JJ, Di GH, Liu GY, Yang WT, Hu X, Xia Y, Liang QN, Jiang YZ, Shao ZM. Optimising first-line subtyping-based therapy in triple-negative breast cancer (FUTURE-SUPER): a multi-cohort, randomised, phase 2 trial. Lancet Oncol. 2024 Jan 8:S1470-2045(23)00579-X. doi: 10.1016/S1470-2045(23)00579-X. Epub ahead of print. PMID: 38211606.
Carcinomas: Triple-negative breast cancer (TNBC)
The study titled "TORCHLIGHT" explored the effectiveness and safety of combining toripalimab, an immune-checkpoint inhibitor, with nab-paclitaxel (nab-P) in the treatment of advanced triple-negative breast cancer (TNBC) (1). This was a randomized, double-blinded phase 3 trial. The population under investigation comprised women with metastatic or recurrent TNBC. The study consisted of two arms: the experimental arm, which involved 353 patients receiving toripalimab and nab-P, and the control arm, which included 178 patients receiving a placebo alongside nab-P.
The primary endpoint of the study was progression-free survival (PFS), assessed by a blinded independent central review, focusing on two populations: those with PD-L1-positive TNBC and the intention-to-treat population. Secondary endpoints included overall survival and safety. Of the participants, 200 in the toripalimab arm and 100 in the placebo arm were PD-L1-positive.
The results from the prespecified interim analysis revealed a significant improvement in PFS in the experimental arm among the PD-L1-positive population. The median PFS was 8.4 months in the experimental arm compared to 5.6 months in the control arm. This improvement was statistically significant, with a hazard ratio (HR) of 0.65 and a 95% confidence interval (CI) ranging from 0.470 to 0.906, and a P-value of 0.0102. Additionally, the median overall survival was notably better in the experimental arm, at 32.8 months versus 19.5 months in the control arm, with an HR of 0.62, a 95% CI of 0.414-0.914, and a P-value of 0.0148.
The safety profile was comparable between the two groups. The incidence of treatment-emergent adverse events (AEs) was similar in both arms, with 99.2% in the experimental arm and 98.9% in the control arm. Grade ≥3 treatment-emergent AEs were observed in 56.4% of patients in the experimental arm and 54.3% in the control arm. Fatal AEs occurred in 0.6% of patients in the experimental arm and 3.4% in the control arm.
In summary, the addition of toripalimab to nab-P demonstrated a significant improvement in progression-free survival for patients with PD-L1-positive metastatic or recurrent TNBC, while maintaining an acceptable safety profile. The study's findings suggest potential benefits of this combination treatment for this specific patient population. The study is registered with ClinicalTrial.gov (identifier NCT03777579).
Reference
Jiang Z, Ouyang Q, Sun T, Zhang Q, Teng Y, Cui J, Wang H, Yin Y, Wang X, Zhou X, Wang Y, Sun G, Wang J, Zhang L, Yang J, Qian J, Yan M, Liu X, Yi T, Cheng Y, Li M, Zang A, Wang S, Wang C, Wu X, Cheng J, Li H, Lin Y, Geng C, Gu K, Xie C, Xiong H, Wu X, Yang J, Li Q, Chen Y, Li F, Zhang A, Zhang Y, Wu Y, Nie J, Liu Q, Wang K, Mo X, Chen L, Pan Y, Fu P, Zhang H, Pang D, Sheng Y, Han Y, Wang H, Cang S, Luo X, Yu W, Deng R, Yang C, Keegan P. Toripalimab plus nab-paclitaxel in metastatic or recurrent triple-negative breast cancer: a randomized phase 3 trial. Nat Med. 2024 Jan 8. doi: 10.1038/s41591-023-02677-x. Epub ahead of print. PMID: 38191615.
Gastrointestinal Cancers: Gastric and gastroesophageal junction adenocarcinoma
The study in question, titled "Neoadjuvant atezolizumab plus chemotherapy in gastric and gastroesophageal junction adenocarcinoma: the phase 2 PANDA trial" focused on the effectiveness and safety of neoadjuvant immunotherapy combined with chemotherapy in patients with nonmetastatic gastric and gastroesophageal junction (G/GEJ) cancer (1). This was a phase 2 clinical trial, as indicated by its title.
The population under investigation comprised patients with previously untreated, resectable G/GEJ tumors. A total of 21 patients were enrolled in the study. The intervention under investigation was a combination of neoadjuvant treatment with one cycle of atezolizumab monotherapy followed by four cycles of atezolizumab plus docetaxel, oxaliplatin, and capecitabine. The abstract does not explicitly mention a control group, suggesting that this trial may have been a single-arm study focusing on the efficacy and safety of the intervention itself.
The primary endpoint of the trial was the safety and feasibility of the treatment regimen, as evidenced by the fact that all patients were able to undergo resection without treatment-related delays. The study reported that the treatment was well-tolerated, with grade 3 immune-related adverse events occurring in two of 20 patients (10%) but no grade 4 or 5 immune-related adverse events.
Regarding the results, the study found a major pathologic response (defined as ≤10% residual viable tumor) in 14 of 20 evaluable patients (70%, with a 95% confidence interval of 46-88%), including 9 patients (45%, with a 95% confidence interval of 23-68%) achieving pathologic complete responses. At a median follow-up of 47 months, 13 of 14 responders were alive and disease-free, while five of six nonresponders had died due to recurrence. The study also noted a significant difference in baseline anti-programmed cell death protein 1 (PD-1)(+)CD8(+) T cell infiltration between responders and nonresponders. Additionally, it was observed that there was an increased immune activation on single-agent PD-1/L1 axis blockade compared to the combination therapy.
The authors concluded that the monotherapy anti-PD-L1 before its combination with chemotherapy showed promising results and suggested that this approach warrants further exploration and validation in a larger cohort of patients with nonmetastatic G/GEJ cancer. The trial was registered at ClinicalTrials.gov (NCT03448835).
Reference
Verschoor YL, van de Haar J, van den Berg JG, van Sandick JW, Kodach LL, van Dieren JM, Balduzzi S, Grootscholten C, IJsselsteijn ME, Veenhof AAFA, Hartemink KJ, Vollebergh MA, Jurdi A, Sharma S, Spickard E, Owers EC, Bartels-Rutten A, den Hartog P, de Miranda NFCC, van Leerdam ME, Haanen JBAG, Schumacher TN, Voest EE, Chalabi M. Neoadjuvant atezolizumab plus chemotherapy in gastric and gastroesophageal junction adenocarcinoma: the phase 2 PANDA trial. Nat Med. 2024 Jan 8. doi: 10.1038/s41591-023-02758-x. Epub ahead of print. PMID: 38191613.
Leukemias: T-prolymphocytic leukemia
The study investigated the efficacy and safety of ibrutinib and venetoclax in treating T-prolymphocytic leukemia (T-PLL) (1). This was an open-label, single-arm, phase 2 study with an adaptive 2-stage design. The initial stage involved 14 adult patients with relapsed or refractory T-PLL, who were suitable for additional therapy and had not been previously treated with BCL-2 inhibitors. The intervention under investigation was a combination of 420 mg ibrutinib orally once daily and oral venetoclax, starting with a 5-day dose-acceleration from 20-400 mg and then continued at 400 mg. The primary endpoint was the overall response rate (ORR), while secondary outcomes included safety, tolerability, progression-free survival (PFS), duration of response, disease control rate, and overall survival (OS).
The study enrolled 14 patients, with a median age of 66 years and a median of 2 prior lines of T-PLL therapy. The median treatment duration was approximately 14 weeks for both drugs. The results showed that out of the 14 patients evaluated, only 1 achieved partial remission, leading to an ORR of 7.1%. The disease control rate was 28.6%, with three patients showing stable disease. However, the majority (64.3%) had progressive disease. The median PFS was 11.7 weeks, and the median OS was 31.8 weeks. No patients achieved complete remission or were eligible for consolidating or salvage stem cell transplantation.
All patients experienced at least one treatment-emergent adverse event, with most experiencing grade 3/4 events. The most common grade 3/4 adverse events were anemia, nausea, and neutropenia. The study concluded that the combination of ibrutinib and venetoclax did not demonstrate significant activity in patients with relapsed/refractory T-PLL and does not warrant further study in this population.
Reference
Herling M, Dearden C, Zaja F, El-Sharkawi D, Ding W, Bellido M, Khot A, Tick LW, Jacobsen E, Eyre TA, Roos-Weil D, Kadia TM, Lucchini E, Pflug N, Davids MS, Pena G, Mukherjee N, Badawi M, Vizkelety T, Staber PB. Limited efficacy for ibrutinib and venetoclax in T-prolymphocytic leukemia: results from a phase 2 international study. Blood Adv. 2024 Jan 8:bloodadvances.2023012248. doi: 10.1182/bloodadvances.2023012248. Epub ahead of print. PMID: 38190628.
Pediatric Cancers: Relapsed or refractory solid tumors, including CNS tumors
This study focused on determining the optimal dose of ramucirumab in children and adolescents with relapsed or refractory solid tumors, including central nervous system tumors (1). The study was conducted as a phase 1 trial, which primarily aimed to establish the recommended phase 2 dose (RP2D) based on pharmacokinetic (PK) analysis. The design of the trial was a rolling six design, utilizing a PK primary endpoint.
The population under investigation comprised children with recurrent or refractory solid tumors. The intervention under investigation was ramucirumab, a monoclonal antibody that targets the extracellular domain of the vascular endothelial growth factor receptor (VEGFR-2). Ramucirumab was administered intravenously at two planned dose levels: 8 mg/kg and 12 mg/kg, with administrations occurring every two weeks. The control group or comparative intervention details are not provided in the abstract.
A total of 29 patients were enrolled in the study, out of which 28 were eligible, and 22 were evaluable for the PK endpoint. The median age of the participants ranged from 1 to 21 years, with a median of 13.5 years. The assessment of the maximum tolerated dose (MTD) was based on toxicity observed during the initial 6 weeks, focusing particularly on dose-limiting proteinuria.
The results indicated that ramucirumab was well tolerated in the study population. At the higher dose level of 12 mg/kg, the median Day 42 trough concentration (C(min)) was 87.8 µg/mL, and 15 out of 16 patients achieved a C(min) ≥ 50 µg/mL. This finding led to the determination that the RP2D for ramucirumab is 12 mg/kg administered intravenously every two weeks. The study concluded that incorporating a primary PK endpoint is feasible for determining dose escalation and the RP2D in pediatric patients. Ongoing studies are investigating the use of ramucirumab in children with selected solid tumors.
Reference
Pilbeam KL, Pradhan K, Croop J, Minard CG, Liu X, Voss SD, Isikwei E, Berg SL, Reid JM, Fox E, Weigel BJ. A phase 1 trial utilizing a pharmacokinetic endpoint to determine the optimal dose of ramucirumab in children and adolescents with relapsed or refractory solid tumors, including central nervous system tumors. Pediatr Blood Cancer. 2024 Jan 8:e30817. doi: 10.1002/pbc.30817. Epub ahead of print. PMID: 38189770.
Pediatric Cancers: Neuroblastoma
The BEACON Neuroblastoma trial, registered under EudraCT 2012-000072-42, was conducted to evaluate the efficacy of different chemotherapy regimens combined with the antiangiogenic agent bevacizumab for children suffering from relapsed and refractory high-risk neuroblastoma (RR-HRNB) (1). The study was designed as a phase II trial, focusing on patients aged between 1 and 21 years who had RR-HRNB with sufficient organ function and performance status. Participants were randomly assigned in a 3 × 2 factorial design to one of three chemotherapy regimens: temozolomide (T), irinotecan-temozolomide (IT), or topotecan-temozolomide (TTo), with or without the addition of bevacizumab.
The primary endpoint of the trial was the best overall response rate (ORR), which was evaluated during the first six courses of treatment. ORR was defined as either a complete or partial response, assessed by RECIST or International Neuroblastoma Response Criteria for patients with measurable or evaluable disease, respectively. Secondary endpoints included safety, progression-free survival (PFS), and overall survival (OS) time.
In total, 160 patients with RR-HRNB were included in the study. For the group receiving bevacizumab (n = 160), the ORR was 26% (95% Confidence Interval [CI], 17 to 37) with bevacizumab and 18% (95% CI, 10 to 28) without it. The risk ratio (RR) for this outcome was 1.52 (95% CI, 0.83 to 2.77; P = .17). The adjusted hazard ratios for PFS and OS were 0.89 (95% CI, 0.63 to 1.27) and 1.01 (95% CI, 0.70 to 1.45), respectively. Within the subgroups, for the irinotecan (n = 121) and topotecan (n = 60) random assignments, the RRs for ORR were 0.94 and 1.22, respectively. An interaction between irinotecan and bevacizumab was suggested. Specifically, in the bevacizumab-irinotecan-temozolomide (BIT) arm, the ORR was 23% (95% CI, 10 to 42), and the 1-year PFS estimate was 0.67 (95% CI, 0.47 to 0.80).
The study concluded that the addition of bevacizumab met the protocol-defined success criteria for ORR and seemed to improve PFS. The BIT combination exhibited signs of antitumor activity and was tolerably accepted. The trial's findings indicated a need for future trials to confirm these results in the context of chemoimmunotherapy.
Reference
Moreno L, Weston R, Owens C, Valteau-Couanet D, Gambart M, Castel V, Zwaan CM, Nysom K, Gerber N, Castellano A, Laureys G, Ladenstein R, Rössler J, Makin G, Murphy D, Morland B, Vaidya S, Thebaud E, van Eijkelenburg N, Tweddle DA, Barone G, Tandonnet J, Corradini N, Chastagner P, Paillard C, Bautista FJ, Gallego Melcon S, De Wilde B, Marshall L, Gray J, Burchill SA, Schleiermacher G, Chesler L, Peet A, Leach MO, McHugh K, Hayes R, Jerome N, Caron H, Laidler J, Fenwick N, Holt G, Moroz V, Kearns P, Gates S, Pearson ADJ, Wheatley K; Innovative Therapies for Children with Cancer (ITCC) and European Association for Neuroblastoma Research (SIOPEN). Bevacizumab, Irinotecan, or Topotecan Added to Temozolomide for Children With Relapsed and Refractory Neuroblastoma: Results of the ITCC-SIOPEN BEACON-Neuroblastoma Trial. J Clin Oncol. 2024 Jan 8:JCO2300458. doi: 10.1200/JCO.23.00458. Epub ahead of print. PMID: 38190578.
Pediatric Cancers: Osteosarcoma, Neuroblastoma
The study focused on the efficacy of Chimeric Antigen Receptor T cells (CAR-Ts) in solid tumors, specifically targeting GD2-expressing tumors with a novel GD2 CAR-T cell therapy (GD2-CAR.OX40.28.z.iC9) (1). This was set in the context of the well-established efficacy of CAR-Ts in liquid tumors but their limited responses in solid tumors. The research was conducted as a Phase I trial, as indicated by the trial identifier NCT02107963. The population under investigation comprised children and young adults diagnosed with osteosarcoma and neuroblastoma. These participants were administered the GD2 CAR-T cell therapy.
The study's design involved grouping patients into categories of good or poor CAR-T cell expanders across different dose levels, which is a crucial factor for the efficacy of CAR-T therapies. The intervention under investigation, namely the GD2 CAR-T cell therapy, was evaluated for its feasibility and safety in this patient population.
One of the key aspects of the study was the comprehensive analysis of patient samples. This included multi-dimensional proteomic, transcriptomic, and epigenetic analyses, which provided insights into the immune determinants of CAR-T cell expansion. The T cell assessments revealed that naive T cells in pre-treatment apheresis were associated with good expansion, while exhausted T cells in CAR-T products correlated with poor expansion. Additionally, the study found that CXCR3(+) monocytes in pre-treatment apheresis were also associated with good expansion. In contrast, an increase in CXCR3(-) classical monocytes was observed in post-treatment samples across all groups as CAR-T cell numbers decreased.
The number of patients involved in the study was not specified in the provided text. Similarly, the control group, if any, was not mentioned. The results of the study, including specific numerical values related to the efficacy, safety, or expansion of the CAR-T cells, were not detailed in the text. Also, information regarding the follow-up duration was not available.
In summary, the study provided significant insights into the immune determinants of CAR-T cell expansion in solid tumors, specifically in the context of GD2 CAR-T cell therapy in children and young adults with osteosarcoma and neuroblastoma. The findings highlighted the potential of using specific T cell and myeloid cell characteristics to predict and possibly enhance the efficacy of CAR-T therapies in solid tumors.
Reference
Kaczanowska S, Murty T, Alimadadi A, Contreras CF, Duault C, Subrahmanyam PB, Reynolds W, Gutierrez NA, Baskar R, Wu CJ, Michor F, Altreuter J, Liu Y, Jhaveri A, Duong V, Anbunathan H, Ong C, Zhang H, Moravec R, Yu J, Biswas R, Van Nostrand S, Lindsay J, Pichavant M, Sotillo E, Bernstein D, Carbonell A, Derdak J, Klicka-Skeels J, Segal JE, Dombi E, Harmon SA, Turkbey B, Sahaf B, Bendall S, Maecker H, Highfill SL, Stroncek D, Glod J, Merchant M, Hedrick CC, Mackall CL, Ramakrishna S, Kaplan RN. Immune determinants of CAR-T cell expansion in solid tumor patients receiving GD2 CAR-T cell therapy. Cancer Cell. 2024 Jan 8;42(1):35-51.e8. doi: 10.1016/j.ccell.2023.11.011. Epub 2023 Dec 21. PMID: 38134936.
Lymphomas: Peripheral T-cell lymphoma (PTCL)
This was a first-in-human phase 1 study focusing on the efficacy of the enhancer of zeste homolog 2 (EZH2) inhibitor SHR2554 in patients with relapsed or refractory (r/r) peripheral T-cell lymphoma (PTCL) (1). The study was a multicenter, two-part investigation, primarily designed to evaluate SHR2554, an oral inhibitor targeting EZH2, a protein deemed significant in the treatment of lymphomas.
During the first part of this phase 1 study, the recommended phase 2 dose (RP2D) of SHR2554 was identified as 350 mg, administered twice daily. This dosage was established based on the outcomes observed during the dose-escalation and expansion phases of the study. Subsequently, the clinical expansion cohorts, which included selected lymphoma subtypes, were administered SHR2554 at the established RP2D.
The study included a total of 28 patients with r/r PTCLs for analysis. This population comprised 17 patients with angioimmunoblastic T-cell lymphoma and 11 patients classified as not otherwise specified. Notably, 18 of these patients, representing 64% of the total, had previously undergone at least two lines of anti-cancer therapies.
The results of the study were significant. The objective response rate among the patients was 61%, with a 95% confidence interval (CI) of 41-78%. Of the responders, 59% (10 out of 17) were still showing ongoing responses at the time of the analysis. The estimated median duration of response was observed to be 12.3 months, with a 95% CI of 7.4 months to an undefined upper limit. Furthermore, the median progression-free survival was recorded at 11.1 months (95% CI: 5.3-22.0), and the 12-month overall survival rate was impressively high at 92% (95% CI: 72-98%).
The study also reported on the safety and tolerability of SHR2554. The most commonly observed grade 3 or 4 treatment-related adverse events included a decreased platelet count in 32% of the patients (nine individuals), as well as decreased white blood cell count, decreased neutrophil count, and anemia, each affecting 14% of the patients (four individuals in each category). It is noteworthy that no treatment-related deaths were reported in this study.
In conclusion, this extended follow-up analysis of SHR2554 in patients with r/r PTCLs suggests that SHR2554 presents a promising therapeutic opportunity for this patient population. The findings indicate a favorable response rate and a manageable safety profile, making SHR2554 a potential candidate for further clinical development in the treatment of PTCLs.
Reference
Song Y, Jin Z, Li ZM, Liu Y, Li L, He C, Su H, Zhou H, Li K, Hao S, Zuo X, Wu J, Li D, Wu M, Sun X, Qi J, Cai Z, Li Z, Li Y, Huang Y, Shen J, Xiao Z, Zhu J. Enhancer of zeste homolog 2 inhibitor SHR2554 in relapsed or refractory peripheral T-cell lymphoma: data from the first-in-human phase 1 study. Clin Cancer Res. 2024 Jan 8. doi: 10.1158/1078-0432.CCR-23-2582. Epub ahead of print. PMID: 38190117.
Metastatic Cancers
This study, titled "Combined stereotactic body radiotherapy and immune checkpoint inhibition for liver metastases: safety and outcomes in a pooled analysis of three phase I trials" investigated the safety and efficacy of combining stereotactic body radiotherapy (SBRT) with immune checkpoint inhibitors (ICIs) for the treatment of liver metastases (1). The analysis focused on data from three phase I trials conducted between 2016 and 2020, involving patients with metastatic solid tumors.
The population under investigation comprised 200 patients, including 81 with liver metastases, out of whom 57 received liver metastasis SBRT (LM-SBRT). The intervention under investigation was the combination of SBRT and ICI, where LM-SBRT was delivered to a dose of 45 Gy in 3 fractions, ensuring a mean liver dose of less than 16 Gy and sparing at least 700cc of normal liver a dose of 17.1 Gy or less. The control group in this context included patients who did not receive LM-SBRT but were still part of the ICI treatment cohort.
The study's primary objective was to evaluate the risk of hepatotoxicity when combining LM-SBRT with ICI. Hepatotoxicity was assessed through hepatic adverse events (HAEs), defined as hepatic failure, autoimmune hepatitis, or elevation of liver enzymes and bilirubin. The incidence of HAE and local failure was modeled with death as a competing risk, using Fine-Gray modeling for competing risks regression. Survival estimates were made using the Kaplan-Meier method.
The results showed that the 12-month rate of grade ≥2 HAE was similar in patients who received LM-SBRT (11%) and those who did not (10%). Factors significantly associated with HAEs included radiographic evidence of liver disease and the use of dual-agent ICI, whereas liver dose metrics did not show a significant association. It was observed that patients with liver metastases had notably worse progression-free and overall survival compared to those without liver metastases. Additionally, local failure of treated liver metastases was significantly higher compared to treated extrahepatic metastases (28% vs 4% at 12 months).
In conclusion, the combination of LM-SBRT and ICI did not significantly increase the risk of HAE compared to ICI alone, suggesting that hepatotoxicity is influenced more by factors other than liver radiotherapy, such as the type of ICI used. Furthermore, liver metastasis was found to be associated with poorer overall survival and local control outcomes. The follow-up duration, if any, was not specified in the provided text.
Reference
Lynch C, Korpics MC, Katipally RR, Wu T, Bestvina CM, Pitroda S, Chmura SJ, Juloori A. Combined stereotactic body radiotherapy and immune checkpoint inhibition for liver metastases: safety and outcomes in a pooled analysis of three phase I trials. Int J Radiat Oncol Biol Phys. 2024 Jan 8:S0360-3016(24)00007-5. doi: 10.1016/j.ijrobp.2024.01.002. Epub ahead of print. PMID: 38199382.