Oncology Daily Report: 01/12/2024
Central Nervous System Cancers: Glioblastoma
In this phase 1 trial, the researchers investigated the efficacy and safety of a combination therapy for patients with newly diagnosed, EGFRvIII(+) glioblastoma (GBM) (1). The study focused on the administration of chimeric antigen receptor (CAR) T-cell therapy targeting epidermal growth factor receptor variant III (EGFRvIII) alongside the anti-PD1 monoclonal antibody pembrolizumab. A total of seven patients were included in the study.
The primary objective of the trial was to evaluate safety, and it was reported that no dose-limiting toxicity was observed in the participants. This outcome indicated a positive safety profile for the combination therapy under investigation. As for the secondary outcomes, the study assessed the median progression-free survival and median overall survival. The median progression-free survival recorded was 5.2 months, with a 90% confidence interval (CI) ranging from 2.9 to 6.0 months. Meanwhile, the median overall survival was observed to be 11.8 months, with a 90% confidence interval of 9.2 to 14.2 months.
Additionally, the study involved exploratory analyses that compared the tumor microenvironment (TME) in tumors harvested before and after the administration of CAR T-cells and anti-PD1 therapy. This comparison revealed significant changes in the infiltrating myeloid and T cells within the TME. Notably, at the point of relapse, there was an increased presence of exhausted, regulatory, and interferon (IFN)-stimulated T cells.
Despite these findings, the researchers concluded that the combination of CAR T cells and PD-1 inhibition in treating GBM, while safe and biologically active, did not demonstrate efficacy in this patient population. Consequently, the study underscored the need for exploring alternative therapeutic strategies for glioblastoma.
Reference
Bagley SJ, Binder ZA, Lamrani L, Marinari E, Desai AS, Nasrallah MP, Maloney E, Brem S, Lustig RA, Kurtz G, Alonso-Basanta M, Bonté PE, Goudot C, Richer W, Piaggio E, Kothari S, Guyonnet L, Guerin CL, Waterfall JJ, Mohan S, Hwang WT, Tang OY, Logun M, Bhattacharyya M, Markowitz K, Delman D, Marshall A, Wherry EJ, Amigorena S, Beatty GL, Brogdon JL, Hexner E, Migliorini D, Alanio C, O'Rourke DM. Repeated peripheral infusions of anti-EGFRvIII CAR T cells in combination with pembrolizumab show no efficacy in glioblastoma: a phase 1 trial. Nat Cancer. 2024 Jan 12. doi: 10.1038/s43018-023-00709-6. Epub ahead of print. PMID: 38216766.
Central Nervous System Cancers: Glioblastoma
The study titled "Carcinoembryonic antigen-expressing oncolytic measles virus derivative in recurrent glioblastoma: a phase 1 trial" primarily focused on evaluating the safety, toxicity, and efficacy of an oncolytic measles virus derivative (MV-CEA) in patients with recurrent glioblastoma (GBM) (1). The trial was registered under the identifier NCT00390299.
The design of the study was a phase 1 clinical trial. This initial phase in clinical research is typically aimed at assessing the safety and feasibility of a new treatment. In this specific trial, the intervention under investigation was the administration of MV-CEA. This was conducted in two different approaches: Group A received the treatment at the resection cavity, while Group B received an intratumoral dose on day 1 and a second dose in the resection cavity post-tumor resection on day 5.
The population under investigation comprised patients with recurrent GBM. A total of 22 patients were included in the study, divided into two groups with 9 patients in Group A and 13 in Group B. The study did not specify a control group, which is common in early-phase trials focusing primarily on safety and feasibility.
Regarding the results, the study reported that the treatment was well tolerated among the patients, with no dose-limiting toxicity observed up to the maximum feasible dose of 2×10^7 TCID50. The median overall survival (OS) was noted as 11.6 months, and the one-year survival rate was 45.5%, which favorably compared with contemporary controls. This suggests a potentially beneficial effect of the treatment, although without a direct control group, these results should be interpreted with caution.
Additionally, secondary endpoints included the assessment of viremia, MV replication and shedding, and both humoral and cellular immune responses to the injected virus. Notably, a post-hoc analysis using a 22 interferon stimulated gene (ISG) diagonal linear discriminate analysis (DLDA) classification algorithm revealed an inverse correlation (R = -0.6, p = 0.04) with viral replication and changes in the tumor microenvironment. This included proinflammatory changes and CD8 + T cell infiltration in post-treatment samples, suggesting a potential mechanism of action for the treatment.
The findings indicate that oncolytic MV derivatives are a promising avenue for further clinical investigation, particularly in the context of treatment personalization, as indicated by the ISG-based DLDA algorithm's potential utility.
Reference
Galanis E, Dooley KE, Keith Anderson S, Kurokawa CB, Carrero XW, Uhm JH, Federspiel MJ, Leontovich AA, Aderca I, Viker KB, Hammack JE, Marks RS, Robinson SI, Johnson DR, Kaufmann TJ, Buckner JC, Lachance DH, Burns TC, Giannini C, Raghunathan A, Iankov ID, Parney IF. Carcinoembryonic antigen-expressing oncolytic measles virus derivative in recurrent glioblastoma: a phase 1 trial. Nat Commun. 2024 Jan 12;15(1):493. doi: 10.1038/s41467-023-43076-7. PMID: 38216554; PMCID: PMC10786937.
CNS Cancers, Pediatric Cancers: Malignant Brain Tumors
The study presented focused on evaluating the safety and accuracy of intratumoral catheter placement for infusing viral immunotherapies in children with malignant brain tumors (1). This multi-institutional research combined data from two phase I clinical trials, which utilized viral immunotherapy to treat children with progressive or recurrent supratentorial malignant tumors. The primary interventions under investigation were two types of therapies: the recombinant polio:rhinovirus (lerapolturev) and the genetically modified oncolytic herpesvirus (G207).
The study included a population of 19 patients, all of whom were children with a mean age of 14.1 years. These patients were treated across the two trials with a total of 49 catheters. All the tumors in these patients were classified as either grade 3 or 4 gliomas. The accuracy of catheter placement was a crucial aspect of this study, and it was analyzed using neuronavigation software for one of the clinical trials (NCT03043391). The study did not specify a control group, which is common in early-phase clinical trials focusing on safety and feasibility.
In terms of results, the study reported that 31.6% of patients (6 out of 19) experienced minor hemorrhage noted on CT scans post-procedure. However, these instances were clinically asymptomatic, and no patients required intervention related to these findings. One patient experienced a delayed cerebrospinal fluid (CSF) leak after catheter removal, necessitating surgical intervention. There were no reports of infection or neurological deficit in the study population. In terms of catheter placement accuracy, for the 7 patients with available data, the mean distance from the planned trajectory to the catheter tip was 1.57 mm, the mean angle discrepancy was 2.43°, and the greatest distance in the parallel plane was 1.54 mm. The study deemed 6.1% (3 out of 49) of the catheters as misplaced.
The conclusion drawn from this study was that while minor hemorrhages were encountered, they did not result in symptomatic issues for the patients. The stereotactic placement of catheters was found to be accurate in the majority of cases, with about 95% of catheters being adequately placed. This finding was in line with previous literature.
Reference
Barkley A, Butler E, Park C, Friedman A, Landi D, Ashley DM, Bigner D, Bernstock JD, Friedman GK, Johnston JM, Thompson EM. The safety and accuracy of intratumoral catheter placement to infuse viral immunotherapies in children with malignant brain tumors: a multi-institutional study. J Neurosurg Pediatr. 2024 Jan 12:1-8. doi: 10.3171/2023.12.PEDS23404. Epub ahead of print. PMID: 38215438.
Gastrointestinal Cancers: Biliary Tract Cancer
The study under discussion was a phase II clinical trial, designed to evaluate the safety and efficacy of anlotinib combined with toripalimab in patients with advanced biliary tract cancer (BTC) (1). The research was prospective, single-arm, and conducted at a single centre, focusing on an experimental approach for treating unresectable BTC.
The population under investigation comprised patients with locally progressed or metastatic BTC. These patients were subjected to a treatment regimen involving anlotinib, administered orally at a dosage of 12 mg daily for two weeks followed by a one-week break (constituting a 21-day cycle), and toripalimab, given intravenously at a dose of 240 mg every three weeks.
The number of patients enrolled and treated in this study was 15. The primary endpoint of the study was the objective response rate (ORR), assessed according to the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 criteria.
The study reported an ORR of 26.7%. Additionally, the median progression-free survival (mPFS) was found to be 8.6 months, with a 95% confidence interval (CI) ranging from 2.1 to 15.2 months. The median overall survival (mOS) recorded was 14.53 months, with a 95% CI of 0.8 to 28.2 months. The disease control rate (DCR) was observed to be 87.6%.
A notable case in the study was a patient with hilar cholangiocarcinoma who, after three cycles of treatment, was successfully converted to a state eligible for surgical resection. Furthermore, the study identified that patients with a mutation in the STK11 gene tended to have poorer outcomes. Additionally, a higher survival rate was associated with patients having a CD8/Foxp3 ratio greater than 3, a finding that reached statistical significance (P = 0.0397).
The study concluded that the combination of anlotinib and toripalimab showed promising anti-tumor potential in advanced BTC, evident from the increased ORR and longer durations of overall survival and progression-free survival. The researchers also proposed STK11 and the CD8/Foxp3 ratio as potential biomarkers for predicting the effectiveness of targeted therapy in combination with immunotherapy in this patient population.
Reference
Zhou M, Jin Y, Zhu S, Xu C, Li L, Liu B, Shen J. A phase II study to evaluate the safety and efficacy of anlotinib combined with toripalimab for advanced biliary tract cancer. Clin Transl Immunology. 2024 Jan 12;13(1):e1483. doi: 10.1002/cti2.1483. PMID: 38223257; PMCID: PMC10786709.
Gastrointestinal Cancers: Metastatic Colorectal Cancer
The study in question focused on assessing the efficacy and safety of SCT200, an anti-EGFR monoclonal antibody, in treating patients with metastatic colorectal cancer (mCRC) resistant to fluorouracil, irinotecan, and oxaliplatin (1). It was a phase II, open-label, single-arm, multicenter study. The population under investigation comprised patients with RAS and BRAF wild-type mCRC who had previously shown resistance to fluorouracil, oxaliplatin, and irinotecan treatments. The intervention was the administration of SCT200, starting with a dose of 6 mg/kg weekly for the first six weeks, followed by an increased dose of 8 mg/kg every two weeks. This regimen was continued until disease progression or the emergence of unacceptable toxicity.
A total of 110 patients, aged between 26 and 77 years, were enrolled from 22 hospitals in China. The study's primary endpoint was the objective response rate (ORR) assessed by an independent review committee (IRC), while secondary endpoints included the ORR in patients with left-sided tumors, disease control rate (DCR), duration of response (DoR), time to response (TTR), progression-free survival (PFS), overall survival (OS), and safety.
The findings revealed that of the 110 patients, 31% (34/110) achieved a confirmed partial response, with an IRC-assessed ORR of 31% and a DCR of 75%. The median PFS was 5.1 months, and the median OS was 16.2 months. Notably, the most common severe treatment-related adverse events were hypomagnesemia and acneiform dermatitis, occurring in 17% and 11% of patients, respectively. There were no reported deaths due to the treatment. Genomic analysis indicated a positive association between MYC amplification and patient response, and identified RAS/RAF mutation and MET amplification as common resistance mechanisms. Additionally, patients with high levels of circulating tumor DNA (ctDNA) at baseline or without ctDNA clearance at the 7th week post-first dose had poorer PFS and OS outcomes.
The study concluded that SCT200 demonstrated promising clinical efficacy and manageable safety profiles in the specified patient population. The status of baseline ctDNA and ctDNA clearance at the 7th week post-first dose were proposed as potential prognostic biomarkers for patients receiving SCT200 therapy. The study was sponsored by Sinocelltech Ltd., Beijing, China, and partially supported by the National Science and Technology Major Project for Key New Drug Development.
Reference
Yang L, Zhang W, Fan N, Cao P, Cheng Y, Zhu L, Luo S, Zong H, Bai Y, Zhou J, Deng Y, Ba Y, Liu T, Aili M, Yin X, Gu K, Dai G, Ying J, Shi J, Gao Y, Li W, Yu G, Xie L, Gai W, Wang Y, Meng P, Shi Y. Efficacy, safety and genomic analysis of SCT200, an anti-EGFR monoclonal antibody, in patients with fluorouracil, irinotecan and oxaliplatin refractory RAS and BRAF wild-type metastatic colorectal cancer: a phase Ⅱ study. EBioMedicine. 2024 Jan 12;100:104966. doi: 10.1016/j.ebiom.2024.104966. Epub ahead of print. PMID: 38217945.
Lymphomas, Leukemias: Chronic Lymphocytic Leukemia, B-cell Non-Hodgkin Lymphoma
The study under analysis primarily focused on evaluating the safety, pharmacology, and antitumor activity of nemtabrutinib, an orally bioavailable, reversible inhibitor of Bruton tyrosine kinase (BTK) and C481S mutant BTK (1). Nemtabrutinib was investigated in the context of relapsed or refractory hematologic malignancies.
The study was designed as an open-label, single-arm, phase I trial, specifically identified as the MK-1026-001 study (NCT03162536). It employed a dose-escalation design, specifically using a 3 + 3 dose escalation scheme, to determine the safety and optimal dosing of nemtabrutinib.
The population under investigation included patients suffering from chronic lymphocytic leukemia (CLL), B-cell non-Hodgkin lymphoma (NHL), or Waldenström macroglobulinemia (WM), who had relapsed or were refractory after receiving at least two prior therapies. A total of 48 patients were enrolled in the study. However, 47 of these patients received the treatment, with the breakdown being 29 patients with CLL, 17 with NHL, and 1 with WM. Nemtabrutinib was administered in doses ranging from 5 to 75 mg once daily, in 28-day cycles.
Regarding the results, the study reported that grade ≥3 treatment-emergent adverse events occurred in 37 out of 47 patients (approximately 89%). The most common adverse events included neutropenia in 11 patients (23.4%), febrile neutropenia in 7 patients (14.9%), and pneumonia, also in 7 patients (14.9%). The recommended phase II dose (RP2D) was established at 65 mg daily. Notably, an overall response rate of 75% was observed in CLL patients treated with the 65 mg daily dose.
The study's significance lies in demonstrating the safety and preliminary efficacy of nemtabrutinib in treating relapsed/refractory B-cell malignancies. These findings were deemed sufficient to warrant further exploration of nemtabrutinib in larger clinical studies.
Reference
Woyach JA, Stephens DM, Flinn IW, Bhat SA, Savage RE, Chai F, Eathiraj S, Reiff SD, Muhowski EM, Granlund L, Szuszkiewicz L, Wang W, Schwartz B, Ghori R, Farooqui MZH, Byrd JC. First-in-Human Study of the Reversible BTK Inhibitor Nemtabrutinib in Patients with Relapsed/Refractory Chronic Lymphocytic Leukemia and B-Cell Non-Hodgkin Lymphoma. Cancer Discov. 2024 Jan 12;14(1):66-75. doi: 10.1158/2159-8290.CD-23-0670. PMID: 37930156.
Various Solid Tumors
The study in question was designed as a single-centre, open-label, non-inferiority, randomised, controlled trial, conducted at the Tata Memorial Centre, Homi Bhabha National Institute in Mumbai, India (1). It was classified as a phase 3 trial. The population under investigation included patients aged 13-75 years with an Eastern Cooperative Oncology Group performance status of 0-2. These patients were receiving doxorubicin-cyclophosphamide or high-dose cisplatin for a solid tumour, primarily breast cancer, as 91% of the participants had this condition.
The intervention under investigation was the administration of low-dose versus standard-dose olanzapine. Participants were randomly assigned to receive either low-dose (2.5 mg) or standard-dose (10.0 mg) oral olanzapine daily for 4 days, combined with a triple antiemetic regimen. The randomisation was done in a 1:1 ratio, with block sizes of 2 or 4, and stratified by sex, age (≥55 or <55 years), and chemotherapy regimen.
A total of 275 patients were enrolled and randomly assigned to either the 2.5 mg olanzapine group (134 patients) or the 10.0 mg olanzapine group (141 patients). However, the modified intention-to-treat (mITT) population, which excluded those with eligibility violations and who withdrew consent after randomisation, consisted of 267 patients (132 in the 2.5 mg group and 135 in the 10.0 mg group).
The primary endpoint of the study was complete control, defined as no emetic episodes, no rescue medications, and no or mild nausea in the overall phase (0-120 hours).
In the mITT population, 45% of patients in the 2.5 mg olanzapine group achieved complete control, compared to 44% in the 10.0 mg group. This difference of -1.0% fell within the one-sided 95% confidence interval (-100.0 to 9.0), with a p-value of 0.87, indicating non-inferiority of the lower dose.
The study also examined daytime somnolence as a safety endpoint. Significantly fewer patients in the 2.5 mg group experienced any grade of daytime somnolence (65%) compared to the 10.0 mg group (90%), and severe grade somnolence on day 1 was also lower in the 2.5 mg group (5% vs 40%).
In conclusion, the study found that low-dose olanzapine (2.5 mg) is non-inferior to the standard-dose (10.0 mg) in terms of antiemetic efficacy for patients undergoing highly emetic chemotherapy, with the added benefit of reduced occurrence of daytime somnolence. The study was funded by the Progressive Ladies Welfare Association.
Reference
Bajpai J, Kapu V, Rath S, Kumar S, Sekar A, Patil P, Siddiqui A, Anne S, Pawar A, Srinivas S, Bhargava P, Gulia S, Noronha V, Joshi A, Prabhash K, Banavali S, Sarin R, Badwe R, Gupta S. Low-dose versus standard-dose olanzapine with triple antiemetic therapy for prevention of highly emetogenic chemotherapy-induced nausea and vomiting in patients with solid tumours: a single-centre, open-label, non-inferiority, randomised, controlled, phase 3 trial. Lancet Oncol. 2024 Jan 12:S1470-2045(23)00628-9. doi: 10.1016/S1470-2045(23)00628-9. Epub ahead of print. PMID: 38224701.
Thoracic Cancers: Non-Small-Cell Lung Cancer
This study, designed as a phase Ib trial, focused on assessing the safety and efficacy of a combination therapy involving IBI310 and sintilimab in a specific patient population: individuals with advanced non-small-cell lung cancer (NSCLC) who had previously experienced progression after undergoing anti-PD-1/L1 therapy (1). The intervention under investigation involved two cohorts of patients receiving different dosages of IBI310, an anti-cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) antibody, combined with a constant dosage of sintilimab, an anti-programmed death 1 (PD-1) antibody. Specifically, cohort A received a lower dose of IBI310 (1 mg/kg every 3 weeks) while cohort B was administered a higher dose (3 mg/kg every 3 weeks). Both cohorts received sintilimab at a dosage of 200 mg every 3 weeks.
The total number of patients enrolled was 30, with an equal distribution of 15 patients in each cohort. The primary endpoints of this study were the objective response rate (ORR) and safety. Additionally, secondary endpoints included disease control rate (DCR), progression-free survival (PFS), and overall survival (OS).
The results, as of November 2, 2023, indicated an ORR of 13.3% (2 out of 15 patients) in cohort B. The DCR was reported as 46.7% for cohort A and 66.7% for cohort B. In terms of PFS and OS, median values were observed; for cohort A, the median PFS was 1.45 months and the median OS was 7.03 months. In comparison, cohort B exhibited a median PFS of 2.73 months and a median OS of 8.90 months. The follow-up duration varied between the two cohorts, with a median of 4.2 months for cohort A and 5.6 months for cohort B.
The study also reported on the incidence of treatment-related adverse events (TRAEs). A significant proportion of patients, 86.7% in both cohorts, experienced TRAEs. Furthermore, grade 3 or higher TRAEs occurred in 40% of patients in cohort A and 53.3% in cohort B.
In conclusion, the study found that the higher dose of IBI310 (3 mg/kg every 3 weeks) combined with sintilimab showed effectiveness in a subset of previously treated NSCLC patients who were resistant to anti-PD-1/L1 therapy. However, the study also noted a considerable incidence of treatment-related adverse events.
Reference
Zhao Y, Chen X, Yao J, Long J, Mao Y, Wu D, Zang A, Zhao J, Liu Z, Meng R, Chen Y, Luo Y, Guo Q, Li L, Cui J. A phase Ib study evaluating the safety and efficacy of IBI310 plus sintilimab in patients with advanced non-small-cell lung cancer who have progressed after anti-PD-1/L1 therapy. Cancer Med. 2024 Jan 12. doi: 10.1002/cam4.6855. Epub ahead of print. PMID: 38214075.