Oncology Daily Report: 01/13/2024
Non-Small-Cell Lung Cancer (NSCLC), Breast Cancer
The study in question was a phase 2, open-label, randomized controlled trial conducted to evaluate the efficacy of stereotactic body radiotherapy (SBRT) in patients with oligoprogressive metastatic breast cancer or non-small-cell lung cancer (NSCLC) (1). The research was carried out following patients' progression on at least first-line systemic therapy. The eligibility criterion was the presence of five or fewer progressive lesions, as confirmed by PET-CT or CT scans. The study enrolled participants aged 18 years or older from a tertiary cancer center in New York, NY, USA, and six affiliated regional centers in New York and New Jersey.
The study design involved a 1:1 randomization of patients into two groups: one receiving standard of care only (standard-of-care group) and the other receiving SBRT in addition to standard of care (SBRT group). The randomization process was computer-based and stratified by several factors, including the number of progressive metastatic sites, receptor or genetic alteration status, primary cancer site, and type of systemic therapy previously received.
In total, 106 patients were enrolled in the study between January 1, 2019, and July 31, 2021. Of these, 51 were assigned to the standard-of-care group (23 with breast cancer and 28 with NSCLC) and 55 to the SBRT plus standard-of-care group (24 with breast cancer and 31 with NSCLC). Notably, 16 (34%) of the 47 breast cancer patients had triple-negative disease, and 51 (86%) of the 59 NSCLC patients lacked actionable driver mutations.
The primary endpoint of the study was progression-free survival, measured up to 12 months. Additionally, a prespecified subgroup analysis of this primary endpoint by disease site was conducted. The study, however, was closed to further accrual before reaching its targeted sample size because the primary efficacy endpoint was met during a preplanned interim analysis.
The median follow-up duration was 11.6 months for the standard-of-care group and 12.1 months for the SBRT group. The results showed a significant difference in median progression-free survival: 3.2 months (95% CI 2.0-4.5) in the standard-of-care group versus 7.2 months (4.5-10.0) in the SBRT group, with a hazard ratio of 0.53 (95% CI 0.35-0.81; p=0.0035). For NSCLC patients, the median progression-free survival was notably higher in the SBRT group (10.0 months [7.2-not reached]) compared to the standard-of-care group (2.2 months [95% CI 2.0-4.5]; HR 0.41, 95% CI 0.22-0.75; p=0.0039). However, no significant difference was observed in patients with breast cancer (4.4 months [2.5-8.7] in the SBRT group versus 4.2 months [1.8-5.5] in the standard-of-care group; HR 0.78, 95% CI 0.43-1.43; p=0.43).
Regarding safety, grade 2 or worse adverse events occurred in 41% of patients in the standard-of-care group and 62% in the SBRT group. Specifically, 16% of patients in the SBRT group experienced grade 2 or worse toxicities related to SBRT, including gastrointestinal reflux disease, pain exacerbation, radiation pneumonitis, brachial plexopathy, and low blood counts.
In conclusion, the study demonstrated that adding SBRT to standard care significantly improved progression-free survival in patients with oligoprogressive metastatic NSCLC, with a more than fourfold increase compared to standard care alone. However, this benefit was not observed in patients with oligoprogressive breast cancer. The results indicate the potential for differential benefits of this approach, suggesting the need for further studies to validate these findings. The study was supported by funding from the National Cancer Institute.
Reference
Tsai CJ, Yang JT, Shaverdian N, Patel J, Shepherd AF, Eng J, Guttmann D, Yeh R, Gelblum DY, Namakydoust A, Preeshagul I, Modi S, Seidman A, Traina T, Drullinsky P, Flynn J, Zhang Z, Rimner A, Gillespie EF, Gomez DR, Lee NY, Berger M, Robson ME, Reis-Filho JS, Riaz N, Rudin CM, Powell SN; CURB Study Group. Standard-of-care systemic therapy with or without stereotactic body radiotherapy in patients with oligoprogressive breast cancer or non-small-cell lung cancer (Consolidative Use of Radiotherapy to Block [CURB] oligoprogression): an open-label, randomised, controlled, phase 2 study. Lancet. 2024 Jan 13;403(10422):171-182. doi: 10.1016/S0140-6736(23)01857-3. Epub 2023 Dec 14. PMID: 38104577.
Head and Neck Cancers: Head and Neck Squamous Cell Carcinoma
The study was a phase I trial in head and neck cancer, specifically investigating the maximum tolerated dose of an ATR inhibitor used in conjunction with radiotherapy for patients with head and neck squamous cell carcinoma (1). This trial design, known as the PO-TITE-CRM (time-to-event continual reassessment method in the presence of partial orders), is an advancement of the TITE-CRM, which is tailored to accommodate scenarios where the monotonicity assumption does not hold, meaning the ordering of doses in terms of toxicity is not fully understood.
The population under investigation in this study includes patients with head and neck squamous cell carcinoma. The intervention under investigation is the administration of an ATR inhibitor in combination with radiotherapy. The study's unique feature is its focus on dose toxicity and the approach to determining the maximum tolerated dose, particularly in the context of partial orders.
The study's methodology and results are primarily based on simulations used iteratively to determine the best parameterization of the design. The final set of simulations and the methodology used provide insights into how the PO-TITE-CRM is applied in the trial. While the design is noted for its efficiency, the study also acknowledges the challenges and difficulties in implementing such a design, particularly as partial ordering may become more prevalent in investigations of combination therapies.
The study, registered under the European Clinical Trials Database with EudraCT number 2020-001034-35, was added on 2020-08-07. This registration suggests a formal and recognized approach to the trial, ensuring adherence to standard clinical trial protocols.
Reference
Patel A, Brock K, Slade D, Gaunt C, Kong A, Mehanna H, Billingham L, Gaunt P. Implementing the time-to-event continual reassessment method in the presence of partial orders in a phase I head and neck cancer trial. BMC Med Res Methodol. 2024 Jan 13;24(1):11. doi: 10.1186/s12874-024-02142-4. PMID: 38218799; PMCID: PMC10787975.
Advanced Solid Tumors including Thymoma, GBM, Pancreatic Cancer, etc.
This study was a first-in-human, phase I dose escalation trial focusing on VT1021, a novel tumor microenvironment modulator, in patients with advanced solid tumors (1). VT1021 is characterized as a cyclic peptide that functions by inducing the expression of thrombospondin-1 in myeloid-derived suppressor cells within the tumor microenvironment. This induction leads to apoptosis in tumor and endothelial cells, as well as immune modulation.
The design of the study, labeled VT1021-01 and registered under ClinicalTrials.gov ID NCT03364400, employed a modified 3 + 3 design. The primary objective was to establish the recommended Phase 2 dose (RP2D) of VT1021. Secondary objectives included assessing the safety, tolerability, and pharmacokinetics of the compound. Patients in the study were administered VT1021 intravenously, twice weekly, across nine different cohorts with dosage levels ranging from 0.5 to 15.6 mg/kg. Safety evaluations were conducted in accordance with the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0, and the anti-tumor activity was assessed using the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1.
The results of the study determined that the RP2D for VT1021 is 11.8 mg/kg. Throughout the study, VT1021 was found to be well-tolerated with no dose-limiting toxicities reported among the 38 participants. The most frequent drug-related adverse events observed were fatigue, nausea, and infusion-related reactions, occurring in 15.8%, 10.5%, and 10.5% of the participants, respectively. Pharmacokinetic analysis revealed that exposure to VT1021 increased proportionally from 0.5 to 8.8 mg/kg. In terms of efficacy, the disease control rate was noted at 42.9%, with 12 out of 28 patients showing clinical benefit. This included a partial response in one patient with thymoma, lasting for 504 days.
Conclusively, the study indicates that VT1021 is safe and tolerable across all the tested doses. The selected RP2D is intended for use in future clinical studies. Observations of partial response and stable disease with tumor shrinkage in multiple patients highlight the potential of VT1021 as a single-agent treatment. The study also notes that expansion studies in glioblastoma multiforme (GBM), pancreatic cancer, and other solid tumors at the RP2D have been completed, with results to be reported separately.
Reference
Mahalingam D, Harb W, Patnaik A, Bullock A, Watnick RS, Vincent MY, Chen JJ, Wang S, Pestana H, Chao J, Mahoney J, Cieslewicz M, Watnick J. First-in-human phase I dose escalation trial of the first-in-class tumor microenvironment modulator VT1021 in advanced solid tumors. Commun Med (Lond). 2024 Jan 13;4(1):10. doi: 10.1038/s43856-024-00433-x. PMID: 38218979; PMCID: PMC10787778.