High Impact Studies: 01/01/2024

INTERIM Study Reveals Superior Efficacy of Continuous Dosing in Advanced Melanoma Therapy

The phase 2 INTERIM trial (1) investigated the efficacy of two dosing regimens of dabrafenib and trametinib in patients with advanced melanoma. The study involved 79 patients, with two groups: one receiving continuous dosing (CONT), and the other intermittent dosing (INT). The INT group exhibited inferior outcomes in progression-free survival, overall survival, and objective response rate compared to the CONT group. Additionally, a higher incidence of severe adverse events was observed in the INT group, despite fewer overall treatment-related adverse events.

 

Clinical Impact Evaluation: The potential clinical impact of the INTERIM study is considered to be high. This assessment is based on several factors:

  • The study provides crucial data regarding the efficacy of dosing regimens in the treatment of BRAF(V600) mutant advanced melanoma.

  • It reinforces the superiority of continuous dosing over intermittent dosing for these specific inhibitors, influencing clinical decision-making.

  • The study contributes to the broader understanding of targeted therapy in melanoma, guiding future research and potentially impacting the standard of care for this patient population.

    1. Dayimu A, Gupta A, Matin RN, Nobes J, Board R, Payne M, et al. A randomised phase 2 study of intermittent versus continuous dosing of dabrafenib plus trametinib in patients with BRAF(V600) mutant advanced melanoma (INTERIM). Eur J Cancer. 2024;196:113455.

Decitabine-Cedazuridine Shows Promise in Treating Blood Cancers with Convenience and Efficacy

This phase 3 study compared the safety and pharmacokinetics of oral decitabine-cedazuridine and intravenous decitabine in patients with myelodysplastic syndromes (MDS) or chronic myelomonocytic leukaemia (CMML) (2). Conducted across 37 sites in Canada and the USA, it included 138 participants, predominantly male (65%) and white (91%). The study demonstrated that oral decitabine-cedazuridine provided equivalent pharmacokinetic exposure to intravenous decitabine with a similar safety profile, marked by severe adverse events like thrombocytopenia, neutropenia, and anaemia. The primary outcome was the total exposure of the drugs measured as the area under the curve (AUC), where the oral formulation achieved 98.93% of the AUC of intravenous decitabine.

Clinical Impact Evaluation:

The study's potential clinical impact is evaluated as high. The introduction of an oral form of decitabine (in combination with cedazuridine) marks a significant advance in treating MDS and CMML. Oral medications improve patient convenience and quality of life, as they can be taken at home, reducing the need for hospital visits required for intravenous administration. The equivalent efficacy and safety profile of the oral form compared to its intravenous counterpart suggest that it can be a safe, effective, and more convenient treatment option. This could lead to changes in clinical practice, potentially improving adherence to therapy and overall patient outcomes. However, further research is needed to assess long-term benefits and cost-effectiveness in real-world settings.

2. Garcia-Manero G, McCloskey J, Griffiths EA, Yee KWL, Zeidan AM, Al-Kali A, et al. Oral decitabine-cedazuridine versus intravenous decitabine for myelodysplastic syndromes and chronic myelomonocytic leukaemia (ASCERTAIN): a registrational, randomised, crossover, pharmacokinetics, phase 3 study. Lancet Haematol. 2024;11(1):e15-e26.

Promising Advances in Resistant LANPC: Nimotuzumab Enhances Chemoradiotherapy Efficacy

The JCOG1104 (OPAS-1) phase III trial, a significant study in the field of oncology, focused on the effectiveness of S-1 adjuvant chemotherapy in patients with pathological stage II gastric cancer (3). The trial aimed to determine if four courses of S-1 treatment were as effective as the conventional eight courses. Conducted with 590 patients post-radical gastrectomy, the study was a non-inferiority trial that compared relapse-free and overall survival rates between two groups: one receiving eight courses and the other four courses of S-1 chemotherapy. After a 5-year follow-up, the results revealed that the four-course regimen was slightly inferior to the eight-course regimen, with survival rates consistently lower in the four-course group. Thus, the standard treatment of eight-course S-1 adjuvant chemotherapy remains recommended for patients with stage II gastric cancer, as it provides slightly superior outcomes in terms of survival. This trial validates the current treatment standard and highlights the need for ongoing research to optimize treatment duration while maintaining efficacy.

Potential Clinical Impact:

The clinical impact of the JCOG1104 (OPAS-1) trial is evaluated as high. This study reinforces the current standard of eight-course S-1 chemotherapy as the more effective treatment for stage II gastric cancer. It provides crucial data for oncologists in treatment planning and highlights the importance of the treatment duration in affecting survival outcomes. The findings are instrumental in guiding clinical decision-making and future research directions, aiming to balance treatment efficacy with patient quality of life.

3. Yoshikawa T, Terashima M, Mizusawa J, Nunobe S, Nishida Y, Yamada T, et al. 5-year follow-up results of a JCOG1104 (OPAS-1) phase III non-inferiority trial to compare 4 courses and 8 courses of S-1 adjuvant chemotherapy for pathological stage II gastric cancer. Gastric Cancer. 2024;27(1):155-63.

Revolutionizing Cervical Cancer Treatment: High Success Rate in Combining Chemotherapy and Immunotherapy in the NACI Study

The "Neoadjuvant chemotherapy plus camrelizumab for locally advanced cervical cancer (NACI study)" is a single-arm, phase 2 trial conducted across multiple tertiary hospitals in China, focusing on the treatment of locally advanced cervical cancer (4). This study enrolled patients aged 18-70 years with untreated cervical cancer stages IB3, IIA2, or IIB/IIIC1r. The intervention combined chemotherapy (cisplatin and nab-paclitaxel) and the immune checkpoint inhibitor camrelizumab. The primary outcome, the objective response rate, was impressively high at 98%, with a majority of patients showing complete or partial responses. The treatment was generally well-tolerated, with manageable severe adverse events and no treatment-related deaths. This study demonstrates the potential of neoadjuvant chemo-immunotherapy as a novel therapeutic strategy in this patient population.

Potential Clinical Impact Evaluation

  • Evaluation: High

  • Rationale: The study presents a novel treatment approach combining chemotherapy and immunotherapy, showing a high response rate and manageable safety profile. If these results are validated in larger, randomized trials, this approach could change the standard treatment for locally advanced cervical cancer, representing a significant advancement in the field.

4. Li K, Chen J, Hu Y, Wang YZ, Shen Y, Chen G, et al. Neoadjuvant chemotherapy plus camrelizumab for locally advanced cervical cancer (NACI study): a multicentre, single-arm, phase 2 trial. Lancet Oncol. 2024;25(1):76-85.

Revolutionizing Pancreatic Cancer Treatment: The nITRO Trial's Promising Results.

The nITRO trial, an open-label, multicenter, phase II study, explores a groundbreaking perioperative treatment approach for resectable pancreatic ductal adenocarcinoma (rPDAC) (5). The trial focuses on patients with rPDAC, particularly those with limited vein involvement. The intervention, NALIRIFOX, combines liposomal irinotecan, 5-fluorouracil, leucovorin, and oxaliplatin, administered over six cycles around surgical resection. Although the study lacks a control group, its outcomes are significant: a 92.9% disease-control rate and a 65.3% R0 resection rate. Moreover, the median overall survival (OS) reaches 32.3 months, an encouraging figure compared to traditional treatments. Despite some patients discontinuing due to adverse events, the manageable side effects and effectiveness of NALIRIFOX suggest its potential as an alternative to the conventional surgery-first approach, warranting further validation in randomized trials.

Evaluation of Potential Clinical Impact: The potential clinical impact of the study is High. This is due to several factors:

  • The promising improvement in R0 resection rates and overall survival.

  • The innovative approach of using perioperative chemotherapy, which could redefine treatment protocols.

  • The relative safety and manageable adverse effects of the NALIRIFOX regimen. However, the necessity for further investigation in randomized trials is crucial for confirming these results and fully establishing NALIRIFOX's role in treating rPDAC.

5. Melisi D, Zecchetto C, Merz V, Malleo G, Landoni L, Quinzii A, et al. Perioperative NALIRIFOX in patients with resectable pancreatic ductal adenocarcinoma: The open-label, multicenter, phase II nITRO trial. Eur J Cancer. 2024;196:113430.

Revolutionizing HPV+ OPSCC Treatment: The IChoice-01 Trial's Approach to Deintensification

The IChoice-01 trial, a pivotal phase 2 study, investigated a novel treatment strategy for human papillomavirus (HPV)-associated oropharyngeal squamous cell carcinoma (OPSCC) (6). This single-arm trial focused on selective treatment deintensification, examining the impact of reducing radiation dose and omitting concurrent chemotherapy in patients who showed significant response to induction chemotherapy (IC) with docetaxel and cisplatin. The study divided patients into two cohorts based on their response to IC. Cohort D, demonstrating major response (≥50% reduction in tumor size), received reduced-dose radiation therapy alone, while Cohort C, not meeting these criteria, underwent standard-dose radiation with concurrent cisplatin. The primary outcomes were 2-year progression-free survival (PFS) and overall survival (OS), with cohort D achieving remarkable 100% rates in both measures. This trial also recorded lower toxicity levels in cohort D, emphasizing the potential of personalized treatment protocols in reducing treatment-related side effects while maintaining high efficacy.

Clinical Impact Evaluation:

The potential clinical impact of the IChoice-01 study is evaluated as high. This trial's approach marks a significant advancement in personalizing cancer treatment, potentially revolutionizing the standard care for HPV+ OPSCC. By demonstrating the efficacy of treatment deintensification in patients responding well to IC, it paves the way for more nuanced, patient-specific treatment plans, significantly reducing toxicity while maintaining high survival rates. However, further large-scale, controlled trials are essential to validate these findings and ascertain their applicability in broader clinical settings.

6. Xu T, Shen C, Zhou X, Zhu L, Xiang J, Wang Y, et al. Selective Treatment Deintensification by Reducing Radiation Dose and Omitting Concurrent Chemotherapy Based on Response to Induction Chemotherapy in Human Papillomavirus-Associated Oropharyngeal Squamous Cell Carcinoma: A Single-Arm, Phase 2 Trial (IChoice-01). Int J Radiat Oncol Biol Phys. 2024;118(1):169-78.