Study Design Parameters and Endpoints in Key NET Trials

Several studies have examined the design and reporting quality of NET clinical trials, revealing key parameters and endpoints. A significant challenge lies in the heterogeneity of NETs, impacting both study design and interpretation.

Phase II Trials:

• Primary Endpoint Concerns: Traditionally, the objective response rate (ORR) has served as the primary endpoint in phase II NET trials. However, research indicates a lack of significant correlation between ORR and median progression-free survival (PFS). A stronger correlation exists between 12-month PFS rates and median PFS, suggesting its potential as a more reliable primary endpoint for these trials. This is crucial as phase II trials aim to identify promising agents for further development, necessitating earlier and more predictive endpoints.
• Heterogeneity Issues: A review of phase II/III trials highlighted significant heterogeneity in study populations. Over half of the trials included tumors from various primary sites, while a substantial portion either allowed both well- and poorly-differentiated tumor morphology or failed to specify. Furthermore, a majority of trials did not consistently report crucial markers like proliferative indices and tumor grade. This heterogeneity poses challenges in interpreting trial results and generalizing findings.
• Radiological Progression: Less than 40% of trials mandated radiological disease progression at enrollment using validated measures, further complicating comparisons and potentially influencing outcomes.

Phase III Trials:

• Improved Homogeneity: While randomized phase III trials demonstrated better homogeneity in study populations and clearer study designs compared to phase II trials, challenges persist. Less than half mandated radiological progression at baseline using RECIST criteria, and reporting of health-related quality of life remained suboptimal.
• Example - RETNET Trial: This randomized controlled trial aimed to compare different embolotherapy techniques (bland embolization, lipiodol chemoembolization, and drug-eluting microsphere chemoembolization) for NET liver metastases. The primary endpoint was hepatic progression-free survival (HPFS), with secondary endpoints including overall PFS, duration of symptom control, quality of life, adverse events, and interval between embolotherapy cycles.
• Example - Everolimus Combination Trial: A randomized phase III trial in Japan investigated the combination of everolimus and lanreotide versus everolimus alone in patients with advanced gastroenteropancreatic NETs. The primary endpoint was PFS, with overall survival as a key secondary endpoint, alongside response rate, disease control rate, and adverse events.

General Trial Design Considerations:

• Patient Homogeneity: Careful selection and stratification of patients based on tumor characteristics, primary site, and grade are crucial for meaningful results.
• Standardized Response Assessment: Consistent use of validated measures like RECIST is essential for accurate evaluation of treatment efficacy.
• Rigorous Design and Execution: Well-defined study designs, appropriate statistical methods, and comprehensive reporting are necessary for valid conclusions.
• Patient-Reported Outcomes: Incorporating measures of health-related quality of life is important for a holistic assessment of treatment benefit.

Overall, the design and reporting of NET clinical trials, particularly single-arm phase II trials, require improvement. Addressing the heterogeneity of NETs, standardizing response assessments, and incorporating patient-reported outcomes are crucial for generating robust evidence to guide clinical practice.

Cabozantinib (Cabometyx) is being investigated for various solid tumors beyond its approved indications for renal cell carcinoma, medullary thyroid cancer, and hepatocellular carcinoma. These include:

• Castration-resistant prostate cancer: Several studies have investigated cabozantinib in combination with other therapies for castration-resistant prostate cancer. One study suggested potential for improved progression-free survival compared to some standards of care when combined with other therapies. Another study explored cabozantinib as a second-line treatment after disease progression despite checkpoint inhibitor therapy.
• Urothelial carcinoma: Cabozantinib has been studied in combination therapies and as monotherapy for urothelial carcinoma.
• Ewing sarcoma and Osteosarcoma: A phase 2 trial investigated cabozantinib monotherapy in patients with advanced Ewing sarcoma or osteosarcoma, showing antitumor activity and acceptable tolerability. Another study reviewed preclinical findings and clinical development of cabozantinib in osteosarcoma, suggesting promising activity.
• Uveal melanoma: Cabozantinib monotherapy has been investigated for uveal melanoma.
• Non-small-cell lung cancer: Studies have explored cabozantinib in combination therapies and suggested potential for improved progression-free survival compared to some standards of care.
• Merkel cell carcinoma: Cabozantinib monotherapy has been investigated for Merkel cell carcinoma.
• Glioblastoma: Cabozantinib monotherapy has been investigated for glioblastoma.
• Pheochromocytomas and paragangliomas: Cabozantinib monotherapy has been investigated for these tumor types.
• Cholangiocarcinoma: Cabozantinib monotherapy has been investigated for cholangiocarcinoma.
• Gastrointestinal stromal tumor (GIST): Studies have explored cabozantinib's activity in GIST, including imatinib-resistant models, and reported clinical activity in phase 2 trials.
• Colorectal cancer: Cabozantinib monotherapy has been investigated for colorectal cancer. A phase 3 trial is ongoing, investigating zanzalintinib (related to cabozantinib) in combination with immune checkpoint inhibitors for colorectal cancer.
• Salivary gland cancer: Cabozantinib monotherapy has been investigated for salivary gland cancer.
• Carcinoid and pancreatic neuroendocrine tumors: While approved for some neuroendocrine tumors, cabozantinib continues to be investigated in other settings, including extrapancreatic and pancreatic neuroendocrine tumors, showing improved progression-free survival in some studies.
• Breast, endometrial, and ovarian cancers: Cabozantinib monotherapy has been investigated for these cancer types. One study evaluated cabozantinib in women with endometrial cancer with progression after chemotherapy, showing activity in serous and endometrioid histology. Another study explored the combination of nivolumab and cabozantinib in immunotherapy-naive and immunotherapy-pretreated endometrial cancer, showing improved outcomes.
• Differentiated thyroid cancer (DTC): Cabozantinib is approved for DTC that has progressed following prior VEGFR-targeted therapy and is RAI-refractory or ineligible.
• Advanced renal cell carcinoma (RCC): Cabozantinib is approved for advanced RCC and has been studied in various settings, including first-line treatment and in patients with bone metastases, showing improved outcomes. A phase II trial evaluated cabozantinib as a second-line treatment in patients with unresectable, locally advanced, or metastatic RCC whose disease progressed despite checkpoint inhibitor therapy.
• Hepatocellular carcinoma (HCC): Cabozantinib is approved for advanced HCC after failure of sorafenib. Studies have shown prolonged overall survival and progression-free survival compared to placebo.

Intervention models for these trials include monotherapy and combination therapies with other agents such as immune checkpoint inhibitors, VEGFR-targeted therapies, and chemotherapy. Trials also explore different lines of therapy (first-line, second-line, etc.) and patient subgroups based on prior treatments, disease characteristics, and biomarkers.