RANO and Oncology Trial Endpoints MERIT Webinar Key Takeaways

The Response Assessment in Neuro-Oncology (RANO) Working Group provides various central nervous system-related tumor response criteria and guidance for assessments. In this webinar, MERIT discussed the principles and recommendations of RANO response criteria for high grade glioma (HGG) and the imaging endpoint information that needs to be collected for clinical trials.

IN-DEPTH TAKEAWAYS

MERIT’s webinar also provided more in-depth information on the key topics outlined above.
The webinar provided further details regarding what’s required for each of the key eCRF form elements:

• Individual lesion level
  • Lesion ID
  • Anatomical location
  • Lesion state
  • Short Axis (SA) x Long Axis (LA) mm
• Lesion category level
  • Target lesion Sum of Product of Perpendicular Diameters (SPD)
  • SPD absolute change from baseline/Nadir
  • SPD percent change from baseline/Nadir
  • Target lesion response
  • Non-target lesion response
  • New lesion response
  • Overall timepoint response
  • Imaging date and visit date
• Clinical data
  • Corticosteroid dose change outcome
  • Clinical status
• Subject level data
  • Best Overall Response (BOR)
  • Progression Date (PD)

The definition of the imaging endpoints derived from RANO along with and more details about each were discussed in the webinar:

• Tumor response rate endpoint: ORR
  • Defined as the proportion of patients with tumor size reduction of a predefined amount and for a minimum time period
  • Proportion of patients with BOR of Complete Response (CR) or Partial Response (PR)
  • Often used in Phase I/II settings or single arm studies
• Time-to-event endpoint: PFS
  • Defined as the time from randomization until objective tumor progression or death, whichever occurs first
  • Usually used as surrogate endpoint in advanced disease setting
  • Phase II and III
  • Radiologic progression date (PD by imaging assessment)

There are many special considerations during data collection of RANO, including imaging modality, corticosteroid dose change, clinical status change, pseudoresponse, surgical resection, pseudoprogression, and lesions with cystic components. The following additional information was provided:

• Imaging modality
  • Preferred imaging modality is Magnetic Resonance Imaging (MRI)
  • Consistent MRI imaging is crucial
  • Recommended imaging parameters guidance by Brain Tumor Imaging Protocol (BTIP)
• Corticosteroid dose change
  • Record the baseline and each visit dose in dexamethasone equivalent dose per day
  • Steroid dose collection date must be within 5 days of MRI acquisition date to be acceptable data (otherwise, Not Evaluable is entered for dose data) Record the change in dose outcome as one of the following:
    • Decreased, Increased, Stable, None, Physiologic Replacement Dose, and New
• Clinical status change
  • Clinical status assessment criteria can be selected at discretion of treating physician
  • Commonly recommended assessment criteria are Karnofsky performance status, ECOG, WHO performance score, or Neurologic Assessment in Neuro-Oncology (NANO)
  • Cause of deterioration due to non-tumor related changes should also be documented
• Anti-angiogenic therapy and pseudoresponse
  • VEGF inhibitor may decrease the enhancement portion of the lesions by its drug mechanism
  • Read with caution per RANO
  • T2/FLAIR sequence as supplementary to assess any progression while enhancement may seem improved
  • RANO always requires confirmation of response, and that response must be sustained for a minimum of 4 weeks
• Surgical resection
  • Obtain MRI scan within 24 – 48 hours of surgery
  • No later than 72 hours after surgery
  • This is due to enhancement of surgical wall that may not be a true lesion
• Pseudoprogression after chemoradiation therapy
  
  • Increased contrast enhancement due to therapy that may not be true progression
  • Pseudoprogression is most prevalent in first 12 weeks
  • PD can be only determined within 12 weeks if:
    • Imaging: New enhancement is out of the radiation field (beyond 80% isodose line)
    • Tissue sampling: Unequivocal progressive disease evidence via pathologic confirmation
• Chemoradiation therapy clinical data collection should include:
  • Isodose curve annotation
  • Chemoradiation planning report
• Lesions with cystic component
  • When lesions show enhancing nodular component with less predominant cystic components
  • Bidimensional measurement can be source of inter-reader variability
  • Importance of having experienced Independent Reading Center (IRC)
    • Masked IRC can reduce inter-reader variability
    • Training MRI library should include images with high adjudication risk for readers
    • Clarify and standardize within procedure manual/charter

HIGHLIGHTS FROM Q & A

Q What if my interest is in Grade 2 and Grade 3 gliomas? Can I still use RANO High Grade Glioma (HGG)?
A There is a separate RANO response criterion for Grade 1 and 2 gliomas called RANO Low Grade Glioma (LGG). The recommended method would be to use two response criteria if you are interested in both Grade 2 and Grade 3. Use the RANO LGG for the Grade 2 gliomas and use RANO HGG for Grade 3.

Q Could you clarify the definition of Nadir?
A The Nadir is defined as the lowest SPD at any timepoint. It could be at baseline but it could also occur later. When calculating the 25% change in the SPD to determine if patient is showing progressive disease, it should always be calculated from the Nadir.

Q What if you are studying solid tumors and brain metastases? Can you use RANO as the response criteria?
A There is a specific version of RANO called RANO-Brain Metastases (RANO-BM) that is used when assessing solid tumors with secondary brain tumors. It is used in conjunction with RECIST 1.1. RANO-BM is unidimensional (instead of bidimensional like RANO) but it still does incorporate a clinical status and corticosteroid dose component.

Q What are the differences between RANO and iRANO?
A iRANO is designed especially for assessment of immunotherapy treatments such as anti-PD1/PDL1 inhibitors. It deals with pseudoprogression that can occur after immunotherapy treatment and allows for patients to remain on trials after what appears to be progression until the response is confirmed.

 
Watch the webinar in its entirety HERE