FDA issues draft guidance for adjuvant trials in bladder cancer, renal cell carcinoma

The FDA has released guidance providing recommendations for clinical trials evaluating investigational drugs and biologics intended for the adjuvant treatment of patients with urothelial carcinoma (UC) or renal cell carcinoma (RCC).¹

The 2 guidances remain in draft form and still need to be finalized before becoming official FDA recommendations. The FDA stipulated that the guidances do not establish any legal responsibilities or requirements for the adjuvant trials, they are merely intended to advise and inform.

“Currently, there is significant variability in the design, conduct, and analysis of clinical trials for adjuvant (additional) treatment of both kidney cancer and bladder cancer. This variability negatively affects our ability to interpret trial results. Researchers need a consistent approach to eligibility criteria and imaging disease assessments to improve trials designed to facilitate development of therapies,” Richard Pazdur, MD, director of the FDA’s Oncology Center of Excellence and acting director of the Office of Oncologic Diseases in the FDA’s Center for Drug Evaluation and Research, stated in a press release.

“The FDA has actively encouraged a more uniform approach to developing clinical trials to evaluate adjuvant treatments for renal cell carcinoma and bladder cancer, including hosting a public workshop in partnership with the National Cancer Institute and releasing draft guidances on clinical trial eligibility for these cancer types, added Pazdur. “Today, we are releasing draft guidances which, if finalized, would provide recommendations on development of adjuvant treatments in patients with renal cell carcinoma and bladder cancer. These draft guidances, if finalized, will assist researchers with recommendations on trial eligibility criteria, standardized imaging assessments, and determining disease recurrence that will improve interpretation of trial results for patients enrolled in clinical trials for these two cancer types."

Bladder Cancer

The FDA guidance for muscle-invasive bladder cancer is titled, “Bladder Cancer: Developing Drugs and Biologics for Adjuvant Treatment.”² It focuses on disease-free survival (DFS) as the primary efficacy end point.

Some of the noteworthy recommendations include:

• The studies should include patients with predominant UC with a component of variant histology. Trials that include patients with pure non-UC histology, such as mixed endocrine/small cell tumors, should analyze those patients separately.
• Patients with invasive upper-tract UC should be allowed to enroll.
• Patients without gross residual disease who have microscopic positive margins should be eligible as long as the randomization process in the study design ensures an even distribution of patients at high-risk for recurrence between the study cohorts.
• Prior neoadjuvant treatment should be allowed when it has been administered in accordance with consensus guidelines.
• Patient should not be allowed to enroll if they have residual or recurrent disease.
• The first imaging analyses should be conducted within 4 weeks of patient enrollment.
• Although overall survival (OS) is not required by the FDA as a study end point, the agency recommends that the study design includes an official interim analysis of OS when the final DFS analysis is conducted.

Of note, findings from the phase 3 CheckMate-274 adjuvant trial were recently announced showing that nivolumab (Opdivo) improved DFS when used after surgery in patients with high-risk, muscle-invasive UC. Bristol Myers Squibb, the developer of the PD-1 inhibitor, reported in a press release that the data from the study would be presented at a future scientific meeting.³

“The positive results from CheckMate-274 point to the potential for nivolumab to become a new standard of care in the adjuvant setting, extending disease-free survival for post-surgery patients with muscle-invasive urothelial cancer without the use of chemotherapy,” Matthew Galsky, MD, professor of Medicine, director of Genitourinary Medical Oncology, director of the Novel Therapeutics Unit, and co-director of the Center of Excellence for Bladder Cancer at The Tisch Cancer Institute and the Icahn School of Medicine at Mount Sinai, stated in the press release.

Kidney Cancer

The kidney cancer guidance is titled, “Renal Cell Carcinoma: Developing Drugs and Biologics for Adjuvant Treatment.”⁴

Some of the noteworthy recommendations include:

• In addition to patients with clear cell histology, the study should patients with non-clear subtypes of RCC, including individuals with a sarcomatoid component.
• Patients without gross residual disease who have microscopically positive soft tissue or vascular margins should be eligible as long as the randomization process in the study design ensures an even distribution of patients at high-risk for recurrence between the study cohorts.
• The first imaging analyses should be conducted within 4 weeks of patient enrollment.
• When investigators define disease recurrence in the study design, the terminology should reference the development of localized disease, (eg, a new lesion in the in the contralateral kidney).
• Although OS is not required by the FDA as a study end point, the agency recommends that the study design includes an official interim analysis of OS when the final DFS analysis is conducted.

References

1. FDA In Brief: FDA Issues Two Draft Guidances to Help Facilitate the Development of Adjuvant Treatment for Kidney and Bladder Cancer. Published online October 1, 2020. Accessed October 1, 2020. https://bit.ly/30pRMqP.

2. Bladder Cancer: Developing Drugs and Biologics for Adjuvant Treatment, Guidance for Industry. FDA Draft Guidance. Published online October 1, 2020. Accessed October 1, 2020. https://www.fda.gov/media/142544/download.

3. Opdivo (nivolumab) Significantly Improves Disease Free-Survival vs. Placebo as Adjuvant Therapy for Patients with High-Risk, Muscle-Invasive Urothelial Carcinoma in Phase 3 CheckMate -274 Trial. Bristol Myers Squibb. Posted September 24, 2020. Accessed September 24, 2020. https://bit.ly/3cs3mGM.

4. Renal Cell Carcinoma: Developing Drugs and Biologics for Adjuvant Treatment, Guidance for Industry. FDA Draft Guidance. Published online October 1, 2020. Accessed October 1, 2020. https://www.fda.gov/media/142553/download