Abstract 2675
Background
The estimand framework requires a precise definition of the clinical question of interest (estimand) to account for “intercurrent” events, eg in RCC the appearance of second primary malignancies or the start of new therapy. Selection of the appropriate estimand will drive trial design and support discussions about relevant treatment effects, interpretation of study results, and the added value of drugs.
Methods
A cross-industry collaboration of statisticians and clinicians has worked on connecting estimand framework concepts to different applications. Data from previously reported phase 3, placebo-controlled studies S-TRAC (NCT00375674) and PROTECT (NCT01235962) will be used to illustrate the effect of different estimands on adjuvant treatment outcomes in RCC.
Results
Table shows the treatment outcomes for different estimands. Treatment outcomes were similar to the specified primary analysis irrespective of the clinical question asked; however, the studies were not powered to address each of these questions and not all reached statistical significance. The new framework clarifies that different analyses address different questions. The choice of the primary estimand impacts study design and may have regulatory implications. In RCC, considerations as to whether all second primary malignancies or non-disease related deaths should be considered disease-free survival events are required to further specify study objectives and to determine the events needed for the final analysis.Table:
980P
S-TRAC (N = 615) | PROTECT (N = 1538) | |||
---|---|---|---|---|
Clinical question of interest | Number of events | HR (95% CI) | Number of events | HR (95% CI) |
Specific primary analysis – does the drug improve disease-free survival if no patient received therapy? | 257 | 0.76 (0.59, 0.98) | 513 | 0.80 (0.68, 0.95) |
Does the drug improve disease-free survival and delay the start of new therapy? | 282 | 0.77 (0.61, 0.97) | N/A | N/A |
Does the drug improve disease-free survival regardless of whether the patient had received new therapy? | 289 | 0.81 (0.65, 1.02) | 519 | 0.81 (0.68, 0.96) |
Does the drug improve recurrence free survival in no patient had received new therapy? | 233 | 0.78 (0.60, 1.01) | N/A | N/A |
Conclusions
In S-TRAC and PROTECT, there are similar treatment effects irrespective of the estimand selected and the clinical question asked. However, this may not be the case in all trials and considerations should be given to the clinical question of interest during trial design. Dialogue between all stakeholders is required and physicians will play a key role in such discussions to select the appropriate estimand.
Clinical trial identification
NCT003756674 and NCT01235962.
Editorial acknowledgement
David Cope, PhD, of Engage Scientific Solutions and funded by Pfizer.
Legal entity responsible for the study
Pfizer.
Funding
Pfizer.
Disclosure
D.J. George: Honoraria (self), Advisory / Consultancy: Sanofi; Honoraria (self), Advisory / Consultancy, Research grant / Funding (self): Exelixis; Honoraria (self), Advisory / Consultancy: Bayer; Advisory / Consultancy: Merck; Research grant / Funding (self): Genentech/Roche; Research grant / Funding (self): Novartis; Research grant / Funding (self): Astellas; Research grant / Funding (self): Celldex; Research grant / Funding (self): Acerta; Advisory / Consultancy, Research grant / Funding (self): Janssen; Advisory / Consultancy, Research grant / Funding (self): Pfizer; Advisory / Consultancy, Research grant / Funding (self): Innocrin Pharma; Advisory / Consultancy, Research grant / Funding (self): Bristol-Myers Squibb. M. Casey: Shareholder / Stockholder / Stock options, Full / Part-time employment: Pfizer. E. Degtyarev: Full / Part-time employment: Novartis. M.J. Lechuga Frean: Shareholder / Stockholder / Stock options, Full / Part-time employment: Pfizer. P. Aimone: Full / Part-time employment: Novartis. A. Ravaud: Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Pfizer; Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Novartis; Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Bristol-Myers Squibb; Advisory / Consultancy, Travel / Accommodation / Expenses: AstraZeneca; Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Ipsen; Advisory / Consultancy: Roche; Travel / Accommodation / Expenses: Merck Sharp & Dohme. R.J. Motzer: Advisory / Consultancy, Research grant / Funding (institution): Pfizer; Advisory / Consultancy, Research grant / Funding (institution): Eisai; Advisory / Consultancy, Research grant / Funding (institution): Novartis; Advisory / Consultancy, Research grant / Funding (institution): Genentech/Roche; Advisory / Consultancy: Merck; Advisory / Consultancy: Incyte; Advisory / Consultancy, Research grant / Funding (institution): Exelixis; Research grant / Funding (institution): Bristol-Myers Squibb; Research grant / Funding (institution): GlaxoSmithKline. All other authors have declared no conflicts of interest.
Resources from the same session
2115 - Preclinical in vivo screening to predict responder patients depend on EGFR status
Presenter: Yejin Kim
Session: Poster Display session 3
Resources:
Abstract
3349 - Interplay between miR-17-5p and MALAT-1 Shapes The Cytokine Storm in Triple Negative Breast Cancer (TNBC) Tumor Microenvironment
Presenter: Raghda Soliman
Session: Poster Display session 3
Resources:
Abstract
4014 - Clinical verification on the relationship between lipid metabolism and the immune microenvironment of breast cancer
Presenter: Wataru Goto
Session: Poster Display session 3
Resources:
Abstract
4158 - The clinical and transcriptional signatures of human CD204 reveal an applicable marker for tumor associated macrophage in breast cancer
Presenter: Yunjie He
Session: Poster Display session 3
Resources:
Abstract
5392 - Activated effector T cells co-expressing multiple inhibitory receptors (IRs) are enriched in the tumor immune microenvironment in high grade serous ovarian cancer (HGSOC)
Presenter: Alice Bergamini
Session: Poster Display session 3
Resources:
Abstract
2617 - Oncolytic reovirus as a new anti-tumor strategy in castration resistant prostate cancer
Presenter: Yunlim Kim
Session: Poster Display session 3
Resources:
Abstract
2995 - Dysregulation of helper T lymphocytes in esophageal squamous cell carcinoma (ESCC) patients is highly associated with aberrant production of miR-21
Presenter: Ali Memarian
Session: Poster Display session 3
Resources:
Abstract
3597 - Myeloid derived suppressor cells but not regulatory T cells are associated with adaptive immunity and clinical outcomes in anal squamous cell carcinoma
Presenter: Christophe Borg
Session: Poster Display session 3
Resources:
Abstract
3430 - Evaluation of immune responses among responders (R) and non-responders (non-R) in a humanized mouse model with colorectal cancer (CRC) xenografts treated with combination immunotherapy
Presenter: Juan Marín Jiménez
Session: Poster Display session 3
Resources:
Abstract
1995 - ¬¬Advanced melanoma patients with high CD16+ macrophages have better response and survival to anti-PD-1 based immunotherapy
Presenter: Hansol Lee
Session: Poster Display session 3
Resources:
Abstract