Developing the Evidence in Oncology

• Life-threatening diseases with rapidly evolving standards of care

• Greater reliance on accelerated approvals and surrogate endpoints

• Frequent single-arm, biomarker-selected cohorts—good for signaling, weaker for comparative efficacy

• High heterogeneity by tumor type, stage, and line of therapy make cross trial comparisons difficult

• Endpoints, designs, and sources of bias differ from other therapeutic areas

• Key groups under-represented (older adults; renal/hepatic

impairment), limiting generalizability

Why is the oncology literature different?

screening, prognosis, and tx

What are the types of studies?

Screening Study

• RCTs preferred, including clinical and cost-effectiveness outcomes

• Methodological issues include lead-time bias and length bias

• Overdiagnosis can be harmful?

lead-time bias

earlier diagnosis inflates longer survival

length bias

overestimation of survival due to slow progression

Prognosis study

-Patient's expected chance of recovery from disease

• Quality of life (QoL) should be considered in addition to survival

-Outcomes usually expressed as survival rates

• e.g., progression-free survival 5 years since diagnosis or start of treatment

-Prognostic factors of interest are generally:

• Tumor-related

• Treatment-related

• Sociodemographic-related (predominantly age and comorbidities)

Treatment study

-patient-centered clinical outcomes, tumor-centered clinical outcomes, surrogate endpoints

-Crossover & open-label designs meet ethics considerations, but blur interpretation of OS

patient-centered clinical outcomes

-overall survival

-health related quality of life

overall survival (OS)

median survival or survival probabilities at a pre-specified time point using time-to-event analyses

randomization -> death from any cause

health-related quality of life (HR-QoL)

perceived physical and mental health overtime

biomarkers

define a response to a therapeutic intervention (mainly imaging, laboratory, or histological data) and some time-to-event endpoints

surogate endpoints

"a biomarker intended to substitute for a clinical endpoint', the latter being 'acharacteristic or variable that reflects how a patient feels, functions, or survives"

Is it safe?

-new targeted therapy

-early phase

-DLT/tox endpoint

Does it have activity?

-drug in refractory disease

-often phase II

-ORR/PFS endpoint

Is it better?

-new first-line regimen

-comparative trial

-PFS/OS endpoint

Does it improve pt experience?

-two effective therapies

-comparative/PRO study

-QoL/symptoms endpoint

phase 1

-safety

-dose

-dose limiting tox

phase 2

-antitumor activity

-response

-early efficacy

phase 3

-comparative efficacy

-benefits vs harms

postapproval

-long-term safety

-pearl-world effectiveness

-new populations

Single-Arm Trials

• Rare disease / rare mutation

• Few available therapies

• Large expected treatment effect

• Early development

• Ethical or practical constraints

basket, umbrella, platform, adaptive

What are the contemporary oncology trial designs?

basket

one alteration -> several tumor types

umbrella

one tumor type -> several molecular alterations/tx

platform

multiple therapies enter/leave a common trial infrastructure

adaptive

features of the trial may change according to pre-specified rules as data accumulate

basket trial

A therapy targets the same rare mutation found in lung, colorectal, pancreatic, and thyroid cancers.

umbrella trial

Patients with NSCLC undergo genomic testing and are assigned to different targeted treatments based on their tumor alteration.

Platform trial

Several treatments are evaluated against a shared control, with ineffective arms discontinued and new arms added.

How was the question studied?

What does the design ask?

what outcome was used to answer it?

What does the endpoint ask?

patient-centered enpoints

-overall survival

-tx tox

-hospitalization

-function

disease/tumor-centered endpoints

-PFS

-DFS/EFS

-ORR

-Duration of response

patient-reported endpoints

-global QoL

-functional status

-symptoms

-tx burden

-easy to define

-pt important

-little ambiguity about the event

Strengths of Overall survival

-long follow up

-larger samples

-subsequent therapies

-crossover

Challenges of Overall survival

progression-free survival

randomization -> progression or death

-earlier outcome

-more events sooner

-not affected as much of subsequent therapies

Why do investigators like progression-free survival?

-progression definitions matter

-assessment timing matters

-imaging interpretation may matter

-improved PFS does not necessarily establish improved OS or QoL

Why do evaluators have to be cautious with progression-free survival?

objective response rate

percentage of pts achieving a predefined tumor response

duration of response

how long the response is maintained

global quality of life

-symptoms

-physical function

-emotional/social function

-global health/QoL

complications to interpretation

• Crossover

• Subsequent treatment

• Open-label design

• Biomarker-selected population