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The Keynote-177 Randomized Controlled Trial of First-line PD-1 Blockade for Microsatellite-High or Mismatch
S L Gerritse1,2, E van Meerten3, A J Duits4,5,6,7
1Department of Medical Oncology, Renier de Graaf Gasthuis, Delft, the Netherlands.
Abstract:
Some new oncology drugs offer substantial patient health benefit. However, due to high costs, many remain unavailable to patients in low- and middle-income countries. Next to exorbitant drug pricing, uncertainty of the magnitude of benefit of new treatments can contribute to differences in global access to cancer treatments, even in high-income countries. Health technology assessment (HTA) organizations employ predetermined criteria to assess whether a drug's efficacy suffices for local approval, ideally informed by randomized controlled trials (RCTs) that provide data on the clinically relevant endpoints overall survival (OS) and quality of life (QoL). Contemporary oncology RCTs increasingly suffer from design and interpretation issues that lead to inadequate data for HTA assessments. The Keynote-177 RCT was the landmark study demonstrating the superiority of pembrolizumab over chemotherapy in terms of progression free survival and subsequently OS, as a first-line treatment for patients with metastatic microsatellite instable high (MSI) colorectal cancer (CRC). However, in a trial testing the initial efficacy of immunotherapy in advanced MSI CRC, the allowance of crossover delayed the OS signal. Along with other design-related limitations, this complicates the precise determination of the absolute benefit of first-line immunotherapy on OS or quality of life in advanced MSI CRC.
Insights
High drug costs and trial design issues limit access to new oncology treatments globally. The Keynote-177 trial
Area of Science:
- Oncology
- Health Technology Assessment
- Clinical Trial Design
Background:
- New oncology drugs offer significant patient benefits but high costs and pricing disparities limit global access, even in high-income nations.
- Health Technology Assessment (HTA) organizations evaluate drug efficacy using criteria based on randomized controlled trials (RCTs) focusing on overall survival (OS) and quality of life (QoL).
- Contemporary oncology RCTs often present design and interpretation challenges, yielding insufficient data for robust HTA.
Purpose of the Study:
- To evaluate the impact of trial design elements, specifically crossover allowance, on the assessment of first-line immunotherapy efficacy in metastatic microsatellite instable high (MSI) colorectal cancer (CRC).
- To analyze how design limitations in landmark trials like Keynote-177 complicate the determination of absolute benefits for overall survival (OS) and quality of life (QoL).
Main Methods:
- Review of the Keynote-177 randomized controlled trial (RCT) design and its reported outcomes for first-line treatment of metastatic microsatellite instable high (MSI) colorectal cancer (CRC).
- Analysis of how progression-free survival (PFS) and overall survival (OS) data were affected by trial design, including the allowance of treatment crossover.
- Assessment of the implications of these design features on the reliable determination of quality of life (QoL) benefits.
Main Results:
- The Keynote-177 RCT demonstrated pembrolizumab's superiority over chemotherapy for progression-free survival (PFS) and overall survival (OS) in first-line advanced MSI-high CRC.
- The allowance of crossover in the Keynote-177 trial design delayed the definitive overall survival (OS) signal, impacting the clarity of treatment benefit.
- Design-related limitations within the trial complicate the precise quantification of the absolute benefit of first-line immunotherapy on OS and QoL.
Conclusions:
- While landmark trials establish efficacy, design choices like crossover can obscure the precise magnitude of survival and quality of life benefits for new oncology drugs.
- Inconsistencies in RCT data due to design issues pose challenges for Health Technology Assessment (HTA) and equitable global access to innovative cancer therapies.
- Further refinement in RCT methodologies is crucial for accurately assessing the value of novel cancer treatments like immunotherapy in advanced MSI CRC.
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