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Clinical trial design in the current age of immunotherapy and - - PowerPoint PPT Presentation
Clinical trial design in the current age of immunotherapy and - - PowerPoint PPT Presentation
Clinical trial design in the current age of immunotherapy and targeted therapy Martijn Lolkema, MD/PhD Medical Oncologist Erasmus MC Cancer Institute Content Clinical trial design: the old paradigm The challenges posed by immunotherapy
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Content
- Clinical trial design: the old paradigm
- The challenges posed by immunotherapy
- The challenges posed by targeted therapy
- How to deal with the exploding trial portfolio
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CLINICAL TRIAL DESIGN: THE OLD PARADIGM
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Drug development in oncology
Oncology Drug Development
Phase I Phase II Phase III/IV
Preclinical hypothesis/ compound generation
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Phase I studies
- Dose selection
- Toxicity determination
- PK analysis
- PD analysis
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Phase I: dose selection
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PK = Pharmacokinetics
- What does the body do to the drug?
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PD = Pharmacodynamics
- What does drug to its target?
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Phase II study
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Phase 3 studies
R Standard of care (Standard of care +) novel treatment
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Conclusies
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HOW TO TACKLE THE MOST IMPORTANT PROBLEMS IN ONCOLOGY DRUG DEVELOPMENT
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There are >900 drugs in development Only 5% of novel drugs in cancer treatment become FDA/EMA approved
SOURCE: I. Kola, J. Landis “Can the pharmaceutical industry reduce attrition rates?” Nature Reviews drug discovery, ‘04
90 80 70 60 50 40 30 20 100% 10 Overall Registration Phase III Phase II Phase I
x
~30% ~40% ~70% ~5%
x x =
~60% Success rate Phases in the drug development process
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Where should we look for improvements?
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Success in phase I essential, phase II less important
- 100
- 75
- 50
- 25
25 50 75 100 %Change From Baseline (Sum of Lesion Size)
Onderzoeker bepaald Inclusief bevestigde & onbevestigde tumorrespons
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How to improve translation
- Efficacy/ Efficacy/ Efficacy
Adjust the clinical trial paradigm
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Drug development in oncology
Phase I Phase II Phase III/IV
Preclinical hypothesis/ compound generation Safety Efficacy
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Fase II onderzoek
Phase I Phase II Phase III Traditional Modern
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Kwak EL, et al. N Engl J Med. 2010;363:1693-703. Anaplastic lymphoma kinase inhibition in non-small-cell lung cancer. After screening tumor samples from approximately 1500 patients with non– small cell lung cancer for the presence of ALK rearrangements, we identified
82 patients with advanced ALK-positive disease
The overall response rate was 57%; 27 patients (33%) had stable disease. A total of 63 of 82 patients (77%) were continuing to receive crizotinib at the time of data cutoff, and the estimated probability of 6-month progression-free survival was 72%, with no median for the study reached.
Focussed phase I trials
Proof of concept!
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Challenges in performing these studies
All-comer Disease specific Mutation specific
All cancer patients without standard treatment options
Disease and Mutation specific
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Patient Centered studies
Verkoop
In study Patient population: etc In study A In study B Patient TEST In study X
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Basket and Umbrella studies
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SOME THOUGHTS ON BIOMARKERS AND PHARMACODYNAMICS
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Patient population
RCT Chemotherapy
placebo Active agent
50% response can be detected easily! RCT Targeted therapy
placebo Active agent
5% response cannot be detected, but: 50% response in the blue dots could!
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Biomarkers: I-SPY trial an example of how to perform biomarker studies
Rugo HS et al. N Engl J Med 2016;375:23-34.
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Results from I-SPY study: Her2 negative patients were selected for randomization
Rugo HS et al. N Engl J Med 2016;375:23-34.
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Outcome: based on pathologic complete response
Rugo HS et al. N Engl J Med 2016;375:23-34.
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The strength of Bayesian statistics
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Conclusion on I-SPY trial
- Well-designed studies that include biomarker based stratification and
randomization are essential in determining predictive biomarkers
- Early and well-defined outcome variable are essential in producing
results that can be interpreted
- BUT: we need confirmation in a phase III trial…….
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MSI: the first approved context independent, predictive biomarker
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Anti-PD1 in MSI high patients
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Why is MSI the first?
- Strong biological rationale (Lynch syndrome/ high immune infiltrate/
high mutational load)
- Can be detected easily (routine diagnostics exist/ IHC and PCR based)
- Correlation with response robust among different tumor types
Biology over ontology!
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So do we incorporate PD/ biomarker research in all early phase trials?
Sweiss et al JCO 2016
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Impact of biopsies
A statistically significant biomarker result was reported in 17% of studies (n = 12)
Sweiss et al JCO 2016
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Biomarkers in clinical practice
- If you add invasive procedures: make them obligatory so you get the
numbers
- Think about ways to obviate the need for invasive procedures
- The best place to do this would be at the end of phase I studies.
- Once you have a biomarkers make sure you get the patient numbers
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Overall conclusions
- Old fashioned oncology drug development paradigm is linear in its
thinking
- Biggest problem we face in oncology drug development is the lack of
early signs of efficacy
- The trial design has developed into a more parallel thinking model:
early studies gain in impact
- Selection is the main item: we need to use better algorithms to select
- ur patients for treatment
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