Johns Hopkins Masters Project: Basket Trial: Cancer

1. Presented by Shubhda Roy
Molecular Targets and Cancer (410.750) Fall 2015
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2. *
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3. *
*BRAF Mutation at position 600 leads to overactive signaling
leads to
*Excessive Cell Proliferation
*Resistance to Apoptosis
*Results
*50% melanoma tumors
*40% papillary thyroid tumors
*30% serous ovarian tumors
*10 colorectal tumors
*10% prostate tumors
http://www.biooncology.com/research-education/braf/braf#resourcePlayer/all

4. *
http://cenblog.org/the-haystack/2011/08/the-right-kinase-part-2/
• Treating Melanoma
• Mutation = BRAF V600 Gene
• Oral Inhibitor = BRAF V600 Protein in MAPK Pathway
• Response rate = 50%

5. *
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6. *
*Basket Trial/Study:
Study design allows patients with multiple diseases and one or more
target to be enrolled in cohorts or groups in one trial (the basket)
http://cancerprogressreport.org/2014/Pages/transforming.aspx?Page=2
http://err.ersjournals.com/content/23/133/367
Study One Drug – One Target – Many diseases

7. *
• All Cancers listed below have BRAF V600 mutations
colorectal cancer, non–small-cell lung cancer, Papillary thyroid cancer
Diffuse gliomas, Cholangiocarcinoma, Hairy-cell leukemia, Multiple myeloma, Langerhans’-cell
histiocytosis, Erdheim–Chester disease
• Cancers show aggressive disease phenotype
• Shorted “disease – free and overall” survival
• Incidence of mutation is 5%
• Rarity of disease
• Disease specific study not been systematically explored using vemurafenib
• Diseases are rare, frequency of tumors are low and involve too many tumor
types
• UNMET CLINICAL NEED TO STUDY THESE DISEASES USING vemurafenib
Basket study - different tumor types with the same molecular biomarker might
differ in their sensitivity to therapy targeted at that biomarker

8. *
* histology-independent, biomarker- selected, early phase 2 basket study
* Enrollment Dates: April 11, 2012, through June 10, 2014
* Number of Patients: 122
* Most important Eligibility Criteria:??
(Hint: Its in the title of the paper )
* Cancer Centers: 23 International centers
* Mutation identified using: Mutational analysis assays
* Ineligible Patients:
* Treated with BRAF or MEK Inhibitor
* Having Melanoma, papillary thyroid cancer, leukemia, or lymphoma
* Informed consent was obtained
Positive BRAF V600 Mutation

9. *
*ECD/LCH denotes Erdheim–Chester disease or Langerhans’-cell histiocytosis, and NSCLC non–small-cell lung cancer
** all-others cohort included cervical cancer, brain tumors, head and neck cancer, esophageal and gastric cancers,
pancreatic cancer, sarcoma, and carcinoma of unknown primary type

10. *
Eighty-nine percent of patients had received at least one previous line of therapy.
Ninety-five patients received vemurafenib monotherapy, and 27 patients with colorectal carcinoma received vemurafenib and
cetuximab combination

11. *
*Indicates patients in the dose escalation stage (dose levels 1 and 2)
†Indicates patient has LCH

12. *
(A) Non-small cell lung cancer.
(B) Cholangiocarcinoma.
(F) Erdheim-Chester disease.

13. *
C) Anaplastic thyroid cancer.
(D) Ovarian Cancer.
(E) Pancreatic cancer.
(G) Langerhans cell histiocytosis.
(H) Glioblastoma.
(I) Salivary Gland Cancer

14. *
* Complete Response: CR – 100% decrease from baseline
* Partial Response: PR – 50 % decrease from baseline
* Progressive disease : PD – Increase of 25% from baseline
* Overall Response : %(Complete Response + Partial Response)
* Clinical benefit rate : partial response+ complete response + and stable disease.
* Median progression-free survival : Median of the number of days survival without disease
* Median overall survival : Median of number of days overall survival
* Stable Disease: SD - Not meeting criteria for complete response, very good partial response
(not recommended for use as indicator of response)

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17. *
* Tumor Types do not respond uniformly to BRAF – Targeted therapy
* Tumor nosology based on organ site (Breast Cancer vs. Colorectal Caner) cannot be entirely replaced by molecular nosology
(BRAF-Mutated Cancers)
* BRAF Mutation does not respond to a drug in the same way, if it is lung vs. breast
Different Strokes for different Folks
Starbucks
Dunkin’ Donuts
Wawa
McCafe
Java
Saxbys

18. * Discussion – BRAF inhibitor may be clinically significant for certain diseases
* Vemurafenib showed efficacy with
* non–small-cell lung cancer (19 Patients) [90% receives Pt Chemo)
* 42% overall response
* Tumor regression in majority (14/19)
* Median progression free survival is 7.3 months
* Overall 12 month survival rate was 66%
* Erdheim–Chester disease/Langerhans’-cell histiocytosis (no approved theray for adults)
* 43% overall response
* Tumor Regression in majority (12/14)
* Overall 12 month survival rate was 99%
* Median progression free survival is 5.9 months
* No disease progression while receiving therapy
* Colorectal Cancer - Monotherapy
* No response
* Median Progression free survival is 4.5 months
* Overall Survival is 9.5 months
* Colorectal Cancer - vemurafenib and cetuximab
* 1 patient response
* Tumor regression in 50% of patients (did not meet criteria of partial response)
* Median Progression free survival is 3.7 months
* Overall Survival is 7.1 months
- Colorectal cancer patients were pretreated with an average of at least two lines of therapy

19. *
* Basket study shows antitumor activity in cancers with low incidences rate of BRAF V600 mutation
* Pros of Basket Trial
* Basket study allows to use existing biomarkers to detect early signals of activity across multiple tumor
types for
* Orphan/Rare diseases which will never go through disease specific trial
* Flexible Biostatical design
* Not specific to a tumor
* Model changed on the go for e.g. Colorectal Cancer
* Helps detect sensitivity of targeted therapy of different tumor types to the same molecular biomarker
* Cons of Basket Trials
* Lacks precision (due to limited sample size)
* At times, there was only one patient enrolled for a tumor type
* Almost guessing in the dark
* Clinician cannot make informed decisions about rare diseases based on genomic profiling from such
studies

20. *
*Basket Trail is good starting point to use for genetic mutation in rare
diseases
*Can act as a tool
* To weed out certain tumor types with higher response
* To zoom in on tumor types needing further studies
* To develop molecular target cancer therapy for tumor types with good
response
*In the future – further studies are required make the model more precise

21. *Questions ??

22. *
Resistance to BRAF Inhibitors: Unraveling Mechanisms and Future Treatment Options.
Jessie Villanueva, Adina Vultur and Meenhard Herlyn
Cancer Res 2011;71:7137-7140. Published online November 29, 2011
Fig 1.

23. *
GRADE ECOG PERFORMANCE STATUS
0
Fully active, able to carry on all pre-disease performance
without restriction
1
Restricted in physically strenuous activity but ambulatory and
able to carry out work of a light or sedentary nature, e.g., light
house work, office work
2
Ambulatory and capable of all selfcare but unable to carry out
any work activities; up and about more than 50% of waking
hours
3
Capable of only limited selfcare; confined to bed or chair more
than 50% of waking hours
4
Completely disabled; cannot carry on any selfcare; totally
confined to bed or chair
5 Dead