Session 8: Accelerating the Development and Approval of New Drugs

Top Tier Recommendations

What are the top 3 recommendations that would significantly accelerate progress and what must be done to achieve them? Please be as specific as possible.

Recommendations from the presentations and notes from the discussion can be found beginning on page 2.

Key Questions, Panelist Recommendations, and Discussion Notes

Key Questions

1)Is there a need for centralized infrastructure for diagnostic testing, IRB, or umbrella protocols?

2)Is cross validation of tumor-based testing or blood-based testing pre-competitive?

3)What is the threshold of rarity that defines the need for national scale investigation (NCTN or private sector)?

Recommendations

Susan M. Galbraith

Drug development for rarer sub-types

•Identifying and accruing patients to studies

–Currently too slow and too costly – makes randomised trials with n>100-200 patients very challenging

–Most patients with rarer genetic aberrations not able to access relevant clinical trials

–Data on outcome of patients with rarer genetic aberrations on standard of care therapy is often unavailable or patchy/inadequate – a challenge for approval of single-arm trial designs

–Requirements to show differential activity in ‘biomarker positive’ vs ‘biomarker negative’ and clinical utility of testing in tumour and/or plasma ctDNA is challenging – barrier to development

•Recommendations:

–Enable and accelerate high quality NGS routine multigene testing at sites

–Facilitate clinical trial set-up to enable patients to travel or to access clinical trials via rapid n=1 protocol approval

–Support efforts such as AACR GENIE initiative to provide accessible databases with outcome information on well annotated, high quality NGS based analyses

–Consider post-approval commitments vs pre-approval requirements for data on ctDNA vs tumour testing or in very rare groups for demonstrating diagnostic clinical utility

Enabling Combination Drug Development

•Identifying patients less likely to do well on monotherapy

•Recommendations:

–Consider absence of early elimination of genetic aberration as patient selection tool for combination/switch therapy trial designs to accelerate development

–Consider low allelic fraction/clonality of genetic aberrations as predictors for need for combination therapy

Jeffrey S. Abrams

  • What is the threshold (of rarity) that defines the need for national scale investigation (NCTN or private sector)?
  • Nationwide screening effort is needed to find molecular subtype – new cost sharing structure seems necessary (gov’t, industry, philanthropy)
  • Central IRBs are critical for multi-arm studies and for studies of rare diseases – system depends on volunteers
  • Multiple agents are available for the target – Medical system needs a “bake-off” study to rationalize care

John C. Byrd

•Attitude in disease field to this type of study is mixed but NCI, ASH, FDA, and industry have been highly cooperative and collaborative

•Biomarker assessment and group stratification is not straight forward

–Variant allele frequency prioritization versus targetable lesion?

–When variant allele frequency not easy (FLT3-ITD)?

–Desire to be inclusive to most patients by marker negative group versus having a true distinct molecular group

–Incorporation of different technologies often difficult (NGS, mRNA, cytogenetics)

•Obtaining single central IRB oversight outside of an NCI study not always easy but essential to assure appropriate transition of study

•Model of de-emphasizing credit to any individual as part of bylaw has helped this move forward at quick pace (Jan 2015-current)

•As study develops, more targets for specific arms become apparent

José Baselga

  • Test prior to the time when they may need to make a therapy decision. “Test when you can”
  • Analytical performance of NGS assays is far superior to many currently approved IHC assays. Enable different platforms

Gideon M. Blumenthal

•Establish trials of multiple novel agents against a common control

•Investment in centralized diagnostic testing platforms, cross-validation to credential multiple drugs, multiple platforms

•Investment in federated registries to understand predictive/prognostic implications of rare biomarker subsets, link ‘omics data to clinical outcome data

Discussion Notes

Keith Flaherty

  • Barriers:
  • MAJOR BARRIER: Who pays for sequencing?
  • Public versus private sector
  • diagnostic or therapeutic company to take primary ownership?
  • Efficiency of broad versus targeted sequencing by tumor type (different strategies for certain tumor types?)
  • Can NSCLC and melanoma cleared for standard-of-care NGS for 2 or more genetic markers?
  • Others remain investigational
  • Who conducts the trial(s)?
  • Public versus private sector that is ultimate venue to host this trial
  • Efficiency of umbrella protocol versus maintenance of control by sponsors
  • Opportunities
  • NCI-MATCH has uncovered very strong demand for free NGS and relatively early drug investigation
  • Across NCTN in entirety, appetite is huge.
  • What follows MATCH?
  • Start thinking of national scale strategies – this is showing demand and ability to do this at a community scale
  • Initially wanted 3000 patients, and now expanding to 5000 patients to be screened.
  • What’s the follow-on act?
  • Swapping out the screening system for MATCH (NCI-funded) to concept of qualified commercial/academic lab that has met appropriate standards, where do we focus our effort?
  • Shift to combinations and exhaust new single-agent opportunities
  • More sparse phenotypes might be where this can help
  • Have been focusing on single agents since combination therapy hasn’t been “ready for prime time yet”

Susan Galbraith

  • Challenges:
  • Drug development for rarer subtypes
  • Identifying and accruing patients to studies(2-5% is the range)
  • Understanding prognosis – access to information on outcome on standard of care treatment
  • Accelerating multigene testing platforms (because we will know where patients are)
  • Approval of evolving ‘me-too’ diagnostics
  • Sharing data across drugs in same class?
  • Competitive vs pre-competitive
  • Pre-approval vs post approval
  • Enabling combination drug development(real gains will be in combos and how can we do this rapidly?)
  • Early identification of patients less likely to benefit – switch/add therapy
  • Consideration of impact of allelic fraction for genetic aberrations
  • SHINE study example
  • Despite massive efforts, recruitment was painfully SLOW.
  • 736 patients signed pre-consent
  • Only 10 patients dosed
  • HAS TO BE A BETTER WAY! For patients, companies, everyone.
  • AZD5363 (AKTi) fulvestrant combo Ph2 recruitment in ER+ breast cancer
  • Main recruiter is MSKCC b/c they have a system that WORKS successfully for detecting AKT1 mutations
  • Tagrisso example for circulating tumor cell DNA: Plasma T790M correlations
  • Negative result? Still get a tissue biopsy
  • Drug development for rarer sub-types
  • Identifying and accruing patients to studies
  • Currently too slow and too costly – makes randomised trials with n>100-200 patients very challenging
  • Most patients with rarer genetic aberrations not able to access relevant clinical trials
  • Data on outcome of patients with rarer genetic aberrations on standard of care therapy is often unavailable or patchy/inadequate – a challenge for approval of single-arm trial designs
  • Requirements to show differential activity in ‘biomarker positive’ vs ‘biomarker negative’ and clinical utility of testing in tumour and/or plasma ctDNA is challenging – barrier to development
  • Recommendations:
  • Enable and accelerate high quality NGS routine multigene testing at sites
  • Facilitate clinical trial set-up to enable patients to travel or to access clinical trials via rapid n=1 protocol approval
  • Support efforts such as AACR GENIE initiative to provide accessible databases with outcome information on well annotated, high quality NGS based analyses
  • Consider post-approval commitments vs pre-approval requirements for data on ctDNA vs tumour testing or in very rare groups for demonstrating diagnostic clinical utility
  • Accelerating combination therapy for patients
  • Enabling Combination Drug Development
  • Identifying patients less likely to do well on monotherapy
  • Recommendations:
  • Consider absence of early elimination of genetic aberration as patient selection tool for combination/switch therapy trial designs to accelerate development
  • Consider low allelic fraction/clonality of genetic aberrations as predictors for need for combination therapy

Jeffrey S. Abrams

  • NCTN as a network in the era of precision medicine
  • Activated:
  • Lung-MAP (S1400) – led by SWOG
  • ALCHEMIST (A151216) – led by Alliance and ECOG-ACRIN
  • Exceptional Responders (9671) – open in NCTN and beyond
  • NCI MATCH –led by ECOG-ACRIN (
  • 15 companies on a single IND, FDA involvement – had to pause because accrual exceeded expectations
  • Enrollment has picked up again after opening back up again.
  • 12 days for sequencing turn-around
  • In development:
  • NCI Pediatric MATCH – led by COG
  • One nice feature of MATCH – bringing in junior investigators for some of the arms.
  • Key Aspects of NCI Precision Medicine Trials
  • Single IND – multiple company partners working together within NCI IP agreement framework
  • Public- private partnerships to extend the trials’ reach (FNIH, FOCR, Companies)
  • Biopsies, NGS & other diagnostic tests paid for either by NCI or by company partners – trials are very expensive
  • New educational issues for clinicians and patients – significance of diagnostic tests – somatic (variants, allelic fraction) and germline
  • Correlative science: cfDNA, whole exome/genome, RNA seq
  • NCI Precision Medicine Trials: Lessons Learned
  • Multi-Lab Concordance for NGS testing is achievable
  • Assay turnaround time is adequate
  • Biopsies from sites nationwide are feasible
  • Central IRB is a critical component
  • Pre-screening is valuable (especially if patients relapse)
  • Multiple arms can be difficult to manage when new data intrudes
  • Especially when trial in another part of world changes standard of care. Have to start/stop to get new consent protocol (e.g. lung cancer trial)
  • Adjuvant studies of rare variants are challenging
  • E.g. ALCHEMIST trial.
  • Will barely get 300-400 randomized patients.
  • Mutation rate is low (3%) for ALK variants
  • NCI’s Early Therapeutics Clinical Trials Network (ETCTN)
  • Looking to do other things with drugs
  • Rare tumors
  • Complementary with drug companies
  • Taking advantage at cancer centers of translational scientists
  • Hope to come up with better trials with indications
  • Opportunity to participate in rare trials program
  • ~45 nationwide
  • Basket trials can be done on a national basis at well-qualified centers in early drug development
  • Recently developed NCI IND agents
  • Agents that have achieved FDA approval based in part on early development in CTEP collaborative early phase programs
  • Bortezomib- Mantle Cell Lymphoma
  • Ipilumumab- Melanoma
  • Lenalidomide and bortezomib- Multiple Myeloma
  • Romidepsin- Peripheral T cell Lymphoma
  • Sorafenib- Thyroid Cancer
  • Ziv-aflibercept- Colorectal Cancer
  • Dinutuximab (ch14.18)- Neuroblastoma
  • Pending FDA approval
  • Nivolumab – Anal and Nasopharyngeal Cancer
  • Pembrolizumab – Merkel Cell, Mycosis Fungoides
  • In pivotal trials based on development in CTEP program
  • Cediranib and Oliparib- Ovarian Cancer
  • Selumetinib- Uveal Melanoma
  • Molecularly Targeted Combinations: Accrual Data
  • Active Studies 2011-2016: 263
  • 97 Investigational/Investigational
  • 127 Investigational/Commercial
  • 39 Commercial New indication
  • 29 Trials in review using investigational combinations
  • Total Accrual: 11,432 across all histologies (phase 1, phase 2, and pilot studies only – ETCTN and Cooperative Group Network)
  • NCI Drug Formulary Initiative: Industry-NCI/CTEP Investigator Agreements
  • 30 companies met at ASCO
  • 6 Pledged to participate (30 agents)
  • Provide framework of investigator initiated studies
  • Recommendations:
  • What is the threshold (of rarity) that defines the need for national scale investigation (NCTN or private sector)?
  • Nationwide screening effort is needed to find molecular subtype – new cost sharing structure seems necessary (gov’t, industry, philanthropy)
  • Especially for diagnostic testing
  • Central IRBs are critical for multi-arm studies and for studies of rare diseases – system depends on volunteers
  • 4 boards running – need a lot of volunteers b/c not the Western IRB for pay. Need incentives to reward people
  • Multiple agents are available for the target – Medical system needs a “bake-off” study to rationalize care
  • Tried to do a 2nd generation ALK inhibitor study. But never started
  • Might come back to haunt for immuno-oncology

John C. Byrd

  • AML: The Disease
  • Most common adult leukemia (20,830 cases in 2015, median age 67 years)
  • Diagnosis
  • Average age of patient with AML is 67 years old
  • Symptoms include bruising, fatigue, infections, and/or headache with sub-acute presentation
  • Standard therapy (7/3 cytarabine/daunorubicin followed by consolidation or allogeneic stem cell transplant) resulting in hospitalization 1-6 months; has not changed
  • Until recently, classified predominately by metaphase cytogenetics and select mutations with some potentially targetable [MLL rearrangements and CBF leukemia]
  • Growing number of gene mutations identified that offer potential for targeted therapy
  • Relatively small number per case (average 7 with approximately 100 common variants)
  • Significant differences between cases with co-mutational patterns
  • Groups of mutations converge on common mechanisms of transformation (TET/IDH/WT1)
  • Relapse represents more complex mixture of disease
  • Presence of pre-existence and/or evolution of resistant subsets within single AML patient making ability to target “one disease” unlikely
  • Outcome for ALL AML Patients with Standard Therapy Not Good
  • 10 yr DFS is 2% over 60 and 15% if under 60.
  • Poor prognosis, despite many therapies
  • Little change in AML Treatment: How can we accelerate this?
  • Lack of change in treatment options is not due to a lack of resources or interest although NO agents approved by FDA for AML since 2nd generation athracyclines
  • Heterogeneous disease with a growing number of mutations makes it difficult to develop treatments which work for all AML patients regardless of genotype (i.e. herceptin story) with rare exception (we are not giving up on the gleevac or ibrutinib for AML)
  • AML until recently has lead sequencing efforts, although clinical translation of this is still needed. Low frequency of mutations does allow more sophisticated assessment of driver clone and subclones for choice of therapy
  • Majority of patients with AML relapse and at this time have impaired immune system and also sequencing studies show much more diversity in driver and subclones
  • Drug development in AML has often focused on AML as a common disease and also in the setting of relapse
  • History tells us that even active drugs (azacitidine, decitabine, clofarabine) have minimal or no activity in relapse
  • Idea for a Master Trial for AML – looking to inform therapy with new genomic findings.
  • Done at time patients were coming in
  • Overall intent to yield measurable efficiencies in terms of
  • Improving genomic screening of AML patients at the time of clinical trial entry
  • Feasibility of 7 day waiting period while genomic studies completed
  • Assign therapy on basis of molecular marker targetable with a novel agent
  • Different from other studies, also incorporate a marker negative arm so all patients are offered a opportunity to gain benefit
  • Improved timelines for drug biomarker testing of targeted agent and adaptation
  • Use chemotherapy only when benefit demonstrated (NPM1 mut/FLT3 wt; CBF AML)
  • Multi-arm master protocol
  • Each arm independent from one another with consistent eligibility
  • Provide network for junior and senior AML clinical investigators to lead trials
  • Window design allows for testing of “large effects”
  • Focus initially on age >60 years as this group does poorly with 7/3 chemotherapy
  • Designed to facilitate FDA approval of new drugs where big effects are observed
  • Could expand to 12 arms –
  • This study idea started in Jan 2015 – current
  • Establish purpose of WHY we are doing this study
  • Partnership with FDA on how best to proceed (multiple interactions)
  • Identifying AML patients that are appropriate for (NCTN Group data)
  • Listening to what patients want (FDA and LLS patient meeting)
  • Identifying molecular vendor for testing
  • Attracting and collaborating with industry partners in novel trial design and cost model relative to industry standards
  • Identifying a CRO to coordinate novel study
  • Compiling both master protocol and also sub-protocols
  • Identifying an ideal biorepository
  • Identifying second generation of clinical sites
  • Fundraising to fulfill LLS commitment to this effort
  • What have they learned?
  • Attitude in disease field to this type of study is mixed but NCI, ASH, FDA, and industry have been highly cooperative and collaborative
  • Biomarker assessment and group stratification is not straight forward
  • Variant allele frequency prioritization versus targetable lesion?
  • When variant allele frequency not easy (FLT3-ITD)?
  • Desire to be inclusive to most patients by marker negative group versus having a true distinct molecular group
  • Incorporation of different technologies often difficult (NGS, mRNA, cytogenetics)
  • Obtaining single central IRB oversight outside of an NCI study not always easy but essential to assure appropriate transition of study
  • Model of de-emphasizing credit to any individual as part of bylaw has helped this move forward at quick pace (Jan 2015-current)
  • As study develops, more targets for specific arms become apparent

Jose Baselga

  • Issue at hand:
  • A plethora of active new agents drugging the actionable genome to be tested and (hopefully) approved
  • Considerations
  • The “long tail” of genomic mutations preclude use of small gene panels
  • Who and when to test
  • Don’t let the perfect be the enemy of the good
  • Current portfolio of basket studies at MSK
  • Seeing responses in all of their studies
  • Focusing on Breast Cancer Genomic Landscape
  • Most are actionable (>60%) in critical pathways
  • But some are rare (AKT, 3%)
  • Developing cell lines that are carrying these mutations
  • Working in reverse (see the mutation in human and then work to develop non-clinical model)
  • Long Tail
  • 85% of all hotspot mutations affect <5% of any cancer type in which they are found
  • Need to go BROAD b/c they are rare
  • MSKCC Clinical Sequencing Initiative
  • Run broad NGS panel for patients with recurrent/metastatic cancer
  • Provide improved diagnosis and prognosis for patients
  • Select targeted therapies based on molecular profile
  • Screen patients for clinical trial eligibility
  • Billable tumors
  • Lung, colon, melanoma, thyroid, GIST
  • Non-billable tumors
  • Center for Molecular Oncology and philanthropy cover costs
  • All patients consented tumor genomic profiling research protocol (PI: Hyman) to allow:
  • Additional investigational ‘omic’ testing (WGS/RNAseq, etc)
  • Curation of longitudinal outcome data
  • Data sharing / release (dbGaP, AACR GENIE, etc)
  • MSK-IMPACT: Clinical Volume
  • 77% alive
  • Who and when to test?
  • Any patient with metastatic disease in tumor types with actionable mutations
  • System will self-adjust
  • Bulk of sequencing will be lung, breast, colorectal
  • Genomic testing uncoupled in time to clinical trial participation
  • Patients are waiting to join
  • Selected patients prior to the time when they may need to make a therapy decision
  • Need to consent every patient that qualifies
  • Be liberal in types of assays to incorporate
  • E.g. Histiocytosis – repeatedly failed sequencing
  • “Don’t let the perfect be the enemy of the good”
  • Test prior to the time when they may need to make a therapy decision. “Test when you can”
  • Analytical performance of NGS assays is far superior to many currently approved IHC assays. Enable different platforms

Gideon M. Blumenthal