Moving forward, where are we with Clinical Trials?

Moving forward, where are we with Clinical Trials? Dennis A. Wigle Division of Thoracic Surgery Mayo Clinic AATS/STS General Thoracic Surgery Symposium Sunday, April 27 th 2014 2012 MFMER slide-1

Where are we with Clinical Trials? (Thoracic Surgical Oncology) Overview: Funding status at NCI for co-op group studies Alternative funding routes Current studies Trials pipeline concepts on the horizon Reflection: are we really addressing key questions in thoracic surgical oncology? 2012 MFMER slide-2

Where are we with Clinical Trials? Tough times for surgical trials: Little interest except from surgeons ACOSOG officially dead Recent demise of high profile trials (Z4099) Funding crunch at NCI affecting trials network despite re-organization 2012 MFMER slide-3

Number of Alliance Active Studies Excluding LCTB No. Active Studies year

Where are we with Clinical Trials? Potential opportunities: Currently no/little AATS/STS involvement as a coordinating force Examples like the Alliance Thoracic Surgery Group Industry relationships Need to stay engaged particularly for multimodality studies 2012 MFMER slide-5

Where are we with Clinical Trials? Alternative funding routes: R01/R21 funding Foundation $$ Industry relationships Institutional $$ 2012 MFMER slide-6

Current studies Highlighting 2 studies: CALGB 140503 (Alliance) RTOG 0849 2012 MFMER slide-7

CALGB 140503 A Phase III Randomized Trial Of Lobectomy Versus Sublobar Resection For Small ( 2 Cm) Peripheral Nonsmall Cell Lung Cancer Study Chair: Nasser Altorki Activated: 6/15/07 # CALGB / CTSU Sites Open: 48 / 104 Target / Current Accrual: 692 / 411 Accrual Last 90 / 30 Days: 17 / 7 Planned Accrual Rate: 10 / month

CALGB 140503 Pre-Register Suspected Peripheral T 1 N 0 lung cancer 2cm RANDOMIZATION Confirm N 0 by Frozen: Right: Levels 4,7, 10 Left: Levels 5 or 6, 7, 10 Lobectomy Limited resection (Wedge or segmental) Stratification : Tumor size (< 1cm, 1-1.5cm, 1.5-2.0cm) Histology (Sq. cell, AdenoCa, Other) Smoking status (Never, Former, Current)

Imaging Study Objectives Correlate preoperative CT and PET characteristics with outcome Determine false negative rate for PET in hilar and mediastinal nodal mets Determine utility of annual follow-up CT after resection

RTOG 0839: Randomized Phase II Study of Pre-operative Chemoradiotherapy +/- Panitumumab Followed by Consolidation Chemotherapy in Potentially Operable Locally Advanced (Stage IIIA, N2+) Non-Small Cell Lung Cancer Primary Objective: Mediastinal nodal clearance following completion of induction chemoradiation +/- panitumumab Surgical PI - Jessica Donington New York University School of Medicine 2012 MFMER slide-11

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Concepts in development ALCHEMIST Neoadjuvant immunotherapy 2012 MFMER slide-13

ALCHEMIST Adjuvant Lung Cancer Enrichment Marker Identification and Sequencing Trial

Trial Protocol Details E4512 A081105 A151216 Target ALK+ EGFRmut Registry Prevalence ~5% ~10% all comers n 336 410 6000 8000 Primary Endpt DFS OS -- Power 80% 85% -- One-sided α 0.025 0.05 -- HR 0.67 0.67 -- Adjunct Peripheral screening for ALK; RTPCR to identify fusion partners Targeted sequence and kinome analysis; PRO and QOL Extended sequencing for additional targets; correlation with local testing

Proposed ALCHEMIST schema ALCEMIST screening trial Register post op Register pre op Assess & obtain FFPE tissue SOP for FFPE tissue Collect blood; central EGFR & ALK genotyping Patients on adjuvant trials followed separately Follow q6 months for 5 years

ALCHEMIST-related Adjuvant Therapy Trials (A081105 & E4517) A081105 Stage IB- IIIA NSCLC Complete Surgical Resection Screen for EGFR mutation+ cancers Adjuvant Therapy (if indicated) R a n d o m i z e Erlotinib X 2 years Placebo E4517 Stage IB- IIIA NSCLC Complete Surgical Resection Screen for ALK+ cancers Adjuvant Therapy (if indicated) R a n d o m i z e Crizotinib X 2 years Placebo

ALCHEMIST aims Primary objectives 1. Determine feasibility of central EGFR and ALK genotyping to facilitate accrual to adjuvant studies 2. To collect research-grade tissue for advanced genomics by the Center for Cancer Genomics (CCG) at the NCI

ALCHEMIST aims Secondary objectives 1. To characterize the natural history of resected EGFR and ALK wild-type lung cancers 2. To cross-validate local EGFR and ALK assays with a central standard

Evaluation of Tumor Response after Neoadjuvant Nivolumab with or without Ipilimumab in Non-small Cell Lung Cancer (NSCLC) Neoadjuvant immunotherapy in NSCLC

Figure 1 Mechanism of action of cancer vaccines Drake, C. G. et al. (2013) Breathing new life into immunotherapy: review of melanoma, lung and kidney cancer Nat. Rev. Clin. Oncol. doi:10.1038/nrclinonc.2013.208

Figure 2 Immune checkpoint blockade Nivolumab Ipilimumab Drake, C. G. et al. (2013) Breathing new life into immunotherapy: review of melanoma, lung and kidney cancer Nat. Rev. Clin. Oncol. doi:10.1038/nrclinonc.2013.208

Concept Histologically or cytologically documented NSCLC Clinical stage IB ( 4cm per CT), Stage IIA/IIB, or Stage III (N0-2) amenable to surgical resection. Patient must be deemed a surgical candidate.

Concept Arm A: Nivolumab 3 mg/kg IV every 2 weeks x 3 doses Arm B: Nivolumab 3 mg/kg IV every 2 weeks x 3 doses plus Ipilimumab 1mg/kg IV one dose day 1 Followed by surgery at ~4-6 weeks Primary objective: Evaluate whether the combination of neoadjuvant nivolumab plus ipilimumab increases the tumor response rate compared to nivolumab alone from 20% to 30% in stage 1B, 2 or 3A non-small cell lung cancer.

Concept Imaging, molecular correlates in resected tumor Opportunity for adjuvant immunotherapy regimen for responders after completion of conventional Rx

Are we really addressing key questions in thoracic surgery? Lung e-tumor board frequent dilemmas: Rx for mesothelioma in fit patient? Best management of IIIA NSCLC? Early stage NSCLC in the compromised patient? Role of SBRT in early stage NSCLC? Surgery post SBRT/conventional rads?.and so on 2012 MFMER slide-26

Lots of opportunities Thinking of good trials is easy, getting them done is hard work Many opportunities to get involved Institutional co-op group Multi-center alliances Single institution studies GTSC trials list we will update for 2014 http://gtsc.org/home/clinical-trials/ 2012 MFMER slide-27

Closing thoughts. Need to stay engaged and participate Treat patients on study as much as possible We need you to advance the science of what we do 2012 MFMER slide-28

Questions & Discussion Thank you!! 2012 MFMER slide-29