How can we deal with the explosion of new treatments?

Steven Lemery, MD, MHS FDA New drugs approved since 2011 Ruxolitinib, crizotinib, vemurafenib, abiraterone, ipilimumab, vandetanib, asparaginase Erwinia, ponatinib, bosutinib, cabozantinib, regorafenib, omacetaxine, pertuzumab, enzalutamide, ziv-aflibercept, vismodegib, carfilzomib, ibrutinib, radium RA 233 dichloride, obinutuzumab, afatinib, trametinib, ado-trastuzumab emtansine, trametinib, pomalidomide, dabrafenib, nivolumab, ramucirumab, belinostat, olaparib, blinatumomab, ceritinib, pembrolizumab, siltuximab, idelalisib, alectinib, elotuzumab, ixazomib, daratumumab, trifluridine/tipiracil, osimertinib, cobimetinib, trabectedin, sonidegib, dinutuximab, panobinostat, lenvatinib, palbociclib, olaratumab, atezolizumab, venetoclax, acalabrutinib, abemaciclib, copanlisib, inotuzumab ozogamicin, neratinib, durvalumab, enasidenib, midostaurin, brigatinib, niraparib, avelumab, lutetium LU 177 dotatate, apalutamide 2 Why is it tougher in GI oncology?

• Fewer patients with “drugable” targets? • Lower mutation burden? • Is investment different?

• Biology is paramount!

3 Progress

• Pancreatic cancer • CRC – FOLIRINOX/mFOLFINOX – Adjuvant duration – Nab-paclitaxel – Screening – Cape/Gem (adjuvant) – EGFR/KRAS wt – Liposomal irinotecan – MSI/dMMR – Everolimus (pNET) – FOLFOXIRI – Sunitinib (pNET) – 2nd line anti-VEGF – Avastin biosimilar approved – Consensus molecular subtypes 4 Regulatory Progress

(PPT clip art)

5 FDA Historical Perspective: Oncology Efficacy Endpoints

• 1970s: Limited Available Therapies – Tumor shrinkage (response rate) accepted for regular approval

• 1980s: A change in this interpretation occurred: – 10-20% ORR may not translate into benefit (given the toxicity of the agents) – Ideally, measurement, should reflect Direct Clinical Benefit • How one “Feels, Functions or Survives” • A move away from ORR and a focus on Overall Survival

FDA Guidance for Industry: Clinical Trial Endpoints for the Approval of Cancer Drugs and Biologics 6 And then this started to happen…

Complete hematologic response in 53 of 54 patients with IFN refractory chronic phase CML…

“Our results…demonstrate the potential for the development of anticancer drugs based on the specific molecular abnormality present in human cancer.” 7 Unprecedented Response Rates in Solid Tumors • Enriched populations • Strong basic science • Durability Pembrolizumab: Phase 2 Le et al Science 2017 2nd line ALK+ NSCLC: ORR BRAF+ anaplastic thyroid (ORR from labeling) 54% cancer: ORR 61% MSI-H: ORR 39%

DabrafenibBrentuximab + trametinib:Vedotin: Phase Phase 2 2 Pembrolizumab: Phase 2 Brigatinib: Phase 2 SubbiahYounesetet al., al JCOJCO 20122018 Le et al., Science 2017 Kim et al., JCO 2017 (ORR from labeling) (ORR from labeling) (ORR from labeling) 8 Looking Closer at ORR

• Multiple variables for “Response Rate” – Tumor location / burden – Available therapy / unmet need – # Complete responses – Durability – How many patients tumor reduced, but <30%? – Not currently captured in RECIST ORR – Value of the waterfall plot – Disease prevalence

9 Where are the tumors that are responding? When “Response Rate” may be considered Direct Clinical Benefit…

•Near complete responses of disfiguring or fungating skin lesions •Prevention of severely morbid surgical procedures •Traditional approval granted based on clinical response rate (and duration), the cosmetic improvement and the high likelihood of tumor related symptomatic relief

Denosumab Response (sacral GCTB). Vismodegib Response. Ueda et al., Ann Oncol, 2015; Von Hoff et al., NEJM, 2009; 26: 2149-2154 361: 1164-72 10 The appropriate trial design and endpoint depends on context

• Equipoise is important for ethical conduct of randomized trials

Crizotinib: ROS-1+ NSCLC regorafenib: mCRC Response IRR (n=50) Invest (n=50) Response N=505 Vs. ORR 66% 75% ORR 1% Duration Demonstrated OS effect in RCTs Median, mo 18.3 NR FDA Review: >65% ORR, median duration of over 18 months with deep responses and favorable B-R in RCTs in ALK+ NSCLC

11 Randomization still has value

OS as an endpoint PFS as an endpoint

TAS-102 Mayer et al., NEJM, 2015 lutetium LU 177 dotatate Strosberg et al., NEJM, 2017

12 Guiding Principles Moving Forward • Investigational agents – More inclusive trails – Better trials – Learn from the past • Best access for patients is – Approval for an effective drug – Affordability

13 More inclusive trials

14 Eligibility Criteria? Many potential participants excluded from trials:

CNS Response to alectinib ALK+ NSCLC • CNS involvement • Performance status • Organ dysfunction • HIV positivity • Prior malignancy • Autoimmune Ignatious Ou et al., JCO, 2016

15 Elderly Patients with Colorectal Cancer Enrolled on FDA Trials Compared with New Cases by Age Group

70% 65% 60% 50% 43% 40% 33% 30% 27% 24% 20% 8% 10% 0% <65 65-74 75+ Clinical Trial Participants New Cases by Age Group

FDA Registration Trials 2005-2015 SEER 18 2010-2014, All Races, Both Sexes (Slide courtesy of Bindu Kanapuru) 16 Predicted elderly enrollment when exclusion criteria are relaxed

70%

60% 60%

50% 47%

40%

32% 30%

20%

10%

0% Baseline Relaxing Organ System Exclusions Relaxing Functional Status and Organ System Exclusions

Modified from Lewis J.H et al .Journal of Clinical Oncology 21, no. 7 (April 2003) 1383-1389. Slide courtesy of 17 Bindu Kanapuru Trial Designs

18 Novel designs are facilitated by biomarkers

• Test multiple drugs at one time – One cancer • MRC-FOCUS 4 • Precision Promise • LUNG-MAP – Multiple cancers • NCI-MATCH • Expansion Cohort Trials • Registries or RWD – e.g., ASCO TAPUR • Seamless designs (drug development in a single trial)

19 Seamless Design: KN-001

Cohort A All Patients Advanced NSCLC Advanced solid tumors N = 1235 n = 550 n = 30

1 mg/kg Q2W Cohort C Cohort F1 (Randomized) Cohort F2 Cohort F3 n = 4 Any PD-L1 PD-L1+ Previously Treated PD-L1+ ≥2 prior therapies Treatment naive n = 356 ≥1 prior therapy 10 mg/kg Q3W n = 101 2 mg/kg Q3W n = 38 n = 55 3 mg/kg Q2W n = 3 2 mg/kg Q3W n = 6

10 mg/kg Q2W Nonrandomiz Nonrandomize Randomized n = 10 10 mg/kg ed d PD-L1+ Q3W PD-L1+ PD-L1– ≥1 prior n = 49 ≥2 prior ≥2 prior therapy therapies therapies n = 280 2 mg/kg Q3W 10 mg/kg 10 mg/kg Q3W 10 mg/kg Q2W n = 7 Q2W n = 33 n = 43 10 mg/kg n = 46 Q3W n = 167 10 mg/kg Q3W n = 6 Advanced Melanoma 10 mg/kg n = 655 Q2W n = 113

Cohort B1 Cohorts B2, B3, D Nonrandomized Randomized n = 135 n = 520

IPI Naive IPI treated Cohort D Cohort B2 Cohort B3 n = 87 n = 48 IPI naive IPI IPI naive or IPI treated n = 103 refractory n = 244 n = 173 10 mg/kg Q2W 10 mg/kg Q2W n = 41 n = 16 2 mg/kg 2 mg/kg 10 mg/kg Q3W Q3W Q3W n = 122 n = 51 n = 89 10 mg/kg Q3W 10 mg/kg Q3W n = 24 n = 32 10 mg/kg Q3W 10 mg/kg Q3W 10 mg/kg Q2W n = 52 n = 84 n = 122

2 mg/kg Q3W n = 22 Slide courtesy of Eric Rubin, National Cancer Policy Forum, 12/12/16 20 KN-001 Amendments and trial accrual…

2011 2012

Amendment Part A 1 Part B

32 0 50 100 150 200 250 300 350 www.fda.gov Number of Patients 21 Getting complicated

2011 2012

Amendment Part A 1 2 Part B

84 0 50 100 150 200 250 300 350 www.fda.gov Number of Patients 22 Complex!

2011 2012 2013 2014

Part A Amendment A1 1 A2 2 Part B1 3 B2 4 B3 5 Part C 6 Part D 7 Part F1 8 F2

1200+ 0 50 100 150 200 250 300 350 www.fda.gov Number of Patients 23 Regulatory Perspective on Seamless Designs • Implications of full drug development program within a protocol – Level of IRB scrutiny of these trials – Meetings between FDA/EMA & companies – Oversight by relevant disease experts/divisions within FDA/EMA – Size and quality of safety database – Adequacy of data to support global regulatory approvals – Informed consent • Should not be the default for FIH trials (may be appropriate for Breakthrough drugs) • Independent oversight for patient safety, trial integrity • Provide justification for design and sample size 24 Learn from prior experience (pancreatic cancer trials)

Tanomastat Tipifarnib Marimastat Algenpantucel-L Pemetrexed Rigosertib Rubitecan Glufosamide Bevacizumab Aflibercept Cetuximab Masitinib

Axitinib CRS-207/GVAX Exatecan Ruxolitinib

Ganitumab

Sources: Rahib et al., JAMA Oncol 2016; Fuchs et al., Annals of Oncology, 2015, NewLink Genetics Press Release (May 9, 2016), Hurwitz et al., JCO, 2017 (abstract), Le et al, JCO, 2017 (abstract) 25 Lessons to learn

• Don’t over-interpret trial results – e.g., single arm combination studies – Single arm PFS/OS – p values • Adapt!

– Move onto next drug earlier Hugo Lloris, Wikipedia Commons – Expand if unprecedented effects – Multiple drugs in a single trial – You have power regarding enrollment!

26 Finally…this is the future!

PD-1 (g) CTLA4 (g) Potential for TKI (h) endless Cytokine #2 (g) PD-L1 (f) combinations in PD-L1 (d) each tumor type CTLA4 (e) LAG3 (d) Cytokine (b) PD-1 (i) Cytokine #3 (i) PD-1 (Sponsor b) CTLA4 (a) IDO (b) Chemo (c) Cytokine (b) PD-1 (Sponsor a) PD-1 (Sponsor a) + CTLA4 (a), IDO (a) CD40 (a) 27 Summary In an era of unprecedented drug effects in targeted populations • Use appropriate / context-specific regulatory approaches • Inclusive enrollment • Consider new trial designs…..but thoughtfully so • Thoughtful use of biomarkers • Learn from prior negative trials • You as investigators can control what drugs are studied!

28 Acknowledgements

• Thank you to the following who shared insights and/or slides: – Richard Pazdur – Paul Kluetz – Leigh Marcus – Tatiana Prowell – Patricia Keegan – Gideon Blumenthal – Damiette Smit – Martha Donoghue – Naomi Horiba – Amy McKee – Sandra Casak – Patricia Keegan – Bindu Kanapuru – Gwynn Ison

29