1) The document summarizes results from several studies presented at the 2016 ASCO conference related to thoracic cancers. 2) A study of adjuvant chemotherapy regimens for non-small cell lung cancer found no difference in outcomes between regimens containing vinorelbine, docetaxel, gemcitabine, or pemetrexed. Pemetrexed had less toxicity. 3) A trial of twice-daily vs once-daily radiation therapy for limited stage small cell lung cancer found no difference in overall survival between the arms.

1. The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute
ASCO 2016: Thoracic
Greg Otterson
June 18, 2016

2. Disclosures
§ Research Funding
§ BMS, Boehringer, Boston Biomedical, Celgene, Clovis,
Genentech, GSK, Pfizer, PUMA, Xcovery
§ Consultant
§ Boehringer, Clovis, Genentech
§ ASCO
§ I viewed ASCO in “virtual meeting”
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3. Outline
§ Adjuvant NSCLC
§ SCLC
§ Other tumors
§ Targeted Therapies
§ Liquid Biopsy
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4. E1505: Adjuvant Chemotherapy +/- Bev:
Outcomes based on Chemo Subsets (Abs 8507)
§ E1505 initiated to test whether Bev added anything to
adjuvant chemo
§ Four chemo options (all cisplatin based) all 3 week cycles
§ Vinorelbine 30 mg/m2 d1, 8
§ Docetaxel 75 mg/m2 d1
§ Gemcitabine 1200 mg/m2 d1, 8
§ Pemetrexed 500 mg/m2 d1
§ Bevacizumab 15 mg/m2 d1 for up to 1 year
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X 4 cycles

5. Rationale for choices
§ Cisplatin/vinorelbine most common regimen in the mid 2000s
positive adjuvant trials
§ Metastatic NSCLC regimens showed no preference to
cisplatin/docetaxel or cisplatin/gemcitabine
§ Cisplatin/pemetrexed added in 2009 when approved in 1st line
§ TREAT study showed less toxicity and better tolerance of cis/
pem compared with cis/vinorelbine (Ann Oncol 2013;24:986)
§ 1501 pts accrued 2007-2013
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6. Demographics by chemotherapy group
Presented By Heather Wakelee at 2016 ASCO Annual Meeting

7. E1505 OS +/- Bevacizumab E1505 DFS+/- Bevacizumab
Presented By Heather Wakelee at 2016 ASCO Annual Meeting

8. Pooled Chemo Analysis (all patients regardless of treatment arm)<br /> OS by chemo group
OS by chemo group <br />Non-squamous : Logrank p=0.18 Squamous: Logrank p=0.99
Presented By Heather Wakelee at 2016 ASCO Annual Meeting

9. Chemotherapy Group Comparisons: Vinorelbine as reference*
Presented By Heather Wakelee at 2016 ASCO Annual Meeting

10. Conclusions E1505 chemo subsets
§ No difference in OS/DFS +/- Bev
§ No difference OS/DFS with different chemo regimens
§ More neutropenia/FN with vinorelbine
§ More thrombocytopenia with gemcitabine
§ Pemetrexed less Gr 3-5 toxicity
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11. CONVERT Trial (Abs 8504)
§ Limited stage SCLC
§ Once daily vs twice daily radiation therapy
§ Twice daily (45 Gy in 30 fractions) consider SOC (Turrisi NEJM
1999)
§ This study looks at 45 Gy in bid fractions vs 66 Gy in 33
fractions, starting with cycle 2 (four to six cycles) of cisplatin/
etoposide
§ Primary endpoint OS, 532 pts planned
§ Similar to CALGB 30610 – 45 Gy in bid fractions vs 70 Gy in
once daily fractions – also OS primary endpoint, 729 pts
planned
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12. Treatment delivered (RT)
Presented By Corinne Faivre-Finn at 2016 ASCO Annual Meeting

13. Overall survival
Presented By Corinne Faivre-Finn at 2016 ASCO Annual Meeting

14. Progression free <br />survival
Presented By Corinne Faivre-Finn at 2016 ASCO Annual Meeting

15. Conclusions
Presented By Corinne Faivre-Finn at 2016 ASCO Annual Meeting

16. Rovalpituzumab (DLL3) targeted ADC in SCLC
(Abs 8505)
§ While ORR high to first line chemo, terrible response to
second line chemo, no biomarker driven therapies identified
§ Delta-like Protein 3 (DLL3)
§ Inhibitory Notch ligand
§ Aberrant cell surface expression in 80% of SCLC and large cell
NE tumors
§ Seen on tumor stem cells, but no normal adult tissues
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17. Rovalpituzumab Tesirine (Rova-T™, SC16LD6.5)
Presented By Charles Rudin at 2016 ASCO Annual Meeting

18. Subject Baseline Characteristics (n=74)
Presented By Charles Rudin at 2016 ASCO Annual Meeting

19. Adverse Event Profile in SCLC Subjects (n=74)
Presented By Charles Rudin at 2016 ASCO Annual Meeting

20. Best Responses per Investigator by DLL3
Presented By Charles Rudin at 2016 ASCO Annual Meeting

21. Conclusions: Rovalpituzumab tesirine in SCLC
Presented By Charles Rudin at 2016 ASCO Annual Meeting

22. Tremelimumab as 2nd/3rd line for Mesothelioma
(Abs 8502)
§ Treme – anti CTLA4 antibody
§ Phase II trials with interesting DCR/OS/PFS
§ DETERMINE study – 571 pts (283 Treme, 189 Placebo), 2:1
randomization, primary endpoint OS
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23. DETERMINE: Overall Survival (ITT Population)
Presented By Hedy Kindler at 2016 ASCO Annual Meeting

24. OS Across Subgroups (ITT Population)
Presented By Hedy Kindler at 2016 ASCO Annual Meeting

25. Most Frequent Grade ≥3 AEs
Presented By Hedy Kindler at 2016 ASCO Annual Meeting

26. Alectinib vs Crizotinib in ALK Positive, ALK TKI
Naive Patients – J-ALEX (Abs 9008)
§ Alectinib is highly potent and active, good CNS penetration
§ Phase I/II study (in Japan) included previously untreated
patients
§ J-ALEX
§ Randomized 200 pts 1:1 to Alectinib (300 mg bid) or Crizotinib
(250 mg bid)
§ Assumed improvement in PFS from 9 to 14 months
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27. Study Overview
Presented By Hiroshi Nokihara at 2016 ASCO Annual Meeting

28. Common AEs, ≥20% of Patients in Either Arm
Presented By Hiroshi Nokihara at 2016 ASCO Annual Meeting

29. Objective Tumor Response
Presented By Hiroshi Nokihara at 2016 ASCO Annual Meeting

30. Primary Endpoint: PFS by IRF (ITT Population)
Presented By Hiroshi Nokihara at 2016 ASCO Annual Meeting

31. Alectinib vs Crizotinib First Line
§ At least a doubling in PFS (10 to > 20 months)
§ Crizotinib PFS (first line) 10.9 months (Solomon, NEJM
2014;371:2167-77)
§ Alectinib PFS 8.9 months (Ou, JCO 2016 Mar 1;34(7):661-8)
§ 10.9 + 8.9 =??
§ Is tolerability a factor?
§ Is CNS penetration a factor?
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32. EGFR Genotyping from Urine, Plasma, Tumor in
Patients Treated with Rociletinib (abstract 9001)
§ Analysis of Tiger X phase I/II study of Rociletinib (T790M
positive required only for phase 2 portion)
§ 500-100 mg bid
§ Safety population 548, Efficacy population 443 (ORR 33.9%)
§ Samples
§ Tissue 540
§ Plasma 482
§ Urine 213
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33. TIGER-X: Tissue, Plasma, and Urine EGFR <br />Test Platforms
Presented By Heather Wakelee at 2016 ASCO Annual Meeting

34. Plasma, Tissue, and Urine Identify Unique and Overlapping Subsets of T790M-Positive Patients
Presented By Heather Wakelee at 2016 ASCO Annual Meeting

35. Investigator-Assessed Confirmed Response Rate Is Similar for T790M-Positive Patients Identified by Plasma, Tissue, and Urine Test
Presented By Heather Wakelee at 2016 ASCO Annual Meeting

36. Detection of T790M in Liquid Biopsies of Patients with Distant Metastatic vs Intrathoracic Disease
Presented By Heather Wakelee at 2016 ASCO Annual Meeting

37. Conclusions
§ Though Rociletinib has been discontinued, T790M detection
is feasible in tissue, urine and plasma
§ Responses to treatment similar across platform/sample
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38. Somatic Genomic Landscape of over 15,000
Advanced Stage Cancer Patients from Clinical
NGS Analysis of ctDNA (LBA 11501)
§ Presented at Tumor Biology oral session 6/7/16
§ Basically a report from > 15,000 clinical samples assayed
via the Guardant360 system
§ Compared indirectly with TCGA dataset
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39. Workflow
§ ctDNA (circulating tumor DNA) isolation from ~ 5 ml plasma
§ 5-30 ng DNA
§ Representing 1500-9900 “genome equivalents”
§ Molecular tagging – “bar coding”
§ Target capture and PCR amplification
§ Illumina sequencing platform
§ Noise filtering and Variant allele calls
§ Mutant allele frequency (MAF) able to differentiate between benign
“SNPs” and somatic variants
§ SNPs typically 50% or 100% of calls, true mutations typically 1% or
less
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40. ctDNA vs TCGA
ctDNA (Plasma) TCGA (Tissue)
Number of patients 15,191 9,077
Number of samples 17,628 9,077
Patients with alteration 12,664 (83.4%) 8,492 (94%)
Alterations per sample (mean,
range)
3 (0-166) 2 (0-110)
Cancer types/stage 50+, stage 3 and 4 27, mostly stage 1 and 2
FDA approved therapy available 7,499 (49%)
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41. Positive Predictive Value
Mutation PPV N
EGFR L858R 100% 61
EGFR del19 98% 147
ALK/RET/ROS fusion* 96% 23
BRAF V600E 95% 19
KRAS G12/G13/Q61 94% 30
EGFR T790M** 27% 22
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*One ALK positive ctDNA/negative tissue received crizotinib with response noted
** “Subclonal” mutations lower PPV

42. Under-Genotyped Tissue NSCLC
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33%
63%
4%
Tissue Testing
(N=362)
Biomarker
Positive
QNS, Partially
Genotyped
Biomarker
Negative
33%
14%
49%
4%
ctDNA Biomarker
Tissue
Biomarker
Positive
ctDNA Positive in
Tissue QNS
ctDNA Negative
in tissue QNS
Tissue/ctDNA
Negative

43. Under-Genotyped Tissue NSCLC
GENE Number
EGFR 98
KRAS 11
ALK 5
ROS1 2
RET 1
BRAF V600E 1
MET/ERBB2 AMP 2
120
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GENE Number
EGFR 8
KRAS 28
ALK 1
ROS1 0
RET 3
BRAF V600E 4
MET/ERBB2 AMP 7
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Tissue Genotyped Tissue QNS, ctDNA Genotyped

44. Liquid Biopsy Conclusions
§ An appropriate alternative/additive to tissue testing
§ NGS is proper
§ Resistance mutations (in EGFR and ALK especially) may be
demonstrated (and does have relevance)
§ No particular bias (by me) towards Guardant (compared with
other available platforms)
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45. Thank You
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