Clinical Updates in Solid Tumor Oncology

Panama City, Panama

Jonathan Riess, MD, MSAssistant Professor of Medicine

UC Davis School of Medicine

17th Annual Advances in OncologySeptember 30-October 1, 2016

Sacramento, CA

Jonathan Riess, M.D.Clinical Updates in Solid Tumor Oncology.

Relevant financial relationships in the past twelve months by presenter or spouse/partner:

Grant/Research Support: Merck, Novartis, MilleniumConsultant: Celgene, Ariad, Clovis, MedTronic

The speaker will directly disclosure the use of products for which are not labeled (e.g., off label use) or if the product is still investigational.

Abstracts: NSCLC/MetastaticAbstract 108: Efficacy and safety of crizotinib in patients (pts) with advanced MET exon 14-altered non-small cell lung cancer (NSCLC). (Alexander E. Drilon)

Abstract 9004: Local Consolidative Therapy (LCT) to improve progression-free survival (PFS) in patients with oligometastatic non-small cell lung cancer (NSCLC) who receive induction systemic therapy (IST): Results of a multi-institutional phase II randomized study. (Daniel Richard Gomez)

Abstract 9008: Primary analysis for alectinib versus crizotinib in ALK-inhibitor naïve ALK positive non-small cell lung cancer (ALK+ NSCLC) in randomized open-label phase III trial (J-ALEX study). (Hiroshi Nokihara)

Abstract 8500: Bayesian randomized trial comparing intensity modulated radiation therapy versus passively scattered proton therapy for locally advanced non-small cell lung cancer. (Zhongxing X. Liao)

Antitumor Activity and Safety of Crizotinib <br />in Patients with Advanced MET Exon 14-Altered <br />Non-Small Cell Lung Cancer

Slide 3

Distribution of genotypes among 933 patients with nonsquamous non–small-cell lung cancer (NSCLC).

Mark M. Awad et al. JCO doi:10.1200/JCO.2015.63.4600

©2016 by American Society of Clinical Oncology

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Conclusions

• MET exon 14 alterations should now be assessed routinely in advanced NSCLC – Next generation sequencing assays are adequate

• Presence of MET exon 14 alterations predicts for response to MET inhibitors

• Recommended algorithm for MET exon 14 altered NSCLC:– Refer for clinical trial consideration– In absence of clinical trial, crizotinib is appropriate

NCCN Guidelines

Local Consolidative Therapy (LCT) Improves Progression-Free Survival (PFS) in Patients with Oligometastatic Non-Small Cell Lung Cancer (NSCLC) who do not Progress after Front Line Systemic Therapy (FLST): Results of a Multi-Institutional Phase II Randomized Study

Daniel Gomez, George Blumenschein, Jack Lee, Mike Hernandez, Ross Camidge, Robert Doebele, Laurie Gaspar, Don Gibbons, Jose Karam, Brian Kavanagh, Ritsuko Komaki, Alexander Louie, David Palma, Anne Tsao, William William, Jianjun Zhang, Stephen Swisher*, John Heymach*, on behalf of the MD Anderson Cancer Center Lung Cancer Moon Shot Initiative

*Co-senior authors

Trial Design

Presented by: Daniel Gomez, M.D.

Surgery and RT Allowed

Crossover Allowed at

ProgressionStep 1:

Enrollment

Front Line Systemic Therapy

Step 2: EnrollmentNon-PD, Enroll,

Randomize

Physician choice for standard

maintenance or surveillance*

LCT(surgery ± radiation

to primary and metastases)

Physician choice for standard

maintenance or surveillance*

Consider LCT(surgery ± radiation

to primary and metastases)

Local Consolidative Therapy

No Local Consolidative Therapy

PD/Toxicity

PD

All patients had stage IV disease, three or fewer metastases, and no progression

after initial treatment with chemotherapy

CONSORT Diagram

Presented by: Daniel Gomez, M.D.

N=12 progression N=5 refused randomization

N=4 lost to follow-upN=3 further studies deemed

ineligibleN=1 study closed prior to

randomization

74 PatientsEnrolled into Step 1(Induction Phase)

49 PatientsEnrolled into Step 2

andRandomization

25 Patients NotEnrolled into Step 2

andRandomization

25 PatientsReceiving LCT

24 PatientsReceiving No LCT

At DSMC review in 1/2016, study closed due to observed efficacy in experimental arm after randomization of 49 patients

PFS Outcomes (updated data)One patient inevaluable (24 in each group)

Median PFS times:

No-LCT arm: 3.9 months (95% CI 2.2-6.6 months)

LCT arm: 11.9 months (95% CI 5.4 months-NA)

P-value = 0.005

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ree S

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24 2 0 0No LCT:24 8 2 0LCT:

Number At Risk

0 1 2 3

Time in Years

LCT

No LCT

Presented by: Daniel Gomez, M.D.

Patterns of Failure

• Difference in patterns of failure trended towards significance (p=0.09)– Higher proportion of locoregional only failures in no-LCT

arm (17% in no-LCT vs. 4% in LCT arm)– Higher proportion of metastatic only failures in LCT arm

(40% in LCT vs. 25% in no-LCT arm)– Higher proportion of both locoregional and metastatic

failures in no-LCT arm (29% in no-LCT vs. 8% in LCT arm)

Presented by: Daniel Gomez, M.D.

Time to New Site Failure (TNSF)

Median TNSF time 11.9 months in LCT arm vs. 5.7 months in no-LCT arm (p=0.0497)

P-value = 0.0497

0.0

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.25

0.5

00

.75

1.0

0

Su

rviv

al F

ree

of

Ne

w L

esio

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rob

ab

ilit

y

24 2 1 0No LCT:24 8 2 0LCT:

Number At Risk

0 1 2 3

Time in Years

LCT

No LCT

Presented by: Daniel Gomez, M.D.

Conclusions

• In oligometastatic (1-3 mets) NSCLC, local consolidative therapy after systemic therapy appears to improve PFS– Exploratory analysis: LCT increased time to development of new

lesions• Results of trial are intriguing but not yet practice

changing– Population: highly heterogeneous (clinically and

biologically)– Sample size: limited– Quality of life: unknown– Crossover design confounds overall survival endpoint

Alectinib versus Crizotinib in ALK Inhibitor Naïve ALK-Positive Non-Small Cell Lung Cancer:

Primary Results from the J-ALEX Study

Hiroshi Nokihara, Toyoaki Hida, Masashi Kondo, Young Hak Kim, Koichi Azuma, Takashi Seto, Yuichi Takiguchi, Makoto Nishio, Hiroshige Yoshioka, Fumio Imamura, Katsuyuki Hotta,

Satoshi Watanabe, Koichi Goto, Kazuhiko Nakagawa, Tetsuya Mitsudomi, Nobuyuki Yamamoto, Hiroshi Kuriki, Ryoichi Asabe, Tomohiro Tanaka, Tomohide Tamura

Presented by: Hiroshi Nokihara

J-ALEX Phase III Study Design

Stratification factors:

R1:1

Key Entry Criteria• Stage IIIB/IV or recurrent

ALK-positive NSCLC• ALK centralized testing

(IHC and FISH or RT-PCR)• ECOG PS 0-2• ≥1 measurable lesion

assessed by investigator• Treated/asymptomatic brain

metastases allowed• ≤1 prior chemotherapy

Alectinib 300 mg BID PO, 28-day cycle

(N=100)

Crizotinib 250 mg BID PO, 28-day cycle

(N=100)

Endpoints• Primary

- PFS assessed by IRF*

• Secondary- OS- ORR- PK- QOL- CNS PFS- Safety

25

Clinical stage (IIIB/IV vs. Recurrent)Prior chemotherapy (0 vs. 1)ECOG PS (0/1 vs. 2)

JapicCTI-132316

*IRF Independent Review Facility

Presented by: Hiroshi Nokihara

Safety Overview

Alectinib(N=103)

Crizotinib(N=104)

Any AEs 100 (97.1%) 104 (100.0%)

Grade 3/4 AEs 27 (26.2%) 54 (51.9%)

Treatment-related deaths 0 0

Serious AEs 15 (14.6%) 27 (26.0%)

Discontinuation of study drug due to AEs 9 (8.7%) 21 (20.2%)

Dose interruptions due to AEs 30 (29.1%) 77 (74.0%)

26Presented by: Hiroshi Nokihara

Alectinib (n=83)

Crizotinib (n=90)

ORR [95%CI]

91.6% [85.6 -97.5]

78.9% [70.5 -87.3]

ORR* assessed by IRF

Objective Tumor Response

Presented by: Hiroshi Nokihara 27

ORR assessed by investigator in ITT population

Alectinib(n=83)

Water fall plot* assessed by IRF

CR or PR SD, PD or NE

Crizotinib(n=90)

Alectinib (N=103)

Crizotinib (N=104)

ORR [95%CI]

85.4% [78.6 -92.3]

70.2% [61.4 -79.0]

Primary Endpoint: PFS by IRF (ITT Population)

0 6 12 18 27

100

80

60

40

20

0

Prog

ress

ion-

free

surv

ival

rate

(%)

24213 9 151

7665

3621

94

19386

4940

2714

103102

No. of patients at riskAlectinib

Crizotinib103104

Presented by: Hiroshi Nokihara 28

Time (months)

10.2 months

NR

HR = 0.34, p<0.001

Presented by: Hiroshi Nokihara 29

Conclusions

• Alectinib is superior to crizotinib as frontline therapy of ALK-positive NSCLC– RR: 85% vs 70%– PFS HR = 0.34 (p<0.001)

• mPFS: Not reached vs. 10 months– Time to progression for those with brain metastases: PFS was 92%

better for alectinib– Toxicity profile favored alectinib

• Caveats: Japanese-only trial, cost (third party reimbursement) • Bottom line:

– Alectinib can be considered as frontline ALK-targeted therapy (particularly pts with brain mets)

– We await definitive results of global ALEX trial

A Bayesian Randomization Trial of Intensity Modulated Radiation Therapy (IMRT) vs.

3-Dimensional Passively Scattered Proton Therapy (3DPT) for Locally Advanced Non-Small Cell

Lung Carcinoma

(clinicaltrials.gov identifier NCT00915005)

Zhongxing Liao, J. Jack Lee, Ritsuko Komaki, Daniel R. Gomez, Michael O’Reilly, Pamela K. Allen, Frank Fossella, John V. Haymach, George R. Blumenschein,Noah Chan Choi, Thomas F. Delaney, Stephen M. Hahn, Charles Lu, James D.

Cox, and Radhe Mohan

Supported in part by NCI grants P01 CA021230 and U19 CA021239.

Hypothesis

Proton therapy will – Reduce irradiated lung volume, hence

reduce radiation pneumonitis (RP)– Achieve same local control (LC) with

same biological effective radiation dose (Proton relative biological equivalence=1.1)

Primary Objective

Protocol Failure (Dual endpoints):• Radiation Pneumonitis grade > 3

(CTCAE 3.0)– IMRT = 15%– 3DPT = 5%

• Local failure (PET, CT, biopsy):– IMRT = 3DPT– 15% at 6mo & 25% at 12mo.

Randomized and Treated According to Randomization Analysis

Comparative IMRT and 3DPSPT plans evaluated

N = 225

Treated with IMRTN=92

Preferred protons

N = 6

IMRT N = 105

Signed informed consent N= 274

Excluded from analysis N=49:1. Chemotherapy only : 12. Consented twice3. Closed to patient accrual: 34. Disease progression: 85. GTV movement > 2 cm: 16. Ineligible body weight: 17. Insurance denied: 88. No Chemo: 29. No good for proton: 110. Poor PFT : 411. Patient wants proton only: 212. Screening Failure: 4 (Stage I:

1 & Stage IV:2)13. Surgery: 114. tumor too large: 115. TX at local facility: 116. Violation of the study: 417. Withdraw IC: 5

Plans randomizable

N = 181

3DPT N = 76

Treated with 3DPTN = 57

Insurance denied protons so treated

with IMRTN=15

3DPT betterN = 13

Off study due to Unacceptable plan

N =3

IMRT plan betterN = 28

Plans not randomizable

N=44

Off protocolN = 4

Off protocolN = 7

(3 insurance denial protocol)

Baseline Characteristics

• Demographics (age, gender, ECOG, smoking status, histology, stage) no difference.

• Target Volumes:

Target Volumes (cc) IMRT 3DPT Total P valuesGTV Median 66.10 77.7 70.3 0.141

Min-Max (5.75-686.59) (1.9-673.7) (1.9-686.59)ITV

Median 257.655 320.7 292.7 0.055Min-Max (42.01-1316.24) (30-1384) (30-1384)

PTVMedian 429.35 524.9 480.31 0.071Min-Max (103.92-1776.06) (76-1906) (76-1906)

• RT dose 74 Gy: IMRT vs. 3DPT = 63% vs. 75.4% (p<0.001)

0.00

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Pro

port

ion

57 38(12) 21(7) 12(1) 9(0) 3(0) 1(1)Proton92 62(16) 36(10) 20(1) 13(0) 6(0) 0(1)IMRT

Number at risk

0 12 24 36 48 60 72Months

Protocol Failure

0.00

0.25

0.50

0.75

1.00

Pro

port

ion

57 56(0) 48(5) 44(1) 41(0)Proton92 86(1) 78(3) 74(2) 72(0)IMRT

Number at risk

0 3 6 9 12Months

Grade >3 TRP

0.00

0.25

0.50

0.75

1.00

Pro

port

ion

57 40(6) 21(8) 12(1) 9(0) 3(0) 1(1)Proton92 66(10) 38(11) 21(1) 14(0) 6(1) 0(1)IMRT

Number at risk

0 12 24 36 48 60 72Months

Local Failure

P=0.55

Protocol Failure - Randomized and Treated According to Protocol

Protocol Failure (Dual endpoints):RP grade > 3 (CTCAE 3.0)IMRT = 15% vs. 6.5% 3DPT = 5% vs. 10.5%

Local Failure at 12 month (PET, CT, biopsy):IMRT = 3DPT = 25% vs. 10.7%

Overall SurvivalWhole Group IMRT vs. 3DPT

Cox Regression Analysis for OS Variable HR p-value 95% CI Comparison

Age Continuous 1.03 0.012 1.01 1.06 ContinuousRT Dose >=74 0.62 0.036 0.39 0.97 <74GyGTV Continuous 1.002 0.02 1.000 1.003 Continuous

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1.00

Prop

ortio

n

149 119(30) 76(31) 42(22) 28(5) 12(3) 1(2) Number at risk

0 12 24 36 48 60 72Analysis Time (Months)

0.00

0.25

0.50

0.75

1.00

Prop

ortio

n

57 43(14) 30(10) 18(10) 12(3) 5(3) 1(0)Proton92 76(16) 46(21) 24(12) 16(2) 7(0) 0(2)IMRT

Number at risk

0 12 24 36 48 60 72Analysis Time (Months)

MST=28.8 month MSTIMRT= 29.5 monthMST3DPT=26.1 monthP=0.30

Conclusions

• Proton beam RT is no better than standard IMRT– Primary endpoint not met

• Pneumonitis numerically worse with protons• No significant differences in treatment failure rates• Trend for worse survival with proton beam

– IMRT 29.5 months vs. Proton 26.1 months

• Results dispel prevailing notion that proton beam RT is superior to standard RT

• Lack of clear benefits of proton beam RT do not justify its higher cost in this patient context

Nivolumab versus Investigator’s Choice Chemotherapy for R/ M SCCHN,

from ASCO 2016

Robert L. Ferris, George Blumenschein, Jr, Jerome Fayette, Joel Guigay, A. Dimitrios Colevas, Lisa Licitra, Kevin Harrington, Stefan Kasper, Everett E. Vokes, Caroline Even,

Francis Worden, Robert Haddad, Makoto Tahara, Naomi Kiyota, Manish Monga, Mark Lynch, William J. Geese, Justin Kopit, James W. Shaw, Maura L. Gillison

Nivolumab versus Investigator’s Choice Chemotherapy for R/ M SCCHN, second line and beyond

from ASCO 2016

Slide 8

Presented By Robert Ferris at 2016 ASCO Annual Meeting

The fine print. What you should ask:

Pembrolizumab, “ KEYNOTE-012” ASCO 2016

With permission, Ranee Mehra et al.

Pembrolizumab, “ KEYNOTE-012”

With permission, Ranee Mehra et al.

Prediction of response to pembrolizumab

With permission, Laura Chow et al. ASCO 2016.

Prediction of OS to pembrolizumab

With permission, Laura Chow et al. ASCO 2016.

Prediction of OS to pembrolizumab By IFN gene score

With permission, Laura Chow et al. ASCO 2016.