June 2016 ASCO in Review #CRCWebinar

2016 ASCO In Review

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• Speaker: Dr. Emily Chan

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Speaker:Emily Chan, MD, PhD, Associate Professor of Medicine (Hematology/Oncology) Vanderbilt University

Dr. Chan joined the faculty of the Vanderbilt-Ingram Cancer Center after finishing her Medical Oncology/Hematology fellowship training at Memorial Sloan-Kettering Cancer Center. At Vanderbilt, her clinical interest is in gastrointestinal malignancies, including cancers of the colon, rectum, anal canal, esophagus, stomach, small intestine, gallbladder, pancreas, liver, and bile duct. Her research interests reside in the development of more effective treatment regimens for these diseases, particularly colorectal cancer, and the identification of markers that may predict response to specific therapies.

Colorectal Cancer

Emily ChanJune 15, 2016

ASCO Colorectal Highlights

Immunotherapy:Abstract 3501: CheckMate-142Abstract 3502: Cobimetinib and Atezolizumab in CRC

Chemotherapy:Abstract 3512: PRODIGE 14-ACCORD 21Abstract 3521: STAR-01

Abstract 3501: CheckMate-142: Nivolumab +/-

ipilimumab in mCRC interim results• MSI-H is found in 4% of mCRC

• High mutation burden• Increased neoantigen load• Nivolumab: Fully human IgG4 immune checkpoint

inhibitor antibody. – Binds PD-1 receptors on T cells– Disrupts PD-L1/PD-L2 signaling to restore antitumor immunity

• Ipilimumab: Anti CTLA-4 antibody• Nivolumab and ipilimumab enhance T cell antitumor

activity through distinct but complementary mechanisms.

Abstract 3501: CheckMate-142: Nivolumab +/- ipilimumab in mCRC

interim results• Inclusion:

– ECOG PS 0-1– Disease progression after > 1 prior tx (MSI-H) or latest tx (all), or intolerance or

refusal to take chemotherapy)– MSI status determined locally

• Exclusion:– CNS involvement– Prior malignancy within 3 years– Active or history of autoimmune disease– Need for immunosuppressive medications– Prior tx targeting T cell costimulation or immune checkpoint pathways


interim results

• Independent safety cohort: MSS• Third line or later non MSI-H mCRC• Nivo 1 mg/kg + Ipi 1 mg/kg q3w x 4 then nivo 3 mg/kg q2

wk. N > 3• If tolerable, 1:1 randomization to two different doses of

nivo/ipi combination N=10 per arm


interim results

• MSI-H• Nivo 3 mg/kg q2w >7/19 =>stage 2• Nivo 3 mg/kg + Ipi 1 mg/kg q3 weeks x 4 then nivo 3

mg/kg q2 weeks >7/19 =>stage 2


interim results

• Primary endpoint was investigator assessed ORR• Secondary endpoint was independent radiology review

committee assessed ORR• Exploratory endpoints:

– Safety and tolerability– PFS– OS– Investigator assessed ORR in MSS– Biomarkers


interim results

Nivolumab 3 mg/kg(n=70)

Nivolumab 3 mg/kg + ipilimumab 1 mg/kg

(n=30)

Continuing treatment, n (%) 47 (67.1) 18 (60.0)

Not continuing treatment, n (%) 23 (32.9) 12 (40.0)

Reasons for not continuing, n (%) Disease progression Study drug toxicity Withdrew consent/otherNot reported

19 (27.1)2 (2.9)1 (1.4)1 (1.4)

6 (20.0)4 (13.3)1 (3.3)1 (3.3)

MSI-H subjects:


interim results

Nivolumab 3 mg/kg(n = 47)

Nivolumab 3 mg/kg +Ipilimumab 1 mg/kg

(n = 27)

ORR, n (%) (95% exact CI)

12 (25.5)(15.4, 38.1)

9(33.3)(18.6, 50.9)

Complete response 0 0

Partial response 12 (25.5) 9 (33.3)

Stable disease 14 (29.8) 14 (51.9)

Progressive disease 17 (36.2) 3 (11.1)

Unable to determine 4 (8.5) 0

Median time to response, mo (range) 2.12 (1.3-13.6) 2.73 (1.2-6.9)

Median duration of response, mo (range) NE (0.0-15.2) NE (NE-NE)

Investigator assessed best ORR in MSI-H patients

Abstract 3501: CheckMate-142: Nivolumab +/- ipilimumab in

mCRC interim results



(n = 30)

PFS rate, % (95% CI) 6 mo 9 mo 12 mo

45.9 (29.8, 60.7)45.9 (29.8, 60.7)45.9 (29.8, 60.7)

66.6 (45.5, 81.1)NENE

Median PFS, mo (95% CI) 5.3 (1.5, NE) NE (3.4, NE)

Investigator assessed PFS in MSI-H





(n = 30)

OS rate, % (95% CI) 6 mo 9 mo 12 mo

75.0 (58.5, 85.7)65.6 (48.0, 78.6)65.6 (48.0, 78.6)

85.1 (65.0, 94.2)85.1 (65.0, 94.2)

NE

Median OS, mo (95% CI) 17.1 (8.6, NE) NE (NE, NE)

OS in patients with MSI-H



Nivolumab 1 mg/kg +Impilimumab 3 mg/kg

(n = 10)


(n = 10)

ORR, n (%) 1 (10) 0

Median PFS, mo (95% CI) 2.28 (0.62, 4.40) 1.31 (0.89, 1.71)

Median OS, mo (95% CI) 11.53 (0.62, NE) 3.73 (1.22, 5.62)

Efficacy in patients with MSS


interim results

Event, n (%) Nivolumab 3 mg/kg(n = 70)


(n = 30)

Any grade Grade 3-4 Any grade Grade 3-4

Any event 41 (58.6)* 10 (14.3) 25 (83.3) 8 (26.7)

Fatigue 13 (18.6) 1 (1.4) 6 (20.0) 0

Diarrhea 10 (14.3) 1 (1.4) 13 (43.3) 0

Pruritus 8 (11.4) 0 5 (16.7) 1 (3.3)

Nausea 5 (7.1) 0 6 (20.0) 0

Pyrexia 3 (4.3) 0 7 (23.3) 0

Any event leading to discontinuation

4 (5.7) 2 (2.9) 4 (13.3) 4 (13.3)

Treatment related AE’s in > 15% of patients with MSI-H

* One grade 5 event of sudden death

Abstract 3501: CheckMate-142: Nivolumab +/- ipilimumab in mCRC interim results

Event, n (%) Nivolumab 1 mg/kg +Ipilimumab 3 mg/kg

(n = 10)


(n = 10)

Any grade Grade 3-4 Any grade Grade 3-4

Any event 8 (80.0) 7 (70.0) 8 (80.0) 3 (30.0)

Diarrhea 4 (40.0) 1 (10.0) 2 (20.0) 0

Asthenia 3 (30.0) 2 (20.0) 1 (10.0) 0

Nausea 3 (30.0) 1 (10.0) 2 (20.0) 0

Pyrexia 3 (30.0) 0 2 (20.0) 0

Vomiting 3 (30.0) 1 (10.0) 1 (10.0) 0

Fatigue 2 (20.0) 0 2 (20.0) 1 (10.0)

Dry skin 1 (20.0) 0 0 0

Cough 0 0 2 (20.0) 0

Any event leading to discontinuation 5 (50.0) 5 (50.0) 2 (20.0) 2 (20.0)

Treatment related AE’s in > 15% of patients with MSS

Abstract 3502: Cobimetinib and Atezolizumab in CRC

• Cobimetinib: Highly selective MEK1/2 inhibitor• Atezolizumab: Anti-PDL1 antibody

MEK inhibition can result in intratumoral T cell accumulation and upregulation of MHC1 in cell lines

MEK inhibitor + PDL1 inhibitor results in increased tumor regression in preclinical studies


• Study design: 3 + 3 dose escalation in solid tumors• Predefined expansion cohort of KRAS mutated mCRC

• mRCRC n = 23• MSI-H: 0%• MSI-low or stable: 30%• Unknown: 70%

• PD-L1 expression– IC2/3 17%– IC0/1 70%– Unknown 13%


Patients with CRC (n = 23) Treatment related N (%)

All grade 23 (100%)

Grade 3 8 (35%)

Grade 4 0 (0%)

Grade 5 0 (0%)

Serious 2 (9%)

AEs leading to withdrawal from cobimetinib 4 (17%)

AEs leading to withdrawal from atezolizumab 0 (0%)

Treatment related SAEs included nausea, vomiting, CVA (n = 1 each)


Treatment related Aes (>15% incidence) All grade Grade 3

Diarrhea 70% 9%

Fatigue 52% 4%

Dermatitis acneiform 44% 0%

Rash 35% 4%

Nausea 26% 4%

Maculopapular rash 26% 4%

Pruritus 26% 0%

AST increased 22% 0%

Blood creatine phosphokinase increased 22% 0%

Edema peripheral 17% 0%

Stomatitis 17% 0%

Vomiting 17% 4%

Total of 21 patients collectively reported rash, maculopapular rash and dermatitis acneiform.9% were grade 3.

Abstract 3502: Cobimetinib and Atezolizumab in CRC: Efficacy

Confirmed Response per RECIST v1.1

KRAS mutant CRC cohort

(n = 20)

All CRC patients(n = 23)

ORR (95% CI) 20% (5.7, 43.7) 17% (5.0, 38.8)

PR 20% 17%

SD 20% 17%

PD 50% 52%

NE 10% 9%

Response did not correlate with PD-L1 status: IC0 (n=2), IC1 (n=1) and IC3 (n=1)

Abstract 3502: Cobimetinib and Atezolizumab in CRC: Efficacy

KRAS mutant CRC cohort

(n = 20)

All CRC patients(n = 23)

Median PFS (95% CI) 2.3 mo (1.8, 9.5) 2.3 mo (1.8, 9.5)

6 mo PFS (95% CI) 39% (0.16, 0.61) 35% (0.14, 0.56)

Median OS (95% CI) NE (6.5, NE) NE (6.5, NE)

6 mo OS (95% CI) 77% (0.57, 0.97) 72% (0.52, 0.93)

Abstract 3512: PRODIGE14-ACCORD 21

• Randomized phase II study in mCRC with initially unresectable liver mets• Stratified by: RAS status, metastatic sites (lung mets y/n), causes of

unresectability (surgical vs oncological)

• Arm A: – A1: FOLFIRI + targeted therapy (n=56)– A2: FOLFOX4 + targeted therapy (n = 70)

• Arm B: FOLFIRINOX + targeted therapy (n = 130)

• Primary endpoint: Increase rate of R0-R1 resection from 50% to 70% with Arm B

Abstract 3512: PRODIGE 14-ACCORD 21

• R0/R1 resection rate: 45.2% in Arm A; 56.9% in Arm B. P = 0.062• OS: Improved in Arm B (median NR vs 36 m, p = 0.048)

Abstract 3521: STAR-01 Final Results

• STAR 01:• Locally advanced rectal cancer: Chemoradiation with 5-

FU vs FOLFOX• FOLFOX: more toxicity but no improved pCR• 5 yr OS: No statistically significant improvement in 5 yr

OS

Summary

• Immunotherapy shows promise in MSI-H tumors• Challenge is to sensitize MSS patients. MEK inhibition in

combination with PD-L1 inhibition looks promising.• Chemotherapy: More is sometimes better but not always.

Want More on ASCO Research?!

Read more about the research presented at ASCO 2016 here . In this blog, the Currently Incurable Scientist dives into his top 5 abstract picks from ASCO 2016: http://fightcolorectalcancer.org/research-treatment/currently-incurable-scientist/asco-2016-pre-conference-insights/ Also, check out the Fight CRC immunotherapy blog and immunotherapy video to learn more about this exciting new treatment and developing research: http://fightcolorectalcancer.org/research-treatment/crc-immunotherapy-blueprint-presented-at-aacr-2016/

https://www.youtube.com/watch?v=RhdnYdghPd4

http://fightcolorectalcancer.org/research-treatment/currently-incurable-scientist/asco-2016-pre-conference-insights/




http://fightcolorectalcancer.org/research-treatment/crc-immunotherapy-blueprint-presented-at-aacr-2016/

https://www.youtube.com/watch?v=RhdnYdghPd4

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June 2016 ASCO in Review #CRCWebinar

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