1. Cobimetinib + Atezolizumab Well Tolerated and Shows Promising Activity in KRAS-Mutant mCRC
CCO Independent Conference Coverage* of the 2016 ASCO Annual Meeting, June 3-7, 2016
*CCO is an independent medical education company that provides state-of-the-art medical information to healthcare professionals through conference coverage and other educational programs.
mCRC, metastatic colorectal cancer.
This activity is supported by educational grants from Amgen, Ariad, Bayer Healthcare Pharmaceuticals, Celgene Corporation, Genentech, Incyte, Merck, and Taiho Pharmaceuticals.

2. Cobimetinib + Atezolizumab in KRAS-Mutant mCRC: Background
Chemotherapy with targeted agents standard of care for unresectable mCRC[1]
MSI-H CRC, which is DNA mismatch repair deficient, responds well to anti–PD-L1/PD-1 inhibitors[2]
However, most mCRCs are MSS or DNA mismatch repair proficient, necessitating additional new treatment options beyond the PD-L1/PD-1 axis
MEK inhibition synergistic with anti–PD-L1 agents, promoting durable tumor regression[3]
Study investigated the combination of MEK inhibitor, cobimetinib, and anti–PD-L1 inhibitor, atezolizumab, in advanced solid tumors, including KRAS-mutant mCRC[4]
DNA, deoxyribonucleic acid; mCRC, metastatic colorectal cancer; MSI-H, microsatellite instability-high; MSS, microsatellite stable.
1. Seow HF, et al. Onco Targets Ther. 2016;9: Le DT, et al. N Engl J Med. 2015;372: Ebert PJ, et al. Immunity. 2016;44: Bendell J, et al. ASCO Abstract 3502.
Slide credit: clinicaloptions.com

3. Cobimetinib + Atezolizumab in KRAS-Mutant mCRC: Study Design
Open-label phase Ib dose escalation and expansion study
Dose-escalation: 3 mCRC pts (2 KRAS mutant, 1 KRAS WT); 28-day DLT window for MTD determination
Dose-expansion: 20 mCRC pts (all KRAS mutant); other cohorts included NSCLC, metastatic melanoma, solid tumors serial biopsy
Primary objectives: safety, clinical activity
3 + 3 Dose Escalation
Pts with chemo-refractory solid tumors, ECOG PS 0-1, measurable disease per RECIST v1.1
Cobimetinib* 20,† 40, or 60‡ mg PO QD +
Atezolizumab 800 mg IV Q2W
*Dosed in cycles of 21 days on/7 days off.
†1 KRAS mutant pt, 1 KRAS WT pt.
‡1 KRAS mutant pt.
mCRC, metastatic colorectal cancer; DLT, drug-limiting toxicity; ECOG, Eastern Cooperative Oncology Group; MTD, maximum tolerated dose; NSCLC, non-small cell lung cancer; PS, performance status; RECIST, Response Evaluation Criteria in Solid Tumors; WT, wild type.
Slide credit: clinicaloptions.com
Bendell J, et al. ASCO Abstract 3502.

4. Cobimetinib + Atezolizumab
Cobimetinib + Atezolizumab in KRAS-Mutant mCRC: Patient Characteristics
Characteristic
Cobimetinib + Atezolizumab
(N = 23)
Median age, yrs (range)
57 (31-69)
Female, % 52
Race/ethnicity, %
White/Asian
61/39
Region, %
North America, Australia
Asia 65 35
ECOG PS, %
0/1
Stage at initial diagnosis, %
I-II/III/IV
13/48/30
Previous systemic treatments, median (range)
Oxaliplatin and irinotecan, %
Adjuvant therapy, %
3 (1-5)
100
mCRC, metastatic colorectal cancer; ECOG, Eastern Cooperative Oncology Group; PS, performance status.
Slide credit: clinicaloptions.com
Bendell J, et al. ASCO Abstract 3502.

5. Cobimetinib + Atezolizumab in KRAS-Mutant mCRC: Tumor Characteristics
Cancer type at diagnosis
Colon/rectum
83/17
Location of primary tumor
Left (splenic flexure to rectum)
Right (cecum to hepatic flexure)
Transverse 74 26
Metastatic pattern at study entry
Liver only
Liver metastases and other sites
Extra-hepatic 48 52
KRAS mutant 96
PD-L1 expression
IC 2-3/IC 0-1/unknown
17/70/13
Investigator-reported MSI status
High/low or stable/unknown
0/30/70
mCRC, metastatic colorectal cancer; IC, immune cell.
Slide credit: clinicaloptions.com
Bendell J, et al. ASCO Abstract 3502.

6. Cobimetinib + Atezolizumab in KRAS-Mutant mCRC: Safety
Median safety follow-up: 3.8 mos (range: )
No DLTs or grade 4/5 TRAEs
100% of pts had any grade TRAEs (35% grade 3)
9% of pts had treatment-related SAEs: nausea/vomiting and cerebrovascular accident (n = 1 each)
17% of pts had AEs leading to withdrawal from cobimetinib
TRAE Occurring in > 15% of Pts, %
All Pts (N = 23)
All Grades
Grade 3
Diarrhea 70 9
Fatigue 52 4
Dermatitis acneiform 44
Rash 35
Nausea 26
Maculopapular rash
Pruritus
AST increase 22
Blood CPK increase
Peripheral edema 17
Stomatitis
Vomiting
AE, adverse event; AST, aspartate aminotransferase; CPK, creatine phosphokinase; mCRC, metastatic colorectal cancer; SAE, serious adverse event; TRAE, treatment-related adverse event.
Slide credit: clinicaloptions.com
Bendell J, et al. ASCO Abstract 3502.

7. Cobimetinib + Atezolizumab in KRAS-Mutant mCRC: Efficacy
Response/tumor volume reduction not associated with PD-L1 status
4 pts had PRs, 3 of which were mismatch repair proficient (1 not evaluable)
Median time to first response: mos (range: 1.8 to 4.1)
Median DOR: NR (range: 5.4 to mos)
2 pts with ongoing responses
Increased intratumoral CD8 T-cell infiltration over BL in the mCRC cohort
Outcome
KRAS-Mutant CRC (n = 20)
All CRC
(N = 23)
ORR, % PR SD PD NE 20 50 10 17 22 52 9
PFS
Median, mos (95% CI)
6-mo, % (95% CI)
2.3 ( )
39 ( )
35 ( ) OS
NE (6.5-NE)
77 ( )
72 ( )
BL, baseline; mCRC, metastatic colorectal cancer; NE, not evaluable; NR, not reached; PD, progressive disease; SD, stable disease.
Slide credit: clinicaloptions.com
Bendell J, et al. ASCO Abstract 3502.

8. Cobimetinib + Atezolizumab in KRAS-Mutant mCRC: Conclusions
Early-phase study suggests that the combination cobimetinib and atezolizumab has promising activity and an acceptable safety profile in treatment-experienced pts with chemo-refractory KRAS-mutant mCRC
17% ORR, 72% 6-mo OS higher than rates observed for individual agents or standard of care[1]
According to study investigators: cobimetinib promotes MHC I expression, inducing accumulation of intratumoral CD8 T-cells, thereby sensitizing tumors to atezolizumab
Activity demonstrated in mCRC with MSI-low or stable status
Current phase Ib study accumulating more mCRC pts[2,3]
Phase III trial also recruiting mCRC pts to evaluate this combination therapy[4]
mCRC, metastatic colorectal cancer; MHC, major histocompatibility complex.
1. Grothey A, et al. Lancet. 2013;381: Bendell J, et al. ASCO Abstract ClinicalTrials.gov. NCT ClinicalTrials.gov. NCT
Slide credit: clinicaloptions.com

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