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.

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;9:1899-1920. 2. Le DT, et al. N Engl J Med. 2015;372:2509-2520. 3. Ebert PJ, et al. Immunity. 2016;44:609-621. 4. Bendell J, et al. ASCO 2016. Abstract 3502. Slide credit: clinicaloptions.com

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 2016. Abstract 3502.

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 2016. Abstract 3502.

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 2016. Abstract 3502.

Cobimetinib + Atezolizumab in KRAS-Mutant mCRC: Safety Median safety follow-up: 3.8 mos (range: 1.1-15.1) 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 2016. Abstract 3502.

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: 3.7 mos (range: 1.8 to 4.1) Median DOR: NR (range: 5.4 to 11.1 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 (1.8-9.5) 39 (0.16-0.61) 35 (0.14-0.56) OS NE (6.5-NE) 77 (0.57-0.97) 72 (0.52-0.93) 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 2016. Abstract 3502.

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;381:303-312. 2. Bendell J, et al. ASCO 2016. Abstract 3502. 3. ClinicalTrials.gov. NCT01988896. 4. ClinicalTrials.gov. NCT02788279. Slide credit: clinicaloptions.com

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