LOTUS: Investigation of Ipatasertib, a Novel Akt Inhibitor, in Combination With Paclitaxel as Frontline Therapy for Metastatic TNBC CCO Independent Conference Highlights* of the 2017 ASCO Annual Meeting; June 2-6, 2017; Chicago, Illinois *Clinical Care Options (CCO) is an independent medical education organization that provides conference coverage and other unique educational programs for healthcare professionals TNBC, triple-negative breast cancer. This activity is supported by educational grants from AbbVie, Amgen, AstraZeneca, Celgene Corporation, Genentech, Halozyme, Incyte, and Merck & Co., Inc.

LOTUS: Background PI3K/Akt pathway frequently activated in TNBC[1] Promotes tumor cell survival and growth[2] Loss of PTEN leads to increased PI3K/Akt pathway activation[3] Ipatasertib: selective, oral, ATP-competitive, small-molecule Akt inhibitor under investigation in diseases with extensive PI3K/Akt pathway activation[4] In proof-of-concept phase Ib/II trial, ipatasertib activity observed in pts with metastatic prostate cancer[3] PTEN loss associated with significantly longer rPFS with ipatasertib vs placebo LOTUS evaluated safety, preliminary efficacy of frontline ipatasertib + paclitaxel vs placebo + paclitaxel in pts with advanced/metastatic TNBC[4] rPFS, radiographic PFS; TNBC, triple-negative breast cancer. 1. Basho RK, et al. JAMA Oncol. 2017;3:509-515. 2. LoRusso PM. J Clin Oncol. 2016;34:3803-3815. 3. De Bono JS, et al. ESMO 2016. Abstract 718O. 4. Dent RA, et al. ASCO 2017. Abstract 1009. Slide credit: clinicaloptions.com

Until PD, unacceptable toxicity, or consent withdrawal LOTUS: Study Design International, randomized, placebo-controlled phase II trial Stratified by (neo)adjuvant therapy (yes vs no), chemotherapy-free interval (no prior chemo vs ≤ 12 mos vs > 12 mos), PTEN status (H-score of 0 vs 1-150 vs > 150) Pts with locally advanced/metastatic TNBC, ineligible for curative resection, ECOG PS 0/1, no previous systemic tx for advanced or metastatic disease, tumor tissue available for PTEN assessment by IHC, chemotherapy free for ≥ 6 mos (N = 124) Ipatasertib 400 mg QD Days 1-21 + Paclitaxel Days 1, 8, 15 Q28D (n = 62) Until PD, unacceptable toxicity, or consent withdrawal Placebo Days 1-21 + Paclitaxel Days 1, 8, 15 Q28D (n = 62) Coprimary endpoints PFS in ITT population PFS in PTEN-low subgroup DoR, duration of response; ECOG, Eastern Cooperative Oncology Group; ITT, intent to treat; PRO, patient-reported outcomes; PS, performance status; TNBC, triple-negative breast cancer; tx, therapy. Secondary and exploratory endpoints ORR, DoR, OS in ITT and PTEN-low pts PFS, ORR, DoR, OS in pts with PIK3CA/AKT1/PTEN-altered tumors Safety, tolerability, PRO Slide credit: clinicaloptions.com Dent RA, et al. ASCO 2017. Abstract 1009.

LOTUS: Baseline Characteristics ITT PIK3CA/AKT1/PTEN Altered Ipatasertib + Paclitaxel (n = 62) Placebo + Paclitaxel (n = 26) (n = 16) Median age, yrs (IQR) 53.5 (44-63) 53 (45-63) 52 (44-63) 53 (46-60) ECOG PS 0, n (%) 44 (71) 36* (58) 13 (50) 9 (56) Prior (neo)adjuvant tx, n (%) With taxane 41 (66) 31 (50) 40 (65) 34 (55) 18 (69) 12 (46) 10 (63) 7 (44) Time since chemotherapy, n (%) ≤ 12 mos > 12 mos No prior chemotherapy 18 (29) 23 (37) 21 (34) 16 (26) 24 (39) 22 (35) 7 (27) 11 (42) 8 (31) 3 (19) 6 (38) PTEN H-score: 0/1-150/> 150, % 16/44/40 18/44/39 31/23/46 19/38/44 Metastatic site: lung/liver/LN/bone,† % 44/31/58/26 52/27/61/27 50/27/58/19 56/31/75/50 ECOG, Eastern Cooperative Oncology Group; IQR, interquartile range; ITT, intent to treat; LN, lymph node; PS, performance status; tx, therapy. *n = 4 pts missing data. †Pts could have ≥ 1 site. Slide credit: clinicaloptions.com Dent RA, et al. ASCO 2017. Abstract 1009.

LOTUS: PFS in ITT and PTEN-Low Populations Ipat + Pac (n = 62) Pbo + Pac PFS events, n (%) 39 (63) 45 (73) mPFS, mos (IQR) 6.2 (3.6-12.9) 4.9 (1.9-6.5) Stratified HR (90% CI) 0.60 (0.40-0.91) Log-rank P value .037 Ipat + Pac (n = 25) Pbo + Pac (n = 23) PFS events, n (%) 16 (64) 18 (78) mPFS, mos (IQR) 6.2 (3.6-10.9) 3.7 (1.9-9.1) Stratified HR (90% CI) 0.59 (0.30-1.16) Log-rank P value .18 100 100 ITT PTEN Low 80 80 60 Ipatasertib + Paclitaxel (n = 62) Placebo + Paclitaxel (n = 62) 60 Ipatasertib + Paclitaxel (n = 25) Placebo + Paclitaxel (n = 23) PFS (%) PFS (%) 40 40 Ipat, ipatasertib; IQR, interquartile range; ITT, intent to treat; Pac, paclitaxel; Pbo, placebo. 20 20 2 4 6 8 10 12 14 16 18 2 4 6 8 10 12 14 16 18 Pts at Risk, n Ipat + Pac Pbo + Pac Mos Mos 62 50 43 31 23 22 13 14 10 11 6 6 3 2 1 25 23 21 15 12 8 9 6 5 4 3 2 Slide credit: clinicaloptions.com Dent RA, et al. ASCO 2017. Abstract 1009. Reproduced with permission.

PIK3CA/AKT1/PTEN Altered* LOTUS: PFS in PIK3CA/AKT1/PTEN-Altered Population (Prespecified Secondary Endpoint) PIK3CA/AKT1/PTEN Altered* Ipat + Pac (n = 26) Pbo + Pac (n = 16) PFS events, n (%) 12 (46) 13 (81) mPFS, mos (IQR) 9.0 (3.7-NE) 4.9 (1.9-6.3) Unstratified HR (90% CI) 0.44 (0.22-0.87) 100 80 60 PFS (%) 40 20 Ipatasertib + Paclitaxel (n = 26) Placebo + Paclitaxel (n = 16) Ipat, ipatasertib; IQR, interquartile range; NE, not estimable; NGS, next-generation sequencing; Pac, paclitaxel; Pbo, placebo. 2 4 6 8 10 12 14 16 18 Mos Pts at Risk, n Ipat + Pac Pbo + Pac 26 16 22 11 13 7 10 4 7 3 5 2 3 1 1 1 *As determined by NGS assay. Slide credit: clinicaloptions.com Dent RA, et al. ASCO 2017. Abstract 1009. Reproduced with permission.

LOTUS: Other Secondary Efficacy Endpoints Outcome ITT PTEN Low PIK3CA/AKT1/PTEN Altered Ipatasertib + Paclitaxel (n = 62) Placebo + (n = 25) (n = 23) Ipatasertib (n = 26) (n = 16) ORR, n (%) 25 (40) 20 (32) 12 (48) 6 (26) 13 (50) 7 (44) Median DoR, mos (IQR) 7.9 (5.6-NE) 7.4 (3.8-9.2) 6.5 (4.4-NE) 7.5 (7.3-NE) 11.2 6.1 (3.8-7.6) CBR,* n (%) 30 (48) 23 (37) 14 (56) 7 (30) 14 (54) *Defined as best overall response (CR, PR, or SD) + PFS ≥ 24 wks. CBR, clinical benefit rate; DoR, duration of response; IQR, interquartile range; ITT, intent to treat; NE, not estimable; SD, stable disease. Slide credit: clinicaloptions.com Dent RA, et al. ASCO 2017. Abstract 1009.

Ipatasertib + Paclitaxel LOTUS: Overall Safety Most common any grade AEs in either arm (> 20% of pts): GI effects, alopecia, neuropathy, fatigue, rash No colitis or grade 4 diarrhea Most common grade ≥ 3 AEs in ipatasertib arm: diarrhea, neutropenia, peripheral neuropathy, asthenia, pneumonia No treatment-related deaths Diarrhea manageable and reversible 2 pts (3%) discontinued ipatasertib due to diarrhea AE-Related Endpoint, n (%) Ipatasertib + Paclitaxel (n = 61) Placebo + Paclitaxel (n = 62) Tx discontinuation Ipatasertib/placebo Paclitaxel 4 (7)* 5 (8) 1 (2) Tx interruption 22 (36) 31 (51) 12 (19) 30 (48) Dose reduction 13 (21) 23 (38) 4 (6) 7 (11) AE, adverse event; GI, gastrointestinal; TB, tuberculosis; Tx, treatment. *n = 1 diarrhea/asthenia/vomiting; n = 1, diarrhea; n = 1, TB; n = 1, embolism. Slide credit: clinicaloptions.com Dent RA, et al. ASCO 2017. Abstract 1009.

Ipatasertib + Paclitaxel (n = 61) Placebo + Paclitaxel (n = 62) LOTUS: Specific AEs AE, n (%) Ipatasertib + Paclitaxel (n = 61) Placebo + Paclitaxel (n = 62) Any Grade Grade ≥ 3 Diarrhea 57 (93) 14 (23) 12 (19) Peripheral neuropathy 33 (54) 4 (7) 30 (48) 3 (5) Nausea 30 (49) 1 (2) 21 (34) Asthenia 29 (48) 26 (42) 4 (6) Neutropenia 11 (18) 24 (39) 5 (8) Rash 20 (33) 18 (29) Vomiting 17 (28) 2 (3) Oral mucositis 15 (25) 9 (15) Hyperlipidemia Hepatotoxicity Hyperglycemia Pneumonia Pneumonitis AE, adverse event. Slide credit: clinicaloptions.com Dent RA, et al. ASCO 2017. Abstract 1009.

LOTUS: Conclusions First-line ipatasertib + paclitaxel improved mPFS vs placebo + paclitaxel in TNBC Greatest PFS benefit observed in prespecified subgroup analysis of pts with PIK3CA/AKT1/PTEN-altered tumors mPFS: 9.0 vs 4.9 mos; HR: 0.44 (90% CI: 0.22-0.87) Most common AE was diarrhea, which was generally manageable and reversible Ipatasertib discontinued due to diarrhea in only 2 pts (3%) Investigators concluded that LOTUS results support further examination of ipatasertib + paclitaxel in diseases with PI3K/Akt pathway activation Pts with PIK3CA/AKT1/PTEN-altered tumors may benefit most Ipatasertib + paclitaxel being evaluated for MBC in phase III trial and as neoadjuvant for TNBC in randomized phase II FAIRLANE trial (NCT02301988) AE, adverse event; MBC, metastatic breast cancer; mPFS, median PFS; TNBC, triple-negative breast cancer. Slide credit: clinicaloptions.com Dent RA, et al. ASCO 2017. Abstract 1009.

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