1. 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.

2. 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: LoRusso PM. J Clin Oncol. 2016;34: De Bono JS, et al. ESMO Abstract 718O. 4. Dent RA, et al. ASCO Abstract 1009.
Slide credit: clinicaloptions.com

3. 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 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
Paclitaxel Days 1, 8, 15 Q28D
(n = 62)
Until PD, unacceptable toxicity, or consent withdrawal
Placebo Days
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 Abstract 1009.

4. 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 Abstract 1009.

5. 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 ( )
4.9 ( )
Stratified HR (90% CI)
0.60 ( )
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 ( )
3.7 ( )
Stratified HR (90% CI)
0.59 ( )
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 Abstract Reproduced with permission.

6. 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 ( )
Unstratified HR (90% CI)
0.44 ( )
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 Abstract Reproduced with permission.

7. 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
( )
6.5
(4.4-NE)
7.5
(7.3-NE)
11.2
6.1
( )
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 Abstract 1009.

8. 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 Abstract 1009.

9. 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 Abstract 1009.

10. 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: )
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 (NCT )
AE, adverse event; MBC, metastatic breast cancer; mPFS, median PFS; TNBC, triple-negative breast cancer.
Slide credit: clinicaloptions.com
Dent RA, et al. ASCO Abstract 1009.

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