1. Updated Safety Data from a Randomized Phase 2 Trial of Hedgehog Pathway Inhibitor GDC-0449 vs. Placebo with FOLFOX or FOLFIRI and Bevacizumab in Patients with Previously Untreated Metastatic Colorectal Cancer (mCRC)
Johanna Bendell, Lowell Hart, Irfan Firdaus, Ira Gore, Robert Hermann, Howard Mackey, Richard Graham, Gordon Bray, Jennifer Low, Jordan Berlin

2. Hedgehog Signaling Pathway
Hedgehog (Hh) signaling pathway is a key regulator of cell growth and differentiation during embryogenesis and early development.1-3
In the inactive state, patched-1 (PTCH1) inhibits Hh pathway signaling by smoothened (SMO) (Figure 1, left panel).
In the active state, Hh ligand binds to PTCH1 resulting in de-repression of SMO-mediated signaling (Figure 1,right panel).
Signaling by SMO results in activation of GLI transcription factors and consequent induction of Hh target genes, including GLI1 and PTCH1.2,3
1. Hahn H, Christiansen J, Zaphiropoulous PG, et al. A mammalian patched homolog is expressed in target tissues of sonic hedgehog and maps to a region associated with developmental abnormalities. J Biol Chem 271: , 1996
2. Ingham PW, McMahon AP: Hedgehog signaling in animal development: paradigms and principles. Genes Dev 15:3059−3087, 2001
3. Rubin LL, de Sauvage FJ: Targeting the hedgehog pathway in cancer. Nat Rev Drug Disco. 5: , 2006

3. Mechanisms of Hh Pathway-mediated Oncogenesis and Pathway Inhibition by GDC-0449
Footnote to Figure
Left Panel: The “Type 1” (ligand-independent) mechanism of aberrant Hh pathway activation is implicated in the pathogenesis of BCC and medulloblastoma:
Middle Panel: The “Type 3” (paracrine) mechanism of aberrant Hh pathway activation involves the production of Hh ligand by tumor cells that activates the Hh pathway in adjacent non-malignant stromal tissue which, as part of the tumor microenvironment, supports tumor growth and proliferation.
Right panel: GDC-0449 inhibits Hh pathway signaling by inhibiting the activity of SMO.
Additional notes
Hh pathway activation has been implicated in the pathogenesis of several cancers.4-12
Excessive or inappropriate expression of the Hh ligand has been implicated in the pathogenesis of sporadic cancers of the gastrointestinal tract,8 pancreas, lung, and prostate.
Hh ligands produced by tumor cells can activate the Hh pathway in surrounding stromal cells in a paracrine manner, leading to the secretion of stromal mediators that enhance tumor growth and survival9,10 (Figure 2, center panel).
The rate of Hh overexpression in colorectal cancer ranges from 20% to 35%.
Disruption of Hh pathway signaling may therefore be beneficial in a broad array of tumor types.
*GDC-0449 was discovered by Genentech under a collaboration with Curis, Inc

4. Efficacy of GDC-0449 Correlates with Hedgehog Expression

5. GDC-0449 Phase I Study: Key Findings*
GDC-0449 was generally well-tolerated.
most common toxicities were mild-to-moderate fatigue, anorexia, muscle spasms, alopecia and dysgeusia.
Single-agent activity was demonstrated in patients with locally-advanced or metastatic basal cell CA and one patient with extra-neural medulloblastoma.
55% ORR in 33 patients with advanced BCC.
*Von Hoff DD et al. N Engl J Med 2009;361:
Rudin CM et al. N Engl J Med 2009;361:

6. Phase II Study of GDC-0449 in 1st Line mCRC Study Schema
Biomarker Strategy
Archival tissue biopsies mandatory
Secondary objective of study-to evaluate Hh ligand expression
Relationship with PFS, OS
Ligand expression evaluated by both IHC and qRT-PCR

7. Phase II Study of GDC-0449 in 1st Line mCRC Study Population
199 patients randomized to receive either GDC-0449 or placebo.
195 patients are evaluable for safety.
4 patients (2 randomized to GDC-0449; 2 randomized to placebo) did not receive any investigational drug treatment after randomization.
123 evaluable patients were treated with FOLFOX-bev.
72 evaluable patients were treated with FOLFIRI-bev.
All but one patient had at least one RECIST measurable lesion.
The data cutoff date for this safety data analysis was March 15, 2010.
Median duration of follow-up*: months.
*safety evaluable patient population

8. Phase II Study of GDC-0449 in 1st Line mCRC Baseline Patient Demographic Characteristics
FOLFOX/bev (%)
FOLFIRI/bev (%)
Placebo
(n=64)
GDC-0449
(n=60)
(n=37)
(n=38)
Median Age
Years (range)
59.0 (33–86)
61.0 (31–82)
61.0 (42–79)
62.0 (31–81)
Sex, n (%)
Male
36 (56)
38 (63)
19 (51)
21 (55)
Female
28 (44)
22 (37)
18 (49)
17 (45)
Race, n (%)
White
58 (92)
45 (75)
29 (78)
33 (87)
African-American
4 (6)
9 (15)
4 (11)
2 (5)
Asian
1 (2)
1 (3)
Othera
5 (8)
a Includes unknown, American Indian or Alaska Native and multi-racial
Baseline patient demographic characteristics were balanced between placebo and GDC-0449 treatment groups (Table 1).
FOLFOX, (oxaliplatin 85 mg/m2, leucovorin [LV] 400 mg/m2, 5-fluorouracil [5-FU] bolus 400 mg/m2, 5-FU infusion 2400 mg/m2 over 46 hours);
FOLFIRI, (irinotecan 180 mg/m2, LV 400 mg/m2, 5-FU bolus 400 mg/m2, 5-FU infusion 2400 mg/m2 over 46 hours);
ECOG PS, Eastern Cooperative Oncology Group Performance Status
a not available, Native American, and multiple

9. Phase II Study of GDC-0449 in 1st Line mCRC Baseline patient disease characteristics
FOLFOX/bev (%)
FOLFIRI/bev (%)
Placebo
(n=64)
GDC-0449
(n=60)
Placebo (n=37)
(n=38)
ECOG PS, n (%)
35 (56)
29 (48)
22 (60)
22 (58) 1
29 (45)
31 (52)
15 (41)
16 (42)
Prior Adjuvant/Neo-Adjuvant Systemic Therapy, n (%)
Yes
8 (12)
7 (11)
18 (49)
17 (45) No
56 (88)
54 (89)
19 (51)
21 (55)
Location of primary tumor, n (%)
Colon
48 (75)
49 (82)
30 (81)
33 (87)
Rectum
16 (25)
11 (18)
7 (19)
5 (13)
Median (SD) months since primary diagnosis of CRC
1.5 (19.7)
14. (28.3)
17.1 (14.3)
7.7 (17.5)
Median (SD) months since diagnosis of mCRC
1.1 (0.6)
1.0 (0.7)
1.0 (6.5)
0.9 (3.2)
More patients treated with FOLFIRI on the study received prior adjuvant therapy compared with those treated with FOLFOX
FOLFOX, (oxaliplatin 85 mg/m2, leucovorin [LV] 400 mg/m2, 5-fluorouracil [5-FU] bolus 400 mg/m2, 5-FU infusion 2400 mg/m2 over 46 hours);
FOLFIRI, (irinotecan 180 mg/m2, LV 400 mg/m2, 5-FU bolus 400 mg/m2, 5-FU infusion 2400 mg/m2 over 46 hours);
ECOG PS, Eastern Cooperative Oncology Group Performance Status

10. NCI-CTC, Selected Grade 1-2 AEs ≥10% Incidence in One or More Treatment Groups†
Event
FOLFOX/bev (%)
FOLFIRI/bev (%)
Placebo
(n=62)*
GDC-0449
(n=61)*
(n=36)*
Anemia
17 (27.4)
15 (24.6)
10 (27.8)
5 (13.9)
Granulocytopenia
10 (16.1)
7 (11.5)
1 (2.8)
4 (11.1)
Thrombocytopenia
18 (29.0)**
3 (8.3)
Fatigue/Asthenia/ Malaise
38 (61.3)
31 (50.8)
26 (72.2)
23 (63.9)
Nausea
39 (62.9)
37 (60.7)
21 (58.3)
Vomiting
14 (22.6)
21 (34.4)
14 (38.9)
15 (41.7)
Mucositis
16 (25.8)
14 (23.0)
7 (19.4)
11 (30.6)
Stomatitis
11 (17.7)
8 (13.1)
6 (16.7)
Anorexia
27 (44.3)**
9 (25.0)
Weight loss
8 (12.9)
16 (26.2)
Muscle Spasms
1 (1.6)
6 (9.8)
8 (22.2)**
Dysgeusia
30 (49.2)**
17 (47.2)**
Peripheral neuropathy
39 (62.9)**
27 (44.3)
9 (25.0)**
2 (5.6)
Dyspnea
5 (8.1)
12 (19.7)
Infections
29 (47.5)**
18 (50.0)
20 (55.6)
*For each event, incidence is expressed as number and percent (in parentheses) of patients affected in the respective treatment group.
** p < 0.05
Infections includes mainly sino-pulmonary infections (e.g. URI, sinusitis, bronchitis, nasopharyngitis) and UTIs
† data cut-off date: 15 March 2010
*For each event, incidence is expressed as number and percent (in parentheses) of patients affected in the respective treatment group.
** p < 0.05.

11. NCI-CTC, Grade 3-4 AEs ≥5% Incidence in One or More Treatment Groups†
Event:
FOLFOX/bev (%)
FOLFIRI/bev (%)
Placebo
(n=62)*
GDC-0449
(n=61)*
(n=36)*
Any event
49 (79)
48 (78.7)
27 (75.0)
29 (80.6)
Anemia
5 (8.1)**
1 (2.8)
Granulocytopenia
16 (25.8)
12 (19.7)
12 (33.3)
Diarrhea
9 (14.5)
5 (8.2)
6 (16.7)
7 (19.4)
Nausea
2 (3.2)
6 (9.8)
3 (8.3)
4 (11.1)
Vomiting
4 (6.6)**
2 (5.6)
Asthenia/Fatigue
6 (9.7)
9 (14.8)
5 (13.9)
11 (30.6)
Mucositis
3 (4.9)
Weight loss
1 (1.6)
4 (6.6)
5 (13.9)**
Anorexia
Dehydration
9 (14.8)**
Hypokalemia
3 (4.8)
Peripheral neuropathy
11 (18.0)
Pulmonary embolism
Hypertension
Thrombosis
Infections
5 (8.1)
*For each event, incidence is expressed as number and percent (in parentheses) of patients affected in the respective treatment group.
** p < 0.05
Infections AEs includes patients with one or more of the following: abdominal abscess, sepsis, diverticulitis, peri-rectal abscess, UTI, skin infection, pneumonia, tooth abscess, catheter-site infection, gastroenteritis, clostridial or E. coli infection
† data cut-off date: 15 March 2010
*For each event, incidence is expressed as number and percent (in parentheses) of patients affected in the respective treatment group.
** p < 0.05.

12. Treatment Exposure FOLFOX/bev FOLFIRI/bev Placebo (n=62)*
FOLFOX/bev
FOLFIRI/bev
Placebo (n=62)*
GDC-0449 (n=61)*
Placebo (n=36)*
GDC-0449 (n=36)*
5-FU:
Number of Doses*
14 (1–43)
12 (1–42)
16 (2–43)
14 (2–34)
Cumulative Dose (mg) **
62,125
(800–160,384)
48,775
( ,063)
72,008
(10, ,760)
59,271
( ,008)
Oxaliplatin/Irinotecan:
11 (1–27)
10 (1–34)
13 (2–39)
12 (2–30)
Cumulative Dose (mg)**
1730
(170–3780)
1480
(159–5180)
4793
(684–14,196)
4007
(576–10,449)
Bevacizumab:
15 (1–38)
10 (1–29)
15.5 (2–39)
14.5 (2–31)
GDC-0449/Placebo:
206.5 (6–589)
166 (7–550)
260 (25–525)
211.5 (12–491)
Cumulative Dose (mg)*
30,975 (900–88,350)
24,900 (1050–82,500)
39,000 (3750–78,750)
31,468 (1800–73,650)
* Expressed as the median (range) for each treatment group; ** Expressed as the median (range) for each treatment group; figures are uncorrected for BSA

13. Study Treatment Discontinuation Due to Adverse Events†
FOLFOX/bev (%)
FOLFIRI/bev (%)
Placebo (n=62)*
GDC (n=61)*
Placebo (n=36)*
GDC-0449 (n=36)*
Chemotherapy
8 (12.9)
11 (18.0)
1 (2.8)
6 (16.7)
Bevacizumab
7 (11.3)
9 (14.8)
3 (8.3)
7 (19.4)
GDC-0449/Placebo
9 (14)
8 (13)
1 (3)
7 (18)
†as of the data cut-off date: 15 March, 2010.
*For each event, incidence is expressed as number and percent (in parentheses) of patients affected in the respective treatment group.

14. Phase II Study of GDC-0449 in 1st Line mCRC Steady-state Plasma Concentrations
The geometric mean values for studies sHH3925 and sHH4429 were similar
The geometric mean values for studies sHH3925 and sHH4429 were similar.

15. Phase II Study of GDC-0449 in 1st Line mCRC Summary and Conclusions
Grade 1 or 2 toxicity of GDC-0449 in combination with chemotherapy is consistent with the toxicity profile for GDC-0449 monotherapy.
Overall Grade 3 or 4 AE incidence was comparable in the GDC-0449 vs. placebo arms.
Chemotherapy and investigational drug exposure duration of treatment were shorter in GDC-0449-treated patients in both study regimens.
Neither chemotherapy regimen appears to impact GDC-0449 steady-state pharmacokinetics.
Roche/Genentech has announced that GDC-0449 does not confer additional progression-free survival benefit to the standard of care for first-line treatment of mCRC (additional efficacy analyses are ongoing).
the potential role of lower grade, chronic toxicities (e.g. anorexia, dysgeusia, weight loss) on treatment duration is under investigation

16. Back-up Slides

17. Phase II Study of GDC-0449 in 1st Line mCRC Grade 1 or 2 Adverse Events of Interest*
Grade 1 or 2 AEs noted more frequently in GDC-0449-treated patients, regardless of the chemotherapy backbone used were:
anorexia, weight loss, muscle spasms, dysgeusia.
Other Grade 1 or 2 AEs were more frequent among GDC treated vs. placebo-treated patients in a regimen specific manner.
There is a trend toward more mild-moderate myelosuppression (particularly anemia and thrombocytopenia) among placebo- treated vs. GDC-0449-treated patients.
*≥10% incidence in one or more treatment groups.

18. Phase II Study of GDC-0449 in 1st Line mCRC Grade 3 or 4 Adverse Events*
The number of patients experiencing any Grade 3 or 4 AEs was balanced across treatment arms.
Grade 3 or 4 AEs occurring more frequently in GDC treated patients regardless of the chemotherapy regimen used were:
asthenia/fatigue, mucositis, weight loss, anorexia, and dehydration.
Other Grade 3 or 4 AEs were more frequent among GDC treated vs. placebo-treated patients in a regimen-specific manner.
There is a trend toward less Grade 3 or 4 anemia and granulocytopenia among GDC-0449-treated patients only in those who received FOLFOX/bev.
* ≥5% incidence in one or more treatment groups.

19. Grade 5 Adverse Events
Adverse Events Leading to Death = 4/97 or 4.1% (95% CI: %) in GDC-0449-treated patients
Two patients experienced sudden death unattended by medical personnel; two patients died from complications of pneumonia.
Three patients were treated with FOLFOX/bev; one was treated with FOLFIRI/bev.
One event attributed possibly to GDC-0449, 5-FU, oxaliplatin and bev
No patient in either placebo arm experienced a Grade 5 adverse event.

20. Phase II Study of GDC-0449 in 1st Line mCRC Grade 5 Adverse Events
Study Treatment:
Study Day:
Cause of Death:
Investigator Causality Assessment:
FOLFOX/bev; GDC-0449
231
Sudden Death (probable acute MI)*
Unrelated to GDC-0449
FOLFIRI/bev; GDC-0449
155
Pneumonia 95
Attributed to GDC-0449, 5-FU, oxaliplatin and bev 91
Sudden death at home†
No Grade 5 AEs reported in placebo-treated patients.
Grade 5 AEs in GDC-0449-treated patients = 4/97 or 4.1% (95% CI: 1.4–9.7%)
Abbreviations: FOLFOX – 5-FU/leucovorin, oxaliplatin; FOLFIRI – 5-FU/leucovorin, irinotecan; bev – bevacizumab; MI – myocardial infarction.
*Unattended by medical personnel; no post-mortem examination performed.
† Patient was seen and treated for dehydration one week prior to the event; no post-mortem examination was performed.