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

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Hedgehog Signaling Pathway

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Mechanisms of Hh Pathway-mediated Oncogenesis and Pathway Inhibition by GDC-0449

*GDC-0449 was discovered by Genentech under a collaboration with Curis, Inc

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Efficacy of GDC-0449 Correlates with Hedgehog Expression

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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;361:1164-72.Rudin CM et al. N Engl J Med 2009;361:1173-78.

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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*safety evaluable patient population

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*: 12.6 months.

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FOLFOX/bev (%) FOLFIRI/bev (%)

Placebo(n=64)

GDC-0449(n=60)

Placebo (n=37)

GDC-0449(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 (2) 0 1 (3)

Othera 0 5 (8) 4 (11) 2 (5)

Phase II Study of GDC-0449 in 1st Line mCRCBaseline Patient Demographic Characteristics

a not available, Native American, and multiple

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FOLFOX/bev (%) FOLFIRI/bev (%)

Placebo(n=64)

GDC-0449(n=60)

Placebo (n=37)

GDC-0449(n=38)

ECOG PS, n (%)

0 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)

Phase II Study of GDC-0449 in 1st Line mCRCBaseline patient disease characteristics

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Event

FOLFOX/bev (%) FOLFIRI/bev (%)

Placebo (n=62)*

GDC-0449(n=61)*

Placebo (n=36)*

GDC-0449 (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)** 7 (11.5) 5 (13.9) 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) 23 (63.9)

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) 3 (8.3) 6 (16.7)

Anorexia 14 (22.6) 27 (44.3)** 9 (25.0) 14 (38.9)

Weight loss 8 (12.9) 16 (26.2) 4 (11.1) 9 (25.0)

Muscle Spasms 1 (1.6) 6 (9.8) 1 (2.8)1 (2.8) 8 (22.2)**8 (22.2)**

Dysgeusia 8 (12.9) 30 (49.2)** 1 (2.8)1 (2.8) 17 (47.2)**17 (47.2)**

Peripheral neuropathy 39 (62.9)** 27 (44.3) 9 (25.0)**9 (25.0)** 2 (5.6)2 (5.6)

Dyspnea 5 (8.1) 12 (19.7) 4 (11.1) 5 (13.9)

Infections 17 (27.4) 29 (47.5)** 18 (50.0) 20 (55.6)

NCI-CTC, Selected Grade 1-2 AEs ≥10% Incidence in One or More Treatment Groups†

† 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.

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 Event:

FOLFOX/bev (%) FOLFIRI/bev (%)

Placebo (n=62)*

GDC-0449 (n=61)*

Placebo (n=36)*

GDC-0449 (n=36)*

Any event 49 (79) 48 (78.7) 27 (75.0) 29 (80.6)

Anemia 5 (8.1)** 0 1 (2.8) 1 (2.8)

Granulocytopenia 16 (25.8) 12 (19.7) 12 (33.3) 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 0 4 (6.6)** 2 (5.6) 3 (8.3)

Asthenia/Fatigue 6 (9.7) 9 (14.8) 5 (13.9) 11 (30.6)

Mucositis 0 3 (4.9) 1 (2.8) 3 (8.3)

Weight loss 1 (1.6) 4 (6.6) 00 5 (13.9)**5 (13.9)**

Anorexia 0 4 (6.6)** 1 (2.8) 4 (11.1)

Dehydration 2 (3.2) 9 (14.8)** 0 2 (5.6)

Hypokalemia 3 (4.8) 4 (6.6) 0 1 (2.8)

Peripheral neuropathy 6 (9.7) 11 (18.0) 1 (2.8) 1 (2.8)

Pulmonary embolism 3 (4.8) 5 (8.2) 3 (8.3) 2 (5.6)

Hypertension 3 (4.8) 0 2 (5.6) 1 (2.8)

Thrombosis 0 4 (6.6)** 4 (11.1) 1 (2.8)

Infections 5 (8.1) 5 (8.2) 5 (13.9) 2 (5.6)

NCI-CTC, Grade 3-4 AEs ≥5% Incidence in One or More Treatment Groups†

† 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.

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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

(5236-204,063)

72,008(10,640-247,760)

59,271(5280-151,008)

Oxaliplatin/Irinotecan:

Number of Doses* 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:

Number of Doses* 15 (1–38) 10 (1–29) 15.5 (2–39) 14.5 (2–31)

GDC-0449/Placebo:

Number of Doses* 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

Treatment Exposure

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Study Treatment Discontinuation Due to Adverse Events†

FOLFOX/bev (%) FOLFIRI/bev (%)

Placebo (n=62)*

GDC-0449 (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.

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Phase II Study of GDC-0449 in 1st Line mCRCSteady-state Plasma Concentrations

The geometric mean values for studies sHH3925 and sHH4429 were similar.

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Phase II Study of GDC-0449 in 1st Line mCRCSummary 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

Back-up Slides

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Phase II Study of GDC-0449 in 1st Line mCRCGrade 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-0449-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.

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• 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-0449-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-0449-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.

Phase II Study of GDC-0449 in 1st Line mCRCGrade 3 or 4 Adverse Events*

* ≥5% incidence in one or more treatment groups.

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Grade 5 Adverse Events

• Adverse Events Leading to Death = 4/97 or 4.1% (95% CI: 1.4-9.7%) 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.

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Phase II Study of GDC-0449 in 1st Line mCRCGrade 5 Adverse Events

Study Treatment: Study Day: Cause of Death:Investigator Causality

Assessment:

FOLFOX/bev; GDC-0449 231Sudden Death

(probable acute MI)*Unrelated to GDC-0449

FOLFIRI/bev; GDC-0449 155 Pneumonia Unrelated to GDC-0449

FOLFOX/bev; GDC-0449 95 PneumoniaAttributed to GDC-0449, 5-FU,

oxaliplatin and bev

FOLFOX/bev; GDC-0449 91Sudden death at

home† Unrelated to GDC-0449

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.