Safety, Pharmacokinetics, and Activity of the Anti-NaPi2b Antibody-Drug Conjugate DNIB0600A: A Phase I Study in Patients with Non-Small Cell Lung Cancer and Platinum-Resistant Ovarian Cancer

Gerber DE,1 Infante JR,2 Gordon MS,3 Schiller JH,1 Spigel D,2 Wang Y,4 Shames DS,4 Choi YJ,4 Kahn R,4 Xu J,4 Lin K,4 Wood K,4 Maslyar D,4 Burris HA 3rd2

1Harold C. Simmons Cancer Center, UT Southwestern Medical Center, Dallas, TX; 2Sarah Cannon Research Institute/Tennessee Oncology, PLLC, Nashville, TN; 3Pinnacle Oncology Hematology, Scottsdale, AZ; 4Genentech, Inc., South San Francisco, CA

BACKGROUND • NaPi2b (SLC34A2) is a multi-transmembrane, sodium-dependent phosphate transporter (Xu et al., 1999) normally expressed in lungs, testis, salivary gland, thyroid gland, small intestine, mammary gland, and uterus (Nishimura and Naito, 2008) and is involved in transcellular absorption of inorganic phosphate

• NaPi2b is highly expressed in non-squamous non-small cell lung cancer (NSCLC) and non-mucinous ovarian cancer (OC).

• NaPi2b-positive tissue immunoreactivity is present in 61% of NSCLC, and 92% OC cancer specimens.

• Mutations in NaPi2b have been associated with clinical syndromes of alveolar and testicular microlithiasis

• DNIB0600A is a monoclonal antibody conjugated to the cytotoxic agent monomethyl auristatin E (MMAE) via a protease-cleavable peptide linker (vc-MMAE platform, Seattle Genetics)

Figure 1. NaPi2b Structure and Mechanism of Action.

METHODSStudy Design • This study evaluated safety, pharmacokinetics (PK), and pharmacodynamics of DNIB0600A (0.2–2.8 mg/kg) given every 3 weeks (q3w) to patients with non-squamous NSCLC or platinum-resistant, non-mucinous OC

• A traditional 3+3 design was used for dose escalation followed by expansions in NSCLC and OC at the recommended Phase 2 dose (RP2D)

• No pre-medication was required or recommended prior to study drug treatment, but was instituted per study guidelines in the event of infusion related reactions or onset of AEs

Pharmacokinetic and Pharmacodynamic Evaluations • PK analysis was performed for total antibody, antibody-conjugated MMAE (acMMAE) and unconjugated MMAE

• Tumor NaPi2b expression was evaluated in archival tissue by immunohistochemistry (IHC)

Clinical Evaluations • Anti-tumor activity was evaluated per RECIST 1.1 every 6 weeks

RESULTS • As of 18 September 2013, 73 patients have enrolled (43 NSCLC; 30 OC) • Forty-one patients have discontinued due to progressive disease, 13 based on physician decision, 9 due to any AEs, and 1 patient withdrew consent

Patient Characteristics, Patient Status • Patients received a median of 4 (range 1–28) doses of DNIB0600A

Table 1. Patient Demographics and Disease Characteristics.

Characteristic All Patients, n (%) (N=73)

Age in years, median (range) 62 (39–85)Female/male 54/19 (74/26)Tumor type NSCLC Ovarian

43 (59) 30 (41)

ECOG status 0 1

39 (53) 34 (47)

Lung Cancer Patients 43 (59)Female/male 24/19 (56/44)Histologic subtype Adenocarcinoma Large cell Other

38 (8) 1 (2) 4 (9)

Number of prior systemic therapies, median (range) 1 2 3 4+

3 (1–10) 5 (12) 6 (14) 11 (26) 21 (49)

Exposure to prior platinum compounds 37 (86)Exposure to prior microtuble inhibitors Taxanes Vinca alkyloids*

28 (65) 7 (16)

Prior Radiotherapy 24 (56)Ovarian cancer patients 30 (41)Histologic subtype Serous Endometroid Clear cell Other

21 (70) 2 (7) 2 (7) 5 (17)

Number of prior systemic therapies, median (range) 5 (1–12)Prior Radiotherapy 5 (17)

*All patients exposed to vinca alkyloids were also exposed to a taxane regimen.

Safety

Table 2. Most Common AEs by Grade Related to DNIB0600A in >10% of Patients.

Event Term 0.2 mg/kg (n=3)

0.4 mg/kg (n=3)

0.7 mg/kg (n=3)

1.2 mg/kg (n=3)

1.8 mg/kg (n=6)

2.4mg/kg (n=49)

2.8 mg/kg (n=6)

Total, n (%) (N=73)

Grade 1/2 3/4 1/2 3/4 1/2 3/4 1/2 3/4 1/2 3/4 1/2 3/4 1/2 3/4 1/2 3/4Any AE 2 - 3 1 - - 3 - 5 1 47 11 6 2 51 (70) 15 (21)Fatigue 1 - 1 - - - 2 - 2 - 29 1 5 - 39 (53) 1 (1)Nausea - - 1 - - - 1 - 2 - 21 - 3 - 28 (38) -Decreased appetite - - 2 - - - 3 - 1 - 16 - 3 - 25 (34) -Peripheral neuropathy* - - - - - - - - 3 - 19 1 1 1 23 (32) 2 (3)

Vomiting - - - - - - 1 - . - 15 - 3 - 19 (26) -Alopecia - - - - - - - - 1 - 13 - - - 14 (19) -Pain - - - - - - - - 1 - 12 - - - 13 (18) -Diarrhea - - 1 - - - - - 1 - 8 - 1 - 11 (15) -Dysgeusia - - - - - - - - 1 - 8 - 2 - 11 (15) -Headache - - 1 - - - 1 - - - 8 - 1 - 11 (15) -Constipation 1 - - - - - - - 2 - 6 - 1 - 10 (14) -Myalgia - - - - - - - - - - 9 - 1 - 10 (14) -Asthenia - - - - - - - - 1 - 8 - - - 9 (12) -Chills - - - - - - - - 1 - 8 - - - 9 (12) -

Arthralgia - - - - - - - - - - 7 - 1 - 8 (11) -

*Includes hypoaesthesia, muscular weakness, paraesthesia, and peripheral sensory/motor neuropathy. Additional Grade 3/4 AEs not included in the table above includes the following: at 0.4 mg/kg: anemia (G3); at 1.8 mg/kg dyspnea (G3); at 2.4 mg/kg: neutropenia (G3 or G4) in 5 pts; anemia (G3) in 2 pts; dehydration (G3); LFT increase (G3); hyperglycemia (G3); hyperkalemia (G3); dehydration (G3); hypertension (G3); at 2.8 mg/kg: neutropenia (G3).

• One patient experienced a DLT (Grade 3 dyspnea) at 1.8 mg/kg in NSCLC. No additional DLTs occurred through the maximally administered dose of 2.8 mg/kg. MTD was not reached.

• Seven patients experienced related AEs leading to discontinuation; (reported terms) peripheral sensory neuropathy in 2 patients, peripheral motor neuropathy, dyspnea, fatigue, decreased appetite, diarrhea, AST/ALT increase, and flatulence in 1 patient each

• Ten patients (14%) experienced Grade 1-2 infusion-related reactions, defined as any AE occurring within 24 hours of study drug infusion (most commonly nausea, vomiting or fatigue). Generally, these resolved within 24–48 hours with observation or symptomatic management.

• Four patients reported serious AEs considered related to study treatment; dyspnea (Grade 3) in 1 patient at 1.8 mg/kg (DLT); upper abdominal pain, headache, and nausea (each Grade 2) in 1 patient at 2.4 mg/kg; dehydration and hyperglycemia (each Grade 3) in 1 patient at 2.4 mg/kg); and upper respiratory tract infection x2 and pneumonia (each Grade 3) in 1 patient at 2.4 mg/kg. No deaths occurred on study or were related to study treatment.

Pharmacokinetics • Nine of 36 patients (25%) developed an antibody response to DNIB0600A with no impact on exposure or AE. Linear pharmacokinetics were observed for total antibody, acMMAE, and unconjugated MMAE. PK characteristics support q3w regimen with minimal accumulation of either analyte over dosing cycles. PK is comparable in NSCLC and OC patients.

Figure 2. DNIB0600A Pharmacokinetics.Concentration-time Profiles at RP2D 2.4 mg/kg

PK Parameters at RP2D 2.4 mg/kg

Cancer Typet1/2, days Mean (%CV) CL, mL/day/kg Mean (%CV)

Total Ab acMMAE Unconjugated MMAE Total Ab acMMAE

NSCLC (26) 6.04 (39.7) 4.89 (33.62) 3.74 (26.41) 13.06 (24.53) 19.39 (26.13)

OC (18) 6.92 (38.65) 5.36 (39.36) 3.81 (23.25) 11.38 (19.61) 16.59 (24.61)

Pharmacodynamics, Biomarkers • Approximately 70% of NSCLC and 90% of OC patients expressed high levels (IHC 2+/3+) of NaPi2b

• Anti-tumor activity with DNIB0600A was associated with tumor NaPi2b expression for both NSCLC and OC

Figure 3. NaPi2b Expression in Specialized Normal Lung Cells and can be Readily Distinguished from tumor Expression by IHC.

Clinical Activity/Efficacy • Of the 60 patients with NaPi2b IHC Score of 2+ or 3+, treated at dose levels 1.8–2.8 mg/kg, 14 patients had a confirmed partial response (PR); 3 of 26 (12%) NSCLC and 11 of 22 (50%) OC patients, respectively

• Three NSCLC patients had unconfirmed PRs • No patient was enrolled with NaPi2b IHC Score of 1+; no responses were reported among the 13 patients with NaPi2b IHC Score of 0 or unavailable, at any dose level

Figure 4. DNIB0600A Activity: Confirmed Radiologic Responses in NSCLC.

Bes

t % C

hang

e

−100

−80

−60

−40

−20

0

20

40

60

80

100 2.8 mg/kg2.4 mg/kg1.8 mg/kgIHC score

●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●3+ 0 3+ 3+ 3+ 2+ 3+ 3+ 0 0 0 0 3+ 3+ 3+ 2+ NA 0 NA NA 3+ 2+ 3+ 3+ NA 2+ 3+ 3+ 2+ 2+ 2+ 3+ 3+ 2+

confirmed PR

Figure 5. Lung Cancer Patient Vignettes.

A. 73 y.o woman with NSCLC. Prior treatment included carboplatin/pemetrexed/bevacizumab complicated by pancytopenia and acute renal failure. IHC score 3+, Treated at 1.8 mg/kg q3w, confirmed PR.B. 62 y.o. male with NSCLC. Progressed following treatment with carboplatin / paclitaxel / bevacizumab and docetaxel single agent. Alk neg, EGFR wt, KRAS wt, IHC score 2+, Treated at 2.4 mg/kg, confirmed PR.

CONCLUSIONS • DNIB0600A administered every 3 weeks has an encouraging safety, tolerability, and PK profile and evidence of anti-tumor activity in NSCLC and OC pts whose tumors express NaPi2b detectable by IHC

• This data supports further clinical evaluation of DNIB0600A in NSCLC and OC together with a companion diagnostic

REFERENCES1. Xu H, Bai L, Collins JF, et al. Genomics 1999; 62:281−284.2. Nishimura M, Naito S. Drug Metab Pharmacokinet 2008; 23:22−44.

ACKNOWLEDGMENTS • We thank the patients who participated in the study, and their families • Participating Centers: Pinnacle Oncology Hematology (Michael S. Gordon, David S. Mendelson); Sarah Cannon Research Institute (Johanna C. Bendell, Howard Burris, Jeffrey Infante, David Spigel); UT Southwestern Medical Center (David Gerber, Siobhan Kehoe, Joan Schiller)

• Genentech provided support for this poster

IASLC World Lung, Sydney, Australia, Oct 27-30, 2013

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P3.11-014