Annual Meeting Proceedings Part 1 - American Society of Clinical ...

158s Developmental Therapeutics—Clinical Pharmacology and Immunotherapy
2565 General Poster Session (Board #4F), Mon, 8:00 AM-12:00 PM
IFN-� to improve immunotherapy for melanoma. Presenting Author: Marco
Donia, Center for Cancer Immune Therapy, Department of Hematology,
Copenhagen University Hospital Herlev, Herlev, Denmark
Background: Adoptive cell therapy (ACT) with tumor infiltrating lymphocytes
(TILs) holds the promise to change the long-term prognosis of
patients with metastatic melanoma. In this study we have explored
strategies to improve the efficacy of cell products for infusion through
tumor immune-sensitization. Methods: We examined whether objective
responses in our pilot ACT trial (NCT937625) were associated with the
number of tumor-reactive T cells infused. Subsequently, we assessed the
ability of immune-sensitizing agents to modulate the constitutive response
of 12 clinical grade TIL products to matched autologous short-term
cultured melanoma cell lines. Results: Our data showed that a high absolute
number of infused tumor-reactive T cells is critical to achieve an objective
response. In addition, a defective population of tumor-specific CD8� and
CD4� T cells unable to exert antitumor effector functions ex vivo was
detected in most TIL products. However, an antitumor specific response
could be restored by pretreatment of the autologous tumor cells with low
dose IFN-�. Of note, IFN-� treatment was invariably associated with
increased cancer immunogenicity as demonstrated by up-regulation of
MHC molecules. Conclusions: Combination strategies represent the next
frontier of cancer immunotherapy. Although previous trials in melanoma
showed that IFN-� does not mediate clinical benefit when used as
monotherapy, our findings show that its ability to increase tumor cell
immunogenicity may enhance the efficacy of current immune-based
therapies such as ACT through improved activation of pre-existing but
unresponsive tumor specific lymphocytes. Therefore, additional studies on
the possibility of a sequential combination of low dose IFN-� and ACT are
highly warranted.
2567 General Poster Session (Board #4H), Mon, 8:00 AM-12:00 PM
Human pharmacokinetic (PK) characterization of the novel dual-action
anti-HER3/EGFR antibody MEHD7945A (MEHD) in patients with refractory/
recurrent epithelial tumors. Presenting Author: Manuel Hidalgo, START-
Madrid, Centro Integral Oncológico Clara Campal, Madrid, Spain
Background: MEHD is a novel dual-action human IgG1 antibody that blocks
ligand binding to HER3 and EGFR, and elicits antibody-dependent
cell-mediated cytotoxicity (ADCC). MEHD demonstrates single-agent activity
in a broad panel of tumor models, including models resistant to
anti-HER3 or anti-EGFR treatment alone. The objective of this analysis was
to characterize the PK of MEHD associated with body weight (BW)-based
dosing used in a phase I study in patients with epithelial tumors and to
evaluate the potential for using fixed dosing in future studies. Methods:
Preliminary non-compartmental and population PK analyses were performed
using patient data from the dose-escalation stage [1, 4, 10, 15, 22,
and 30 mg/kg every two weeks (q2w)] and expansion stage (14 mg/kg q2w)
of the phase I study. Patient demographic data and other relevant clinical
covariates were evaluated in the population analysis. PK simulation of
1000 subjects with a log-normal BW distribution was performed to
compare the inter-individual variability of MEHD exposure following fixed
or BW-based dosing. Results: As expected,MEHD exhibited nonlinear PK.
In the noncompartmenal analysis, the apparent clearance (CL) decreased
in a dose-dependent fashion (about 40 to 9.9 mL/day/kg from 1 to 30
mg/kg) and approached linearity at doses �10 mg/kg (q2w). In the
population analysis, the PK profile of MEHD was well described by a two
compartment model with linear and nonlinear clearance. The targetmediated
clearance was consistent with that of anti-EGFR antibodies. The
nonspecific CL and central volume of distribution (V1) values were
approximately 6 mL/day/kg and 52.4 mL/kg, respectively. BW had a
moderate effect on V1, but not on CL. PK simulations suggest that,
compared with BW-based dosing, fixed dosing would result in less
inter-individual variability in MEHD exposure. Both 1100 mg q2w or 1650
mg q3w of MEHD achieve the targeted therapeutic exposure. Conclusions:
The dual-action antibody MEHD demonstrated PK consistent with anti-
EGFR antibodies. Fixed dosing of MEHD on an every 2 or 3 week schedule
is supported.
2566 General Poster Session (Board #4G), Mon, 8:00 AM-12:00 PM
A first-in-human phase Ib study to evaluate the MEK inhibitor GDC-0973,
combined with the pan-PI3K inhibitor GDC-0941, in patients with advanced
solid tumors. Presenting Author: Patricia LoRusso, Karmanos
Cancer Institute, Detroit, MI
Background: Both RAS/RAF/MEK and PI3K/Akt signaling pathways are
deregulated in many tumor types. Targeting both pathways may be more
efficacious than targeting either pathway alone. In preclinical models,
concurrent administration of GDC-0973, a potent, selective, MEK1/2
inhibitor and GDC-0941, a potent class I PI3K inhibitor, shows improved
efficacy compared to either agent alone dosed continuously or intermittently.
Methods: A phase Ib dose-escalation study with 3�3 design was
initiated in patients (pts) with advanced solid tumors to evaluate the safety
and pharmacokinetics (PK) of oral dosing of GDC-0973 and GDC-0941.
Pts received: concurrent GDC-0973 � GDC-0941 once daily (qd) on a 21
day on/7 day off (21/7) schedule; intermittent GDC-0973 on Days 1, 4, 8,
11, 15, 18 of a 28 day cycle � GDC-0941 qd on a 21/7 schedule (MEK
int); or GDC-0973 � GDC-0941 qd on a 7 day on /7 day off schedule (7/7).
Starting doses were 20 mg GDC-0973 � 80 mg GDC-0941 (21/7), 100 mg
GDC-0973 � 130 mg GDC-0941 (MEK int); 40 mg GDC-0973 � 130 mg
GDC-0941 (7/7). Serial plasma PK samples, FDG-PET, and CT scans were
obtained. Results: 78 pts have enrolled. DLTs were G3 lipase (n�1), G4
CPK elevation (n�1). Compared to the 21/7 MTD of 40 mg GDC-0973 �
100 mg GDC-0941, higher doses of GDC-0973 � GDC-0941 were
tolerated on the MEK int schedule. Overall, adverse events related to the
study drug combination in � 20% pts were diarrhea, rash, nausea, fatigue,
vomiting, decreased appetite, dysgeusia, and elevated CPK. Preliminary
analysis indicated PK of GDC-0973 and GDC-0941 are not altered when
dosed in combination. Of 46 evaluable pts, 26 had an FDG-PET partial
metabolic response (� 20% decrease in mean SUVmax from baseline) at �1
time points. Partial responses were observed in 3 pts (mBRAF melanoma,
mBRAF pancreatic ca, mKRAS endometrioid ca); 5 pts had stable disease
� 5 months. Conclusions: Combination dosing of GDC-0973 and GDC-
0941 is generally well tolerated, with toxicities similar to those observed in
single agent GDC-0973 and GDC-0941 phase 1 trials. There are early signs
of anti-tumor activity. Dose escalation on MEK int and 7/7 schedules
continues and updated data will be presented.
2568 General Poster Session (Board #5A), Mon, 8:00 AM-12:00 PM
A phase I study of MEHD7945A (MEHD), a first-in-class HER3/EGFR
dual-action antibody, in patients (pts) with refractory/recurrent epithelial
tumors: Expansion cohorts. Presenting Author: Andres Cervantes-Ruiperez,
Department of Hematology and Medical Oncology, INCLIVA, University of
Valencia, Valencia, Spain
Background: Dysregulated human epidermal growth factor receptor tyrosine
kinase (HER RTK) signaling is an important driver of tumor growth,
metastasis, and survival. Extensive co-expression and heterodimerization
suggest that simultaneous blockade of multiple HER RTKs may be more
effective than blockade of a single RTK. MEHD is a novel dual-action
human IgG1 antibody. Each antigen-binding fragment blocks ligand
binding to HER3 or EGFR, and intended to inhibit signaling from all major
ligand-dependent HER dimers. MEHD has single-agent activity in multiple
tumor models including models resistant to anti-HER3 or anti-EGFR.
Methods: This Phase I study evaluated safety, tolerability, pharmacokinetics
(PK), and pharmacodynamic (PD) activity of intravenous MEHD every 2
weeks (q2w). Tumor PD assessments were pre- and post-dose FDG-PET
and IHC for pS6, pPRAS40 or pERK in tumor biopsies. Tumor CT
assessments were performed q8w. No dose-limiting toxicity (DLT) was
observed in six 3�3 cohorts from 1-30 mg/kg (n�30). We report results
from 4 tumor-specific cohorts receiving 14 mg/kg MEHD (recommended
Phase II dose). Results: As of 21 Nov 2011, 36 pts (CRC�12, NSCLC�9,
SCCHN�10, pancreatic�5), median age 62.5 (35–87), all PS 0-1,
median # prior regimens 3.5 (1-8), received a median of 4 doses (1-9) of
MEHD; 18 pts remain on study. PK data are consistent with human
anti-EGFR antibodies. No related Grade (G) �3 adverse events (AEs) have
been observed. Common related G1/2 AEs included rash/dermatitis (53%),
diarrhea (36%), fatigue (22%), paronychia (19%), dry skin, nausea, and
decreased appetite (all 17%), asthenia and stomatitis/oral pain (all 14%).
Related AEs � 24 h after first infusion included G1/2 headache (42%),
fever (33%), and chills (17%), and decreased in intensity and frequency
with later infusions. Early PD data indicate target inhibition in 8/36 pts
(SCCHN�2, NSCLC�2, CRC�4), and best response by RECIST includes 2
PR (both SCCHN), 6 pts with SD � 8 weeks (NSCLC�2, CRC�4), 7/8
previously treated with EGFR inhibitors. Conclusions: MEHD at 14 mg/kg
q2w has an encouraging safety profile and evidence of anti-tumor activity.
Phase II studies are planned.
Visit abstract.asco.org and search by abstract for the full list of abstract authors and their disclosure information.