Journal Thoracic Oncology

Abstracts Journal of Thoracic Oncology • Volume 12 Issue S1 January 2017
Cell Biology and Regenerative Medicine, Stanford University School of Medicine,
Stanford/CA/USA 4 Forty Seven, Inc., Palo Alto/CA/USA 5 Department of Medicine,
Division of Hematology, Stanford University School of Medicine, Stanford/CA/USA
Background: Hu5F9-G4 is a humanized monoclonal antibody that targets
CD47, blocking its anti-phagocytic “don’t eat me” signal through macrophage
receptor SIRPα, leading to tumor phagocytosis. CD47 is overexpressed on
human cancers and also on red blood cells (RBCs). In primate toxicology
studies, Hu5F9-G4 caused a transient anemia that was improved with a
single lower Priming Dose allowing higher Maintenance Doses. Materials and
Methods: Relapsed/refractory solid tumors and lymphomas were included.
This dose escalation study included: Part A, to determine the Priming Dose
and Part B, to determine the Maintenance Dose. The maximum tolerated
dose (MTD) in part A was used for the single Priming Dose in part B (Hu5F9-G4
dosed weekly). The primary objective is to determine safety and secondary
objectives are to determine PK and PD. Preliminary data reported from data
cutoff of July 22, 2016. Results: 25 patients have enrolled. Part A included
0.1 (N=1), 0.3 (N=2), 1 (N=6), and 3 (N=2) mg/kg. There were 2 dose-limiting
toxicities (DLTs) in Part A at the 3 mg/kg dose: grade (G) 3 abdominal pain
and G3 hemagglutination (H) (protocol-specific scale of G1 H on peripheral
blood smear (PBS) and G2 headache). 1 mg/kg was selected as the Priming
Dose, with no >G2 anemia. Pharmacodynamic studies show almost 100%
RBC receptor occupancy at the Priming Dose. Treatment-related adverse
event (TRAE) in Part A included: anemia (3 G1, 3 G2), hyperbilirubinemia (3
G1, 2 G2; unconjugated), headache (6 G1, 1 G2), H on PBS (8 G1), and nausea
(3 G1). Part B included 3 (N = 4), 10 (N = 3), and 20 mg/kg (N=6, ongoing).
There have been no DLTs in 3 patients on 10 mg/kg, and one DLT (headache
with hemagglutination) in 6 patients at the 20 mg/kg maintenance dose
(ongoing). Most toxicities were was associated with the initial single Priming
Dose and were completely reversible. TRAE in Part B at 3 mg/kg included:
anemia (2 G1, 2 G2), hyperbilirubinemia (1 G1, 1 G3), headache (3 G1), H on
PBS (1 G1), retinal toxicity (G2 protocol-specific scale, asymptomatic). TRAE
at 10 mg/kg included: anemia (3 G1), headache (2 G1), and nausea (1 G1).
Two patients with adenoid cystic carcinoma in Part A had stable disease
for 16 and 8 months. In Part B, 2 of 3 patients have had prolonged stable
disease at 10 mg/kg for 8+ months (follicular thyroid cancer) and 7+ months
(myoepithelioma of the head and neck). Evaluation of subjects in the 20 mg/
kg cohort is ongoing. Conclusions: Hu5F9-G4 is well tolerated at 10 mg/kg
weekly, with 1 mg/kg Priming Dose. Part B with a Maintenance Dose of 20
mg/kg is ongoing. Acknowledgements: Stanford Clinical and Translational
Research Unit; California Institute for Regenerative Medicine; Forty Seven,
Inc. Trial Registration: NCT02216409 1. Willingham SB, et al. The CD47-signal
regulatory protein alpha (SIRPa) interaction is a therapeutic target for
human solid tumors. Proc Natl Acad Sci U S A. 2012 Apr 24;109(17):6662-7. 2.
Liu J t al. Pre-Clinical Development of a Humanized Anti-CD47 Antibody with
Anti-Cancer Therapeutic Potential. PLoS One. 2015 Sep 21;10(9):e0137345.
References:
1. Willingham SB, et al. The CD47-signal regulatory protein alpha (SIRPa)
interaction is a therapeutic target for human solid tumors. Proc Natl Acad Sci
U S A. 2012 Apr 24;109(17):6662-7.
2. Liu J t al. Pre-Clinical Development of a Humanized Anti-CD47 Antibody with
Anti-Cancer Therapeutic Potential. PLoS One. 2015 Sep 21;10(9):e0137345.
Figure: CD47 is a myeloid-specific immune checkpoint.
SESSION SC15: CLINICAL TRIALS: HOW TO SET PRIORITIES?
TUESDAY, DECEMBER 6, 2016 - 11:00-12:30
SC15.01 THE AMERICAN PERSPECTIVE
Suresh Ramalingam
Hematology & Medical Oncology, Winship Cancer Institute of Emory University,
Atlanta/United States of America
The treatment of lung cancer has changed dramatically in the past few years.
From a time when treatment decisions were made without regard to histology
or genotype, an era of personalized therapy, at least for a subset of patients
with lung cancer, is a reality. The treatment of EGFR mutation-positive
patients with EGFR inhibitors has resulted in significant improvements in
outcomes over standard chemotherapy. Similarly, for patients with ALK- and
ROS1-positive non-small cell lung cancer (NSCLC), targeted therapies have
proven to be superior. However, for patients with KRAS mutations, which
are seen in approximately 25-30% of lung adenocarcinomas, there is no
effective targeted therapy option. For nearly 70% of patients with NSCLC,
systemic chemotherapy remains the standard approach. The emergence of
immune-checkpoint inhibitors has resulted in considerable change in the
treatment algorithm for advanced NSCLC. These agents are now preferred
salvage therapy after progression following platinum-based chemotherapy.
As immunotherapy moves to the first-line therapy setting for advanced
NSCLC, it is anticipated that at least 25-30% of the patients without a driver
mutation will be treated with immune-checkpoint inhibitors. All of these
exciting developments call for careful evaluation of ongoing and planned
clinical trials, so that appropriate new priorities are established. The newly
established NCI National Clinical Trials Network (NCTN) includes all the
adult cancer cooperative groups (ALLIANCE, ECOG-ACRIN, SWOG, & NRG
Oncology) is actively engaged in conducting the new generation of clinical
trials for lung cancer. Despite, the success with targeted agents in advanced
stage NSCLC, patients do not achieve a cure. Using these agents in early stage
NSCLC provides the best chance for a cure. The ALCHEMIST study has been
launched by the NCTN to evaluate personalized adjuvant therapy for early
stage NSCLC. In this study, patients with early-stage lung cancer (stages IB,
II and IIIA) are treated with systemic chemotherapy after surgical resection,
as per standard of care. Subsequently, their tumor is subjected to molecular
testing. Patients with ALK-positive disease are randomized to treatment
with crizotinib or placebo. Patients with EGFR mutations are randomized
to erlotinib or placebo. Patients who are negative for EGFR and ALK, are
randomized to nivolumab or observation. These studies will evaluate the
effect of the personalized adjuvant therapy on overall survival and diseasefree
survival. Another ongoing effort is to understand the therapeutic
value of targeted strategies in patients with advanced stage squamous
cell lung cancer. The lung-MAP study enrolls patients with advanced stage
squamous NSCLC. Following next-gen sequencing, patients with selected
targets are treated with an appropriate targeted agent. The study includes
a phase 2 component, which can be rapidly adapted to phase 3 if a agent
demonstrates the pre-defined level of efficacy. This trial is also designed to
accelerate the development of treatments leading to full approval by the
FDA by shortening timelines. These individualized treatment approaches
based on genotype are likely to answer important questions in a definitive
manner. As immunotherapy becomes integrated in the standard treatment
paradigms, considerable changes are also warranted for patients without
driver mutations. For a subset of patients, as immunotherapy becomes
the first line treatment in the advanced stage disease setting, the role of
platinum-based chemotherapy in the second line needs to be investigated.
It is also important to evaluate the need for continued immunotherapy after
disease progression when patients are switched to chemotherapy. Another
key question relates to the duration of therapy for patients receiving immune
checkpoint inhibitors. Appropriately designed trials to understand the
optimum duration of therapy will optimize benefits, reduce toxicity, and
decrease cost. Combination strategies using immune checkpoint inhibitors
Copyright © 2016 by the International Association for the Study of Lung Cancer
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