– 77% Overall Response Rate in RET Fusion Cancers
and 45% Overall Response Rate in RET Mutated Medullary Thyroid
Cancer (MTC) –
Loxo Oncology, Inc. (Nasdaq:LOXO), a biopharmaceutical company
developing highly selective medicines for patients with genomically
defined cancers, today announced interim clinical data from the
LOXO-292 global Phase 1 LIBRETTO-001 (LOXO-292 Investigated to
Block RET-altered Tumors) dose escalation trial. LOXO-292 is
an investigational, highly potent and selective RET inhibitor.
These data are being presented today at the 2018 American Society
of Clinical Oncology (ASCO) Annual Meeting in Chicago (abstract
102).
“The LOXO-292 Phase 1 data are striking,” said Alexander Drilon,
M.D., clinical director in the Early Drug Development Service at
Memorial Sloan Kettering Cancer Center and presenting author. “The
activity we reported is impressive and I am thrilled to see this
promising efficacy with limited adverse events, especially in this
heavily pre-treated patient population of RET fusion cancers,
including those with brain metastases, and RET mutated MTC."
“We are very excited to share the initial LOXO-292 clinical
experience with the oncology community at ASCO,” said Josh
Bilenker, M.D., chief executive officer of Loxo Oncology. “We have
long believed that patients with RET fusion cancers and RET mutated
MTC needed a purpose-built medicine tailored to their tumors. We
hope that LOXO-292 continues to deliver on that premise. Thank you
to the patients, investigators and clinical trial teams who made
possible today’s presentation.”
Trial Background
The LIBRETTO-001 Phase 1 trial contains a dose escalation phase
and a dose expansion phase. The dose escalation phase follows a
“3+3” design. LOXO-292 is dosed orally in 28-day cycles. As dose
cohorts are cleared, additional patients can enroll in these
cleared cohorts. Intra-patient dose escalation is also permitted as
dose cohorts are cleared. The primary endpoint of the trial is the
determination of the maximum tolerated dose (MTD) or recommended
dose for further study. Secondary endpoints include safety, overall
response rate (by RECIST 1.1) and duration of response. The dose
expansion phase is designed to further characterize the overall
response rate, durability of response, and safety of LOXO-292 in
predefined groups of patients with activating RET alterations.
Key Data Presented at ASCO
The data presented at ASCO were based on an April 2, 2018 data
cut-off date. Eighty-two total patients had been enrolled to eight
dose escalation cohorts: 20 mg QD (n=6), 20 mg BID (n=10), 40 mg
BID (n=16), 60 mg BID (n=10), 80 mg BID (n=18), 120 mg BID (n=4),
160 mg BID (n=12) and 240 mg BID (n=6). RET alterations were
identified by local laboratories either in tumor or plasma and
included the following primary diagnoses:
- 38 patients with RET fusion-positive non-small cell lung cancer
(NSCLC) (21 with prior MKI treatment, 17 without)
- 9 patients with RET fusion-positive thyroid cancer (8 with
prior MKI treatment, 1 without)
- 2 patients with RET fusion-positive pancreatic cancer (1 with
prior MKI treatment, 1 without)
- 29 patients with RET-mutated medullary thyroid cancer (MTC) (23
with prior MKI treatment, 6 without)
- 4 patients with no known activating RET alterations
In addition to many patients with prior MKI treatment, 46% of
patients had received prior chemotherapy and 24% had received prior
immunotherapy (47% of those with NSCLC).
Pharmacokinetic analyses during the dose escalation demonstrated
dose-dependent increases in LOXO-292 exposure with increasing dose.
Starting at the 40 mg BID dose and the 80 mg BID dose,
respectively, LOXO-292 delivered sustained >IC90 RET fusion and
>IC90 RET M918T-mutant target coverage, based on cell-based
potencies.
The data presented at ASCO, summarized below, are based on
response assessments performed by each respective clinical trial
site (local, investigator-assessed radiology).
|
RET Fusion-Positive Cancers |
RET- MutatedMTC |
No KnownActivatingRET Alteration |
|
All |
NSCLC |
Other1 |
Enrolled |
49 |
38 |
11 |
29 |
4 |
Eligible for response evaluation2 |
39 |
30 |
9 |
22 |
3 |
Overall response rate (95% CI)3 |
77% (61%-89%) |
77% (58%-90%) |
78% (40%-97%) |
45% (24%-68%) |
0% (0%-71%) |
Confirmed overall response rate3,4 |
74% |
74% |
71% |
33% |
0% |
CR |
-- |
-- |
-- |
1 |
-- |
uCR5 |
-- |
-- |
-- |
1 |
-- |
PR |
25 |
20 |
5 |
5 |
-- |
uPR5 |
5 |
3 |
2 |
3 |
-- |
SD |
6 |
4 |
2 |
9 |
2 |
PD |
-- |
-- |
-- |
2 |
1 |
Not evaluable6 |
3 |
3 |
-- |
1 |
-- |
1. Patients eligible for response evaluation include thyroid
cancer (n=7), pancreatic cancer (n=2).2. Excludes patients recently
enrolled that remain on treatment, but have not had a first
post-baseline response assessment. 3. Response status per RECIST
1.1. Overall response rate = CR+uCR+PR+uPR. Overall response rate,
Confirmed overall response rate: all RET fusion-positive (30/39,
25/34), RET fusion-positive NSCLC (23/30, 20/27), RET
fusion-positive other (7/9, 5/7), RET-mutant MTC (10/22, 6/18).4.
Excludes patients with unconfirmed CR/PR pending confirmation at
time of data cut-off.5. Unconfirmed responses in patients that
remain on treatment awaiting a confirmatory response assessment.6.
Patients that discontinued treatment prior to a first post-baseline
response assessment.
Anti-tumor activity was observed regardless of RET fusion
partner (including KIF5B), RET mutation (including M918T and V804M
gatekeeper mutations), and prior MKI treatment. Twelve patients
with RET fusion cancers had central nervous system (CNS) metastases
at enrollment and all remained on study without progression. Three
of these patients had RECIST target lesions in the CNS, and all
three exhibited intracranial partial responses. In patients with
RET-mutant MTC, LOXO-292 treatment resulted in significant
reductions in the serum tumor markers calcitonin and
carcinoembryonic antigen (CEA).
As of the data cutoff, LOXO-292 demonstrated early evidence of
durable activity, with 90% of RET fusion-positive cancer patients
and 93% of RET-mutant MTC patients remaining on therapy. All
responding patients across all tumor types remained on therapy. The
longest responding patient on therapy was the first RET
fusion-positive NSCLC patient enrolled, who had been on therapy for
more than ten months as of the data cut-off date.
Most treatment-emergent adverse events were Grade 1 in severity.
The treatment-emergent adverse events observed in ≥10% of patients,
regardless of relationship to LOXO-292, were fatigue (12% Grade 1,
7% Grade 2, 0% ≥Grade 3), diarrhea (10% Grade 1, 6% Grade 2, 0%
≥Grade 3), constipation (13% Grade 1, 1% Grade 2, 0% ≥Grade 3), dry
mouth (12% Grade 1, 0% ≥Grade 2), nausea (9% Grade 1, 4% Grade 2,
0% ≥Grade 3), and dyspnea (7% Grade 1, 2% Grade 2, 1% ≥Grade 3).
Only two adverse events ≥Grade 3 were attributed to LOXO-292 (Grade
3 tumor lysis syndrome, Grade 3 increased ALT). An MTD had not been
reached. At the 240 mg BID dose level, one dose limiting toxicity
(DLT) was reported (aforementioned Grade 3 tumor lysis
syndrome).
LOXO-292 also demonstrated robust reduction and clearance of RET
alterations as detected in patients’ plasma cell free DNA (cfDNA).
These data will be presented in a separate poster presentation on
June 3, 2018.
LIBRETTO-001 Trial Update
The expansion cohorts of the LIBRETTO-001 trial are now open and
enrolling at the 160 mg BID dose. This dose was selected for
initial expansion based on its promising activity and tolerability
profile. Additional dose exploration above 160 mg BID is ongoing
and patients enrolled to the expansion cohorts may dose escalate
should a higher dose be advanced.
About the ASCO Presentations
LOXO-292 data are being presented in two presentations at
ASCO:
- “A phase 1 study of LOXO-292, a potent and highly
selective RET inhibitor, in patients with RET-altered
cancers.” This abstract is being presented in an oral
presentation by Dr. Alexander Drilon, Memorial Sloan Kettering
Cancer Center, during a Clinical Science Symposium session
entitled, “Tumor Genomics: Finding the Target, Hitting the Target”
from 8:00 – 9:30AM CT on Saturday, June 2, 2018 (Abstract
102).
- “Detection and clearance of RET variants in plasma cell
free DNA (cfDNA) from patients (pts) treated with
LOXO-292.” This abstract is being presented as a poster by
Dr. Geoff Oxnard, Dana Farber Cancer Institute, during the Lung
Cancer—Non-Small Cell Metastatic poster session from 8:00 – 11:30AM
CT on Sunday, June 3, 2018 (Abstract 9048).
The presentations will be available online at
http://www.loxooncology.com/asco at the time of their scheduled
presentation at ASCO.
Conference Call and Webcast InformationLoxo
Oncology management will host a conference call and live webcast
with slides and Q&A today at 4:00 p.m. CT to discuss the
LOXO-292 data. To participate in the conference call, please dial
(877) 930-8065 (domestic) or (253) 336-8041 (international) and
refer to conference ID 3597058. A live webcast of the presentation
will be available at http://ir.loxooncology.com/. A replay of the
webcast will be available shortly after the conclusion of the call
and archived on the company's website for 30 days following the
call.
About LOXO-292LOXO-292 is a potent, oral and
selective investigational new drug in clinical development for the
treatment of patients with cancers that harbor abnormalities in the
rearranged during transfection (RET) kinase. RET fusions and
mutations occur across multiple tumor types with varying frequency.
LOXO-292 was designed to inhibit native RET signaling as well as
anticipated acquired resistance mechanisms that could otherwise
limit the activity of this therapeutic approach. LOXO-292 is
currently being studied in the global LIBRETTO-001 Phase 1
trial. For additional information about the LOXO-292 clinical
trial, please refer to www.clinicaltrials.gov. Interested patients
and physicians can contact the Loxo Oncology Physician and Patient
RET Clinical Trial Hotline at 1-855-RET-4-292 or
email clinicaltrials@loxooncology.com.
About RET-Altered CancersGenomic alterations in
RET kinase, which include fusions and activating point mutations,
lead to overactive RET signaling and uncontrolled cell growth. RET
fusions have been identified in approximately 2% of non-small cell
lung cancer, 10-20% of papillary and other thyroid cancers, and a
subset of other cancers. Activating RET point mutations account for
approximately 60% of medullary thyroid cancer (MTC). Both RET
fusion cancers and RET-mutant MTC are primarily dependent on this
single activated kinase for their proliferation and survival. This
dependency, often referred to as “oncogene addiction,” renders such
tumors highly susceptible to small molecule inhibitors targeting
RET.
About Loxo OncologyLoxo Oncology is a
biopharmaceutical company developing highly selective medicines for
patients with genomically defined cancers. Our pipeline focuses on
cancers that are uniquely dependent on single gene abnormalities,
such that a single drug has the potential to treat the cancer with
dramatic effect. We believe that the most selective, purpose-built
medicines have the highest probability of maximally inhibiting the
intended target, with the intention of delivering best-in-class
disease control and safety. Our management team seeks out
experienced industry partners, world-class scientific advisors and
innovative clinical-regulatory approaches to deliver new cancer
therapies to patients as quickly and efficiently as possible. For
more information, please visit the company's website at
www.loxooncology.com.
Forward Looking StatementsThis press release
contains "forward-looking" statements within the meaning of the
safe harbor provisions of the U.S. Private Securities Litigation
Reform Act of 1995. Forward-looking statements can be identified by
words such as: "anticipate," "intend," "plan," "goal," "seek,"
"believe," "project," "estimate," "expect," "strategy," "future,"
"likely," "may," "should," "will" and similar references to future
periods. These statements are subject to numerous risks and
uncertainties that could cause actual results to differ materially
from what we expect. Examples of forward-looking statements
include, among others, statements we make regarding the timing and
success of our clinical trials, the potential therapeutic benefits
and economic value of our lead product candidate or other product
candidates, and timing of future filings. Further information on
potential risk factors that could affect our business and its
financial results are detailed in our most recent Quarterly Report
on Form 10-Q, and other reports as filed from time to time with the
Securities and Exchange Commission. We undertake no obligation to
publicly update any forward-looking statement, whether written or
oral, that may be made from time to time, whether as a result of
new information, future developments or otherwise.
Contacts for Loxo Oncology, Inc.
Company: Lauren CohenDirector, Corporate
Communicationslcohen@loxooncology.com
Investors:Peter Rahmer Endurance Advisors, LLC 415-515-9763
prahmer@enduranceadvisors.com
Media:Dan Budwick1AB Media973-271-6085dan@1abmedia.com
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