Kinnate Biopharma Inc. (Nasdaq: KNTE) (Kinnate), a clinical-stage
precision oncology company, today announced positive monotherapy
dose escalation data for its investigational, highly selective and
potent pan-RAF inhibitor, exarafenib, from Part A1 of its ongoing
global Phase 1 KN-8701 clinical trial. These results will be
featured in an oral presentation today at 3:35 p.m. ET during the
Clinical Trials Mini Symposium Session at the American Association
for Cancer Research (AACR) 2023 Annual Meeting. (Abstract #CT032)
The company today also provided details around its monotherapy
dose expansion strategy (Part B) and a preliminary update on the
combination arm (Part A2) evaluating exarafenib with binimetinib, a
MEK inhibitor, in patients with BRAF-altered solid tumors and/or
who have NRAS mutant melanoma.
Kinnate will host a virtual investor webcast today at 5:30 p.m.
ET to discuss these updates, along with the expansion of its early
development pipeline announced separately.
“The exarafenib dose escalation data provide striking proof of
concept for a monotherapy pan-RAF inhibitor,” said Alexander Spira,
MD, PhD, FACP, co-director, Virginia Cancer Specialists Research
Institute. “For the first time, a pan-RAF inhibitor has shown both
promising tolerability as a single agent and has achieved
compelling breadth of activity with durable responses in targetable
mutations. Responses in patients with BRAF Class II or NRAS
alterations is meaningful because no approved targeted therapy is
available today, and physicians are left with limited treatment
options for advanced cancers, which means patients often have poor
survival outcomes. I look forward to the further study of
exarafenib’s therapeutic potential to address these patients who
are currently medically underserved.”
Key Exarafenib Monotherapy Data Presented at AACR
2023
The data at AACR were based on a February 28, 2023 data cutoff.
Sixty patients with a median of three prior therapies had been
enrolled into six monotherapy dose escalation cohorts: 25 mg bid
(dose level; DL 1), 50 mg bid (DL 2), 100 mg bid (DL 3), 200 mg bid
(DL 4), 300 mg bid (DL 5) and 400 mg bid (DL 6). Treated patients
included those with solid tumors driven by BRAF Class I (41.7%),
Class II (13.3%) and Class III (30%) alterations or melanoma with
NRAS mutations (15%). BRAF and NRAS alterations were identified by
local laboratories either in tumor or plasma. As of the data
cutoff, all 60 patients enrolled were part of the safety analysis
population, of which 49 patients were efficacy evaluable.1
Favorable Tolerability Profile; Only 3% (n=2/60) of
Patients Discontinued Therapy Due to Treatment-Related Adverse
Events
- The maximum tolerated dose (MTD) was determined to be 300 mg
bid (n=29). At therapeutically relevant exposures, there was no
cutaneous (skin) evidence of paradoxical activation. Dose limiting
toxicities observed at the highest dose level (400 mg bid) were
Grade 3 acneiform rash (n=1) and Grade 3 macular rash
(n=1).
- Treatment-related adverse events (TRAEs) reported by
investigators at any Grade occurred in 73.3% (n=44) of patients,
with 18.3% of TRAEs reported as Grade 3 or higher (n=11). There
were no Grade 5 TRAEs reported as of the data cutoff.
- The most common TRAEs of any Grade were skin related (21.7%;
n=13), with 3.3% (n=2) of patients having skin events that were
Grade 3 or greater.
- Grade 2 gastrointestinal (GI) TRAEs occurred in 3.3% of
patients (n=2). No Grade 3 GI TRAEs were observed.
- Reversible, asymptomatic increased alanine transaminase and/or
increased aspartate aminotransferase TRAEs were reported at Grade 3
(n=4; 6.7%) and Grade 4 (n=1; 1.7%).
- In all patients (n=60) treated with exarafenib, the overall
relative mean dose intensity was 97% and was 95% in patients
treated at 300 mg bid (n=29). The median for both patient sets was
100%.2
Dose Dependent and Steady State Unbound Exposures with
Exarafenib Treatment
- Pharmacokinetic analyses demonstrated dose-dependent increases
in exarafenib exposure (Cmax; peak plasma concentration and area
under the curve) with increasing dose.
- Exarafenib had a half-life of eight hours in patients, which is
a longer duration range than the predicted half-life preclinically,
supporting a bid dosing strategy.
- At 300 mg bid, exarafenib delivered high target coverage in
patients. Unbound exposures exceeded the IC50 values across BRAF
and NRAS cell lines by two-to-ten-fold, while remaining below the
wild type cells IC50. We believe multiple fold target coverage is
ultimately necessary for meaningful outcomes in these patient
subtypes.
- Treatment with exarafenib also led to significant reductions in
circulating tumor DNA across BRAF and NRAS-altered tumor
types.
Promising Early Efficacy, Including RECIST Responses in
Priority BRAF Class II and NRAS Subtypes
- In total, 6 patients achieved a partial response (PR) with
exarafenib monotherapy treatment during dose escalation, including
five confirmed PRs as evaluated by Response Evaluation Criteria in
Solid Tumors (RECIST). For responders, the average tumor reduction
was 61% and treatment duration was 7 months. Four of the 6
responders continue exarafenib therapy.
- Treatment with exarafenib at 300 mg bid, the MTD, in patients
with BRAF Class II or NRAS alterations led to a 30% (3 of 10)
overall response rate (ORR).
- The ORR in patients with BRAF Class II alterations was 33% (1
of 3) at 300 mg bid, which included a patient with non-small cell
lung cancer (NSCLC) harboring a BRAF Class II fusion.
- In addition, 71% (5 of 7) of patients with BRAF Class II
alterations achieved an objective tumor reduction. In all treated
patients with Class II alterations, the disease control rate was
86% (6 of 7).
- The ORR in patients with NRAS alterations was 29% (2 of 7) at
300 mg bid and included patients with NRAS mutant melanoma and a
patient with colorectal cancer harboring an NRAS alteration
co-occurring with a BRAF Class III alteration.
- The two additional subtypes with confirmed PRs included RAF
inhibitor naïve patients with BRAF Class I (V600E) papillary
thyroid cancer and squamous cell carcinoma. One unconfirmed PR was
reported in a RAF pretreated patient with BRAF Class I
melanoma.
- Twenty-two patients achieved stable disease (SD) across dose
levels, including 10 patients with objective tumor shrinkage (up to
20%), showing encouraging breadth of activity and prolonged disease
control in a broad range of alterations and tumor types.
1Efficacy evaluable set includes all participants with
documented BRAF (or melanoma with NRAS) genomic alterations (as
specified for each study Part) who received at least 1 dose of
exarafenib and have >= 1 measurable lesion at baseline for
disease response assessment and at least 1 post-baseline efficacy
assessment per RECIST Version 1.1 criteria. Response assessments
performed by each respective clinical trial site (local,
investigator-assessed radiology). Disease control rate is defined
as the percent of participants who achieved a complete response, PR
or SD as their best overall response in accordance with RECIST
v1.1.
2Overall relative dose intensity based on assigned dose will use
the full course of dose received (including intrapatient dose
escalation or de-escalation) divided by the total planned dose as
per the originally assigned.
Exarafenib Monotherapy Dose Expansion Strategy Optimized
for Probability of Success
The expansion cohorts of the KN-8701 clinical trial opened
year-end 2022 and are currently enrolling patients at the 300 mg
bid dose.
Kinnate refined its dose expansion strategy to include greater
enrichment of more sensitive tumor and alteration types based on
the emerging profile and clinical signals observed during dose
escalation.
The priority cohorts will enroll patients with BRAF Class II
alterations, including BRAF fusions, across solid tumors, primarily
melanoma and NSCLC. These cohorts are expected to enroll
approximately 55 patients.
The company expects to provide initial monotherapy dose
expansion data in the first half of 2024.
Exarafenib + Binimetinib Dose Escalation Ongoing; Early
Clinical Activity Observed
Key combination updates as of March 31, 2023 include:
- Enrolled 12 patients primarily with NRAS mutant melanoma into 3
combination dose cohorts: (1) exarafenib 100 mg bid and binimetinib
45 mg bid, (2) exarafenib 100 mg bid and binimetinib 15 mg bid, and
(3) exarafenib 200 mg bid and binimetinib 15 mg bid.
- Enrollment continues at exarafenib 200 mg bid dose and
binimetinib 15 mg bid, with safety evaluation ongoing.
- Two of the 7 efficacy evaluable patients achieved RECIST PRs,
including an unconfirmed PR in a patient with NRAS mutant melanoma
and a confirmed PR in a patient with BRAF Class II pancreatic
cancer. One additional patient with NRAS mutant melanoma
experienced a 25% reduction in their target lesions. Patients who
responded continue combination therapy.
- Kinnate will prioritize development of the exarafenib
combination in patients with NRAS mutant melanoma. The trial will
also enroll RAF pre-treated patients with a BRAF Class I
alteration.
- The company expects to provide an update in the second half of
2023 on the combination dose that will be taken into dose
expansion.
"With the selection of the maximum tolerated dose for
exarafenib, we initiated monotherapy dose expansion with enrollment
ongoing in patients with a meaningful unmet medical need and where
we believe we have the highest probability of success with a
single-agent pan-RAF, including in patients with advanced lung
cancer and melanoma that harbor a BRAF Class II alteration,” said
Richard Williams, MBBS, PhD, chief medical officer, Kinnate
Biopharma Inc. “In addition, with a well-tolerated monotherapy
profile, compelling PK/PD and responses as the backbone, we
continue to pursue priority pan-RAF combination approaches, such as
with a MEK inhibitor in NRAS mutant melanoma, where a combination
may offer additive benefit to patients.”
Nima Farzan, Kinnate Biopharma Inc. chief executive officer,
commented, “Kinnate was formed just five years ago, and in that
time, we have evolved from a start up to a global, precision
oncology company with two programs in the clinic and a growing
pipeline of targeted therapy candidates developed by our own
scientists. Today, we are proud to share the first clinical data
from the company on exarafenib, showing early efficacy both as a
monotherapy and as a combination regimen in BRAF and NRAS-altered
cancers. This potential best-in-class pan-RAF inhibitor anchors our
growing pipeline and positions the company for future growth.”
Today’s AACR presentation is available on the company’s website
at Kinnate.com.
Virtual Investor Webcast Information
Kinnate will host a webcast today, Monday, April 17, 2023, at
5:30 p.m. ET. Investors and the general public are invited to
listen to a live webcast of the session through the "Investors and
Media" section on Kinnate.com or by dialing the U.S. toll free
number +1-888-256-1007 and entering confirmation code: 7465233. An
archived edition of the session will be available following the
event.
About Exarafenib
Exarafenib is an orally administered, potent and selective
investigational small molecule pan-RAF inhibitor. Unlike currently
available treatments that target only Class I BRAF kinase
mutations, exarafenib is designed to target BRAF Class II and Class
III alterations, where it has the potential to be a first-line
targeted therapy, in addition to covering BRAF Class I alterations,
and as a potential treatment for NRAS mutation-positive
melanoma.
KN-8701 Clinical Trial Background
KN-8701 is an ongoing, global Phase 1 clinical trial
(NCT04913285) evaluating exarafenib in patients with advanced solid
tumors harboring BRAF Class I, II and III alterations, and/or who
have NRAS mutant melanoma. KN-8701 contains a two-part dose
escalation: Part A1 is evaluating exarafenib as a monotherapy
across BRAF alterations and tumor types, and Part A2 is evaluating
exarafenib in combination with binimetinib, a MEK inhibitor. Part
B, dose expansion, is evaluating exarafenib at the recommended dose
and schedule in patients with BRAF-altered cancers including lung
cancer, melanoma and other solid tumors.
About Kinnate Biopharma Inc.
Kinnate Biopharma Inc. is a clinical-stage precision oncology
company focused on expanding on the promise of targeted therapies
for those battling cancer. The company is developing medicines for
known oncogenic drivers where there are no approved targeted drugs
and to overcome the limitations of marketed cancer therapies, such
as non-responsiveness or acquired and intrinsic resistance. Kinnate
has two lead clinical programs being studied in solid tumors with
RAF, NRAS and FGFR-driven alterations, and is rapidly progressing a
pipeline of additional small molecule drug candidates as part of
the Kinnate Discovery Engine. The company is driven by the urgency
and knowledge that patients are waiting for new, effective cancer
medicines. For more information, visit Kinnate.com and follow
us on LinkedIn.
Forward-Looking Statements
This press release contains forward-looking statements that
involve substantial risks and uncertainties. These forward-looking
statements include, without limitation, statements regarding the
therapeutic potential, efficacy and clinical benefits of
exarafenib; the safety and tolerability profile of exarafenib; the
future conduct of the monotherapy and combination arms of KN-8701;
the size and makeup of KN-8701 priority and dose-expansion cohorts;
plans for KN-8701 patient enrollment; development priorities; the
timing and presentation of clinical data from KN-8701 for
exarafenib monotherapy and of dose selection for the exarafenib and
binimetinib combination; the relationship between the results from
the positive dose escalation data and results of future clinical
trials; the company’s intention to hold a webcast; and statements
by the company’s chief executive officer and others. Words such as
“believes,” “anticipates,” “plans,” “expects,” “will,” “potential”
and similar expressions are also intended to identify
forward-looking statements. We have based these forward-looking
statements largely on our current expectations and projections
about future events and trends. Such expectations and projections
may never materialize or may prove to be incorrect. These
forward-looking statements are subject to a number of risks,
uncertainties, assumptions and other factors, including recently
transitioning to operating as a clinical-stage biopharmaceutical
company with a limited operating history; the timing, progress and
results of ongoing and planned preclinical studies and clinical
trials for our current product candidates; that continued dose
escalation in our clinical trials could increase the risk of the
occurrence of adverse events; the potential for future clinical
trial results to differ from initial results or from our
preclinical studies; our ability to timely enroll a sufficient
number of patients in our clinical trials; our ability to raise
additional capital to finance our operations; our ability to
discover, advance through the preclinical and clinical development
of, obtain regulatory approval for and commercialize our product
candidates; the novel approach we are taking to discover and
develop drugs; our ability to timely file and obtain approval of
investigational new drug applications for our planned clinical
trials; negative impacts of the COVID-19 pandemic on our business,
including ongoing and planned clinical trials and preclinical
studies; competition in our industry; regulatory developments in
the United States and other countries; our ability to attract, hire
and retain highly skilled executive officers and employees;
difficulties in managing our growth; our ability to protect our
intellectual property; reliance on third parties to conduct our
ongoing and planned preclinical studies and clinical trials, and to
manufacture our product candidates; general economic and market
conditions; and other risks. These and other risks, uncertainties,
assumptions and other factors are further described under the
heading “Risk Factors” in our Annual Report on Form 10-K for the
fiscal year ended December 31, 2022 that we have filed with the
Securities and Exchange Commission (“SEC”), as well as in our
subsequent filings we make with the SEC. New risk factors emerge
from time to time and it is not possible for our management to
predict all risk factors, nor can we assess the impact of all
factors on our business or the extent to which any factor, or
combination of factors, may cause actual results to differ
materially from those contained in, or implied by, any
forward-looking statements. Investors should not rely upon
forward-looking statements as predictions of future events.
Although we believe that the expectations reflected in the
forward-looking statements are reasonable, we cannot guarantee
future results, levels of activity, performance or achievements.
Our forward-looking statements speak only as of the date of this
release, and except as required by law, we undertake no obligation
to update publicly any forward-looking statements for any reason in
the future.
Investor & Media Contact:
Priyanka Shah | Priyanka.Shah@kinnate.com | +1-908-447-6134
Kinnate Biopharma (NASDAQ:KNTE)
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