Revolution Medicines, Inc. (Nasdaq: RVMD), a clinical-stage
oncology company developing targeted therapies for RAS-addicted
cancers, today announced encouraging preliminary clinical data for
RMC-6236, its RASMULTI(ON) Inhibitor, and RMC-6291, its RASG12C(ON)
Inhibitor, from the respective Phase 1/1b studies. These data were
presented during the 2023 AACR-NCI-EORTC International Conference
on Molecular Targets and Cancer Therapeutics (“Triple Meeting”) in
Boston, October 11-15, 2023.
“We are pleased to report encouraging clinical data for both
RMC-6236 and RMC-6291, two pioneering RAS(ON) Inhibitors that are
providing strong validation of our RAS(ON) Inhibitor platform
broadly. The RMC-6236 safety data support that this highly
innovative, oral RASMULTI Inhibitor is generally well tolerated
across dose levels in patients, exhibits dose-dependent
pharmacokinetics reaching exposures predicted preclinically to
induce tumor regressions and induces molecular responses (ctDNA)
and radiographic regressions suggestive of anti-tumor activity
targeting multiple common RAS mutants that cause cancer, including
KRASG12D and KRASG12V,” said Mark A. Goldsmith, M.D., Ph.D., chief
executive officer and chairman of Revolution Medicines. “The
RMC-6291 data provide important initial evidence that this
mutant-selective, oral RASG12C(ON) Inhibitor can provide
mechanistic and clinically meaningful differentiation from
KRASG12C(OFF) inhibitors, as indicated by encouraging clinical
responses in NSCLC patients previously treated with a KRASG12C(OFF)
inhibitor and in KRASG12C(OFF) inhibitor naïve CRC patients at
doses that are generally well tolerated.”
“These data support our ongoing development of RMC-6236 and
RMC-6291, both as monotherapy and in various combinations,
including as a RAS(ON) Inhibitor doublet. We will continue
evaluating these exciting compounds toward the goal of bringing new
and effective therapies to patients living with RAS-addicted
cancers, and remain committed to our rich pipeline of
differentiated mutant-selective RAS(ON) Inhibitors, as there is
significant need for new treatment options.”
Phase 1/1b Trial of RMC-6236,
RASMULTI(ON) Inhibitor
The Phase 1/1b trial is a multicenter, open-label, dose-escalation
and dose-expansion study designed to evaluate RMC-6236 as
monotherapy in patients with advanced solid tumors harboring
KRASG12X mutations. As of the September 11, 2023 data cut-off,
the most common G12 mutations in patients enrolled included G12D
(51%); G12V (28%); G12R (11%); G12A (6%); and G12S (4%). Patients
with KRASG12C mutations were excluded from the study due to the
availability of currently approved KRASG12C(OFF) inhibitors. A
total of 131 patients (69 PDAC, 47 NSCLC, 10 CRC, 5 other tumor
types) were treated across multiple dose levels administered once
daily (QD): 10 mg, 20 mg, 40 mg, 80 mg, 120 mg, 160 mg, 200/220 mg,
300 mg, and 400 mg. Patients had received a median of two prior
lines of therapy (range 1–7) with standard of care appropriate for
tumor type and stage.
As of the data cut-off, RMC-6236 demonstrated an acceptable
safety profile that was generally well tolerated across dose
levels. The most common treatment-related adverse events (TRAEs)
were rash and GI-related toxicities that were primarily Grade 1 or
2 in severity. Of these, the reported Grade 3 TRAEs were rash (5%),
stomatitis (2%), and diarrhea (1%). One previously reported Grade 4
TRAE occurred in a PDAC patient at the 80 mg QD dose level who had
a large intestine perforation at the site of an invasive tumor that
reduced in size while on treatment, which resulted in treatment
discontinuation. No safety signals were observed that indicated an
elevated risk of hepatotoxicity, which has been reported for some
KRASG12C(OFF) inhibitors.
RMC-6236 demonstrated dose-dependent increases in exposure at
steady state with minimal accumulation after repeated daily oral
dosing, which is compatible with once daily dosing. Clinical
exposures achieved at dose levels of 80 mg QD and above were
comparable to those that induced tumor regressions in preclinical
xenograft models with KRASG12X mutations. Circulating tumor DNA
(ctDNA) was assessed in 27 patients with detectable baseline plasma
KRASG12X alleles and evaluable for changes in KRAS variant allele
frequency (VAF) on-treatment. Molecular responses were observed
across two tumor types (NSCLC and PDAC) and 4 different KRAS
mutations (KRASG12D, KRASG12V, KRASG12R, and KRASG12A) with
reductions in KRAS VAF consistent with anti-tumor activity. Three
clinical case reports illustrated tumor regressions induced by
RMC-6236 in patients with ovarian cancer (KRASG12V), NSCLC
(KRASG12D) or PDAC (KRASG12D).
Phase 1/1b Trial of RMC-6291,
RASG12C(ON) Inhibitor
The Phase 1/1b trial is a multicenter, open-label, dose-escalation
and dose-expansion study designed to evaluate RMC-6291 as
monotherapy in patients with advanced solid tumors harboring
KRASG12C mutations. As of the October 5, 2023 data cut-off, a total
of 63 patients (23 NSCLC, 33 CRC, 7 with other tumor types)
received RMC-6291 at various doses, beginning at 50 mg once daily
(QD), escalating to 100 mg QD, 200 mg QD, 100 mg twice daily (BID),
200 mg BID, 300 mg BID and 400 mg BID. Patients across all
histologies had received a median of three prior therapies (range
1–7) with standard of care appropriate for tumor type and
stage.
As of the data cut-off, RMC-6291 demonstrated preliminary
evidence of clinical activity and an acceptable safety profile that
was generally well tolerated across dose levels. The activity
analysis included 37 patients (17 NSCLC, 20 CRC) who were evaluable
for efficacy. Of the 10 NSCLC patients previously treated with a
KRASG12C(OFF) inhibitor, 50 percent (n=5; one unconfirmed PR)
achieved a partial response (PR) as best response, with a 100
percent disease control rate (DCR). Of the 7 NSCLC patients naïve
to KRASG12C(OFF) inhibitors, 43 percent (n=3; two unconfirmed PRs)
achieved a PR, with a 100 percent DCR. Among the 20 CRC patients
naïve to KRASG12C(OFF) inhibitors, 40 percent (n=8; 3 unconfirmed
PRs) achieved a PR as best response, with an 80 percent DCR. The
median time to response was 1.3 months (range 1.1–4.1) and 1.4
months (range 1.2–4.1) for NSCLC and CRC patients, respectively. As
of the data cut-off, no disease progressions had occurred among
patients with an objective response, and 68 percent of all patients
remained on treatment.
The most common TRAEs were QTc prolongation and GI-related
toxicities that were primarily Grade 1 or 2 in severity. Grade 3
TRAEs were QTc prolongation (11.1%) and diarrhea (1.6%), and only
one Grade 3 case was reported with a QTc ≥ 501 msec. All QTc
prolongations were asymptomatic with no cardiac sequalae reported.
No Grade 4 or 5 AEs or SAEs were reported. Nine patients (14.3%)
were dose reduced due to TRAEs, and one patient (1.6%) discontinued
treatment due to a Grade 3 QTc prolongation. No safety signals were
observed that suggest an increased risk of hepatotoxicity, which
has been reported for some KRASG12C(OFF) inhibitors.
Investor WebcastRevolution Medicines will host
an investor webcast on Sunday, October 22, 2023 at 12:30 p.m.
Eastern Time to discuss the data presented at both the Triple
Meeting and the 2023 European Society for Medical Oncology
Congress, in addition to other clinical updates. To participate in
the live webcast, participants may register in advance here:
https://edge.media-server.com/mmc/p/eb8agxe6. A live webcast of the
call will also be available on the Investors section of Revolution
Medicines’ website at
https://ir.revmed.com/events-and-presentations. Following the live
webcast, a replay will be available on the company’s website for at
least 14 days.
About Revolution Medicines, Inc.Revolution
Medicines is a clinical-stage oncology company developing novel
targeted therapies for RAS-addicted cancers. The company’s R&D
pipeline comprises RAS(ON) Inhibitors designed to suppress diverse
oncogenic variants of RAS proteins, and RAS Companion Inhibitors
for use in combination treatment strategies. The company’s RAS(ON)
Inhibitors RMC-6236 (RASMULTI), RMC-6291 (KRASG12C) and RMC-9805
(KRASG12D) are currently in clinical development. Additional
RAS(ON) Inhibitors in the company’s pipeline include RMC-0708
(KRASQ61H) and RMC-5127 (KRASG12V) which are currently in
IND-enabling development, RMC-8839 (KRASG13C), and additional
compounds targeting other RAS variants. RAS Companion Inhibitors in
clinical development include RMC-4630 (SHP2) and RMC-5552
(mTORC1/4EBP1).
Forward-Looking Statements This press release
contains forward-looking statements within the meaning of the
U.S. Private Securities Litigation Reform Act of 1995. Any
statements in this press release that are not historical facts may
be considered "forward-looking statements," including without
limitation statements regarding the company’s development plans and
timelines and its ability to advance its portfolio and R&D
pipeline; progression of clinical studies and findings from these
studies, including the tolerability and potential efficacy of the
company’s candidates being studied; the potential advantages and
effectiveness of the company’s clinical and preclinical candidates,
including its RAS(ON) Inhibitors; the validation of the company’s
platform; potential differentiation between RMC-6291 and RAS(OFF)
inhibitors; the company’s goal of bringing therapies to cancer
patients; and the company’s expectations regarding the potential
market size and size of the potential patient populations for the
company’s product candidates, if approved for commercial use.
Forward-looking statements are typically, but not always,
identified by the use of words such as "may," "will," "would,"
"believe," "intend," "plan," "anticipate," "estimate," "expect,"
and other similar terminology indicating future results. Such
forward-looking statements are subject to substantial risks and
uncertainties that could cause the company’s development programs,
future results, performance, or achievements to differ materially
from those anticipated in the forward-looking statements. Such
risks and uncertainties include without limitation risks and
uncertainties inherent in the drug development process, including
the company’s programs’ early stage of development, the process of
designing and conducting preclinical and clinical trials, the
regulatory approval processes, the timing of regulatory filings,
the challenges associated with manufacturing drug products, the
company’s ability to successfully establish, protect and defend its
intellectual property, other matters that could affect the
sufficiency of the company’s capital resources to fund operations,
reliance on third parties for manufacturing and development
efforts, changes in the competitive landscape and the effects on
the company’s business of the worldwide COVID-19 pandemic. For a
further description of the risks and uncertainties that could cause
actual results to differ from those anticipated in these
forward-looking statements, as well as risks relating to the
business of Revolution Medicines in general, see Revolution
Medicines’ Quarterly Report on Form 10-Q filed with the Securities
and Exchange Commission on August 8, 2023, and its future periodic
reports to be filed with the Securities and Exchange Commission.
Except as required by law, Revolution Medicines undertakes no
obligation to update any forward-looking statements to reflect new
information, events, or circumstances, or to reflect the occurrence
of unanticipated events.
Investors & Media Contact:Erin Graves
650-779-0136 egraves@revmed.com
Revolution Medicines (NASDAQ:RVMD)
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