Revolution Medicines, Inc. (Nasdaq: RVMD), a clinical-stage
oncology company developing targeted therapies for RAS-addicted
cancers, today announced key clinical updates from its RAS(ON)
inhibitor portfolio. The data to be presented during an investor
webcast today at 8:00 a.m. Eastern Time (ET) will focus on updated
clinical data from the Phase 1 RMC-6236 monotherapy study in
pancreatic ductal adenocarcinoma (PDAC) and non-small cell lung
cancer (NSCLC). In addition, new clinical data will be provided
from several combination studies, including those evaluating
RMC-6236 with pembrolizumab, RMC-6291 with pembrolizumab, and the
first-of-its-kind RAS(ON) inhibitor doublet combination of RMC-6291
and RMC-6236.
“Our mission is to revolutionize treatment for
patients with RAS-addicted cancers, and our ongoing progress is
supported by the clinical milestones we continue to achieve in
patients with a range of RAS mutant tumor types, stages of disease
and lines of therapy,” said Mark A. Goldsmith, M.D., Ph.D., chief
executive officer and chairman of Revolution Medicines. “We’ve now
reported initial clinical validation of three differentiated
RAS(ON) inhibitors, shown evidence of promising initial clinical
activity and tolerability profiles in patients with three common,
difficult-to-treat RAS-addicted tumors, and shared growing evidence
of clinical impact delivered through three potential treatment
paradigms – as monotherapy, in combination with pembrolizumab, and
as RAS(ON) inhibitor doublets. With these compelling
results, we are in a strong position to pursue an expansive set of
late-stage development opportunities on behalf of patients with
RAS-addicted cancers, beginning with the ongoing and pending
pivotal trials.”
RMC-6236 Monotherapy Study
RMC-6236-001 is a multicenter, Phase 1/1b study designed to
evaluate RMC-6236, a RAS(ON) multi-selective inhibitor, as
monotherapy, in patients with advanced solid tumors. As of
September 30, 2024, a total of 436 patients were treated across
NSCLC (n=132) and PDAC and other solid tumors (n=304) cohorts.
Patients were treated across a range of doses, from 10 mg to 400 mg
once daily (QD).
PDAC CohortAs an update to data reported at the
EORTC-NCI-AACR (ENA) conference in October 2024, the company shared
a new analysis of safety and activity data from the July 23, 2024
data cutoff date in patients with previously treated PDAC treated
with a 300 mg QD dose, the same dose used in the ongoing RASolute
302 Phase 3 PDAC trial.
Key findings:
- In 76 patients with RAS mutant
PDAC, RMC-6236 at 300 mg QD was generally well tolerated and showed
an overall safety profile consistent with the results reported at
ENA. No differentiated safety signals were observed.
- The most common treatment-related
adverse events (TRAEs) were rash and gastrointestinal (GI)-related
toxicities that were primarily Grade 1 or 2 in severity. No Grade 3
or higher TRAEs were observed in greater than 10% of patients.
- There were no treatment
discontinuations due to TRAEs and the mean dose intensity was
89%.
- In 37 patients with 2L RAS mutant
PDAC, RMC-6236 at 300 mg QD demonstrated compelling antitumor
activity.
- Patients with PDAC harboring a KRAS
G12X mutation (n=22) achieved a median PFS of 8.8 months (95%
confidence interval (CI), 8.5 months – not estimable (NE)), while
the median OS was not estimable (95% CI, NE – NE). Patients with
PDAC harboring any RAS mutation (n=37) achieved a median PFS of 8.5
months (95% CI, 5.9 months – NE), while the median OS was not
estimable (95% CI, 8.5 months – NE).
- The proportion of patients who
remained alive six months after starting treatment with RMC-6236
was 100% and 97% in patients with PDAC harboring a KRAS G12X
mutation and patients with PDAC harboring any RAS mutation,
respectively.
- The objective response rate (ORR)
was 36% and 27% in patients with PDAC harboring a KRAS G12X
mutation and patients with PDAC harboring any RAS mutation,
respectively.
RASolute 302, the company’s randomized Phase 3
study of RMC-6236 versus standard of care chemotherapy in 2L
patients with previously treated metastatic PDAC, is currently
ongoing.
Next steps:
- Based on the encouraging
monotherapy data update, the company aims to advance RMC-6236 into
earlier lines of therapy for patients with metastatic PDAC.
NSCLC CohortAs an update from a smaller initial
cohort reported at ESMO 2023, data from a September 30, 2024 data
cutoff date were reported for 124 patients with previously treated
RAS mutant NSCLC who received RMC-6236 at clinically
active doses in the range of 120 mg to 300 mg QD.
Key findings:
- In patients with previously treated
NSCLC, RMC-6236 was generally well tolerated at doses of 120 mg to
220 mg QD, while the 300 mg QD dose demonstrated a higher frequency
and severity of TRAEs.
- In the 120 mg to 220 mg dose range,
the most common TRAEs were rash and GI-related toxicities that were
primarily Grade 1 or 2 in severity. No Grade 3 or higher TRAEs were
observed in greater than 10% of these patients. In the 120 mg to
220 mg dose range, TRAEs leading to dose modification occurred in
41% of patients with 4% of patients discontinuing treatment due to
TRAEs and the mean dose intensity was 88%.
- RMC-6236 at 120 mg to 220 mg QD
demonstrated encouraging antitumor activity in the population of 40
efficacy-evaluable 2L or third-line (3L) patients with NSCLC who
had received immunotherapy and platinum chemotherapy but had not
received docetaxel.
- These patients achieved a median
PFS of 9.8 months (95% CI, 6 – 12.3 months), a median OS of 17.7
months (95% CI, 13.7 months – NE) and an ORR of 38%.
Next steps:
- The company expects to initiate
RASolve 301, a randomized Phase 3 study of RMC-6236 versus
docetaxel in patients with previously treated, locally advanced or
metastatic RAS mutant NSCLC, in the first quarter of 2025.
RAS(ON) Inhibitor Combination
Studies
RMC-6236 with PembrolizumabRMC-LUNG-101B is an
arm of the Phase 1b study of RMC-6236 in combination with
pembrolizumab, with or without chemotherapy, in patients with RAS
mutant NSCLC. A total of 20 patients treated with RMC-6236 at 200
mg QD and pembrolizumab at the standard dose of 200 mg once every
three weeks (Q3W) were evaluated as of an October 28, 2024 data
cutoff date. The median duration of treatment for these patients
was 2.3 months.
The combination of RMC-6236 with pembrolizumab
was generally well tolerated and the safety profile was consistent
with previously reported results for the individual agents. TRAEs
of Grade 1 aspartate aminotransferase (AST) elevation were reported
in two patients (10%) and a TRAE of Grade 2 AST elevation was
reported in one patient (5%). A TRAE of Grade 1 alanine
transaminase (ALT) elevation was reported in one patient (5%) and a
TRAE of Grade 3 ALT elevation was reported in one patient (5%). The
mean dose intensity for RMC-6236 was 97%.
Next steps:
- The company believes the data from
this study support continued evaluation of the combination of
RMC-6236 with pembrolizumab in 1L NSCLC patients.
RMC-6291 and RMC-6236 RAS(ON) Inhibitor
DoubletRMC-6291-101 is a Phase 1b study of RMC-6291 in combination
RMC-6236 in patients with RAS G12C mutant solid tumors. The study
has evaluated RMC-6291 at doses of 100 mg or 200 mg BID and
RMC-6236 at a dose range of 100 mg to 300 mg QD. As of an October
28, 2024 data cutoff date, 74 patients were evaluated for safety
with a median duration of treatment of 2.3 months.
The combination of RMC-6291 with RMC-6236 was
generally well tolerated across all dose levels evaluated. The most
common TRAEs were rash and GI-related toxicities that were
primarily Grade 1 or 2 in severity. No Grade 3 or higher TRAEs were
observed in greater than 5% of patients. One Grade 4 TRAE of
hypokalemia was associated with Grade 3 diarrhea. TRAEs leading to
dose interruption or reduction occurred in 30% and 10% of patients,
respectively. The mean dose intensities for RMC-6291 and RMC-6236
were 95% and 92%, respectively.
A subset of efficacy-evaluable patients with
colorectal cancer (CRC) who were previously treated with a
KRAS(OFF) G12C inhibitor was evaluated for antitumor activity on
treatment with RMC-6291 with RMC-6236. As reference values, the
company also reported that the ORR for patients with CRC treated
with RMC-6236 monotherapy at a dose of 300 mg daily in the
RMC-6236-001 study as of a data cutoff date of September 30, 2024
was 9%, and the ORR for patients with CRC previously treated with a
KRAS(OFF) G12C inhibitor who were subsequently treated with
RMC-6291 monotherapy at a dose of 200 mg twice daily in the
RMC-6291-001 study as of a data cutoff date of October 28, 2024 was
0%. In the combination study, patients with CRC who were previously
treated with a KRAS(OFF) G12C inhibitor and who received their
first doses of the two study drugs at least 8 weeks prior to data
cutoff were included in the analyses (n=12). The ORR was 25%,
including one patient with an unconfirmed complete response, and
the DCR was 92%. The median treatment duration was 2.3 months.
Next steps:
- The company believes the data from
this combination study support continued development of RAS(ON)
doublets in a broad range of tumor types and earlier lines of
therapy.
RMC-6291 with Pembrolizumab RMC-LUNG-101A is an
arm of the Phase 1b study of RMC-6291, a RAS(ON) G12C-selective
inhibitor, in combination with pembrolizumab, with or without
chemotherapy, in patients with RAS G12C mutant NSCLC. A total of 15
patients treated with RMC-6291 at 200 mg twice daily (BID) and
pembrolizumab at the standard dose of 200 mg Q3W were evaluated as
of an October 28, 2024 data cutoff date. As of this date, 47% of
these patients had been on treatment for 60 days or more.
The combination of RMC-6291 with pembrolizumab
was generally well tolerated and the safety profile was consistent
with previously reported results for the individual agents. A TRAE
of Grade 1 AST elevation was reported in one patient (7%) and a
TRAE of Grade 1 ALT elevation was reported in one patient (7%).
There were no TRAEs of Grade 2 or higher AST or ALT elevations
reported. The mean dose intensity for RMC-6291 was 98%.
Next steps:
- The company believes the three
pairwise combinations of RMC-6291 with RMC-6236, RMC-6236 with
pembrolizumab and RMC-6291 with pembrolizumab justify investigation
of the triplet combination of RMC-6291 and RMC-6236 with
pembrolizumab as a potential chemotherapy-sparing option for
patients with 1L NSCLC.
Investor WebcastThe Revolution
Medicines investor webcast will begin at 8:00 a.m. Eastern Time. A
link to participate in the live webcast can be accessed here and is
also available on the Events and Presentations section of
Revolution Medicines’ investor 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. The company’s RAS(ON) inhibitors RMC-6236, a RAS(ON)
multi-selective inhibitor, RMC-6291, a RAS(ON) G12C-selective
inhibitor, and RMC-9805, a RAS(ON) G12D-selective inhibitor, are
currently in clinical development. Additional development
opportunities in the company’s pipeline focus on RAS(ON)
mutant-selective inhibitors, including RMC-5127 (G12V), RMC-0708
(Q61H) and RMC-8839 (G13C), in addition to RAS companion inhibitors
RMC-4630 and RMC-5552.
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 expected timing and
progression of clinical studies and findings from these studies,
including the safety, tolerability and antitumor activity of the
company’s product candidates alone or in combination with other
therapies, and the durability of these results; the late-stage
development opportunities the company plans to pursue; the expected
timing of initiation of the company’s Phase 3 RASolve 301 clinical
trial; the company’s aim to advance RMC-6236 into earlier lines of
therapy for patients with PDAC; the company’s plans to develop
RAS(ON) doublets in a broad range of tumor types and earlier lines
of therapy; the company’s continued evaluation of the combination
of RMC-6236 with pembrolizumab in 1L NSCLC patients; and the
company’s plans to study the triplet combination of RMC-6291,
RMC-6236 and pembrolizumab. 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’ current stage of development, the
process of designing and conducting preclinical studies and
clinical trials, risks that the results of prior clinical trials
may not be predictive of future clinical trials, clinical efficacy,
or other future results, 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 impacting the company, and the effects on the company’s
business of global events, such as international conflicts or
global pandemics. 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
the company’s Quarterly Report on Form 10-Q filed with the
Securities and Exchange Commission (SEC) on November 6, 2024, and
its future periodic reports to be filed with the SEC. Except as
required by law, the company 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 Contacts:
investors@revmed.com
media@revmed.com
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