G1 Therapeutics, Inc. (Nasdaq: GTHX), a commercial-stage oncology
company, today presented results from 24 patients enrolled in its
Phase 2, single arm mechanism of action study of trilaciclib
administered as a single agent to patients with early-stage
triple-negative breast cancer (TNBC) prior to receiving trilaciclib
and neoadjuvant therapy. These results highlight the potential for
trilaciclib to enhance long term immune surveillance by increasing
T cell function and generation of certain memory T cells and
demonstrate gene expression profiles that may be associated with
improved clinical outcome. These data support earlier findings from
this Phase 2 trial demonstrating an increase in the ratio of CD8+ T
cells to regulatory T cells (Tregs); a high ratio of CD8+ T cell to
Tregs is predictive of overall survival (OS) and is associated with
pathologic complete response (pCR). As expected, high rates of pCR
were observed in patients with PD-L1(+) tumors and in patients with
inflamed tumor immune microenvironments.
Data generated across multiple preclinical and
clinical studies to date show that trilaciclib has the greatest
effect on longer term endpoints including OS rather than earlier
efficacy measures such as objective response rate (ORR), pCR, and
progression free survival (PFS), consistent with other
immunotherapies like checkpoint inhibitors. These results suggest
that this is likely due to trilaciclib’s immune-mediated mechanism
of action that protects the immune system from damage caused by
cytotoxic therapy and enhances long-term immune surveillance by
increasing the generation of certain memory T cells. This dual
benefit may provide important longer-term benefits for patients by
improving their ability to generate robust immune responses,
particularly when treated with future subsequent therapies.
“Trilaciclib is a highly active molecule that
enhances T cell activation, favorably alters the tumor
microenvironment, and improves long term immune surveillance; these
new immune analyses help identify potential correlates of treatment
response and extend our understanding of the mechanism,” said Raj
Malik, M.D., Chief Medical Officer at G1 Therapeutics. “Trilaciclib
drives increases in certain memory T cells which are important for
longer term outcomes like overall survival, consistent with our
understanding of the mechanism of action of trilaciclib.”
These results are being presented today at the 2023
American Society of Clinical Oncology (ASCO) Annual Meeting. The
poster, titled, “Neoadjuvant Single-Dose Trilaciclib Prior To
Combination Chemotherapy in Patients with Early Triple-Negative
Breast Cancer: Safety, Efficacy, And Immune Correlate Data from a
Phase 2 Study,” can be found here.
Patient Demographics
As of the data cut date of April 3, 2023, all
patients (N = 24) had received a median (range) of 16 (3–16) cycles
of treatment; 21 (87.5%) patients received pembrolizumab, and 21
(87.5%) patients received carboplatin, per investigator discretion.
All patients completed the study; five underwent definitive surgery
prior to completing planned study treatment. At diagnosis, 79% of
patients had stage II tumors and 88% had ductal carcinoma; 38% of
patients had PD-L1+ tumors, consistent with early TNBC.
Tumor immune microenvironment status was determined
at baseline. All participants with immune-desert tumor
microenvironments at baseline had PD-L1(-) tumors; an additional
nine participants with immune-excluded tumor microenvironments had
PD-L1(-) tumors. All participants with immune-inflamed tumor
microenvironments at baseline had PD-L1(+) tumors; an additional
five participants with immune-excluded tumor microenvironments had
PD-L1(+) tumors. Data published by G1 and others show that
trilaciclib can promote trafficking of immune cells out of the
stroma and into the tumor microenvironment via chemokine release,
thus leading to an inflamed tumor immune microenvironment
status.
Baseline Correlates of Clinical Outcome:
Pathologic Complete Response (pCR)
Tumor infiltrating lymphocytes (TIL) infiltration
is associated with better outcomes with trilaciclib. In this
mechanism of action trial, the pCR rate is higher (77.8%) in
patients with PD-L1(+) tumors relative to that of the overall
enrolled patient population. The pCR rate in the overall enrolled
population (41.7%) is comparable to that of standard neoadjuvant
therapy in this population of patients. As anticipated, the pCR
rate was higher in patients with an immune-inflamed tumor
microenvironment (75.0%) than those with immune-excluded (35.7%) or
immune desert (33.3%) tumor microenvironments.
The tumor status of four enrolled patients
converted from PD-L1(-) at baseline to PD-L1(+) after trilaciclib
monotherapy (day 7); 50% of these patients achieved pCR during the
study.
Immunomodulatory Effects of
Trilaciclib
Trilaciclib was shown to enhance the number and
function of CD8+ T cells in the tumor microenvironment. Seven days
after monotherapy with trilaciclib, the number of CD8+ T cells and
GZMB+ cells, which is a surrogate marker for T cell function, were
enhanced with statistical significance in patients achieving a pCR.
There was also an increase in stromal TILs within the tumor
microenvironment after a single dose of trilaciclib.
RNA-sequence analysis revealed 59 genes that were
differentially expressed seven days after single-dose trilaciclib
in patients who achieved pCR, compared to those who did not.
Furthermore, assessment of signaling pathways associated with pCR
revealed significant enrichment in pathways associated with immune
modulation including T cell receptor signaling and
cytokine-cytokine receptor interaction that were not observed at
baseline. Key genes associated with memory T cells - SELL (CD62L),
IL-7R, and TCF7 - increased from baseline to Day 7, and a subset
analysis based on pCR status revealed significant increases in
these genes when individually assessed and as a gene signature
among patients who achieved pCR.
These results help confirm the role of trilaciclib
in increasing the pool of functional memory T cells that could
contribute to long-term immune surveillance and efficacy, as
measured by longer term endpoints like OS.
Safety Results (n=24)
Trilaciclib continues to show a strong tolerability
profile. Trilaciclib in combination with anthracycline
(doxorubicin)/ cyclophosphamide/paclitaxel (AC/T) ± pembrolizumab ±
carboplatin in the neoadjuvant setting for early-stage TNBC has a
similar safety and tolerability profile as standard neoadjuvant
regimens. The most common treatment-related adverse events (TRAEs;
any grade) related to any study drug were fatigue, nausea,
alopecia, and neutropenia/neutrophil count decreased. There were no
adverse events leading to discontinuation of trilaciclib.
Trilaciclib Phase 2 Mechanism of Action
Trial Design
Tumor tissue was obtained at baseline prior to
study drug administration. Patients then received a single dose of
monotherapy (240 mg/m2) trilaciclib, followed by a tumor biopsy
approximately one week later to assess the ability of a single dose
of trilaciclib monotherapy to favorably alter the tumor
microenvironment. Paired tumor biopsies were available for 22
patients. Patients then entered the treatment phase in which
trilaciclib is administered on day 1 of each cycle of
anthracycline/cyclophosphamide for four cycles followed by
trilaciclib administered on day 1 of each weekly cycle of taxane
chemotherapy for 12 cycles. Pembrolizumab and/or carboplatin was
added at the discretion of the investigator. Three to five weeks
after the treatment phase, patients had definitive surgery and a
final tumor tissue sample was collected if the patient has residual
disease. pCR was assessed at definitive surgery by a local
pathologist, per the current American Joint Committee on Cancer
staging system .
The primary objective was to evaluate the
immune-based mechanism of action of a single dose of trilaciclib as
measured by the change in the ratio of CD8+ T cells to Tregs in the
tumor microenvironment. Secondary endpoints include assessment of
pCR rate at the time of definitive surgery, and safety of the
combination of trilaciclib with neoadjuvant regimen. Exploratory
endpoints include assessment of the immune response, and
identification of molecular and cellular biomarkers in tumor or
blood samples that may be associated with clinical
response/resistance, pharmacodynamic activity, and/or the mechanism
of action of trilaciclib.
About G1 TherapeuticsG1
Therapeutics, Inc. is a commercial-stage biopharmaceutical company
focused on the development and commercialization of next generation
therapies that improve the lives of those affected by cancer,
including the Company’s first commercial product, COSELA®
(trilaciclib). G1 has a deep clinical pipeline and is executing a
development plan evaluating trilaciclib in a variety of solid
tumors, including breast, lung, and bladder cancers. G1
Therapeutics is based in Research Triangle Park, N.C. For
additional information, please visit www.g1therapeutics.com and
follow us on Twitter @G1Therapeutics.
G1 Therapeutics® and the G1 Therapeutics logo and
COSELA® and the COSELA logo are trademarks of G1 Therapeutics,
Inc.
Forward-Looking Statements
This press release contains forward-looking
statements within the meaning of the Private Securities Litigation
Reform Act of 1995. Words such as "may," "will," "expect," "plan,"
"anticipate," "estimate," "intend" and similar expressions (as well
as other words or expressions referencing future events, conditions
or circumstances) are intended to identify forward-looking
statements. Forward-looking statements in this press release
include, but are not limited to, the potential for trilaciclib to
enhance long term immune surveillance by enhancing T cell function
and the generation of certain memory T cells, the association
between gene expression profiles demonstrated by the Phase 2
Mechanism of Action Trial results and the improved clinical
outcome, the expectations for further Phase 2 Mechanism of Action
Trial results to support the current observation of an increase in
the ratio of CD8+ T cells to regulatory T cells (Tregs), that
trilaciclib’s greatest effect is on longer term endpoints including
OS rather than earlier efficacy measures such as pCR, ORR and PFS,
and that the reason why trilaciclib’s greatest effect on longer
term endpoints is because of its immune-mediated mechanism of
action are based on the company’s expectations and assumptions as
of the date of this press release. Each of these forward-looking
statements involves risks and uncertainties. Factors that may cause
the company’s actual results to differ from those expressed or
implied in the forward-looking statements in this press release are
discussed in the company’s filings with the U.S. Securities
and Exchange Commission, including the "Risk Factors" sections
contained therein and include, but are not limited to, the
company’s dependence on the commercial success of COSELA
(trilaciclib); the development and commercialization of new drug
products is highly competitive; the company’s ability to complete
clinical trials for, obtain approvals for and commercialize any of
its product candidates; the company’s initial success in ongoing
clinical trials may not be indicative of results obtained when
these trials are completed or in later stage trials; the inherent
uncertainties associated with developing new products or
technologies and operating as a commercial-stage company; and
market conditions. Except as required by law, the company assumes
no obligation to update any forward-looking statements contained
herein to reflect any change in expectations, even as new
information becomes available.
G1 Therapeutics Contacts:
Will RobertsVice President, Investor Relations
& Corporate Communications919-907-1944
wroberts@g1therapeutics.com
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