A Phase 1/2, open-label, multicenter, dose escalation and dose expansion study of SAR442720 in combination with other agents in participants with advanced malignancies

The RAS-MAPK pathway is frequently dysregulated in human cancers, typically as
a result of genomic alterations that lead to hyperactivation. These alterations
can occur at 3 levels: 1) upstream of RAS in RTKs, 2) directly within mediators
of the RAS catalytic cycle (RAS isoforms and RAS GTPase activating proteins
[GAPs], such as neurofibromin 1 [NF1]), or 3) in downstream effector kinases,
such as BRAF or MEK.
SAR442720 is a potent, selective, and orally bioavailable SHP2 allosteric
inhibitor. SHP2 is a positive upstream regulator of RAS activation, and thus,
presents a suitable therapeutic target for patients whose tumors harbor
oncogenic mutations that remain dependent on active RAS cycling between GTP-
and GDP-bound state. Examples of these include subsets of KRASG12, NF1 LOF
mutations, class 3 type mutations in BRAF or amplification of wild-type KRAS.
SHP2 is also involved in signaling in T-cells. It binds with PD-1 following
PD-L1 stimulation and inhibits T-cell activation. Therefore, targeting SHP2 may
restore or even enhance T-cell functions. The costimulatory receptor CD-28, and
to some extent the T-cell receptor, are dephosphorylated and de-activate some
critical components of the interferon gamma (IFNγ) signaling cascade, defects
in which have been described as a key component of resistance to anti-PD1
therapy. SHP2 inhibition may increase the efficacy of PD1 inhibitors in
patients with high PD-L1 expression but may also sensitize patients with low
PD-L1 expression to a PD1 inhibitor.
SHP2 is expressed in immune cells and plays a role in signal transduction
downstream of regulatory immunoreceptors, including PD-1. Preclinical studies
have demonstrated a role for SHP2 in tumor immunity through modulation of both
innate and adaptive mechanisms. Consistent with a pleiotropic effect on the
immune system, SHP2 inhibition has been shown to attenuate tumor growth in
syngeneic models of mouse tumors that are apparently insensitive to a direct,
cell intrinsic effect of SHP2 inhibition. Given the potential complementary
mechanisms of action, SAR442720 plus anti-PD-1 represents a rational
combination which was evaluated in preclinical models.
Preclinical testing confirms that SHP2 inhibition does not confer sensitivity
to PD1 refractory tumors. In addition, the preliminary observations from
patients receiving single agent SAR442720 suggest increased T-cell infiltration
and activation of innate immune system in tumors during SHP2i treatment.
Considering that SHP2 plays vital roles in tumor growth and tumor immunity, so
combination of SAR442720 with anti-PD1 therapy would provide a promising
therapeutic strategy.
The TCD16210 study consists of 4 parts.
The purpose of the escalation part (Part-1) is to evaluate the safety, PK, and
preliminary efficacy of escalating doses of SAR442720 in combination with
pembrolizumab in adult participants with relapsed/refractory solid tumors with
specific mutations/rearrangements that result in hyperactivation of the
RAS-MAPK pathway and to identify the RP2D for this combination. The purpose of
the expansion part (Part-2) is to evaluate the anti-tumor activity and safety
of SAR442720 combined with pembrolizumab in first-line treatment of
participants with advanced NSCLC. The purpose of Part-3 (Part-3A: dose
escalation and Part-3B: dose expansion) of this study is to evaluate the
safety, recommended Phase 2 dose (RP2D), anti-tumor effect, and PK of SAR442720
in combination with KRAS G12C inhibitor, adagrasib in participants with NSCLC
harboring KRAS G12C mutations. The purpose of Part-4 of this study is to
evaluate the effect of food on the PK of SAR442720 tablet and the relative
bioavailability of SAR442720 tablet formulation (test) compared to the
SAR442720 capsule formulation (reference), when dosed in combination with
pembrolizumab to participants with advanced malignancies.
Netherlands will only take part in part 3 of the trial where SAR442720 will be
combined with adagrasibin patients with KRAS 12G3 mutant NSCLC.
The rationale for combining SAR442720 with adagrasib is that the addition of
SAR442720 to adagrasib may promote anti-tumor activity by inhibiting the
cycling to GTP-bound KRAS for both mutant and wild type KRAS species, therefore
theoretically preventing resistance. Nonclinical and clinical studies
observations with RAF inhibitors have suggested that inhibition of RAS
signaling may be transient due to feedback activation. Mechanistic studies have
shown that such adaptive resistance may be mediated by SHP2, and clinical trial
observations have implicated RTK signaling. The combination of SAR442720 and
adagrasib may augment anti-tumor activity through inhibition of feedback
activation and consequently prevent resistance.
The KRAS G12C mutation occurs frequently in NSCLC (14%) and effective targeted
therapies for cancers with KRAS mutations remain an unmet medical need. KRAS
G12C mutant NSCLC patients showed a variable and submaximal response to KRAS
G12C inhibitors; objective response rate (ORR) to sotorasib, another KRAS G12C
inhibitor that was granted accelerated approval for NSCLC patients, was 37% and
ORR to adagrasib was 45%. In addition, it was shown in mouse model that
treatment with MRTX849 remodeled the tumor immune microenvironment and was able
to produce sustained complete response when combined with check point
inhibitors in immune competent animals but not in T-cell deficient mice. These
data suggest that SHP2 inhibition in combination with KRAS G12C inhibitor has
potential to enhance the anti-tumor activity by blocking the receptor tyrosine
kinase resistance mechanisms as well as by contributing to immune permissive
tumor microenvironment.

The primary goal of Part 3 of this study is to evaluate the safety, recommended
phase 2 dose (RP2D), antitumor effect and PK of SAR442720 in combination with
KRAS G12C inhibitor adagrasib, in participants with NSCLC with KRAS G12C
mutations

Part-3a is the dose escalation part involving safety. the tolerability and the
recommended phase 2 dose is identified and part-3b is the dose extension at
which the anti-tumor activity is determined.

The secondary goal of Part 3 in this study is:
in Part 3A characterizing the PK of SAR442720 with adagrasib, and the PK of
adagrasib with SAR442720 to estimate the anti-tumor effects of SAR442720 with
adagrasib
in Part 3B, assessing the safety profile of SAR442720 with adagrasib, to assess
other indicators of anti-tumor activity, and
assessing the PK of SAR442720 with adagrasib, and the PK of adagrasib with
SAR442720.

A phase 1/2, open-label, multicenter, dose escalation and dose expansion study

Dose-escalation part 3A;
SAR442720 and adagrasib are administered orally on a continuous basis.

Dose-expansion part 3B:
The dose of SAR442720 confirmed in Part 3a and a fixed dose of adagrasib will
be administered orally continuously.

The risks are related to the blood samples and the tumor biopsies taken and to
the possible side effects of the study drugs.
The increased burden on the patient are the more frequent visits to the
hospital.