Phase I/Ib study with the combination of RMC-4630 and LY3214996 in metastatic KRAS mutant CRC, PDAC and NSCLC - The SHERPA-trial

The RAS-RAF-MEK-ERK pathway plays a pivotal role in the regulation cell
proliferation, survival and differentiation. Constitutive activation of this
pathway is frequently observed in human cancers and is associated with high
rates of cancer cell proliferation. Activating mutations of KRAS occur as
frequent as 45% in colorectal cancer, 35% in non-small cell lung cancer and 90%
in pancreatic cancer. However, very few therapeutic approaches have been
developed that are able to target and block the KRAS protein produced by the
mutated gene effectively. Alternative approaches included the development of
small molecule inhibitors of the downstream effectors of KRAS, e.g. MEK
inhibitors. However, also the results with MEK inhibitors in KRAS mutated
(KRASm) cancers have been disappointing, both in patient-derived xenograft
models and in clinical trials. MEK inhibition in KRASm tumors only yields
cytostatic effects, making the combination with other agents necessary. MEK
mediates the activation of ERK which are serine threonine kinases that serve as
critical downstream targets in the MAPK signaling pathway. ERK is the kinase
that transmits all RAF and MEK signals, and is found activated in >85% of
cancers. This makes ERK an interesting target, as ERK is located at the bottom
of the cascade and therefore may be more efficacious than MEK.

Research has shown that the RAS-RAF-MEK-ERK pathway is modulated by SHP2. SHP2
has been shown to promote the sustained activation of RAS and the downstream
ERK MAP kinases. SHP2 is ubiquitously expressed and regulates cell survival and
proliferation primarily through activation of the RAS-ERK signaling pathway.
Reduction of SHP2 activity suppresses tumour cell growth and is a potential
target of cancer therapy. In vivo, inhibition of SHP2 in KRAS-mutant NSCLC
provokes a senescence response, which is exacerbated by MEK inhibition. This
shows that SHP2 inhibition is a vulnerability of KRAS-mutant NSCLC cells that
remains undetected in cell culture and can be exploited therapeutically. But as
ERK is located downstream of MEK it is to be expected that inhibition of ERK
could be more efficacious. The combination of SHP2 and ERK inhibition could be
a potentially more efficacious than the combination of SHP2 and MEK inhibition.

RMC-4630 is a potent, selective, and orally bioavailable SHP2 allosteric
inhibitor that is being developed for patients with tumors harboring certain
activating mutations or other genotypic aberrations in the RAS-MAPK pathway,
including upstream mutations in RTKs. RMC-4630 is currently being evaluated as
a monotherapy in a first-in-human (FIH), dose escalation, phase 1 study
(RMC-4630-01; NCT03600883) in adult subjects with relapsed/refractory solid
tumors.

LY3214996 is an adenosine triphosphate (ATP) competitive inhibitor of ERK2
kinase. LY3214996 has demonstrated good PK/PD/efficacy relationship and potent
single agent efficacy in RAS/MAPK pathway altered cancers from melanoma, CRC,
NSCLC and PDAC.

This combination could be a potential targeted therapy for KRASm cancers. This
especially accounts for pancreatic cancer for which very limited treatment is
available. Despite 5-fluorouracil/leucovorin with ininotecan and oxaliplatin
(FOLFIRINOX) and gemcitabine/paclitaxel significantly improving outcomes for
metastatic cancers, refractory disease still poses significant challenges.

Part A: To determine the recommended phase 2 dose and schedule of the RMC-4630
and LY3214996 combination in patients with KRASm advanced CRC, NSCLC and PDAC.

Part B: To determine the safety and tolerability of RMC-4630 in combination
with LY3214996 in patients with metastatic KRASm PDAC, as assessed by the
incidence of adverse events.

This is a single-center open-label phase I dose-finding study (3+3 classical
design) evaluating the RP2D of RMC-4630 in combination with LY3214996. Based on
the safety, tolerability, and PK and PD data from the dose-finding stage of the
study, a RP2D will be defined for the expansion phase. The phase Ib expansion
cohort study is intended to further characterize the safety, tolerability and
PK/PD of the selected dose of RMC-4630 in combination with LY3214996 in
patients with advanced KRASm PDAC. Furthermore, it will explore the clinical
activity of RMC-4630 in combination with LY3214996 in patients with advanced
KRASm PDAC.

Patients wil receive RMC-4630 (On day 1 and day 2 every week) and LY3214996
(daily). In addition, biopsies are taken before start treatment, during
treatment and (optional) after disease progression. Furthermore,
pharmacokinetic sampling will be performed on day 1 and day 15 of the first
cycle. Adiitionally, every first day of a new cycle (28 days) a sample will be
taken to determine RMC-4630 and LY3214996 concentrations.

Patients are at risk for toxicity associated with treatment with RMC-4630 en
LY3214996.

Patients will be admitted to the hospital twice for pharmacokinetics at the
beginning of the trial during day 1 and day 15 of the first cycle. A venous
dwelling cathether will be positioned for collection of blood samples. On day 1
of subsequent cycles blood samples will be taken to determine through
concentrations using a venapunction.
Toxicity associated with the bloodsampling consist of bruising, or in a rare
case a minor infection at the place of the puncture.

Patients will be required to visit the hospital every week during the first 8
weeks for safety evaluation. Thereafter this period is extended to every 2
weeks.