Page 52 - ITPS-8-3

INNOSC Theranostics and
Pharmacological Sciences Precision medicine and beyond in oncology

checkpoint-modified CAR constructs to improve efficacy to play a significant role in the aggressive advancement and
and safety. For now, CAR T-cell therapy in CRC should worsening prognosis of PDAC. Sotorasib (Lumakras®), a
be regarded as a promising but investigational modality drug targeting KRAS G12C mutations in solid tumors, is
under active clinical evaluation. recognized as a useful therapy for PDAC. At present, in
Phase I/II trials, this drug restrains the activation of the
4.3. Novel therapies targeting Kirsten rat sarcoma KRAS signaling cascade in cancer development and cell
viral oncogene homolog mutations differentiation by keeping the molecule in a guanosine
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Kirsten rat sarcoma viral oncogene homolog (KRAS) is diphosphate-bound inactive state. Low-grade toxic effects
a guanosine triphosphatase (GTPase) molecular switch of diarrhea and fatigue were frequently observed in trials
that is active when bound to guanosine triphosphate evaluating safety, making it a plausible option for PDAC
and inactive when bound to guanosine diphosphate; this compared to other existing therapies. Out of 38 patients,
cycling is controlled by guanine nucleotide exchange between both Phase I and Phase II trials, diarrhea and
factors and GTPase-activating proteins. In its active form, nausea were reported in nine patients, and eight patients
KRAS controls a signaling cascade of over 80 effector experienced vomiting. The most common Grade 3 adverse
proteins and kinases, including nuclear transcription events observed were diarrhea and fatigue in two patients,
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factors involved in cell growth, proliferation, survival, with no reported Grade 4 or 5 adverse events. Moreover,
migration, and cell differentiation. When mutated sotorasib demonstrated an increased success rate when
at codon 12, the KRAS GTPase is unable to convert combined with panitumumab, an EGFR inhibitor, as
guanosine triphosphate to guanosine diphosphate, causing a chemorefractory cancer therapy in patients without
it to remain in the activated state and continuously previous treatment. The treatment resulted in a median
stimulating the downstream cancerous cellular process. PFS of 5.6 months with a 96 mg dose and 3.9 months
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Hypomethylation of CpG islands in the promoter sequence with a 240 mg dose. The standard care group in this trial
of the KRAS gene can lead to overexpression of KRAS demonstrated a median PFS of only 2.0 months and was
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and ignite the cascade of p53 mutations and associated used as the reference. Further trials with larger patient
overexpression of cyclooxygenase-2. Consequently, cohorts and investigations into combination therapies
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KRAS mutations are strongly associated with CRC and as second-line therapy in previously treated patients are
PDAC. underway, reflecting growing confidence in the efficacy of
sotorasib as a solid tumor cancer therapy.
The current standard-of-care therapy for metastatic
CRC associated with wild-type KRAS typically involves Adagrasib (Krazati®) has been identified as a selective,
the use of EGFR inhibitors, such as panitumumab and covalent inhibitor of the KRAS G12C mutation, with
cabozantinib. Nevertheless, resistance to monotherapy known favorable pharmacokinetic properties and efficient
still arises, particularly due to amplification of the MET bioavailability. With a similar mechanism of action to
oncogene. To combat EGFR treatment resistance, sotorasib, sustained levels of adagrasib above a determined
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combination therapy with the TKI cabozantinib has threshold have been shown to suppress the synthesis and
been investigated in early clinical trials to assess for any rebound of KRAS-dependent signaling in solid tumors,
changes in clinical activity or safety profile compared to especially in NSCLC. The study resulted in a median PFS
monotherapy. A Phase Ib trial treating 25 patients with a of 11.1 months for eight out of the 15 patients who were
combination therapy of cabozantinib and panitumumab determined to have a confirmed partial response to the
reported an ORR of 16% with a median PFS of 3.7 months. drug. Nausea, diarrhea, vomiting, and fatigue are some
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In regard to the safety profile, 20% of the patients of the classically presenting adverse effects with the use
discontinued treatment due to experiencing adverse of adagrasib, similarly seen with other chemotherapies.
events relating to toxicity; however, these adverse events Moreover, adagrasib acts as an inhibitor of cytochrome
were reduced with lower doses of cabozantinib. With a P450 3A4, the enzyme responsible for its metabolism
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PFS that is higher than that of monotherapy, early clinical along with other drugs, causing concern for drug–drug
outcomes of cabozantinib and panitumumab prove to be a interactions when co-administering other therapies.
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promising regimen in the management of KRAS-mediated After promising Phase I/Ib trials, Phase III trials observing
metastatic CRC. Further research is needed to determine adagrasib in combination with drugs such as docetaxel and
the appropriate dosing to improve the safety profile and cetuximab to treat KRAS G12C-mutated solid tumors in
overall tolerability of this combination therapy. NSCLCs and CRCs are underway. 66

The oncogenic KRAS mutation at codon 12 results in Studies comparing the efficacy and toxicity of sotorasib
different subtype allele frequencies, which have been found and adagrasib have been synthesized in meta-analyses to

Volume 8 Issue 3 (2025) 46 doi: 10.36922/ITPS025140018