Page 44 - ITPS-8-3

INNOSC Theranostics and
Pharmacological Sciences Precision medicine and beyond in oncology

extracellular region IV. This combination therapy may chemotherapy, improves survival in patients with advanced
reduce platelet count, fatigue, and anemia. While earlier NSCLC regardless of PDL1 expression level. Similarly, the
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HER2-directed agents targeted tumors with high HER2 KEYNOTE-189 trial demonstrated improved OS across
expression, T-DXd has demonstrated activity beyond all PDL1 strata, including the ˂1% (HR: 0.59), the 1–49%
these, including HER2-positive (immunohistochemistry (HR: 0.55), and the ≥50% (HR: 0.36) groups, by adding
[IHC] 3+ or IHC 2+/in situ hybridization [ISH]+) and pembrolizumab to pemetrexed-platinum chemotherapy.25
HER2 low diseases (IHC 1+ or IHC 2=/ISH-). In HER2-low KEYNOTE-407 reported similar results.26 Despite the
breast cancer patients (IHC 1+ or IHC 2+/ISH-negative), common use of general platinum-based chemotherapies,
T-DXd received the Food and Drug Administration’s targeted therapies like pembrolizumab have resulted in an
(FDA) approval based on the DESTINY-Breast04 trial, increase in OS irrespective of EGFR or ALK sensitizing
which showed a median progression-free survival (PFS) of mutations, regardless of administering it in combination
9.9 months compared to only 5.1 months with physician’s or as a monotherapy.
choice of chemotherapy, corresponding to a hazard ratio Atezolizumab is an immunoglobulin G1 (IgG1)
(HR) of 0.05. Furthermore, in the DENSITY-Breast06 antibody derived from phage display technology. It
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trial, T-DXd showed efficacy in HER2 ultra-low breast binds and blocks PDL1 on tumor cell surfaces and has
tumors (IHC 0 with membrane staining of ≤10%), with shown significant curative results in kidney, bladder
a median PFS of 13.2 months compared to 8.1 months in transitional cell carcinoma, and breast cancer. In a study
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the physician’s choice group (HR: 0.72). In HER-mutated of 3,336 patients who had previously received platinum-
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non-small cell lung cancer (NSCLC) with activated ErbB2 based chemotherapies, those receiving atezolizumab were
exon 20 insertions, T-DXd achieved an objective response associated with a significantly improved OS compared to
rate (ORR) of 49% and a median duration of response of other treatments, including docetaxel and nivolumab. 28
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16.8 months in the DESTINY-Lung02 trial. In addition,
compared to trastuzumab emtansine, another ADC, 3.3. Tyrosine kinase inhibitor (TKI)-EGFR
T-DXd features lysable linkers with an increased drug-to- TKIs target enzymes that are critical in various cellular
antibody ratio, enhancing its antitumor effects. 20,21 With processes, including signaling, growth, and proliferation.
leading success rates in multiple trials and studies, HER2- In several cancer types, these kinases are dysregulated
targeting drugs have demonstrated remarkable efficacy in due to mutations or overexpression, leading to unchecked
treating breast, bladder, NSCLC, ovarian, gastric, colon, cell growth. Targeting these kinases can inhibit tumor
cervical, and endometrial cancers. 16 progression. Osimertinib is a third-generation EGFR-TKI
3.2. Programmed cell death protein 1 (PD-1)/ that selectively targets both EGFR-sensitizing mutations
programmed death ligand 1 (PDL1) and the T790M resistance mutation in patients with
advanced NSCLC. In the FLAURA trial, osimertinib,
PD-1 and PDL1 are transmembrane proteins belonging used as first-line treatment in advanced EGFR-mutated
to the immunoglobulin superfamily. PD-1 can be found NSCLC, demonstrated a median PFS of 18.9 months.
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on activated T-cell membranes, while PDL1 typically acts It also showed a favorable safety profile with lower
as the ligand. The interaction between PD-1 and PDL1 incidences of grade ≥3 adverse events, such as rash,
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inhibits lymphocyte proliferation through the T-cell diarrhea, and interstitial lung disease. Current clinical
receptor, supporting immunosurveillance. However, guidelines recommend molecular testing for EGFR
many tumors exhibit elevated expression of PDL1, mutations in patients with advanced NSCLC to determine
allowing uncontrolled proliferation. Pembrolizumab, a eligibility for EGFR-TKI targeted therapy. Osimertinib
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monoclonal antibody, binds to these PD-1 receptors on is currently the preferred first-line treatment for patients
T cells, prevents further conjugation with PDL1 ligands, harboring these EGFR mutations due to its strong
and restores the immune response against tumor cells. efficacy, central nervous system penetration, and safety
The KEYNOTE-024 trial demonstrated significant overall profile. In addition, for patients who develop resistance
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survival (OS) benefits of pembrolizumab as monotherapy in to first- or second-generation EGFR-TKIs – particularly
NSCLC patients with a tumor total proportion score (TPS) those with the T790M resistance mutation – osimertinib
of PDL1 ≥50%. KEYNOTE-042 revealed a significant remains the recommended treatment option. In February
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OS benefit in tumors with PD-L1 TPS ≥1% (median OS 2024, the FDA approved osimertinib in combination with
16.7 versus 12.1 months; HR: 0.81) and in the 1–49% platinum-based chemotherapy for patients with locally
subgroup (HR 0.88).24 In addition, large-scale clinical advanced or metastatic NSCLC harboring EGFR exon 19
trials such as KEYNOTE-189 and 407 have shown that deletions or exon 21 L858R mutations. 31,32 Furthermore,
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pembrolizumab, when combined with platinum-based the FDA approved osimertinib for adults with locally
Volume 8 Issue 3 (2025) 38 doi: 10.36922/ITPS025140018