Category: Molecular Tidbits

April 2024: Current Tumor-Agnostic Therapies

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The FDA on April 5, 2024, granted accelerated approval to Fam-trastuzumab deruxtecan-nxki (ENHERTU®) for adult patients with unresectable or metastatic HER2-positive (IHC3+) solid tumors who have received prior systemic treatment and have no satisfactory alternative treatment options.

This is the 6th Tumor-Agnostic therapeutic target for which an agent has received regulatory agency approval.

A current summary of the Tumor-Agnostic therapeutic targets, and agents approved, is provided below. Please review the drug Prescribing Information for the respective therapeutic agents, as NOT all products are approved for First Line therapy.

MMRd/MSI-H: Pembrolizumab (KEYTRUDA®) and Dostarlimab (JEMPERLI®)
TMB-H: Pembrolizumab (KEYTRUDA®)
NTRK fusions: Larotrectinib (VITRAKVI) and Entrectinib (ROZLYTREK®)
BRAF V600E: Dabrafenib (TAFINLAR®) plus Trametinib (MEKINIST®)
RET Fusions: Selpercatinib (RETEVMO®)
HER2 Overexpression: Fam-trastuzumab deruxtecan (ENHERTU®)

The National Cancer Institute describes Tumor-Agnostic therapy as a type of targeted treatment that uses drugs or other substances to treat cancer based on the cancer’s genetic and molecular features, without regard to the cancer type or where the cancer started in the body. Tissue-Agnostic therapy uses the same drug to treat all cancer types that have the genetic mutation or biomarker, that is targeted by the drug.

STK11 Mutation

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Both STK11 (also called LKB1) and KEAP1 mutation occur in about 17% of Non Small Cell Lung Cancer (adenocarcinomas), respectively, and correlates with poor outcome with immune checkpoint inhibitors or immune checkpoint inhibitors plus chemotherapy. KRAS is frequently comutated with STK11, KEAP1, and TP53 and these subgroups confer different prognostic outcomes. Within the KRAS mutated population, STK11 and/or KEAP1 mutations are associated with inferior Overall Survival and Progression Free Survival across treatments, compared with STK11-wild type and/or KEAP1-wild type. It appears that anti PD-1/anti-PD-L1 immune checkpoint inhibitors in combination with anti-angiogenic agent and chemotherapy is an efficacious first-line treatment in metastatic NSCLC subgroups with KRAS mutations co-occurring with STK11 and/or KEAP1 or TP53 mutations and/or high PD-L1 expression.

RNF43 Mutations

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RNF43 mutations were identified in 29% of BRAF V600E-mutated MicroSatellite-Stable (MSS) metastatic ColoRectal Cancer tumors, and this finding was strongly associated with a clinical response to anti-BRAF/EGFR-based combination therapy. When compared to BRAF V600E-mutated, MicroSatellite-Stable metastatic CRC patients without the RNF43 mutation (RNF43 wild-type), patients with BRAF V600E-mutated, MicroSatellite-Stable metastatic CRC carrying a RNF43 mutation had a Response Rate of 72.7% versus 30.8% (P=0.03), longer median Progression Free Survival (10.1 months versus 4.1 months, HR=0.30; P=0.01) and longer median Overall Survival (13.6 months versus 7 months, HR=0.26; P=0.008). Conversely, the predictive value of RNF43 mutations seen in MicroSatellite-Stable tumors was not observed in MicroSatellite Instability (MSI)-High tumors.

Folate Receptor Alpha

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Approximately 35-40% of ovarian cancer patients express high levels of Folate Receptor alpha, and this expression correlates with advanced stages of disease and more malignant phenotypes. There is limited expression of Folate Receptor alpha in normal tissues and is limited to the choroid plexus, proximal renal tubules, placenta, and endometrium. Testing for Folate Receptor alpha can be performed on fresh or archived tissue and is considered positive if at least 75% of cells had 2+ staining intensity or greater, based on immunohistochemistry-based scoring. .

ESR1 Gene Mutation

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ESR1 (Estrogen Receptor 1) gene mutation is the most common acquired mutation noted in breast tumors as they progress from primary to metastatic setting. These mutations promote ligand independent Estrogen Receptor activation and have been shown to promote resistance to estrogen deprivation therapy. It appears that ESR1 mutations are harbored in metastatic ER-positive breast cancers treated with prior Aromatase Inhibitor (AI) therapy in the metastatic setting, but not in primary breast cancers, suggesting that ESR1 mutations may be selected by prior therapy with an AI in advanced breast cancer. Approximately 40% of patients who had received AI therapy for metastatic breast cancer have ESR1 mutations. It is best to test for ESR1 mutations with a liquid biopsy following progression on an AI and CDK 4/6 inhibitor.