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Fam-trastuzumab deruxtecan-nxki (Enhertu)

FDA approved fam-trastuzumab deruxtecan-nxki for the treatment of adults with unresectable or metastatic HER2-positive breast cancer who were given prior anti-HER2-based regimens in the metastatic setting.

Antibody-drug Conjugate composed of an anti HER2 antibody, a cleavable tetrapeptide-based linker, and a cytotoxic topoisomerase I inhibitor.

Comprised of a trastuzumab bio similar: a tumor protease cleavable plasma  stable linker and deruxtecan, a membrane permeable topoisomerase 1 inhibitor.

T-DXd binds to HER2 on tumor cells, internalizes, and is cleaved by lysosomal enzymes which causes DNA damage and apoptotic cell death.

A HER2 directed antibody drug conjugate, composed of a humanized anti-HER2 immunoglobulin, covalently linked to a topoisomerase I inhibitor payload, a exatecan derivative tetra peptide based cleavable linker.

T-Dxd binds  to the HER2 receptor on tumor cells and is internalized by endocytosis.

The linker is cleaved by lysosome enzymes, releasing topoisomerase I inhibitor payload that inhibits DNA damage, causing apoptosis of the tumor cell.

It is membrane permeable resulting in the elimination of both target and surrounding tumor cells.

Tradename Enhertu.

Similar to T-DM1, but drug to antibody ratio is larger, 7-8 vs. 3.5 to 1.
The anti-HER2 anybody with the same amino acid sequence as trastuzumab, a cleavable linker, and a payload that is a topoisomerase 1 inhibitor.
Has advocacy in breast, gastric, and lung cancers.

A study of 184 patients with HER2-positive, unresectable and/or metastatic breast cancer who had received 2 prior anti-HER2 therapies in the metastatic setting, given fam-trastuzumab deruxtecan-nxki every 3 weeks with tumor imaging obtained every 6 weeks.

The overall response rate was 60.3%, and the median duration of response was 14.8 months.

Among patients with HER2 positive metastatic breast cancer previously treated with trastuzumab and a taxane the risk of disease progression or death was lower among those who receive trastuzumab deruxtecan than among those who received trastuzumab emtansine.

Efficacy was based on DESTINY-Breast03  a multicenter, open-label, randomized trial that enrolled 524 patients with HER2-positive, unresectable, and/or metastatic breast cancer who received prior trastuzumab and taxane therapy for metastatic disease or developed disease recurrence during or within 6 months of completing neoadjuvant or adjuvant therapy.

Patients were randomized 1:1 to receive either Enhertu or ado-trastuzumab emtansine by intravenous infusion every 3 weeks until unacceptable toxicity or disease progression.

Median PFS was not reached in the Enhertu arm and 6.8 months in the ado-trastuzumab emtansine arm.

The ORR based on the patients with measurable disease was 82.7 percent  in the Enhertu arm and 36.1 percent  for those receiving ado-trastuzumab emtansine.

The most common side effects associated with fam-trastuzumab deruxtecan-nxki use were nausea, fatigue, vomiting, alopecia, constipation, decreased appetite, anemia, decreased neutrophil count, diarrhea, leukopenia, cough, and decreased platelet count.

In this trial there was no clear evidence that the level of expression determined by immunohistochemical assay is associated with benefit from trastuzumab deruxtecan : with outcomes in patients with one plus on IHC analysis and those with the score of 2+ are similar.

In low HER disease, the median progression free survival with this agent nearly doubled traditional chemotherapy treatments in metastatic disease.

Fam-Trastuzumab Deruxtecan-nxki preferred second line option for patients with HER2 low activity.

Fam-Trastuzumab Deruxtecan-nxki approved for HER2+ Gastric or GEjunction Adenocarcinoma

 

Approval was based on results from the phase 2 DESTINY-Gastric01 trial which evaluated patients with HER2-positive locally advanced or metastatic gastric or GEJ adenocarcinoma who had progressed on at least 2 prior regimens. including trastuzumab, a fluoropyrimidine-, or a platinum-containing chemotherapy.

 

The dose of fam-trastuzumab deruxtecan-nxki for gastric cancer is 5.4 mg/kg administered as an intravenous infusion once every 3 weeks during a 21-day cycle, until disease progression or unacceptable toxicity.

 

184 patients were randomized 2:1 to receive either fam-trastuzumab deruxtecan-nxki at a dose of 6.4 mg/kg intravenously every 3 weeks, or physician’s choice of either irinotecan or paclitaxel monotherapy.

Studies show that the use of trastuzumab Deruxetan as a second line therapy in patients with HER2 positive advanced gastric or gastroesophageal junction cancer.

 

Overall survival was 12.5 months in the fam-trastuzumab deruxtecan-nxki arm versus 8.4 months in the irinotecan or paclitaxel arm.

 

Overall response rates was 61% in the fam-trastuzumab deruxtecan-nxki cohort compared with 11.3% for patients receiving irinotecan or paclitaxel.

 

Median progression free survival  was 16.4 months in the fam-trastuzumab deruxtecan-nxki arm compared to 3.5 months in the irinotecan or paclitaxel arm: Median duration of response was 11.3 months versus 3.9 months, respectively.

 

Adverse events: anemia, leukopenia, neutropenia, lymphocytopenia, thrombocytopenia, nausea, decreased appetite, increased LFTs, fatigue, diarrhea, hypokalemia, vomiting, constipation, increased bilirubin, pyrexia, alopecia, interstitial lung disease and pneumonitis.

About 10 to 15% of patients receiving T-Dxd develop ILD with the median time to onset of 5 to 6 months and an overall rate of fatal events of 2.2%: the mainstayfor treating T-Dxt induced ILD is steroids.

The most common toxicity from T-DXd is nausea at 73%,  with less frequent cytopenias and alopecia.

Has efficacy, in HER2 low disease, and is standard of care second line chemotherapy for HER 2 low metastatic breast cancer.

Boxed warning of the risks of interstitial lung disease and embryo-fetal toxicity.

 

The results consisted of a primary cohort of 187 patients from Japan and South Korea with HER2-positive, advanced gastric or GEJ adenocarcinoma who had progressed on 2 or more prior treatment regimens including fluoropyrimidine and platinum chemotherapy and trastuzumab.

 

 

 

 

 

 

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