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Approval of Fam-Trastuzumab Deruxtecan-Nxki for Breast Cancer

The FDA approved fam-trastuzumab deruxtecan-nxki for adult patients with unresectable or metastatic HER2-positive breast cancer who have received a prior anti-HER2-based regimen either in the metastatic setting or in the neoadjuvant or adjuvant setting and have developed disease recurrence during or within 6 months of completing therapy.

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In December 2019, fam-trastuzumab deruxtecan-nxki received accelerated approval for adult patients with unresectable or metastatic HER2-positive breast cancer who have received two or more prior anti-HER2-based regimens in the metastatic setting. The following trial was the confirmatory trial for the accelerated approval.


Efficacy was based on DESTINY-Breast03 (NCT03529110), 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 fam-trastuzumab deruxtecan-nxki or ado-trastuzumab emtansine by intravenous infusion every 3 weeks until unacceptable toxicity or disease progression. Randomization was stratified by hormone receptor status, prior treatment with pertuzumab, and history of visceral disease.


The main efficacy outcome measure was progression-free survival (PFS) as assessed by blinded independent central review based on RECIST v.1.1. Overall survival (OS) and confirmed objective response rate (ORR) were the key secondary outcome measures. Median PFS was not reached (95% CI: 18.5, not estimable) in the fam-trastuzumab deruxtecan-nxki arm and 6.8 months (95% CI: 5.6, 8.2) in the ado-trastuzumab emtansine arm. The hazard ratio was 0.28 (95% CI: 0.22, 0.37; p<0.0001). At the time of the PFS analysis, 16 percent of patients had died and OS was immature. The ORR based on the patients with measurable disease assessed by BICR at baseline was 82.7 percent (95% CI: 77.4, 87.2) in the fam-trastuzumab deruxtecan-nxki arm and 36.1 percent (95% CI: 30.0, 42.5) for those receiving ado-trastuzumab emtansine.


The most common adverse reactions (incidence >30%) in patients receiving fam-trastuzumab deruxtecan-nxki were nausea, fatigue, vomiting, alopecia, constipation, anemia, and musculoskeletal pain. Serious adverse reactions in >1 percent of patients were vomiting, interstitial lung disease, pneumonia, pyrexia, and urinary tract infection. The prescribing information includes a Boxed Warning to advise health professionals of the risk of interstitial lung disease and embryo-fetal toxicity. The recommended fam-trastuzumab deruxtecan-nxki dose for breast cancer is 5.4 mg/kg given as an intravenous infusion once every 3 weeks (21-day cycle) until disease progression or unacceptable toxicity.


Priority Review of Durvalumab + Chemo for Locally Advanced or Metastatic Biliary Tract Cancer

A supplemental Biologics License Application (sBLA) for durvalumab, in combination with standard-of-care chemotherapy, has been accepted and granted Priority Review for patients with locally advanced or metastatic biliary tract cancer (BTC).


The sBLA was based on results from an interim analysis of the TOPAZ-1 Phase III trial presented during the 2022 American Society of Clinical Oncology Gastrointestinal Cancers (ASCO GI) Symposium. The data showed durvalumab plus chemotherapy (gemcitabine plus cisplatin) reduced the risk of death by 20 percent versus chemotherapy alone (HR=0.80; 95% CI: 0.66-0.97; 2-sided P=0.021). An estimated one in four (25%) patients treated with durvalumab plus chemotherapy were alive at 2 years compared to one in 10 (10%) treated with chemotherapy alone.


Results also showed a statistically significant 25 percent reduction in the risk of disease progression or death with durvalumab plus chemotherapy (HR, 0.75; 95% CI, 0.64-0.89; 2-sided P=0.001). The durvalumab combination was generally well-tolerated and did not increase the discontinuation rate due to adverse events compared to chemotherapy alone.


Fast Track Designation for HM43239 in R/R AML Patients & FLT3 Mutation

The FDA granted Fast Track designation to HM43239, an oral, myeloid kinome inhibitor, for the treatment of patients with relapsed or refractory (R/R) acute myeloid leukemia (AML) with FLT3 mutation. Currently, an international Phase I/II clinical trial is ongoing for HM43239 in the R/R AML patient population. HM43239 received orphan drug designation from the FDA for treatment of AML in 2018.


HM43239 is a potent oral genotype-agnostic small molecule inhibitor of a constellation of kinases operative in myeloid malignancies and known to be involved in tumor proliferation, resistance to therapy, and differentiation. Currently being developed for the treatment of patients with AML, HM43239 is a potent inhibitor of FLT3, SYK, mutant forms of cKIT, JAK1/2, and other kinases.


Regarding FLT3, HM43239 is highly active in vivo against FLT3 internal tandem duplication (ITD), as well as resistance-conferring D835 and gatekeeper (F691) tyrosine kinase domain (TKD) mutations. In vivo murine xenograft models suggest superior antitumor activity and favorable tolerability relative to established kinase inhibitor in AML, including gilteritinib (FLT3 inhibitor) and entospletinib (SYK inhibitor). Additionally, in vivo xenograft models suggest synergy with inhibitors of DNMT, BCL-2, and other key therapeutic targets, highlighting the combinatorial optionality of HM43239 in AML.


In an ongoing international Phase I/II clinical trial, HM43239 has delivered complete remissions in a diversity of relapsed or refractory AML patients and continues to be a well-tolerated oral agent.