Fam-Trastuzumab Deruxtecan-Nxki for HER2-Low Breast Cancer
The FDA approved fam-trastuzumab deruxtecan-nxki for adult patients with unresectable or metastatic HER2-low (IHC 1+ or IHC 2+/ISH-) breast cancer who have received prior chemotherapy in the metastatic setting or developed disease recurrence during or within 6 months of completing adjuvant chemotherapy.
Efficacy was based on DESTINY-Breast04 (NCT03734029), a randomized, multicenter, open-label clinical trial that enrolled 557 patients with unresectable or metastatic HER2-low breast cancer. The trial included two cohorts: 494 hormone receptor-positive (HR+) patients and 63 hormone receptor-negative (HR-negative) patients. HER2-low expression was defined as IHC 1+ or IHC 2+/ISH-, determined at a central laboratory. Patients were randomized (2:1) to receive either fam-trastuzumab deruxtecan-nxki 5.4 mg/kg (N=373) by IV infusion every 3 weeks or physician's chemotherapy choice (N=184, including eribulin, capecitabine, gemcitabine, nab-paclitaxel, or paclitaxel).
The primary efficacy measure was progression-free survival (PFS) in patients with HR+ breast cancer, assessed by blinded independent central review using RECIST 1.1. Secondary efficacy measures were PFS in the overall population (all randomized HR+ and HR-negative patients), overall survival (OS) in HR+ patients, and OS in the overall population.
The median age of patients was 57 years (range: 28-81) and 24 percent were 65 or older. Selected demographics were reported as follows: 99.6 percent female, 48 percent White, 40 percent Asian, 2 percent Black or African American, 3.8 percent Hispanic/Latino.
Median PFS in the HR+ cohort was 10.1 months (95% CI: 9.5, 11.5) in the fam-trastuzumab deruxtecan-nxki arm and 5.4 months (95% CI: 4.4, 7.1) in the chemotherapy arm (HR=0.51; 95% CI: 0.40, 0.64; p<0.0001). Median PFS in the overall population was 9.9 months (95% CI: 9.0, 11.3) in the fam-trastuzumab deruxtecan-nxki arm and 5.1 months (95% CI: 4.2, 6.8) for those receiving chemotherapy (HR 0.50; 95% CI: 0.40, 0.63; p<0.0001).
In the HR+ cohort, median OS was 23.9 months (95% CI: 20.8, 24.8) and 17.5 months (95% CI: 15.2, 22.4) in the fam-trastuzumab deruxtecan-nxki and chemotherapy arms, respectively (HR 0.64; 95% CI: 0.48, 0.86; p=0.0028). In the overall population, median OS was 23.4 months (95% CI: 20.0, 24.8) in the fam-trastuzumab deruxtecan-nxki arm versus 16.8 months (95% CI: 14.5, 20.0) in the chemotherapy arm (HR 0.64; 95% CI: 0.49, 0.84; p=0.001).
The most common adverse reactions (incidence >=20%) in patients receiving fam-trastuzumab deruxtecan-nxki in this trial were nausea, fatigue, alopecia, vomiting, anemia, constipation, decreased appetite, diarrhea, and musculoskeletal pain. The prescribing information includes a Boxed Warning advising 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.
Darolutamide Tablets for Metastatic Hormone-Sensitive Prostate Cancer
The FDA approved darolutamide tablets in combination with docetaxel for adult patients with metastatic hormone-sensitive prostate cancer (mHSPC). Efficacy was based on ARASENS (NCT02799602), a randomized, multicenter, double-blind, placebo-controlled clinical trial in 1,306 patients with mHSPC. Patients were randomized to receive either darolutamide 600 mg orally twice daily plus docetaxel 75 mg/m2 intravenously administered every 3 weeks for up to 6 cycles or docetaxel plus placebo. All patients received a gonadotropin-releasing hormone analog concurrently or had a bilateral orchiectomy.
The primary efficacy measure was overall survival (OS). Time-to-pain progression was an additional efficacy measure. Median OS was not reached (NR) (95% CI: NR, NR) in the darolutamide plus docetaxel arm and 48.9 months (95% CI: 44.4, NR) in docetaxel plus placebo arm (HR 0.68; 95% CI: 0.57, 0.80; p<0.0001). Treatment with darolutamide and docetaxel resulted in a statistically significant delay in time-to-pain progression (HR 0.79; 95% CI: 0.66, 0.95; 1-sided p=0.006).
The median age of patients was 67 years (41-89) and 17 percent were 75 years or older. Selected demographics were reported as follows: 52 percent White, 36 percent Asian, 4 percent Black or African American, and 7 percent Hispanic/Latino. Three percent of patients had M1a disease (spread to distant lymph nodes), 83 percent had M1b (spread to bones), and 14 percent had M1c (spread to organs).
The most common adverse reactions experienced by patients (incidence >=10% with a >=2% increase over placebo with docetaxel) were constipation, decreased appetite, rash, hemorrhage, increased weight, and hypertension. The most common laboratory test abnormalities (>=30%) were anemia, hyperglycemia, decreased lymphocyte count, decreased neutrophil count, increased AST, increased ALT, and hypocalcemia.
The recommended darolutamide dose for mHSPC is 600 mg (two 300 mg tablets) taken orally, twice daily, with food until unacceptable toxicity or disease progression. Docetaxel, 75 mg/m2 intravenously is administered every 3 weeks for up to 6 cycles. The first dose of docetaxel should be administered within 6 weeks after the start of darolutamide treatment.
Capmatinib for Metastatic Non-Small Cell Lung Cancer
The FDA granted regular approval to capmatinib for adult patients with metastatic non-small cell lung cancer (NSCLC) whose tumors have a mutation leading to mesenchymal-epithelial transition (MET) exon 14 skipping, as detected by an FDA-approved test.
Capmatinib was previously granted accelerated approval for the same indication on May 6, 2020, based on initial overall response rate and duration of response in the GEOMETRY mono-1 trial (NCT02414139), a multicenter, non-randomized, open-label, multi-cohort study. The conversion to regular approval was based on data from an additional 63 patients, as well as an additional 22 months of follow-up time to assess durability of response and verify clinical benefit.
Efficacy was demonstrated in 160 patients with metastatic NSCLC with a mutation leading to MET exon 14 skipping. Patients received capmatinib 400 mg orally twice daily until disease progression or unacceptable toxicity.
The primary efficacy measures were ORR and duration of response (DOR) as determined by a Blinded Independent Review Committee. Among 60 treatment-naive patients, ORR was 68 percent (95% CI: 55, 80) with a DOR of 16.6 months (95% CI: 8.4, 22.1). Among 100 previously treated patients, ORR was 44 percent (95% CI: 34, 54) with a DOR of 9.7 months (95% CI: 5.6, 13).
The median age of patients was 71 years (48-90). Selected demographics were reported as follows: 61 percent female, 77 percent White, 61 percent never smoked, 83 percent had adenocarcinoma, and 16 percent had CNS metastases. Among previously treated patients, 81 percent received one, 16 percent received two, and 3 percent received three prior lines of systemic therapy. Among previously treated patients, 86 percent received prior platinum-based chemotherapy.
The most common adverse reactions (>=20%) in patients were edema, nausea, musculoskeletal pain, fatigue, vomiting, dyspnea, cough, and decreased appetite. The recommended capmatinib dose is 400 mg orally twice daily with or without food.
Accelerated Approval of Fam-Trastuzumab Deruxtecan-Nxki for HER2-Mutant Non-Small Cell Lung Cancer
The FDA granted accelerated approval to fam-trastuzumab deruxtecan-nxki for adult patients with unresectable or metastatic non-small cell lung cancer (NSCLC) whose tumors have activating HER2 (ERBB2) mutations, as detected by an FDA-approved test, and who have received a prior systemic therapy. This is the first drug approved for HER2-mutant NSCLC.
FDA also approved the Oncomine Dx Target Test (tissue) and the Guardant360 CDx (plasma) as companion diagnostics for fam-trastuzumab deruxtecan-nxki. If no mutation is detected in a plasma specimen, the tumor tissue should be tested.
Fam-trastuzumab deruxtecan-nxki was evaluated at a 6.4 mg/kg dose (n=152) across multiple trials and at a 5.4 mg/kg dose (n=102) in a randomized dose-finding trial. Response rates were consistent across dose levels. Increased rates of interstitial lung disease/pneumonitis were observed at the higher dose. The efficacy results of the approved recommended dose of 5.4 mg/kg given intravenously every 3 weeks are described below.
Efficacy for accelerated approval was based on DESTINY-Lung02, a multicenter, multi-cohort, randomized, blinded, dose-optimization trial. Eligible patients were required to have unresectable or metastatic HER2-mutant non-squamous NSCLC with disease progression after prior systemic therapy. They were selected for treatment with fam-trastuzumab deruxtecan-nxki based on the presence of activating HER2 (ERBB2) mutations in a tumor specimen. Patients received fam-trastuzumab deruxtecan-nxki 5.4 mg/kg by intravenous infusion every 3 weeks until unacceptable toxicity or disease progression.
Of the 52 patients in the primary efficacy population of DESTINY-Lung02, the median age was 58 years (range 30-78), 69 percent were female, 79 percent were Asian, 12 percent were White, and 10 percent were of other races. The major efficacy outcome measures were confirmed objective response rate (ORR) as assessed by blinded independent central review using RECIST v1.1 and duration of response (DOR). The confirmed ORR was 58 percent (95% CI: 43, 71) and the median DOR was 8.7 months (95% CI: 7.1, not estimable).
The most common (>=20%) adverse reactions, including laboratory abnormalities, were nausea, decreased white blood cell count, decreased hemoglobin, decreased neutrophil count, decreased lymphocyte count, decreased platelet count, decreased albumin, increased aspartate aminotransferase, increased alanine aminotransferase, fatigue, constipation, decreased appetite, vomiting, increased alkaline phosphatase, and alopecia. The prescribing information includes a Boxed Warning advising health professionals of the risk of interstitial lung disease and embryo-fetal toxicity.
Ventana MMR RxDx Panel to Identify dMMR Solid Tumor Patients & pMMR Endometrial Cancer Patients Eligible for Pembrolizumab
The FDA approved a label expansion for the Ventana MMR RxDx panel. This approval highlights personalized health care through tests that determine which patients are most likely to respond to specific and targeted therapies.
The Ventana MMR RxDx Panel is the first immunohistochemistry (IHC) companion diagnostic test to aid in identifying patients whose solid tumors are deficient in DNA mismatch repair (dMMR) and who may be eligible for pembrolizumab. The panel is also the first companion diagnostic test to aid in identifying endometrial cancer patients whose tumors are proficient in DNA mismatch repair (pMMR), and who may be eligible for a combination of pembrolizumab and the tyrosine kinase inhibitor (TKI) lenvatinib. The test evaluates a panel of MMR proteins in tumors to provide important treatment information to clinicians.
MMR is a naturally occurring mechanism that scans our DNA, correcting errors that cause disease. When MMR is deficient (dMMR), cells mutate and can lead to cancer. While MMR deficiency is most common in endometrial cancer, other high-prevalence dMMR tumor types include gastric, colorectal, small intestine, cervical, and neuroendocrine cancers. In the U.S., prevalence of dMMR across patients with solid tumors has been estimated at 14 percent. PD-1 inhibitors can be an effective treatment in cancers with MMR deficiency. For endometrial cancer patients without this MMR deficiency (pMMR), PD-1 inhibitors may retain activity when combined with a TKI.
FDA approval of the label expansion for the Ventana MMR RxDx panel provides clinicians with access to a fully automated panel of MMR biomarkers tested by IHC. This label expansion follows the 2021 FDA approval of the Ventana MMR RxDx panel as the first IHC predictive test to identify endometrial carcinoma patients eligible for treatment with the anti-PD1 immunotherapy dostarlimab-gxly. That approval was expanded for the following indications on the dates below:
* August 2021-dMMR solid tumor patients for treatment with dostarlimab-gxly
* March 2022-dMMR solid tumor patients for treatment with pembrolizumab
* June 2022-pMMR solid tumor patients for treatment with a combination of pembrolizumab and lenvatinib.
The dMMR proteins have been clinically proven to be predictive biomarkers for PD-1 targeted therapy; specifically, a loss of expression of one or more MMR proteins might predict an increased likelihood of response to such therapy. PD-1 inhibitors can be effective in cancers with MMR deficiency. MMR is a conserved molecular mechanism that functions to correct the improper base substitutions that spontaneously occur during DNA replication. Defects in the MMR machinery have been attributed to mutations in the MMR proteins.
Phase I Clinical Trial of NSC-CRAd-S-pk7 for Recurrent High-Grade Glioma
The FDA has authorized a Phase I physician-sponsored clinical trial that will use a licensed oncolytic virotherapy platform, NSC-CRAd-S-pk7, a cutting-edge therapeutic candidate comprising tumor-tropic neural stem cells delivering an oncolytic adenovirus selectively to tumor sites in patients with recurrent high-grade glioma.
The clinical trial will be an open-label, non-randomized, multicenter study. Once it is funded, it will address the safety and tolerability of administering serial doses of NSC-CRAd-S-pk7 in adult patients with recurrent, histologically confirmed, high-grade gliomas (WHO Grade 3 or 4). Secondary endpoints will evaluate treatment efficacy, including progression-free and overall survival, as well as any immune response to NSC-CRAd-S-pk7. This physician-sponsored study will be led by Jana Portnow, MD, Professor in the Department of Medical Oncology & Therapeutics Research and Co-Director of the Brain Tumor Program at City of Hope.
A previously completed Phase I dose-escalation clinical trial in newly diagnosed glioma patients included a single dose of NSC-CRAd-S-pk7 given as an adjunct to radiation and temozolomide. The research demonstrated that NSC-CRAd-S-pk7 was well-tolerated in the patient population and showed promising preliminary results of efficacy (Lancet Oncol 2021;22(8):1103-1114).
"Our team at City of Hope is excited to be a part of the development of NSC-CRAd-S-pk7. Despite their potential, the first-generation oncolytic virus therapies given as free virus were not very effective -most likely due to rapid inactivation by the patient's immune system," noted Karen Aboody, MD, Professor in the Department of Stem Cell Biology and Regenerative Medicine and Division of Neurosurgery at City of Hope. "Our new platform uses stem cells like a 'Trojan horse' to shield the oncolytic viral particles from immune inactivation and deliver them to the tumor sites. This results in significantly more virus distributed at the tumor sites, inducing a greater self-amplifying anti-tumor response. This may also result in a secondary anti-tumor immune response."
The NSC-CRAd-S-pk7 platform is an allogeneic, off-the-shelf therapy comprised of an immortalized Neural Stem Cell (NSC) line loaded with an engineered oncolytic adenovirus. Upon surgical resection of a tumor, NSC-CRAd-S-pk7 is injected into the walls of the resection cavity, resulting in viral infection and destruction of any remaining tumor cells.