- Orserdu FDA Approved for ER-Positive, Advanced or Metastatic Breast Cancer with ESR1 Mutation
- Jaypirca Receives FDA Accelerated Approval for Relapsed or Refractory Mantle-Cell Lymphoma
- FDA Grants Lunsumio Accelerated Approval for Relapsed or Refractory Follicular Lymphoma
- Adstiladrin, First Adenoviral Vector–Based Gene Therapy, FDA Approved for High-Risk Non–Muscle-Invasive Bladder Cancer
- Krazati Receives Accelerated FDA Approval for NSCLC with KRASG12C Mutation
- Trodelvy Now Approved for Pretreated Patients with HR-Positive, HER2-Negative Breast Cancer
- Keytruda Receives FDA Approval for Adjuvant Treatment of NSCLC
- Tukysa, in Combination with Trastuzumab, Now FDA Approved for HER2-Positive, Unresectable or Metastatic Colorectal Cancer
- Brukinsa Now FDA Approved for Patients with CLL or SLL
- Tecentriq Now FDA Approved for Treatment of Alveolar Soft-Part Sarcoma
NEW DRUGS
Orserdu FDA Approved for ER-Positive, Advanced or Metastatic Breast Cancer with ESR1 Mutation
On January 27, 2023, the FDA approved elacestrant (Orserdu; Stemline Therapeutics), an estrogen receptor (ER) antagonist, for the treatment of postmenopausal women or adult men with ER-positive, HER2-negative, advanced or metastatic breast cancer and an ESR1 mutation whose disease progressed after ≥1 line of endocrine therapy.
At the same time, the FDA also approved the Guardant360 CDx assay, a companion diagnostic test, for identifying candidates for elacestrant therapy.
The FDA approval was based on results from the randomized, open-label, active-controlled, multicenter EMERALD clinical trial of women and men with ER-positive, HER2-negative, advanced or metastatic breast cancer. All participants had disease progression after 1 or 2 lines of endocrine therapy, including 1 line containing a CDK4/6 inhibitor.
Of the 478 patients in the study, 228 (48%) patients had an ESR1 mutation. The patients were randomized (1:1) to elacestrant 345 mg orally once daily or to the investigator’s choice of endocrine therapy (ie, fulvestrant [Faslodex] or an aromatase inhibitor). Randomization was based on ESR1 mutation status using the Guardant360 CDx assay, previous treatment with fulvestrant, and visceral metastasis.
The progression-free survival (PFS) was significantly different between the participants with an ESR1 mutation and the intention-to-treat (ITT) population. Among the 228 patients with ESR1 mutations, the median PFS was 3.8 months (95% confidence interval [CI], 2.2-7.3) in the elacestrant arm versus 1.9 months (95% CI, 1.9-2.1) in the fulvestrant or aromatase inhibitor arm (hazard ratio, 0.55; 95% CI, 0.39-0.77; 2-sided P = .005).
In an exploratory analysis of PFS in the 250 (52%) patients without ESR1 mutations, the hazard ratio was 0.86 (95% CI, 0.63-1.19), indicating that the improvement in the ITT population was primarily based on the ESR1-positive status.
The most common (≥10%) adverse events were musculoskeletal pain, nausea, increased cholesterol, increased aspartate aminotransferase, increased triglycerides, fatigue, decreased hemoglobin, vomiting, increased alanine aminotransferase, decreased sodium level, increased creatinine, decreased appetite, diarrhea, headache, constipation, abdominal pain, hot flush, and dyspepsia.
Jaypirca Receives FDA Accelerated Approval for Relapsed or Refractory Mantle-Cell Lymphoma
On January 27, 2023, the FDA accelerated the approval of pirtobrutinib (Jaypirca; Eli Lilly) for the treatment of patients with relapsed or refractory mantle-cell lymphoma (MCL) after at least 2 lines of systemic therapy, including a Bruton tyrosine kinase (BTK) inhibitor. The FDA granted this indication an orphan drug designation.
This approval was based on results of the BRUIN study, an open-label, multicenter, single-arm clinical trial with pirtobrutinib monotherapy. The study included 120 patients with MCL who had received a BTK inhibitor; 93% of them received ≥2 previous lines of BTK inhibition, including ibrutinib (Imbruvica; 67%), acalabrutinib (Calquence; 30%), or zanubrutinib (Brukinsa; 8%). In all, 83% of the patients had discontinued their last BTK inhibitor because of progressive or refractory disease. All patients received pirtobrutinib 200 mg orally once daily until disease progression or unacceptable adverse events.
The main efficacy measures were overall response rate (ORR) and duration of response (DOR). The ORR was 50% (95% confidence interval [CI], 41-59), with a 13% complete response rate. At 6 months, the estimated DOR rate was 65.3% (95% CI, 49.8-77.1), with an estimated median DOR of 8.3 months (95% CI, 5.7-not estimable).
The most common (≥15%) adverse reactions were fatigue, musculoskeletal pain, diarrhea, edema, dyspnea, pneumonia, and bruising. The most common (≥10%) grade 3 or 4 laboratory abnormalities were decreased neutrophil, lymphocyte, and platelet counts.
The prescribing information includes warnings about infections, hemorrhage, cytopenias, atrial fibrillation and flutter, and second primary malignancies.
FDA Grants Lunsumio Accelerated Approval for Relapsed or Refractory Follicular Lymphoma
On December 22, 2022, the FDA granted accelerated approval to mosunetuzumab-axgb (Lunsumio; Genentech), a bispecific CD20-directed CD3 T-cell engager, for adults with relapsed or refractory follicular lymphoma after ≥2 lines of systemic therapy. The FDA granted this indication breakthrough therapy and orphan drug designations.
This approval was based on results of the GO29781 study, an open-label, multicenter, multicohort clinical trial of 90 patients with relapsed or refractory follicular lymphoma who received ≥2 lines of systemic therapy.
The main efficacy measure was objective response rate (ORR). The ORR was 80% (95% confidence interval [CI], 70-88), with 60% of the patients achieving a complete response. At a median follow-up of 14.9 months, the estimated median duration of response (DOR) was 22.8 months (95% CI, 10-not reached). At 12 months, the estimated DOR was 62%, and at 18 months, 57%.
The prescribing information for mosunetuzumab includes a boxed warning for cytokine release syndrome (CRS). Among 218 patients with hematologic malignancies who received this drug, 39% had CRS, 17% had serious infections, and 4% had tumor flare. Grade 2 CRS was reported in 15% of patients, grade 3 in 2%, and grade 4 in 0.5%.
The most common (≥10%) grade 3 or 4 laboratory abnormalities were decreased lymphocyte count, decreased phosphate, increased glucose, decreased neutrophil count, increased uric acid, decreased white blood cell count, decreased hemoglobin, and decreased platelets.
Adstiladrin, First Adenoviral Vector–Based Gene Therapy, FDA Approved for High-Risk Non–Muscle-Invasive Bladder Cancer
On December 16, 2022, the FDA granted approval to nadofaragene firadenovec-vncg (Adstiladrin; Ferring Pharmaceuticals), a nonreplicating adenoviral vector–based gene therapy, for adults with high-risk Bacillus Calmette-Guérin (BCG)-unresponsive non–muscle-invasive bladder cancer (NMIBC) and carcinoma in situ, with or without papillary tumors. The FDA granted this indication breakthrough therapy and orphan drug designations.
This approval was based on the results of Study CS-003, a multicenter, single-arm clinical trial of 157 patients with high-risk NMIBC, including 98 patients with BCG-unresponsive carcinoma in situ who were evaluable for response. Patients received nadofaragene firadenovec 75 mL via intravesical instillation (3 × 1011 viral particles/mL) once every 3 months for up to 12 months, until unacceptable adverse events or until recurrent high-grade NMIBC. Patients without high-grade disease recurrence continued to receive nadofaragene firadenovec every 3 months.
The major efficacy measures were a complete response (CR) at any time and the duration of response (DOR). Random bladder biopsies of 5 sites were done in patients with a CR at 12 months. The CR rate was 51% (95% confidence interval, 41%-61%) and the median DOR was 9.7 months (range, 3-≥52); 46% of the responding patients had a sustained CR for at least 1 year.
The most common (≥10%) adverse events, including laboratory abnormalities (>15%), were elevated glucose level, instillation site discharge, increased triglycerides, fatigue, bladder spasm, micturition urgency, increased creatinine, hematuria, decreased phosphate, chills, dysuria, and pyrexia.
Krazati Receives Accelerated FDA Approval for NSCLC with KRASG12C Mutation
On December 12, 2022, the FDA accelerated the approval of adagrasib (Krazati; Mirati Therapeutics), a RAS GTPase inhibitor, for adults with locally advanced or metastatic non–small-cell lung cancer (NSCLC) and KRASG12C mutation (as determined by an FDA-approved test) who have received at least 1 systemic therapy. Adagrasib received breakthrough therapy and orphan drug designations for this indication.
At the same time, the FDA approved the QIAGEN therascreen KRAS RGQ PCR Kit (tissue) and the Agilent Resolution ctDx FIRST Assay (plasma) as companion diagnostics to adagrasib. If no mutation is detected in a plasma specimen, the tumor tissue should be tested.
The approval of adagrasib was based on the results of KRYSTAL-1, a multicenter, single-arm, open-label clinical trial of patients with locally advanced or metastatic NSCLC and KRASG12C mutations. The efficacy was evaluated in 112 patients whose disease progressed during or after platinum-based chemotherapy and an immune checkpoint inhibitor, taken concurrently or sequentially. Patients received adagrasib 600 mg orally twice daily until disease progression or unacceptable adverse events.
The main efficacy measures were confirmed objective response rate (ORR) and duration of response (DOR). The ORR was 43% (95% confidence interval [CI], 34%-53%), and the median DOR was 8.5 months (95% CI, 6.2-13.8).
The most common (≥20%) adverse events were diarrhea, nausea, fatigue, vomiting, musculoskeletal pain, hepatotoxicity, renal impairment, dyspnea, edema, decreased appetite, cough, pneumonia, dizziness, constipation, abdominal pain, and corrected QT interval prolongation. The most common (≥25%) laboratory abnormalities were decreased lymphocytes, increased aspartate aminotransferase, decreased sodium, decreased hemoglobin, increased creatinine, decreased albumin, increased alanine aminotransferase, increased lipase, decreased platelets, decreased magnesium, and decreased potassium.
NEW INDICATIONS
Trodelvy Now Approved for Pretreated Patients with HR-Positive, HER2-Negative Breast Cancer
On February 3, 2023, the FDA approved sacituzumab govitecan-hziy (Trodelvy; Gilead Sciences/Immunomedics) for the treatment of patients with unresectable, locally advanced or metastatic hormone receptor (HR)-positive, HER2-negative (immunohistochemistry [IHC] 0, IHC 1+, or IHC 2+ with a negative in situ hybridization test) breast cancer who have received endocrine-based therapy and at least 2 additional systemic therapies in the metastatic setting.
Sacituzumab govitecan was previously approved for the treatment of patients with unresectable, locally advanced or metastatic triple-negative breast cancer who have had at least 2 previous systemic therapies, and for patients with locally advanced or metastatic urothelial cancer who previously received a platinum-containing chemotherapy and either a PD-1 or PD-L1 inhibitor.
This new approval was based on results of the TROPiCS-02 study, an open-label, multicenter, randomized clinical trial of 543 patients with unresectable, locally advanced or metastatic HR-positive, HER2-negative breast cancer whose disease progressed after receiving other systemic therapies. Patients were randomized (1:1) to sacituzumab govitecan 10 mg/kg as an intravenous infusion on days 1 and 8 of a 21-day cycle or single-agent chemotherapy.
The primary efficacy outcome measure was progression-free survival as determined by blinded independent central review per RECIST version 1.1. A key secondary efficacy outcome measure was overall survival. Median progression-free survival was 5.5 months (95% confidence interval [CI], 4.2-7.0 months) in the sacituzumab govitecan arm versus 4 months (95% CI, 3.1-4.4 months) in the single-agent chemotherapy arm. Median overall survival was 14.4 months in the sacituzumab govitecan arm (95% CI, 13.0-15.7 months) versus 11.2 months (95% CI, 10.1-12.7 months) in the single-agent chemotherapy arm.
The most common (≥25%) adverse events with sacituzumab govitecan in the TROPiCS-02 trial, including laboratory abnormalities, were decreased leukocyte count (88%), decreased neutrophil count (83%), decreased hemoglobin (73%), decreased lymphocyte count (65%), diarrhea (62%), fatigue (60%), nausea (59%), alopecia (48%), increased glucose (37%), constipation (34%), and decreased albumin (32%).
Keytruda Receives FDA Approval for Adjuvant Treatment of NSCLC
On January 26, 2023, the FDA approved pembrolizumab (Keytruda; Merck), a PD-1 inhibitor, as monotherapy for adjuvant treatment of patients with stage IB (T2a ≥4 cm), II, or IIIA non–small-cell lung cancer (NSCLC), after resection and platinum-based chemotherapy.
Pembrolizumab monotherapy was previously approved for the first-line treatment of patients with NSCLC and PD-L1 expression but without ALK or EGFR mutations, and for patients with metastatic NSCLC and PD-L1 expression, following platinum-based chemotherapy.
The FDA approval of pembrolizumab as monotherapy for adjuvant treatment of patients with NSCLC was based on the results of the multicenter, randomized, triple-blind, placebo-controlled KEYNOTE-091 clinical trial of patients who had not received neoadjuvant radiotherapy or chemotherapy. The patients were randomized (1:1) to adjuvant treatment with pembrolizumab 200 mg or to placebo intravenously every 3 weeks for up to 1 year. Of the 1177 patients in the study, 1010 (86%) patients received adjuvant platinum-based chemotherapy after complete resection.
The main end point was disease-free survival (DFS). The results showed a significant improvement in DFS with pembrolizumab versus placebo in the overall population. Among patients who received adjuvant chemotherapy, the median DFS was 58.7 months in the pembrolizumab arm (95% confidence interval [CI], 39.2-not reached) versus 34.9 months in the placebo arm (95% CI, 28.6-not reached; hazard ratio [HR], 0.73; 95% CI, 0.60-0.89). In a subgroup analysis of 167 patients who did not receive adjuvant chemotherapy, the HR for DFS was 1.25 (95% CI, 0.76-2.05).
The adverse events observed in the KEYNOTE-091 clinical trial were similar to those seen with pembrolizumab monotherapy in patients with NSCLC, with the exception of hypothyroidism (22%), hyperthyroidism (11%), and pneumonitis (7%). In addition, myocarditis led to 2 deaths.
Tukysa, in Combination with Trastuzumab, Now FDA Approved for HER2-Positive, Unresectable or Metastatic Colorectal Cancer
On January 19, 2023, the FDA accelerated the approval of tucatinib (Tukysa; Seagen), a Bruton tyrosine kinase inhibitor, in combination with trastuzumab (Herceptin), a HER2/neu receptor agonist, for the treatment of RAS wild-type, HER2-positive unresectable or metastatic colorectal cancer (CRC) that progressed after fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapies. This combination was granted a breakthrough therapy designation for this indication.
The combination of tucatinib plus trastuzumab was previously approved for patients with unresectable advanced or metastatic HER2-positive breast cancer.
This new approval was based on results of the open-label, multicenter MOUNTAINEER clinical trial of 84 patients with HER2-positive, RAS wild-type, unresectable or metastatic CRC who received previous treatment with fluoropyrimidine, oxaliplatin, irinotecan, and an anti-VEGF monoclonal antibody. Patients with mismatch repair-deficient tumor or with microsatellite instability-high tumor also received a PD-L1 inhibitor. Patients who previously received an anti–HER2-targeting therapy were excluded from the study.
Patients received tucatinib 300 mg orally twice daily, plus a trastuzumab loading dose of 8 mg/kg intravenously on day 1 of cycle 1, followed by trastuzumab 6 mg/kg on day 1 of each subsequent 21-day cycle, until disease progression or unacceptable adverse events.
The overall response rate was 38% (95% confidence interval [CI], 28-49), and the median duration of response was 12.4 months (95% CI, 8.5-20.5).
The most common (≥20%) adverse events were diarrhea, fatigue, rash, nausea, abdominal pain, infusion-related reactions, and pyrexia. The most common (≥20%) laboratory abnormalities were increased creatinine, increased glucose, increased alanine aminotransferase, decreased hemoglobin, increased aspartate aminotransferase, increased bilirubin, increased alkaline phosphatase, decreased lymphocytes, decreased albumin, decreased leukocytes, and decreased sodium.
Brukinsa Now FDA Approved for Patients with CLL or SLL
On January 19, 2023, the FDA approved zanubrutinib (Brukinsa; BeiGene USA), a Bruton tyrosine kinase (BTK) inhibitor, for the treatment of patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL). The FDA granted zanubrutinib an orphan drug designation for this indication.
Zanubrutinib was previously approved for mantle-cell lymphoma, Waldenström’s macroglobulinemia, and relapsed or refractory marginal-zone lymphoma.
This new approval for CLL or SLL was based on results of several studies and cohorts. In the SEQUOIA study, a cohort of 479 patients with treatment-naïve CLL or SLL and no 17p deletion were randomized (1:1) to zanubrutinib monotherapy until disease progression or unacceptable adverse events or to bendamustine (Bendeka) plus rituximab (Rituxan) for 6 cycles. The main efficacy measure was progression-free survival (PFS). At an estimated median follow-up of 25 months, the median PFS was not reached (95% confidence interval [CI], not estimable) in the zanubrutinib arm versus 33.7 months (95% CI, 28.1-not estimable) in the bendamustine plus rituximab arm (hazard ratio, 0.42; 95% CI, 0.28-0.63; P ≤.001).
In a separate, nonrandomized cohort of the SEQUOIA study, 110 patients with treatment-naïve CLL or SLL and 17p deletion received zanubrutinib monotherapy. The overall response rate (ORR) was 88% (95% CI, 81-94). At a median follow-up of 25.1 months, the median duration of response (DOR) was not reached.
A second study called ALPINE included 652 patients with relapsed or refractory CLL or SLL who were randomized (1:1) to zanubrutinib or to another BTK inhibitor—ibrutinib (Imbruvica). The median number of previous lines of therapy in this study was 1 (range, 1-8). The ORR was 80% (95% CI, 76-85) in the zanubrutinib arm versus 73% (95% CI, 68-78) in the ibrutinib arm (response rate, 1.10; 95% CI, 1.01-1.20; P = .0264). At a median follow-up of 14.1 months, the median DOR was not reached in either arm.
The most common (≥30%) adverse events with zanubrutinib were decreased neutrophil count (42%), upper respiratory tract infection (39%), platelet count decreased (34%), hemorrhage (30%), and musculoskeletal pain (30%). In addition, 3.7% of patients had atrial fibrillation or flutter, and 0.2% of the patients had grade ≥3 ventricular arrhythmias. In all, 13% of patients had second primary malignancies.
Tecentriq Now FDA Approved for Treatment of Alveolar Soft-Part Sarcoma
On December 9, 2022, the FDA approved atezolizumab (Tecentriq; Genentech), a PD-L1 inhibitor, for patients aged ≥2 years with unresectable or metastatic alveolar soft-part sarcoma (ASPS), a type of soft-tissue sarcoma. The FDA granted atezolizumab breakthrough therapy and orphan drug designations for this indication.
Atezolizumab was previously approved for many indications.
The approval of atezolizumab for ASPS was based on Study ML39345, an open-label, single-arm clinical trial of adult and pediatric patients with unresectable or metastatic ASPS. Patients were excluded if they had primary central nervous system (CNS) malignancy or symptomatic CNS metastases, liver disease, or a history of idiopathic pulmonary fibrosis, pneumonitis, organizing pneumonia, or active pneumonitis on imaging.
Of the 49 patients in the study, 47 were adults and 2 were pediatric patients (aged ≥12 years). Adult patients received atezolizumab 1200 mg intravenously and pediatric patients received 15 mg/kg (up to a maximum of 1200 mg) intravenously once every 21 days, until disease progression or unacceptable adverse events.
The overall response rate was 24% (95% confidence interval, 13-39). Among the 12 patients who had an objective response, 67% had a response lasting ≥6 months, and 42% had a response lasting ≥12 months.
The most common (≥20%) adverse events were musculoskeletal pain (67%); fatigue (55%); rash (47%); cough (45%); nausea, headache, and hypertension (43% each); vomiting (37%); constipation and dyspnea (33% each); dizziness and hemorrhage (29% each); insomnia and diarrhea (27% each); pyrexia, anxiety, abdominal pain, and hypothyroidism (25% each); and decreased appetite and arrhythmia (22% each).