On December 22, 2022, the FDA granted accelerated approval to mosunetuzumab-axgb (Lunsumio; Genentech), a bispecific CD20-directed CD3 T-cell engager, for the treatment of adult patients with relapsed or refractory follicular lymphoma (FL) after 2 or more lines of systemic therapy. The FDA granted mosunetuzumab breakthrough therapy and orphan drug designations for this indication.
Mosunetuzumab was evaluated in the open-label, multicenter, multicohort GO29781 study. The efficacy population was comprised of 90 patients with relapsed or refractory FL who had received ≥2 previous lines of systemic therapy, including an anti-CD20 monoclonal antibody and an alkylating agent.
The main efficacy outcome measure was objective response rate (ORR) assessed by an independent review facility according to standard criteria for non-Hodgkin lymphoma. The ORR was 80% (95% confidence interval [CI], 70-88), with 60% achieving complete responses. With a median follow-up of 14.9 months among responders, the estimated median duration of response (DOR) was 22.8 months (95% CI, 10-not reached) and the estimated DOR rate at 12 months and 18 months was 62% and 57%, respectively.
The prescribing information of mosunetuzumab has a Boxed Warning for serious or life-threatening cytokine release syndrome (CRS). Warnings and precautions include neurologic toxicity, infections, cytopenias, and tumor flare.
Among 218 patients with hematologic malignancies who received mosunetuzumab at the recommended dose, CRS occurred in 39% of the patients, neurologic toxicity in 39%, serious infections in 17%, and tumor flare in 4%. For CRS, grade 2 toxicity occurred in 15% of the patients, grade 3 in 2%, and grade 4 in 0.5%.
In the pooled safety population of 218 patients, the most common (≥20%) adverse reactions were CRS, fatigue, rash, pyrexia, and headache. The most common (≥10%) grade 3/4 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.
Return to Top
On December 12, 2022, the FDA granted accelerated approval to adagrasib (Krazati; Mirati Therapeutics), a RAS GTPase family inhibitor, for the treatment of adults with KRASG12C–mutated locally advanced or metastatic non–small-cell lung cancer (NSCLC), as determined by an FDA-approved test, who have received ≥1 previous systemic therapy. Adagrasib received breakthrough therapy and orphan drug designations for this indication.
The FDA also approved the QIAGEN therascreen KRAS RGQ PCR kit (tissue) and the Agilent Resolution ctDx FIRST Assay (plasma) as companion diagnostic tests for the identification of candidates for adagrasib therapy.
Approval was based on the multicenter, single-arm, open-label KRYSTAL-1 study, which included patients with locally advanced or metastatic NSCLC with KRASG12C mutations. Efficacy was evaluated in 112 patients whose disease has progressed on or after receiving platinum-based chemotherapy and an immune checkpoint inhibitor, given either concurrently or sequentially. Patients received adagrasib 600 mg orally twice daily until disease progression or unacceptable toxicity.
The main efficacy outcome measures were confirmed objective response rate (ORR), as evaluated by blinded independent central review, 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 reactions 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.
On January 19, 2023, the FDA accelerated the approval of tucatinib (Tukysa; Seagen) in combination with trastuzumab (Herceptin) for the treatment of adults with RAS wild-type, HER2-positive, unresectable or metastatic colorectal cancer (CRC) that has progressed after fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy. Tucatinib received a breakthrough therapy designation for this indication.
Tucatinib was previously approved in combination with trastuzumab and capecitabine for adults with advanced, unresectable or metastatic HER2-positive breast cancer, including patients with brain metastases, who have received ≥1 previous anti-HER2–based regimens in the metastatic setting.
Tucatinib was approved for the treatment of CRC based on efficacy results from 84 patients in the open-label, multicenter MOUNTAINEER trial. Patients were required to have HER2-positive, RAS wild-type, unresectable or metastatic CRC and previous treatment with fluoropyrimidine, oxaliplatin, irinotecan, and an anti-VEGF monoclonal antibody. Patients whose tumors had mismatch repair-deficient proteins or were microsatellite instability-high must also have received an anti–PD-L1 monoclonal antibody. Patients who received previous anti-HER2–targeting therapy were excluded from the trial.
Patients received tucatinib 300 mg orally twice daily with trastuzumab (or a non-US–approved trastuzumab product) administered at a loading dose of 8 mg/kg intravenously on day 1 of cycle 1 followed by a maintenance dose of trastuzumab 6 mg/kg on day 1 of each subsequent 21-day cycle. Patients were treated until disease progression or unacceptable toxicity.
Key efficacy measures were overall response rate (ORR) and duration of response (DOR). ORR was 38% (95% confidence interval [CI], 28-49) and median DOR was 12.4 months (95% CI, 8.5-20.5).
The most common (≥20%) adverse reactions 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.
This review was conducted under Project Orbis, an initiative of the FDA Oncology Center of Excellence. Project Orbis provides a framework for concurrent submission and review of oncology drugs among international partners. For this review, the FDA collaborated with the Australian Therapeutic Goods Administration. The application review is ongoing at the other regulatory agency.
On January 19, 2023, the FDA approved a new indication for zanubrutinib (Brukinsa; BeiGene) for the treatment of adult patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL). Zanubrutinib received an orphan drug designation for this indication.
Zanubrutinib was previously approved for marginal-zone lymphoma, Waldenström’s macroglobulinemia, and mantle-cell lymphoma.
Efficacy in patients with treatment-naïve CLL/SLL was evaluated in the open-label, multicenter SEQUOIA trial. In the randomized cohort, which included patients without 17p deletion, a total of 479 participants were randomized 1:1 to receive either zanubrutinib until disease progression or unacceptable toxicity or bendamustine (Bendeka) plus rituximab (Rituxan; BR) for 6 cycles. The main efficacy outcome measure was progression-free survival (PFS) as determined by independent review committee (IRC). The median PFS was not reached (95% confidence interval [CI], not estimable [NE]-NE) in the zanubrutinib arm and was 33.7 months (95% CI, 28.1-NE) in the BR arm (hazard ratio, 0.42; 95% CI, 0.28-0.63; P ≤.0001). Estimated median follow-up for PFS was 25 months. In a separate nonrandomized cohort of SEQUOIA, zanubrutinib was evaluated in 110 patients with previously untreated CLL/SLL with 17p deletion. Overall response rate (ORR) per IRC was 88% (95% CI, 81-94), and the median duration of response (DOR) was not reached after a median follow-up of 25.1 months.
Efficacy in patients with relapsed or refractory CLL/SLL was evaluated in the multinational, head-to-head ALPINE study. A total of 652 patients were randomized 1:1 to receive either zanubrutinib or ibrutinib (Imbruvica). The median number of previous lines of therapy was 1 (range, 1-8). The main efficacy outcome measures at this time of response analysis were ORR and DOR as determined by an IRC. The ORR was 80% (95% CI, 76-85) in the zanubrutinib arm and 73% (95% CI, 68-78) in the ibrutinib arm (response rate ratio, 1.10; 95% CI, 1.01-1.20; P = .0264). The median DOR was not reached in either arm, after a median follow-up of 14.1 months.
In trials of zanubrutinib, the most common (≥30%) adverse reactions were neutrophil count decrease (42%), upper respiratory tract infection (39%), platelet count decrease (34%), hemorrhage (30%), and musculoskeletal pain (30%). Second primary malignancies, including nonskin carcinomas, developed in 13% of patients, atrial fibrillation or flutter in 3.7% of patients, and grade ≥3 ventricular arrhythmias in 0.2% of patients.
On December 9, 2022, the FDA approved atezolizumab (Tecentriq; Genentech) for the treatment of adult and pediatric patients aged ≥2 years with unresectable or metastatic alveolar soft-part sarcoma (ASPS). Atezolizumab received breakthrough therapy and orphan drug designations for this indication.
Efficacy was evaluated in Study ML39345, an open-label, single-arm study in 49 adult and pediatric patients with unresectable or metastatic ASPS. Eligible patients were required to have histologically or cytologically confirmed ASPS incurable by surgery and an Eastern Cooperative Oncology Group performance status of ≤2. Patients were excluded for primary central nervous system malignancy or symptomatic central nervous system metastases, clinically significant liver disease, or a history of idiopathic pulmonary fibrosis, pneumonitis, organizing pneumonia, or active pneumonitis on imaging. Adult patients received 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 toxicity.
The main efficacy outcome measures were overall response rate (ORR) and duration of response (DOR) as determined by an independent review committee. The ORR was 24% (95% confidence interval, 13-39). Of the 12 patients who experienced an objective response, 67% had a DOR of 6 months or more, and 42% had a DOR of ≥12 months.
The most common (≥15%) adverse reactions 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); decreased appetite and arrhythmia (22% each); influenza-like illness and weight decrease (18% each); and allergic rhinitis and weight increase (16% each).
To sign up for our newsletter or print publications, please enter your contact information below.
Subscribe to recieve the free, monthly TON print publication and TON weekly e‑newsletter.