On August 14, 2023, the FDA approved melphalan hydrochloride for injection/Hepatic Delivery System (HDS; Hepzato Kit; Delcath Systems) as a liver-directed treatment for use in adults with uveal melanoma and unresectable hepatic metastases affecting <50% of the liver and no extrahepatic disease, or extrahepatic disease that is limited to the bone, lymph nodes, subcutaneous tissues, or lung that is amenable to resection or radiation.
The FDA granted this approval an orphan drug designation.
The approval was based on the efficacy results of the FOCUS study, a single-arm, multicenter, open-label, phase 3 clinical trial that included 91 patients with uveal melanoma and unresectable hepatic metastases. Patients were allowed to have limited extrahepatic disease in the bone, subcutaneous sites, lymph nodes, or lung if the life-threatening component of the uveal melanoma was in the liver and the extrahepatic disease was amenable to resection or radiation. The main exclusion criteria were metastases in ≥50% of the liver parenchyma, Child-Pugh class B or C cirrhosis, or hepatitis B or C infection.
Patients received 3 mg/kg of melphalan hydrochloride/HDS based on ideal body weight (maximum dose, 220 mg), which was administered every 6 to 8 weeks for up to 6 infusions. The median number of infusions administered per patient was 4 (range, 1-6). In all, 37% of the 91 patients in the study received the maximum 6 infusions.
The main efficacy outcomes were objective response rate (ORR) and duration of response (DOR), as assessed by an independent central review committee using RECIST version 1.1. The results showed an ORR of 36.3% (95% confidence interval [CI], 26.4-47) and a median DOR of 14 months (95% CI, 8.3-17.7).
The most common (≥20%) adverse reactions, including laboratory abnormalities, were thrombocytopenia, fatigue, anemia, nausea, musculoskeletal pain, leukopenia, abdominal pain, neutropenia, vomiting, increased alanine aminotransferase, prolonged activated partial thromboplastin time, increased aspartate aminotransferase, increased blood alkaline phosphatase, and dyspnea.
Overall, treatment with melphalan hydrochloride/HDS was permanently discontinued because of adverse events in 18% of the study patients; neutropenia was the most common cause of permanent treatment discontinuation. In addition, 14% of patients had dose reductions, including 6% of patients because of decreased platelet count; 4.2% because of neutropenia; and 2.1%, each, because of anemia or thrombocytopenia.
The prescribing information for melphalan hydrochloride/HDS includes a boxed warning about the risk for severe periprocedural complications, including hemorrhage, hepatocellular injury, and thromboembolic events, as well as for myelosuppression associated with severe infection, bleeding, or symptomatic anemia. Because of these risks, melphalan hydrochloride/HDS is only available through a restricted Risk Evaluation and Mitigation Strategy (REMS) program called Hepzato Kit REMS.
Melphalan hydrochloride/HDS is contraindicated in patients who have active intracranial metastases or brain lesions with a propensity to bleed; who have liver failure, portal hypertension, or known varices at risk for bleeding; had surgery or medical treatment of the liver in the past 4 weeks; who have uncorrectable coagulopathy, including active cardiac conditions, worsening or new-onset congestive heart failure, significant arrhythmias, or severe valvular disease; who have an inability to safely undergo general anesthesia; who have allergies or hypersensitivity to melphalan; who have allergies to a component or material used in melphalan hydrochloride/HDS, including an allergy to natural rubber latex; who have an allergy or hypersensitivity to heparin or have heparin-induced thrombocytopenia; and who have a severe allergic reaction to iodinated contrast that is not controlled by premedication with antihistamines and steroids.
The recommended dose of melphalan hydrochloride/HDS is 3 mg/kg, based on ideal body weight, with a maximum dose of 220 mg during a single infusion, which is administered every 6 to 8 weeks, for a maximum of 6 infusions.
Return to Top
On August 14, 2023, the FDA accelerated the approval of elranatamab-bcmm (Elrexfio; Pfizer), a bispecific B-cell maturation antigen (BCMA)–directed CD3 T-cell engager, for the treatment of adults with relapsed or refractory multiple myeloma who have received at least 4 previous lines of therapy, including a proteasome inhibitor (PI), an immunomodulatory drug, and an anti-CD38 monoclonal antibody.
The FDA granted this approval priority review and breakthrough and orphan drug designations.
The approval was based on results from cohort A of the MagnetisMM-3 study, an open-label, single-arm, multicenter, phase 2 clinical trial assessing elranatamab monotherapy in 123 patients with relapsed or refractory multiple myeloma whose disease was refractory to at least 1 PI, 1 immunomodulatory drug, and 1 anti-CD38 antibody. At the time of enrollment, patients had measurable disease by International Myeloma Working Group (IMWG) criteria.
The main efficacy measures were objective response rate (ORR) and duration of response (DOR), as assessed by a blinded independent central review based on IMWG criteria. Of the 123 patients enrolled in the study, 97 had not received previous BCMA-directed therapy and had received at least 4 previous lines of therapy, including a PI, an immunomodulatory drug, and an anti-CD38 monoclonal antibody.
The ORR in those 97 patients was 57.7% (95% confidence interval [CI], 47.3-67.7). At 6 months, the DOR was 90.4% (95% CI, 78.4-95.9), and at 9 months it was 82.3% (95% CI, 67.1-90.9). At a median follow-up of 11.1 months, the median DOR was not reached (95% CI, 12 months-not reached).
The most common (≥20%) adverse reactions were cytokine release syndrome (CRS), fatigue, injection-site reaction, diarrhea, upper respiratory tract infection, musculoskeletal pain, pneumonia, decreased appetite, rash, cough, nausea, and pyrexia. The most common (≥20%) grade 3 or 4 laboratory abnormalities were decreased levels of lymphocytes, neutrophils, hemoglobin, white blood cells, and platelets.
The prescribing information for elranatamab includes a boxed warning regarding the risk for life-threatening or fatal CRS and neurologic toxicity, including immune effector cell–associated neurotoxicity syndrome (ICANS). Among patients treated with elranatamab at the recommended dose, 58% had CRS (including 0.5%, grade 3), 59% had neurologic toxicity (including 7%, grade 3/4), and 3.3% had ICANS.
Because of the risks for CRS and neurologic toxicity, including ICANS, elranatamab is available only through a restricted Risk Evaluation and Mitigation Strategy (REMS) program called ELREXFIO REMS.
To reduce the risk for CRS, the recommended dosing for elranatamab includes the following step-up dosing: step-up dose 1 of 12 mg on day 1, step-up dose 2 of 32 mg on day 4, followed by the first treatment dose of 76 mg on day 8, then 76 mg weekly thereafter through week 24. For patients who have received at least 24 weeks of elranatamab and have achieved partial responses or better and maintained responses for at least 2 months, the dose interval should transition to an every-2-week schedule. Treatment with elranatamab may be continued until disease progression or unacceptable toxicity. Patients should be hospitalized for 48 hours after administration of the first step-up dose, and for 24 hours after administration of the second step-up dose.
On August 9, 2023, the FDA accelerated the approval of talquetamab-tgvs (Talvey; Janssen Biotech), a bispecific GPRC5D-directed CD3 T-cell engager, for the treatment of adults with relapsed or refractory multiple myeloma who have previously received at least 4 lines of therapy, including a proteasome inhibitor (PI), an immunomodulatory drug, and an anti-CD38 monoclonal antibody.
The approval was based on efficacy results from 2 phases of the MMY1001 (MonumenTAL-1) study, a single-arm, open-label, multicenter clinical trial of 187 patients who had previously received at least 4 systemic therapies, including a PI, an immunomodulatory drug, and an anti-CD38 monoclonal antibody.
Patients received talquetamab 0.4 mg/kg subcutaneously weekly after 2 step-up doses in the first week of therapy, or talquetamab 0.8 mg/kg subcutaneously every 2 weeks after 3 step-up doses, until disease progression or unacceptable toxicity.
The main efficacy outcomes were overall response rate (ORR) and duration of response (DOR), as assessed by an independent review committee using the International Myeloma Working Group criteria. The primary efficacy population included patients who had previously received at least 4 lines of therapy, including a PI, an immunomodulatory drug, and an anti-CD38 monoclonal antibody.
In the 100 patients treated with 0.4 mg/kg weekly, the ORR was 73% (95% confidence interval [CI], 63.2-81.4), and the median DOR was 9.5 months (95% CI, 6.5-not estimable). Among the 87 patients treated with 0.8 mg/kg biweekly, the ORR was 73.6% (95% CI, 63-82.4), and the median DOR was not estimable. Overall, an estimated 85% of responders maintained their response for at least 9 months.
The most common (≥20%) adverse reactions reported in the 339 patients in the safety population were cytokine release syndrome (CRS), dysgeusia, nail disorder, musculoskeletal pain, skin disorder, rash, fatigue, decreased weight, dry mouth, pyrexia, xerosis, dysphagia, upper respiratory tract infection, and diarrhea.
The prescribing information for talquetamab includes a boxed warning regarding serious adverse reactions associated with this drug, including life-threatening or fatal CRS and neurologic events, including immune effector cell–associated neurotoxicity syndrome (ICANS). Because of the risks for CRS and neurologic toxicity, including ICANS, talquetamab is available only through a restricted Risk Evaluation and Mitigation Strategy (REMS) program called Tecvayli-Talvey REMS.
The recommended dose of talquetamab is 0.4 mg/kg weekly or 0.8 mg/kg biweekly subcutaneous injection after an initial step-up phase to determine the optimal dosing regimen for each patient. For complete dosing schedules, medical professionals should consult the prescribing information.
On August 11, 2023, the FDA accelerated the approval of the fixed-dose combination of niraparib and abiraterone acetate (Akeega; Janssen Biotech), with prednisone, for the treatment of adults with deleterious or suspected deleterious BRCA-mutated, castration-resistant prostate cancer (CRPC), as determined by an FDA-approved test. The FDA granted this approval priority review.
This is the first oral tablet combining the dual mechanisms of action of the poly (ADP-ribose) polymerase inhibitor niraparib (Zejula; GlaxoSmithKline) and the CYP17 inhibitor abiraterone acetate (Zytiga; Janssen Biotech), taken together with prednisone (a steroid).
Niraparib monotherapy was previously approved as maintenance therapy for adults with advanced epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in a complete or a partial response to first-line platinum-based chemotherapy, and as maintenance therapy for adults with deleterious or suspected deleterious germline BRCA-mutated recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in a complete or partial response to platinum-based chemotherapy. Abiraterone acetate was previously approved for use with prednisone for the treatment of patients with metastatic CRPC or metastatic high-risk castration-sensitive prostate cancer.
The approval of this novel combination was based on results from cohort 1 of the MAGNITUDE study, a randomized, double-blind, placebo-controlled, phase 3 clinical trial of 423 patients with homologous recombination repair (HRR) gene–mutated metastatic CRPC. Patients were randomized in a 1:1 ratio to niraparib 200 mg and abiraterone acetate 1000 mg plus prednisone 10 mg daily (n=212) or placebo and abiraterone acetate plus prednisone daily (n=211). Patients were required to have a previous orchiectomy or be receiving gonadotropin-releasing hormone (GnRH) analogues.
Patients with metastatic CRPC were eligible to participate in the study if they had not received previous systemic therapy in the metastatic setting, except for a short duration (up to 4 months) of previous abiraterone acetate plus prednisone, and ongoing androgen-deprivation therapy. Patients could have received previous therapy with docetaxel or targeted therapy with an androgen receptor in earlier disease settings.
Patients were stratified based on previous use of docetaxel, targeted therapy with an androgen receptor, or abiraterone acetate plus prednisone, as well as BRCA status. Of the 423 patients in the study, 225 (53%) had BRCA mutations.
The main end point was radiographic progression-free survival (PFS), per RECIST version 1.1 for soft-tissue and Prostate Cancer Working Group 3 criteria for bone, as assessed by blinded independent central review. An additional end point was overall survival (OS).
A statistically significant improvement in radiographic PFS with the combination of niraparib and abiraterone acetate plus prednisone versus placebo and abiraterone acetate plus prednisone was observed in patients with BRCA mutation (hazard ratio [HR], 0.53; 95% confidence interval [CI], 0.36-0.79; P=.0014), with a median duration of improvement of 16.6 months versus 10.9 months, respectively. An exploratory OS analysis in the patients with BRCA mutation demonstrated a median of 30.4 months in the investigational arm versus 28.6 months in the placebo arm (HR, 0.79; 95% CI, 0.55-1.12).
A statistically significant improvement in radiographic PFS was seen in the overall cohort 1 (N=423) intent-to-treat (ITT) HRR-mutated patient population (HR, 0.73; 95% CI, 0.56-0.96; P=.0217); however, in the subgroup of 198 (47%) patients with non-BRCA and non-HRR mutations, the HR for radiographic PFS was 0.99 (95% CI, 0.67-1.44) and the HR for OS was 1.13 (95% CI, 0.77-1.64), indicating that the improvement in the ITT patient population of those with HRR mutations was attributed to the results seen in the subgroup of patients with BRCA mutation.
No clinical benefit was observed in patients with metastatic CRPC who did not have an HRR gene mutation (cohort 2), which met the study criterion for futility.
The most common (≥20%) adverse reactions, including laboratory abnormalities, were decreased hemoglobin, decreased lymphocytes, decreased white blood cells, musculoskeletal pain, fatigue, decreased platelets, increased alkaline phosphatase, constipation, hypertension, nausea, decreased neutrophils, increased creatinine, increased potassium, decreased potassium, and increased aspartate aminotransferase.
Among the patients with metastatic CRPC who received the investigational combination agent plus prednisone in cohort 1 of MAGNITUDE (N=423), 27% required a blood transfusion, including 11% who required multiple transfusions.
The recommended dose for this new fixed-dose oral agent is 200 mg of niraparib and 1000 mg of abiraterone acetate, plus 10 mg of prednisone, taken daily until disease progression or unacceptable toxicity. It should be taken on an empty stomach (no food intake for at least 2 hours before and at least 1 hour after taking the drug). Patients receiving niraparib and abiraterone acetate plus prednisone should also receive a GnRH analog concurrently unless they have had a bilateral orchiectomy.
On August 2, 2023, the FDA approved a new indication for trifluridine and tipiracil (Lonsurf; Taiho Oncology), in combination with bevacizumab (Avastin), for patients with metastatic colorectal cancer (CRC) previously treated with fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy; an anti–vascular endothelial growth factor biologic therapy; and if RAS wild-type, an anti–epidermal growth factor receptor therapy.
The FDA granted this indication priority review.
Trifluridine plus tipiracil was previously FDA approved for this indication without bevacizumab in September 2015. Trifluridine plus tipiracil is also approved for the treatment of patients with metastatic gastric or gastroesophageal junction adenocarcinoma after previous treatment with ≥2 lines of chemotherapy.
The new approval was based on results from the phase 3 SUNLIGHT study, a randomized, open-label, multicenter, global clinical trial of trifluridine plus tipiracil and bevacizumab compared with trifluridine plus tipiracil alone in 492 patients with metastatic CRC. These patients had received ≤2 previous chemotherapy regimens and had progressive disease or intolerance to the last regimen.
Overall survival (OS) and progression-free survival (PFS) were the study’s primary efficacy measures, and a significant improvement in OS was demonstrated in the patients who received trifluridine plus tipiracil and bevacizumab versus those who received trifluridine plus tipiracil alone (hazard ratio [HR], 0.61; 95% confidence interval [CI], 0.49-0.77; 1-sided P<.001).
In addition, the median OS was longer with trifluridine plus tipiracil and bevacizumab (10.8 months; 95% CI, 9.4-11.8) than with trifluridine plus tipiracil alone (7.5 months; 95% CI, 6.3-8.6). Likewise, the median PFS was longer with trifluridine plus tipiracil and bevacizumab (5.6 months; 95% CI, 4.5-5.9) than with trifluridine plus tipiracil alone (2.4 months; 95% CI, 2.1-3.2; HR, 0.44; 95% CI, 0.36-0.54; 1-sided P<.001).
The most common (≥20%) adverse reactions or laboratory abnormalities with trifluridine plus tipiracil and bevacizumab were neutropenia, anemia, thrombocytopenia, fatigue, nausea, increased aspartate aminotransferase, increased alanine aminotransferase, increased alkaline phosphatase, decreased sodium, diarrhea, abdominal pain, and decreased appetite.
The recommended dose of trifluridine plus tipiracil is 35 mg/m2 orally with food, twice daily, on days 1 through 5 and on days 8 through 12 of each 28-day cycle. The complete dosing information for bevacizumab is available in the prescribing information.
On July 31, 2023, the FDA approved a new indication for dostarlimab-gxly (Jemperli; GlaxoSmithKline), a PD-1 inhibitor, in combination with carboplatin and paclitaxel, followed by single-agent dostarlimab, for primary advanced or recurrent endometrial cancer that is mismatch repair deficient (dMMR), as determined by an FDA-approved test, or microsatellite instability-high (MSI-H). The FDA granted dostarlimab priority review and breakthrough therapy designations for this indication.
Dostarlimab is the newest front-line option approved in decades for dMMR or MSI-H primary advanced or recurrent endometrial cancer and is the only immuno-oncology therapy approved in the front-line setting in combination with chemotherapy for these patients.
Dostarlimab was previously approved as monotherapy for certain adults with dMMR recurrent or advanced endometrial cancer that progressed during or after treatment with a platinum-containing regimen, as well as monotherapy for certain adults with dMMR recurrent or advanced solid tumors that progressed during or after treatment.
The new approval was based on results from the phase 3 RUBY study, a randomized, multicenter, double-blind, placebo-controlled clinical trial. The trial assessed efficacy in a prespecified subgroup of 122 patients with dMMR or MSI-H disease primary advanced or recurrent endometrial cancer. Patients were randomized in a 1:1 ratio to dostarlimab with carboplatin and paclitaxel, followed by dostarlimab, or to placebo with carboplatin and paclitaxel, followed by placebo. The chemotherapy regimens are described in the full prescribing information. The trial stratified randomization by MMR or MSI status, previous external pelvic radiotherapy, and disease status (recurrent, primary stage III, or primary stage IV).
The primary efficacy measure was investigator-assessed progression-free survival (PFS). The patients with dMMR or MSI-H disease had a significant improvement in PFS, with a median PFS of 30.3 months for dostarlimab-containing regimens versus 7.7 months for regimens with placebo (hazard ratio, 0.29; 95% confidence interval, 0.17-0.50; P<.0001).
The immune-mediated adverse reactions occurring with dostarlimab included pneumonitis; colitis; hepatitis; endocrinopathies, such as hypothyroidism; nephritis with renal dysfunction; and skin-related adverse events. The most common (≥20%) adverse reactions with dostarlimab plus carboplatin and paclitaxel included rash, diarrhea, hypothyroidism, and hypertension. A complete list of adverse reactions is included in the prescribing information.
The recommended dose of dostarlimab is 500 mg every 3 weeks for 6 doses with carboplatin and paclitaxel, followed by 1000 mg of monotherapy with dostarlimab every 6 weeks until disease progression or unacceptable toxicity, or for up to 3 years of treatment. When dostarlimab and chemotherapy are administered on the same day, dostarlimab should be administered before chemotherapy.
On July 20, 2023, the FDA approved quizartinib (Vanflyta; Daiichi Sankyo) with standard cytarabine and anthracycline induction and cytarabine consolidation, and as maintenance monotherapy after consolidation chemotherapy, for the treatment of adults with newly diagnosed acute myeloid leukemia (AML) that is FLT3-internal tandem duplication (ITD)–positive, as detected by an FDA-approved test.
Quizartinib is an orally administered small-molecule inhibitor of the tyrosine kinase receptor FLT3.
The efficacy of quizartinib plus chemotherapy was evaluated in QuANTUM-First, a randomized, double-blind, placebo-controlled clinical trial of 539 patients with newly diagnosed FLT3-ITD–positive AML. FLT3-ITD status was determined prospectively with a clinical trial assay and verified retrospectively with the companion diagnostic LeukoStrat CDx FLT3 Mutation Assay.
Patients were randomized to receive quizartinib (n=268) or placebo (n=271) with induction and consolidation therapy and as maintenance monotherapy according to the initial assignment. Efficacy was established based on overall survival (OS), which was measured from the date of randomization until death by any cause. The primary analysis was conducted after a follow-up of ≥24 months after the randomization of the last patient. Results showed a significant improvement in OS in the quizartinib arm (hazard ratio, 0.78; 95% confidence interval, 0.62-0.98; 2-sided P=.0324).
Quizartinib is not indicated as maintenance monotherapy in patients who have received allogeneic hematopoietic stem cell transplantation; improvement in OS with quizartinib in this setting has not been demonstrated.
Quizartinib is only available through a restricted Risk Evaluation and Mitigation Strategy (REMS) program called Vanflyta REMS because of the serious risk for QT prolongation, torsades de pointes, and cardiac arrest. A boxed warning is included in the prescribing information for quizartinib.
The requirements of the Vanflyta REMS program include the following:
A treatment course of quizartinib consists of ≤2 cycles of quizartinib in combination with induction cytarabine and anthracycline, ≤4 cycles of quizartinib in combination with high-dose cytarabine consolidation, and ≤36 cycles of quizartinib as maintenance therapy or until disease progression or unacceptable adverse reactions. Quizartinib maintenance therapy should be initiated after consolidation chemotherapy once the absolute neutrophil count is >500/mm3 and the platelet count is >50,000/mm3.
To sign up for our newsletter or print publications, please enter your contact information below.
