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FDA News: August 9, 2023, to August 14, 2023

September 2023 Vol 16, No 5 – Online Only

NEW DRUGS

FDA Grants Accelerated Approval to Elrexfio for Relapsed or Refractory Multiple Myeloma

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).

“Most multiple myeloma patients will experience relapse or resistance of their disease to treatment, often facing increased symptom burden and lowering their chance of surviving longer with each attempted line of therapy,” Ajay Nooka, MD, MPH, Director, Multiple Myeloma Program, Winship Cancer Institute, Emory University, Atlanta, GA, and study investigator, said in a press release. “By offering durable clinical response with an established safety profile and the convenience of subcutaneous administration, Elrexfio provides a much-needed new option for heavily pretreated multiple myeloma patients who are struggling with relapsed myeloma.”

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.

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Talvey Receives Accelerated Approval for Relapsed or Refractory Multiple Myeloma

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 FDA granted the approval of this new indication priority review and breakthrough and orphan drug designations.

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 clinically meaningful efficacy and safety profile observed with talquetamab in heavily pretreated patients in this clinical trial, which included patients treated with prior [B-cell maturation agent]-targeted bispecific or CAR T-cell therapy, has been notable,” said Ajai Chari, MD, Director, Multiple Myeloma Program, and Professor, Clinical Medicine, University of California, San Francisco. “Patients at this stage of disease have a poor prognosis. Talquetamab as a first-in-class therapy is a new option for patients with this difficult-to-treat blood cancer.”

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 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, consult the prescribing information.

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NEW COMBINATION

FDA Accelerates Approval of Akeega, the First Dual-Action Tablet for BRCA-Mutated Metastatic Prostate Cancer

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.

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REGULAR APPROVAL

Gavreto Receives Regular FDA Approval for Patients With Non–Small Cell Lung Cancer and RET Gene Fusion

On August 9, 2023, the FDA granted regular approval to pralsetinib (Gavreto; Genentech), a kinase inhibitor of wild-type RET and oncogenic RET fusions and mutations, for the treatment of adults with metastatic non–small cell lung cancer (NSCLC) and RET fusion–positive gene mutation, as detected by an FDA-approved test.

Oral pralsetinib is also indicated for the treatment of patients aged ≥12 years with advanced or metastatic RET fusion–positive thyroid cancer who require systemic therapy and who are radioactive iodine refractory (if radioactive iodine is appropriate). Pralsetinib was previously granted accelerated approval for the NSCLC indication on September 4, 2020, based on initial overall response rate (ORR) and duration of response (DOR) in 114 patients with NSCLC and RET fusion–positive disease who were enrolled in the ARROW study, a multicenter, open-label, multicohort clinical trial. During that accelerated approval, the FDA also approved the Oncomine Dx test as a companion diagnostic for pralsetinib.

The FDA’s conversion of the accelerated approval to regular approval for patients with NSCLC and RET fusion–positive disease was based on data from an additional 123 patients and 25 months of additional follow-up to assess durability of response to pralsetinib in patients. The patients received pralsetinib therapy until disease progression or unacceptable toxicity.

The primary efficacy measures in the ARROW study were ORR and DOR, as determined by a blinded independent review committee. Among 107 treatment-naïve patients, the ORR was 78% (95% confidence interval [CI], 68-85), with a median DOR of 13.4 months (95% CI, 9.4-23.1). Among 130 patients who had been previously treated with platinum-based chemotherapy, the ORR was 63% (95% CI, 54-71), with a median DOR of 38.8 months (95% CI, 14.8-not estimable).

The most common (≥25%) adverse reactions in the ARROW trial were musculoskeletal pain, constipation, hypertension, diarrhea, fatigue, edema, pyrexia, and cough.

The recommended dose of pralsetinib is 400 mg orally, once daily. Pralsetinib 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).

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