FDA News: January 27, 2023, to March 22, 2023

TON - April 2023 Vol 16, No 2

NEW DRUGS

Zynyz Receives FDA Accelerated Approval for Merkel-Cell Carcinoma

On March 22, 2023, the FDA granted accelerated approval to retifanlimab-dlwr (Zynyz; Incyte Corporation), a programmed cell death 1–blocking antibody, for the treatment of adult patients with metastatic or recurrent locally advanced Merkel-cell carcinoma (MCC). The FDA granted this approval a priority review, fast-track designation, and orphan drug designation.

This approval was based on results of the PODIUM-201 study, an open-label, multiregional, single-arm clinical trial of patients with metastatic or recurrent locally advanced MCC who had not received previous systemic therapy for advanced disease. Patients were administered retifanlimab 500 mg as an intravenous infusion every 4 weeks until disease progression, unacceptable toxicity, or for up to 24 months.

The primary end point was objective response rate (ORR) as determined by independent central review committee per RECIST version 1.1. Secondary end points included duration of response (DOR), disease control rate, progression-free survival, overall survival, safety, and pharmacokinetics. Among chemotherapy-naïve patients (N = 65), retifanlimab monotherapy resulted in an ORR of 52% (95% confidence interval, 40%-65%), with a complete response rate of 18% and a partial response rate of 34%. Among those who responded to treatment, 76% achieved a DOR of ≥6 months, and 62% had a DOR of ≥12 months.

The most common (≥10%) adverse reactions occurring in patients receiving retifanlimab were fatigue, musculoskeletal pain, pruritus, diarrhea, rash, pyrexia, and nausea. Serious adverse reactions occurred in 22% of those receiving retifanlimab. The most common (≥2%) serious adverse reactions were fatigue, arrhythmia, and pneumonitis.

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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.

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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.

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NEW INDICATIONS

FDA Expands Indication for Verzenio as Adjuvant Treatment for HR-Positive, HER2-Negative, Early Breast Cancer

On March 3, 2023, the FDA approved abemaciclib (Verzenio; Eli Lilly) plus endocrine therapy (tamoxifen or an aromatase inhibitor) for the adjuvant treatment of adult patients with hormone receptor (HR)-positive, HER2-negative, node-positive, early breast cancer at high risk for recurrence. Patients defined as high risk included those having either ≥4 pathologic axillary lymph nodes (pALNs) or 1 to 3 pALNs and either a grade 3 tumor or a tumor size of ≥50 mm. Abemaciclib was previously approved for the same high-risk population with the additional requirement of having a Ki67 score ≥20%; the new approval removes the Ki67 testing requirement.

Efficacy was evaluated in monarchE, a randomized, open-label, 2-cohort, multicenter clinical trial including adult patients with HR-positive, HER2-negative, node-positive, resected, early breast cancer with clinical and pathologic features consistent with a high risk for recurrence. Cohort 1 consisted of patients with ≥4 pALNs or patients with 1 to 3 pALNs and either a grade 3 tumor or a tumor size of ≥50 mm. Cohort 2 consisted of patients not eligible for cohort 1 who had 1 to 3 pALNs and a tumor Ki67 score of ≥20%. Patients were randomized to receive either 2 years of abemaciclib plus physician’s choice of standard endocrine therapy (tamoxifen or an aromatase inhibitor) or standard endocrine therapy alone.

The major efficacy outcome measure was invasive disease–free survival (IDFS). A statistically significant difference was observed in the intent-to-treat population, primarily attributed to the patients in cohort 1 (N = 5120 [91%]; IDFS hazard ratio, 0.653; 95% confidence interval [CI], 0.567-0.753). IDFS at 48 months was 85.5% (95% CI, 83.8-87.0) for abemaciclib plus standard endocrine therapy and 78.6% (95% CI, 76.7-80.4) for standard endocrine therapy alone. Overall survival data remain immature; however, in cohort 2, more deaths were observed with abemaciclib plus standard endocrine therapy compared with standard endocrine therapy alone (10/253 vs 5/264). Therefore, the indication is restricted to patients who meet the criteria for cohort 1.

The most common (≥20%) adverse reactions were diarrhea, infections, neutropenia, fatigue, leukopenia, nausea, anemia, and headache.

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Jemperli Receives Regular FDA Approval for Advanced Endometrial Cancer

On February 9, 2023, the FDA approved dostarlimab-gxly (Jemperli; GlaxoSmithKline) for the treatment of adult patients with mismatch repair-deficient (dMMR), recurrent or advanced endometrial cancer, as determined by an FDA-approved test, whose disease has progressed on or following a previous platinum-containing regimen in any setting and who are not candidates for curative surgery or radiation.

In April 2021, dostarlimab received accelerated approval for adult patients with dMMR, recurrent or advanced endometrial cancer, as determined by an FDA-approved test, whose disease has progressed on or following a previous platinum-containing regimen.

The FDA based the regular approval on additional data collected from the A1 expansion cohort of the ongoing GARNET study, a phase 1, multicenter, open-label, single-arm clinical trial of dostarlimab monotherapy in patients with advanced or recurrent solid tumors. Cohort A1 evaluated the efficacy of dostarlimab in 141 patients with dMMR, recurrent or advanced endometrial cancer whose disease has progressed on or after a platinum-containing regimen.

The major efficacy outcome measures were overall response rate (ORR) and duration of response (DOR) as determined by blinded independent central review per RECIST version 1.1. The confirmed ORR was 45.4% (95% confidence interval, 37.0-54.0), with a 15.6% complete response rate and a 29.8% partial response rate. The median DOR was not reached, with 85.9% of patients having duration of ≥12 months and 54.7% having duration of ≥24 months.

The most common (≥20%) adverse reactions were fatigue/asthenia, anemia, rash, nausea, diarrhea, constipation, and vomiting. The most common (≥2%) grade 3 or 4 adverse reactions were anemia, increased transaminases, urinary tract infection, fatigue/asthenia, and diarrhea.

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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 programmed cell death 1 or programmed cell death ligand 1 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 (PFS) as determined by blinded independent central review per RECIST version 1.1. A key secondary efficacy outcome measure was overall survival (OS). Median PFS 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 OS 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, including laboratory abnormalities, were decreased leukocyte count, decreased neutrophil count, decreased hemoglobin, decreased lymphocyte count, diarrhea, fatigue, nausea, alopecia, increased glucose, constipation, and decreased albumin.

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