- Zynyz Receives FDA Accelerated Approval for Merkel-Cell Carcinoma
- FDA Grants Padcev plus Keytruda Accelerated Approval for Locally Advanced or Metastatic Urothelial Carcinoma
- Tafinlar plus Mekinist Combination Approved for Pediatric Low-Grade Glioma with BRAFV600E Mutation
- FDA Expands Indication for Verzenio as Adjuvant Treatment for HR-Positive, HER2-Negative, Early Breast Cancer
- Jemperli Receives Regular FDA Approval for Advanced Endometrial Cancer
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 PD-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.
FDA Grants Padcev plus Keytruda Accelerated Approval for Locally Advanced or Metastatic Urothelial Carcinoma
On April 3, 2023, the FDA accelerated the approval of a new indication for enfortumab vedotin-ejfv (Padcev; Astellas Pharma), a Nectin-4–directed antibody and microtubule inhibitor conjugate, with pembrolizumab (Keytruda; Merck), a PD-1 inhibitor, for patients with locally advanced or metastatic urothelial carcinoma who are ineligible for cisplatin-containing chemotherapy. The FDA granted this indication priority review and breakthrough therapy designations. This is the first antibody–drug conjugate and PD-1 inhibitor combination approved in the United States for this patient population.
Enfortumab vedotin was previously approved as monotherapy for certain patients with locally advanced or metastatic urothelial cancer. Pembrolizumab was previously approved as monotherapy for several oncology indications, including certain patients with locally advanced or metastatic urothelial carcinoma or with Bacillus Calmette-Guérin–unresponsive non–muscle-invasive bladder cancer.
This new approval was based on results of the phase 1b/2 EV-103/KEYNOTE-869 clinical trial, a multicohort study, in which a total of 121 patients received the combination. Patients in the single-arm cohorts—dose-escalation and cohort A—received enfortumab vedotin plus pembrolizumab, whereas patients in cohort K were randomized to treatment with the combination or enfortumab vedotin alone. Participants were ineligible for cisplatin-containing chemotherapy and had not received previous systemic therapy for locally advanced or metastatic disease.
The major efficacy measures were objective response rate (ORR) and duration of response (DOR). In 121 patients, the confirmed ORR was 68% (95% confidence interval, 59-76), including complete responses in 12% of patients. In the dose-escalation group and cohort A, the median DOR was 22 months (range, 1+-46+); the median DOR was not reached in cohort K (range, 1-24+).
The most common (>20%) adverse reactions, including laboratory abnormalities, were increased glucose, increased aspartate aminotransferase, rash, decreased hemoglobin, increased creatinine, peripheral neuropathy, decreased lymphocytes, fatigue, increased alanine aminotransferase, decreased sodium, increased lipase, decreased albumin, alopecia, decreased phosphate, decreased weight, diarrhea, pruritus, decreased appetite, nausea, dysgeusia, decreased potassium, decreased neutrophils, urinary tract infection, constipation, increased potassium, increased calcium, peripheral edema, dry eye, dizziness, arthralgia, and dry skin.
“The accelerated approval…marks an important milestone for the approximately 8000 to 9000 patients in the United States with locally advanced or metastatic urothelial cancer who are not eligible for cisplatin-containing chemotherapy,” said Ahsan Arozullah, MD, MPH, Senior Vice President, Head of Oncology Development, Astellas.
When the combination of pembrolizumab plus enfortumab vedotin is used, the recommended dose of enfortumab vedotin is 1.25 mg/kg (up to a maximum of 125 mg for patients weighing ≥100 kg) administered as an intravenous infusion over 30 minutes on days 1 and 8 of a 21-day cycle until disease progression or unacceptable toxicity. Pembrolizumab should be administered after enfortumab vedotin on the same day at a recommended dose of 200 mg every 3 weeks or 400 mg every 6 weeks until disease progression, unacceptable toxicity, or up to 24 months.
The continued approval of enfortumab vedotin with pembrolizumab for this indication is contingent on additional confirmatory trials that verify and describe the combination’s clinical benefit.
Tafinlar plus Mekinist Combination Approved for Pediatric Low-Grade Glioma with BRAFV600E Mutation
On March 16, 2023, the FDA approved dabrafenib (Tafinlar; Novartis) in combination with trametinib (Mekinist; Novartis) for the treatment of pediatric patients aged ≥1 year with low-grade glioma that harbors a BRAFV600E mutation and who require systemic therapy.
The FDA also approved new oral formulations of both drugs suitable for patients who cannot swallow pills, making this the first time a BRAF/MEK inhibitor has been developed in a formulation suitable for patients as young as 1 year of age.
With this latest approval, dabrafenib plus trametinib is now FDA-approved across 6 indications for multiple BRAFV600E solid tumors, including melanoma, thyroid cancer, and lung cancer.
The new approval was based on results of the TADPOLE study, an open-label, multicenter, clinical trial of patients with low-grade glioma requiring first systemic therapy. BRAF mutation status was identified prospectively by local or central laboratory tests, and retrospective testing of available tumor samples was also performed by central laboratory tests to evaluate mutation status.
Patients were randomized (2:1) to receive dabrafenib plus trametinib or carboplatin plus vincristine. Patients received age- and weight-based dosing of the dabrafenib plus trametinib combination until they were no longer deriving benefit or experienced unacceptable toxicity.
The major efficacy outcome measure was overall response rate (ORR) by independent review based on RANO LGG (2017) criteria. Additional efficacy outcome measures were progression-free survival (PFS) and overall survival (OS).
The ORR in patients treated with dabrafenib plus trametinib (N=73) was 46.6% (95% confidence interval [CI], 34.8%-58.6%) compared with 10.8% (95% CI, 3.0%-25.4%) in those treated with carboplatin plus vincristine (N=37; P≤.001). The duration of response was 23.7 months (95% CI, 14.5-not estimable [NE]) in the dabrafenib plus trametinib arm and NE (95% CI, 6.6-NE) in the carboplatin plus vincristine arm. PFS was 20.1 months and 7.4 months, respectively.
At the time of the interim analysis of OS conducted when all patients had completed at least 32 weeks of treatment or had discontinued earlier, there was 1 death in the carboplatin plus vincristine arm. The OS results at the interim analysis did not reach statistical significance.
In the pooled safety population of pediatric patients treated with dabrafenib plus trametinib, the most common (>20%) adverse reactions were pyrexia, rash, headache, vomiting, musculoskeletal pain, fatigue, dry skin, diarrhea, nausea, epistaxis and other bleeding events, abdominal pain, and dermatitis acneiform. The most common (>2%) grade 3 or 4 laboratory abnormalities were neutrophil count, increased alanine aminotransferase, and increased aspartate aminotransferase.
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.
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.