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FDA Actions & Updates

The latest approvals, designations, and new indications from the U.S. Food and Drug Administration for oncology drugs.

Friday, May 5, 2023

​Polatuzumab Vedotin-Piiq for Previously Untreated DLBCL Not Otherwise Specified & High-Grade B-Cell Lymphoma

The FDA approved polatuzumab vedotin-piiq with a rituximab product, cyclophosphamide, doxorubicin, and prednisone (R-CHP) for adult patients who have previously untreated diffuse large B-cell lymphoma (DLBCL), not otherwise specified (NOS), or high-grade B-cell lymphoma (HGBL) and who have an international prognostic index (IPI) score of 2 or greater.

Approval was based on POLARIX (NCT03274492), a randomized, double-blind, placebo-controlled trial in 879 patients with previously untreated large B-cell lymphoma and an IPI score of 2-5. The trial evaluated the superiority of substituting polatuzumab vedotin for vincristine in the R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) regimen. Patients were randomized (1:1) to receive either polatuzumab vedotin plus R-CHP (pola + R-CHP) or R-CHOP for six 21-day cycles, followed by two additional cycles of rituximab alone in both arms. The main diagnoses were de novo DLBCL, NOS (84%), and HGBL (11%).

Efficacy was based on investigator-assessed progression-free survival (PFS). PFS was statistically significantly longer in the pola + R-CHP arm, with a hazard ratio (HR) of 0.73 (95% CI: 0.57, 0.95; p=0.0177). This arm also had a statistically significant improvement in modified event-free survival (HR: 0.75; 95% CI: 0.58, 0.96; p=0.0244). No significant difference in complete response rate or overall survival (HR: 0.94; 95% CI: 0.67, 1.33 on final analysis) was observed.
The most common adverse reactions with pola + R-CHP (≥20%), excluding laboratory abnormalities, were peripheral neuropathy, nausea, fatigue, diarrhea, constipation, alopecia, and mucositis. Grade 3-4 laboratory abnormalities (≥10%) were lymphopenia, neutropenia, hyperuricemia, and anemia. Peripheral neuropathy developed or worsened in 53 percent of patients with resolution in 58 percent after a median of 4 months. Serious adverse reactions occurred in 34 percent of patients, including febrile neutropenia and pneumonia.

The recommended dose of polatuzumab vedotin is 1.8 mg/kg as an intravenous infusion every 21 days for 6 cycles in combination with R-CHP. Patients should be premedicated with an antihistamine and antipyretic and receive prophylactic granulocyte colony-stimulating factor.​

Wednesday, April 5, 2023

​Approval of Enfortumab Vedotin-Ejfv With Pembrolizumab for Urothelial Carcinoma

The FDA has granted accelerated approval to enfortumab vedotin-ejfv with pembrolizumab for patients with locally advanced or metastatic urothelial carcinoma who are ineligible for cisplatin-containing chemotherapy.

Efficacy was evaluated in EV-103/KEYNOTE-869 (NCT03288545), a multi-cohort (dose-escalation cohort, Cohort A, Cohort K) study. The dose-escalation cohort and Cohort A were single-arm cohorts treating patients with enfortumab vedotin-ejfv plus pembrolizumab while patients on Cohort K were randomized to either the combination or to enfortumab vedotin-ejfv alone. Patients had not received prior systemic therapy for locally advanced or metastatic disease and were ineligible for cisplatin-containing chemotherapy. A total of 121 patients received enfortumab vedotin-ejfv plus pembrolizumab.

The major efficacy outcome measures were objective response rate (ORR) and duration of response (DoR) determined by blinded independent central review using RECIST v1.1. The confirmed ORR in 121 patients was 68 percent (95% CI: 59, 76), including 12 percent with complete responses. The median DoR for the dose-escalation cohort + Cohort A was 22 months (range: 1+ to 46+) and for Cohort K was not reached (range: 1 to 24+).

The most common adverse reactions (>20%), 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, potassium increased, calcium increased, peripheral edema, dry eye, dizziness, arthralgia, and dry skin.

The recommended enfortumab vedotin-ejfv dose when given with pembrolizumab is 1.25 mg/kg (up to a maximum of 125 mg for patients ≥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. The recommended pembrolizumab dose, administered after enfortumab vedotin on the same day, is 200 mg every 3 weeks or 400 mg every 6 weeks until disease progression, unacceptable toxicity, or up to 24 months.​

Monday, March 20, 2023

​Dabrafenib + Trametinib for Pediatric Patients With Low-Grade Glioma With a BRAF V600E Mutation

On March 16, 2023, the FDA approved dabrafenib with trametinib for pediatric patients 1 year of age and older with low-grade glioma (LGG) with a BRAF V600E mutation who require systemic therapy. The FDA also approved new oral formulations of both drugs suitable for patients who cannot swallow pills. This represents the first FDA approval of a systemic therapy for the first-line treatment of pediatric patients with LGG with a BRAF V600E mutation.

Efficacy was evaluated in Study CDRB436G2201 (NCT02684058), a multicenter, open-label trial in patients with LGG (WHO Grades 1 and 2) requiring first systemic therapy. Patients were randomized 2:1 to dabrafenib plus trametinib (D+T) or carboplatin plus vincristine (C+V). BRAF mutation status was identified prospectively by local or central laboratory tests. Retrospective testing of available tumor samples by the central laboratory was also performed to evaluate mutation status. Patients received age- and weight-based dosing of D+T until they were no longer deriving benefit or experienced unacceptable toxicity. C+V were dosed based on body surface area at 175 mg/m2 and 1.5 mg/m2 (0.05 mg/kg for patients < 12 kg), respectively, as one 10-week induction course, followed by eight 6-week cycles of maintenance therapy.

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 primary analysis was performed when all patients had completed at least 32 weeks of therapy.

In the LGG cohort, 110 patients were randomized to D+T (n=73) or C+V (n=37). ORR was 46.6 percent (95% CI: 34.8, 58.6) in the D+T arm and 10.8 percent (95% CI: 3.0, 25.4) for those receiving C+V (p=<0.001). DOR was 23.7 months (95% CI: 14.5, not estimable) in the D+T arm and not estimable (95% CI: 6.6, not estimable) in the C+V arm. PFS was 20.1 months (95% CI: 12.8, not estimable) and 7.4 months (95% CI: 3.6, 11.8) (HR=0.31 [95% CI: 0.17, 0.55]; p=<0.001) in the D+T and C+V arms, 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 one death on the C+V arm. The OS results at the interim analysis did not reach statistical significance.

In the pooled safety population of pediatric patients receiving D+T (N=166), the most common (>20%) adverse reactions were pyrexia (66%), rash (54%), headache (40%), vomiting (38%), musculoskeletal pain (36%), fatigue (31%), dry skin (31%), diarrhea (30%), nausea (26%), epistaxis and other bleeding events (25%), abdominal pain (24%), and dermatitis acneiform (23%). The most common (>2%) Grade 3 or 4 laboratory abnormalities were decreased neutrophil count (20%), increased alanine aminotransferase (3.1%), and aspartate aminotransferase increased (3.1%).
The recommended doses for dabrafenib and trametinib in pediatric patients are based on body weight; dabrafenib is administered orally twice daily and trametinib is administered orally once daily. Dabrafenib and trametinib are administered until disease progression or unacceptable toxicity.​

Monday, March 6, 2023

​Early Breast Cancer Indication for Abemaciclib With Endocrine Therapy

On March 3, 2023, the FDA approved abemaciclib with endocrine therapy (tamoxifen or an aromatase inhibitor) for the adjuvant treatment of adult patients with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative, node-positive, early breast cancer at high risk of recurrence. Patients defined as high risk included those having either ≥4 pALN (pathologic axillary lymph nodes) or 1-3 pALN and either tumor grade 3 or a tumor size ≥50 mm. Abemaciclib was previously approved for the above high-risk population with the additional requirement of having a Ki-67 score ≥20 percent. This new approval removes the Ki-67 testing requirement.

Efficacy was evaluated in monarchE (NCT03155997), a randomized (1:1), open-label, two-cohort multicenter trial including adult women and men with HR-positive, HER2-negative, node-positive, resected, early breast cancer with clinical and pathological features consistent with a high risk of recurrence. To be enrolled in Cohort 1, patients must have either ≥4 pALN or 1-3 pALN and either tumor Grade 3 or a tumor size ≥50 mm. To be enrolled in Cohort 2, patients could not be eligible for Cohort 1 and must have had 1-3 pALN and tumor Ki-67 score ≥20 percent. Patients were randomized to 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 (ITT) population, primarily attributed to the patients in Cohort 1 (Cohort 1 N=5120 [91%]; IDFS HR: 0.653 (95% CI: 0.567, 0.753)). IDFS at 48 months was 85.5 percent (95% CI: 83.8, 87.0) for abemaciclib plus standard endocrine therapy and 78.6 percent (95% CI: 76.7, 80.4) for standard endocrine therapy alone. Overall survival data remains immature. However, in Cohort 2, more deaths were observed with abemaciclib plus standard endocrine therapy compared to standard endocrine therapy alone (10/253 vs. 5/264). Therefore, the indication was restricted to Cohort 1.

The most common adverse reactions (≥20%) were diarrhea, infections, neutropenia, fatigue, leukopenia, nausea, anemia, and headache. The recommended abemaciclib starting dose is 150 mg taken twice daily with tamoxifen or an aromatase inhibitor until completion of 2 years of treatment or until disease recurrence or unacceptable toxicity.​

Monday, February 13, 2023

​Dostarlimab-gxly Approved for dMMR Endometrial Cancer

The FDA approved dostarlimab-gxly for adult patients with mismatch repair deficient (dMMR) recurrent or advanced endometrial cancer, as determined by an FDA-approved test, that has progressed on or following a prior platinum-containing regimen in any setting and who are not candidates for curative surgery or radiation.

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

Efficacy for the regular approval was evaluated in GARNET (NCT02715284), a multicenter, multicohort, open-label trial conducted in patients with advanced solid tumors. The efficacy population consisted of a cohort of 141 patients with dMMR recurrent or advanced endometrial cancer who had progressed on or after a platinum-containing regimen. Patients treated with prior PD-1/PD-LI blocking antibodies, other immune checkpoint inhibitors, or had autoimmune diseases requiring systemic immunosuppressant agents within 2 years were excluded.

The major efficacy outcome measures were overall response rate (ORR) and duration of response (DOR) as assessed by blinded independent central review according to RECIST v1.1. Confirmed ORR was 45.4 percent (95% CI: 37.0, 54.0), with a 15.6 percent complete response rate and a 29.8 percent partial response rate. Median DOR was not reached, with 85.9 percent of patients having durations ≥12 months and 54.7 percent of patients having durations ≥24 months (range: 1.2+, 52.8+).

The most common adverse reactions (≥20%) were fatigue/asthenia, anemia, rash, nausea, diarrhea, constipation, and vomiting. Immune-mediated adverse reactions can occur including pneumonitis, colitis, hepatitis, endocrinopathies, nephritis with renal dysfunction, and skin adverse reactions.

The recommended dostarlimab-gxly dose and schedule (Doses 1-4) is 500 mg every 3 weeks. Subsequent dosing, beginning 3 weeks after dose 4, is 1,000 mg every 6 weeks until disease progression or unacceptable toxicity. Dostarlimab-gxly should be administered as an intravenous infusion for over 30 minutes.

This review used the Assessment Aid, a voluntary submission from the applicant to facilitate the FDA's assessment. The FDA approved this application 1 month ahead of the FDA goal date. Health care professionals should report all serious adverse events suspected to be associated with the use of any medicine and device to the FDA's MedWatch Reporting System or by calling 1-800-FDA-1088.​