FDA Approved Six New Oncology Indications in March-April 2023

The US FDA approved six new indications for cancer management in March-April 2023. Of these approvals, two were for hematologic malignancies, while others address urothelial carcinoma and Merkel cell carcinoma, as well as an expanded approval in breast cancer. Additionally, one agent received approval for pediatric low-grade glioma. 

  • Abemaciclib for HR-positive, HER2-negative Early-Stage Breast Cancer. Abemaciclib (Verzenio, Eli Lilly and Company) with endocrine therapy (tamoxifen or an aromatase inhibitor) received expanded approval for the adjuvant treatment of patients with HR-positive, HER2-negative, node-positive, early breast cancer at high risk of recurrence. Patients defined as high risk include those having either ≥4 pathologic axillary lymph nodes (pALN) or 1–3 pALN and either tumor grade 3 or a tumor size ≥50 mm. Abemaciclib was approved previously for high-risk patients who also have a Ki-67 score ≥20%. The approval removed the Ki-67 testing requirement. Efficacy was evaluated in the randomized, two-cohort, risk-stratified, phase 3 monarchE trial (NCT03155997), which included 5637 patients with HR-positive, HER2-negative, node-positive, resected, early breast cancer with high-risk clinical and pathological features. Patients from 63 sites in 38 countries received either standard-of-care endocrine therapy for up to 10 years with abemaciclib 150 mg orally twice a day for 2 years (n = 2808) or endocrine therapy alone (n = 2829). Investigators reported a statistically significant improvement in invasive disease-free survival (IDFS), the primary outcome, among patients who received abemaciclib, primarily in cohort 1, in which patients met the high-risk criteria: HR, 0.653; 95% CI: 0.567, 0.753. IDFS at 48 months was 85.5% (95% CI: 83.8, 87.0) in the abemaciclib group of cohort 1 and 78.6% (95% CI: 76.7, 80.4) for endocrine therapy alone. Although overall survival (OS) data are immature, more deaths were seen in the abemaciclib group in cohort 2 (patients with between 1 and 3 positive axillary lymph nodes and Ki-67 of at least 20% as an additional risk feature) than the control group, leading the FDA to limit the indication to cohort 1. 
  • Retifanlimab-dlwr for Advanced Merkel Cell Carcinoma (MCC). Retifanlimab-dlwr (Zynyz, Incyte Corporation) received accelerated approval for adult patients with metastatic or recurrent locally advanced MCC. Efficacy was evaluated in PODIUM-201 (NCT03599713), a phase 2, open-label, multiregional, single-arm study that evaluated 65 chemotherapy-naïve patients with metastatic or recurrent locally advanced MCC. Objective response rate (ORR) and duration of response (DOR) assessed by an independent central review committee according to RECIST v1.1 were the major efficacy outcome measures. The ORR was 52% (95% CI: 40, 65). Twelve patients (18%) had a complete response (CR), while 22 patients (34%) had a partial response (PR). Among responding patients, 26 (76%) had a DOR ≥6 months and 21 (62%) had a DOR ≥12 months. The safety population consisted of 105 patients. The most common (≥10%) adverse events (AEs) were fatigue, musculoskeletal pain, pruritus, diarrhea, rash, pyrexia, and nausea. Serious AEs occurred in 22% of patients, including fatigue, arrythmia, and pneumonitis, and 11% discontinued the study drug permanently due to an AE. 
  • Enfortumab Vedotin-ejfv with Pembrolizumab for Locally Advanced or Metastatic Urothelial Carcinoma (MUC). Enfortumab vedotin-ejfv (Padcev, Astellas Pharma) with pembrolizumab (Keytruda, Merck) received accelerated approval for patients with locally advanced or metastatic urothelial carcinoma who are ineligible for cisplatin-containing chemotherapy. The FDA evaluated efficacy based on results from the multiple-cohort trial EV-103/KEYNOTE-869 (NCT03288545), including ORR and DOR. The trial included a dose-escalation cohort and cohort A, which were single-arm cohorts treating patients with enfortumab vedotin plus pembrolizumab. Patients in cohort K were randomized to receive either the combination, or enfortumab vedotin alone. Patients had not received prior systemic therapy for locally advanced or metastatic disease and were ineligible for cisplatin-containing chemotherapy. Patients treated with the combined regimen (n = 121) had a 68% confirmed ORR (95% CI: 58.7, 76.0) per RECIST v1.1 by blinded independent central review, with 12% of patients experiencing CR. The median DOR for dose-escalation/cohort A was 22.1 months and was not reached in cohort K. Prescribing information includes a boxed warning for serious skin reactions as well as hyperglycemia, pneumonitis/interstitial lung disease, peripheral neuropathy, and ocular disorders.
  • Dabrafenib with Trametinib for Pediatric Patients with Low-Grade Glioma (LGG) with a BRAF V600E Mutation. Approval was granted for a regimen of dabrafenib (Tafinlar, Novartis) with trametinib (Mekinist, Novartis) for pediatric patients 1 year of age and older with LGG harboring a BRAF V600E mutation who require systemic therapy. This is the first FDA approval of a systemic therapy in this setting. Approval was based on the randomized, open-label, phase 2 Study CDRB436G2201 (NCT02684058), with an LGG cohort of children and adolescent patients with WHO grades 1 and 2 disease who require initial systemic therapy. Patients in the LGG cohort were randomized 2:1 to receive either dabrafenib plus trametinib or carboplatin with vincristine. The primary outcome was ORR by central independent assessment using Response Assessment in Neuro-Oncology (RANO) criteria. Additional outcomes were progression-free survival (PFS) and OS. The primary analysis was performed when all patients had completed at least 32 weeks of therapy. ORR was 46.6% (95% CI: 34.8, 58.6) in the dabrafenib plus trametinib arm vs 10.8% (95% CI: 3.0, 25.4) in the chemotherapy arm (P < 0.001). 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]; < 0.001) in the experimental and chemotherapy arms, respectively. The most common serious (grade 3 or 4) laboratory abnormalities were decreased neutrophil count (20%), increased alanine aminotransferase (3.1%), and increased aspartate aminotransferase (3.1%). Doses for both dabrafenib and trametinib are based on bodyweight. Both are oral agents: dabrafenib is taken twice daily and trametinib once daily. The FDA also approved new oral formulations of both drugs suitable for patients unable to swallow pills.
  • Polatuzumab Vedotin for Diffuse Large B-Cell Lymphoma (DLBCL) and High-Grade B-Cell Lymphoma (HGBL). Polatuzumab vedotin-piiq (Polivy, Genentech, Inc.) received approval for use with a rituximab product, cyclophosphamide, doxorubicin, and prednisone (R-CHP) for adult patients who have previously untreated 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. This approval was based on efficacy data from the phase 3 POLARIX trial (NCT03274492), which replaced vincristine with polatuzumab vedotin in the standard R-CHOP regimen. This randomized, double-blind, placebo-controlled study included 879 patients with treatment-naïve large B-cell lymphoma (84% had DLBCL, NOS) and an IPI score of 2–5. They received 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. PFS was the primary endpoint. With a median follow-up of 28.2 months, 76.7% (95% CI: 72.7, 80.8) of the pola-R-CHP group had not progressed, vs a PFS rate of 70.2% (95% CI: 65.8, 74.6) in the R-CHOP group (stratified HR for progression, relapse, or death, 0.73; 95% CI: 0.57, 0.95; = 0.02). The pola-R-CHP arm also saw a statistically significant improvement in modified event-free survival (HR, 0.75; 95% CI: 0.58, 0.96; = 0.0244). No significant different in CR rate or OS was observed (HR, 0.94; 95% CI: 0.67, 1.33 on final analysis. The most common adverse reactions with pola + R-CHP (≥20%), excluding laboratory abnormalities, were peripheral neuropathy, nausea, fatigue, diarrhea, constipation, alopecia, and mucositis. Serious adverse reactions occurred in 34% of patients, including febrile neutropenia and pneumonia.
  • Omidubicel to Reduce Time to Neutrophil Recovery and Infection in Hematologic Malignancies. The allogeneic cell therapy omidubicel-onlv (Omisirge, Gamida Cell Ltd.)received approval for use in adult and pediatric patients (12 years and older) with hematologic malignancies who are planned for umbilical cord blood transplantation following myeloablative conditioning to reduce the time to neutrophil recovery and the incidence of infection. In the open-label, randomized, phase 3 trial Study P0501 (NCT02730299), 125 patients were randomized to receive either omidubicel (n = 62) or standard cord blood (n = 63). The median time to neutrophil recovery was 12 days in the omidubicel arm, compared with22 days for standard cord blood (< 0.001). In the omidubicel arm, 39% of patients developed Blood and Marrow Transplant Clinical Trials Network (BMT CTN) grade 2/3 bacterial or grade 3 fungal infections through 100 days following transplantation vs 60% of patients in the standard cord blood arm. In the omidubicel arm, 87% achieved neutrophil recovery vs 83% in the standard arm. The incidence of BMT CTN grade 2/3 bacterial or grade 3 fungal infections through Day 100 post transplantation was 39% and 60%, respectively. Like approved cord blood products, the prescribing information contains a Boxed Warning for fatal or life-threatening infusion reactions, graft-vs-host disease (GvHD), engraftment syndrome, and graft failure. Among 117 patients who received omidubicel for any disease, infusion reactions occurred in 47% of patients, acute GVHD in 58%, chronic GvHD in 35%, and graft failure in 3%.