The US Food and Drug Administration (FDA) granted approval to ten indications for cancer treatments in January and February, including therapies for four different solid tumors, four types of lymphoma (including one approval for the treatment of children and young adults with lymphoma), and a new treatment for light-chain amyloidosis.

A New Indication for Trastuzumab Deruxtecan in HER2-Positive Gastric Adenocarcinoma.
Antibody–drug conjugate fam-trastuzumab deruxtecan-nxki (Enhertu®, Daiichi Sankyo) was approved for patients with locally advanced or metastatic HER2-positive gastric or gastroesophageal adenocarcinoma who have received a prior trastuzumab-based regimen. Efficacy data from the open-label, randomized, phase II DESTINY trial (n=187) supported the approval. In patients who had progressed on at least two prior regimens, trastuzumab deruxtecan (6.4 mg/kg intravenously every 3 weeks) led to significant improvements in objective response rate (ORR), and overall survival (OS) compared to physician’s choice of chemotherapy (irinotecan or paclitaxel). Confirmed ORR was higher with trastuzumab deruxtecan (43% vs 12%) and the median duration of response (DOR) was longer (11.3 months vs 3.9 months). Median OS was 12.5 months in the trastuzumab deruxtecan arm vs 8.4 months in the irinotecan or paclitaxel arm (hazard ratio [HR], 0.59; P=0.01). The Prescribing Information includes a boxed warning of the risk of interstitial lung disease and embryo-fetal toxicity.


• Tepotinib for METex14-Altered Metastatic Non-Small Cell Lung Cancer (NSCLC). Accelerated approval was granted to tepotinib (Tepmetko®, EMD Serono Inc.), the once-daily oral MET inhibitor, for patients with metastatic NSCLC harboring MET exon 14 skipping alterations, as assessed by tissue and/or liquid biopsy. Approval is based on efficacy and safety data from the non-randomized, open-label, multi-cohort, phase II VISION trial. Among 69 treatment-naïve patients, the ORR per Independent Review Committee (IRC) was 43%, with a median DOR of 10.8 months. Among 83 patients who had received previous treatment, the ORR was 43% with a median DOR of 11.1 months. The recommended tepotinib dose is 450 mg orally once daily with food.
  
  
• New Indications for Cemiplimab in Basal Cell Carcinoma and NSCLC
  A regular approval was granted to cemiplimab-rwlc (Libtayo®, Regeneron Pharmaceuticals, Inc.), a PD-1-blocking antibody, for the treatment of patients with locally advanced basal cell carcinoma (laBCC), and an accelerated approval for the treatment of patients with metastatic BCC (mBCC). For both approvals, patients must have received either previous treatment with a hedgehog pathway inhibitor (HHI) therapy or HHI treatment was considered as not appropriate. ORR data from the ongoing open-label, non-randomized, phase II Study 1620, in which patients with advanced BCC (laBCC or mBCC) received intravenous cemiplimab (350 mg every 3 weeks), supported these approvals. Among 84 patients with laBCC, confirmed ORR was 29% (31% with longer follow-up), the median DOR was not reached, and 79% of responders maintained a response for ≥6 months. Among 28 patients with mBCC, confirmed ORR was 21%, median DOR not reached, and all responders maintained a response for ≥6 months.
  
  Approval was also granted for cemiplimab for first-line treatment of patients with advanced NSCLC, whose tumors have high PD-L1 expression (tumor proportion score ≥50%), with no EGFR, ALK, or ROS1 aberrations. Efficacy was evaluated in the randomized, open-label, phase III EMPOWER-Lung 1 trial (Study 1624), in which 710 patients received either intravenous cemiplimab or platinum-based chemotherapy. Overall, OS was significantly improved with cemiplimab treatment compared with chemotherapy: median OS was 22.1 vs 14.3 months, respectively. For patients with high PD-L1 expression (n=563), median OS was not reached vs 14.2 months, respectively. 
  
  
• Nivolumab Plus Cabozantinib, an Upfront Option for Advanced Renal Cell Carcinoma. The combination of nivolumab (Opdivo®, Bristol Myers Squibb Co.) and cabozantinib (Cabometyx®, Exelixis) was approved as first-line treatment of advanced renal cell carcinoma (RCC) based on results from the randomized, open-label, phase III CHECKMATE-9ER trial. Patients with previously untreated advanced clear cell RCC received either nivolumab 240 mg over 30 minutes every 2 weeks in combination with cabozantinib 40 mg orally once daily (n=323), or sunitinib 50 mg orally daily for the first 4 weeks of a 6-week cycle (n=328). Statistically significant improvements were reported in progression-free survival (PFS), OS, and ORR with the combination vs sunitinib, per blinded independent central review (BICR). Median PFS was 16.6 months vs 8.3 months (HR, 0.51); median OS was not reached in either arm (HR, 0.60), and confirmed ORR was 55.7% vs 27.1%, respectively.
  
  
• Umbralisib, an Oral Dual Kinase Inhibitor for Marginal Zone Lymphoma and Follicular Lymphoma.
  Accelerated approval for umbralisib (Ukoniq™, TG Therapeutics), a dual inhibitor of phosphoinositide 3 kinase (PI3K) delta and casein kinase 1 (CK1) epsilon, was granted for the treatment of patients with relapsed/refractory (R/R) marginal zone lymphoma (MZL), previously treated with at least one anti-CD20-based regimen, and patients with R/R follicular lymphoma (FL) who have previously received at least three lines of systemic therapy. The approval was based on efficacy data from two single-arm cohorts of an open-label, multi-cohort, phase IIb Unity NHL trial. Umbralisib was administered orally at 800 mg once-daily in 28-day treatment cycles until disease progression or unacceptable tolerability. Among 69 patients with R/R MZL, the ORR was 49%, with 16% achieving CR; median DOR was not reached. Among 117 patients with R/R FL, the ORR was 45.3%, with 5.1% achieving CR (updated data); median DOR was 11.1 months. Warnings and precautions in the Prescribing Information include infections, neutropenia, diarrhea, non-infectious colitis, hepatotoxicity, and severe cutaneous reactions.
  
  
• Lisocabtagene Maraleucel for R/R Large B-Cell Lymphoma.
  Lisocabtagene maraleucel (Breyanzi®, Juno Therapeutics), a CD19-directed chimeric antigen receptor (CAR) T cell immunotherapy, was approved for the treatment of patients with R/R large B-cell lymphoma after two or more lines of systemic therapy, including diffuse large B-cell lymphoma (DLBCL) not otherwise specified, high-grade B-cell lymphoma, primary mediastinal large B-cell lymphoma, and FL Grade 3B. The approval was based on results from the single-arm, open-label, phase I TRANSCEND trial. Among 192 patients with heavily pretreated R/R large B-cell lymphoma, the ORR per IRC was 73%, with a CR rate of 54%. Among the 104 patients who achieved CR, remission lasted for ≥6 months in 65% of patients and ≥9 months in 62% of patients. The estimated median DOR was not reached in patients who achieved a CR and was 1.4 months in patients with a partial response. The approval was granted with a Risk Evaluation and Mitigation Strategy due to risk of fatal or life-threatening cytokine release syndrome and neurologic toxicities.
  
  
• Crizotinib for Children and Young Adults With R/R Systemic ALK-Positive Anaplastic Large Cell Lymphoma (ALCL). Approval was granted to crizotinib (Xalkori®, Pfizer Inc.) based on efficacy data from the single-arm, open-label Study ADVL0912 that included 26 patients with R/R systemic ALK-positive ALCL who had received at least one systemic treatment. The ORR was 88%, with a CR rate of 81%; of the 23 patients who achieved ORR, 39% maintained the response for ≥6 months and 22% for ≥12 months. The recommended crizotinib dosage for systemic ALCL is 280 mg/m² orally, twice daily.
  
  

Daratumumab Plus Hyaluronidase in Combination With Bortezomib, Cyclophosphamide, and Dexamethasone for Light-Chain Amyloidosis. Accelerated approval was granted to subcutaneous daratumumab plus hyaluronidase (Darzalex Faspro™, Janssen Biotech Inc.) in combination with bortezomib, cyclophosphamide, and dexamethasone (D-VCd) for newly diagnosed light-chain amyloidosis. The approval was based on response rates reported in the open-label, randomized, active-controlled, phase III ANDROMEDA trial, which included 388 newly diagnosed patients with measurable disease and at least one affected organ (according to consensus criteria). According to a recent update, hematologic CR was 53% with D‑VCd vs 18% with bortezomib, cyclophosphamide, and dexamethasone only (odds ratio = 5.1; P<0.0001). Warnings and precautions in the Prescribing Information include serious or fatal cardiac toxicity.