The US FDA approved seven new indications for cancer management between 1 April and 31 May 2022.

• Regular Approval for Trastuzumab Deruxtecan in Advanced HER2-Positive Breast Cancer. Accelerated approval was upgraded to regular approval for the HER2 antibody-drug conjugate fam-trastuzumab deruxtecan-nxki (Enhertu®, Daiichi Sankyo, Inc.) for patients with unresectable or metastatic HER2-positive breast cancer who have been previously treated with an anti-HER2-based regimen for metastatic disease or have developed disease recurrence during or within 6 months of completing neoadjuvant/adjuvant therapy. This approval was granted based on results from the randomized, global, phase III DESTINY-Breast03 trial (N = 524), which compared the efficacy and safety of trastuzumab deruxtecan with trastuzumab emtansine in patients with HER2-positive metastatic breast cancer following initial treatment with trastuzumab and a taxane. Treatment with trastuzumab deruxtecan led to a highly significant and clinically meaningful progression-free survival (PFS): median PFS was not reached in the trastuzumab deruxtecan arm vs. 6.8 months in the trastuzumab emtansine arm (hazard ratio [HR], 0.28; P < 0.0001); overall survival (OS) data were immature. The overall response rate (ORR) was 82.7% in the trastuzumab deruxtecan arm and 36.1% for patients who received trastuzumab emtansine. The prescribing information includes a boxed warning for interstitial lung disease and embryo-fetal toxicity.

• Nivolumab Combinations for Esophageal Squamous Cell Carcinoma. Approval was granted for nivolumab (Opdivo®, Bristol Myers Squibb) as first-line treatment of patients with advanced or metastatic esophageal squamous cell carcinoma (ESCC) in two combination regimens: with fluoropyrimidine- and platinum-based chemotherapy, and with ipilimumab (Yervoy®, Bristol Myers Squibb). This approval was based on results from the open-label, randomized, phase III CHECKMATE-648 trial, which included 970 patients with previously untreated, unresectable, advanced, recurrent or metastatic ESCC. Patients received either nivolumab + fluorouracil + cisplatin, nivolumab + ipilimumab, or fluorouracil + cisplatin. This study demonstrated statistically significant improvements in OS with both nivolumab-containing regimens when individually compared with chemotherapy, both in the overall population and among patients with tumor-cell PD-L1 expression ≥1% and. Median OS in the overall population was 13.2 months in the nivolumab, fluorouracil, and cisplatin arm vs. 10.7 months with chemotherapy (HR, 0.74; P = 0.002), and 12.7 months in the nivolumab and ipilimumab arm (HR, 0.78; P=0.01). For the PD-L1 ≥1% subgroup, the HRs were 0.54 (P < 0.001) and 0.64 (P = 0.001), respectively.

• Ivosidenib Plus Azacitidine for Newly Diagnosed Acute Myeloid Leukemia. Approval was given to ivosidenib (Tibsovo®, Servier Pharmaceuticals LLC) in combination with azacitidine for patients with newly diagnosed acute myeloid leukemia (AML) with a susceptible IDH1 mutation, as detected by an FDA-approved test, in adults 75 years or older or who have comorbidities that preclude use of intensive induction chemotherapy. Results from the randomized, multicenter, double-blind, placebo-controlled, phase III AGILE study, in which 146 patients received either oral ivosidenib or matched placebo and azacitidine until disease progression, unacceptable toxicity, or hematopoietic stem cell transplantation, supported the approval. According to published data, at a median follow up of 12.4 months, event-free survival (EFS) was significantly longer in the ivosidenib + azacitidine group than in the placebo + azacitidine group (HR, 0.33; P=0.002). Median OS was 24.0 months in the ivosidenib plus azacitidine arm vs. 7.9 months in the placebo plus azacitidine arm (HR, 0.44; P=0.001). Nearly half of patients (47%) achieved complete remission (CR) in the ivosidenib plus azacitidine arm vs. 15% in the placebo plus azacitidine arm.

• Azacitidine for Newly Diagnosed Juvenile Myelomonocytic Leukemia. Azacitidine monotherapy (Vidaza®, Celgene Corp.) was approved for pediatric patients with newly diagnosed juvenile myelomonocytic leukemia (JMML). The approval was based on the international, multicenter, open-label, phase II AZA-JMML-001 trial that evaluated the pharmacokinetics, pharmacodynamics, safety, and activity of azacitidine prior to hematopoietic stem cell transplantation (HSCT) in 18 patients with JMML. The main efficacy outcome measures were clinical complete remission (cCR) or clinical partial remission (cPR). Half of the patients had confirmed clinical responses, including 3 with cCR and 6 with cPR. The proportion of patients undergoing HSCT was 94%, and the median time to HSCT was 4.6 months. Of the 17 patients who received HSCT, 14 (82%) were leukemia-free at a median follow-up of 23.8 months after HSCT.

• New Indications for Two Anti-CD19 Chimeric Antigen Receptor (CAR) T-Cell Therapies in Lymphoma:
  
  Tisa-Cel for Relapsed or Refractory Follicular Lymphoma. Tisagenlecleucel (Tisa-cel; Kymriah®, Novartis Pharmaceuticals) received accelerated approval for adult patients with relapsed or refractory follicular lymphoma (R/R FL) after two or more lines of systemic therapy. This approval was based on the multicenter, single-arm, phase II ELARA trial, which evaluated Tisa-cel in patients with R/R FL who had received at least two lines of systemic therapy (including an anti-CD20 antibody and an alkylating agent) or who relapsed after autologous HSCT. Among 90 patients in the primary efficacy analysis, the ORR was 86% with a complete response (CR) rate of 68%. The median duration of response was not reached, with 75% of responders still responding at 9 months. For the 98 patients who underwent leukapheresis, the ORR was 86% with a CR rate of 67%.
  
  Axi-Cel for Second-Line Treatment of Large B-Cell Lymphoma. Axicabtagene ciloleucel (Yescarta®, Kite Pharma, Inc.) received approval for patients with large B-cell lymphoma (LBCL) that is refractory to first-line chemoimmunotherapy or who relapse within 12 months of first-line chemoimmunotherapy. The indication does not include treatment of patients with primary central nervous system lymphoma. The approval was supported by results from the randomized, open-label, multicenter, phase III ZUMA-7 trial, which included 356 patients with early refractory disease who had not yet received treatment for relapsed or refractory lymphoma and were potential candidates for autologous HSCT. Patients were randomized to receive either axi-cel after lymphodepleting chemotherapy or second-line standard therapy, followed by high-dose therapy and autologous HSCT in patients who attained complete remission or partial remission. At a median follow-up of 24.9 months, median EFS was 8.3 months in the axi-cel group and 2.0 months in the standard-care group, and the 24-month EFS rates were 41% and 16%, respectively (HR, 0.40; P < 0.001). A response occurred in 83% of the patients in the axi-cel group and in 50% of those in the standard-care group, with CR in 65% and 32%, respectively.
  
  The prescribing information for both Tisa-Cel and Axi-Cel include a boxed warning for cytokine-release syndrome and neurological toxicities.

• Alpelisib for PIK3CA-Related Overgrowth Spectrum. Accelerated approval was granted to alpelisib (Vijoice®, Novartis Pharmaceuticals) for adult and pediatric patients ≥2 years with severe manifestations of PIK3CA-related overgrowth spectrum (PROS) who require systemic therapy. PROS is a heterogeneous group of rare disorders that cause overgrowth in the body due to mutations in the PIK3CA gene. Approval was based on the EPIK-P1 trial, a retrospective, single-arm chart review that provides real-world data from patients with PROS who received alpelisib as part of an expanded-access program for compassionate use. Alpelisib’s efficacy was evaluated in 37 PIK3CA-mutated patients with life-threatening clinical manifestations of PROS, who had at least one target lesion identified on imaging performed within 24 weeks prior to receipt of the first dose. The major efficacy outcome measure was the proportion of patients with radiological response at week 24, defined as a ≥20% reduction from baseline in the sum of measurable target lesion volume in up to 3 lesions confirmed by at least 1 subsequent imaging assessment. At week 24, 27% of patients had a radiological response; 60% of responding patients had a response lasting 12 months or longer.