In August, the US Food and Drug Administration (FDA) granted five new indications for the treatment of patients with cancer. Additionally, the agency converted two accelerated approvals to full approvals and authorized a third COVID-19 vaccine dose for immunocompromised patients.

• Ivosidenib for Advanced or Metastatic Cholangiocarcinoma. Approval was granted to an oral isocitrate dehydrogenase-1 (IDH1) inhibitor, ivosidenib (Tibsovo®, Servier Pharmaceuticals LLC), for patients with previously treated, locally advanced or metastatic cholangiocarcinoma with an IDH1 mutation, as detected by a simultaneously FDA-approved test, the Oncomine Dx Target Test (Life Technologies Corp.). The approval was based on efficacy and safety results from the multicenter, double-blind, placebo-controlled, phase III ClarIDHy study, in which 185 patients with IDH-1 mutated cholangiocarcinoma that had progressed after no more than two prior regimens, including at least one gemcitabine- or flurouracil-containing regimen, received either ivosidenib or placebo. Progression-free survival (PFS) was significantly improved for patients who received ivosidenib compared with placebo, with a median PFS of 2.7 versus 1.4 months, respectively (hazard ratio [HR], 0.37; P<0.0001). Of note, 32% of patients receiving ivosidenib remained free of progression at 6 months and 22% at 12 months, versus none on the placebo arm.  

• Evolving Immune Checkpoint Inhibitor Indications in Urothelial Cancer
  Nivolumab as Adjuvant Therapy for Urothelial Carcinoma. Nivolumab (Opdivo®, Bristol-Myers Squibb Co.) received the first FDA approval for adjuvant treatment of patients with urothelial carcinoma (UC) who are at high risk of recurrence after undergoing radical resection. Results from the randomized, double-blind, placebo-controlled, phase III CHECKMATE-274 trial showed that median disease-free survival (DFS) was nearly doubled in patients who received adjuvant nivolumab (n=353) compared with placebo (n=356), with a median DFS of 20.8 versus 10.8 months, respectively (HR, 0.70; P=0.0008). For patients with tumor PD-L1 ≥1%, median DFS was not reached in patients receiving nivolumab versus 8.4 months for placebo (HR, 0.55; P=0.0005).
  
  Furthermore, the results from CHECKMATE-274 also supported the conversion of accelerated approval of nivolumab for patients with advanced/metastatic UC to regular approval.
  
  Pembrolizumab for Advanced UC. The FDA converted the accelerated approval of first-line pembrolizumab (Keytruda®, Merck) for patients with advanced UC to a full approval and revised the indication to cover the treatment of patients with locally advanced or metastatic UC who are not eligible for any platinum-containing chemotherapy. The label update was based on analyses from the phase 3 KEYNOTE-361 trial, in which patients with advanced UC (n=1010) were randomized to receive single-agent pembrolizumab, pembrolizumab plus chemotherapy, or chemotherapy alone. Although the combination did not meet the threshold for statistical significance for PFS and OS improvements, there was a numerical improvement, and the FDA supported the updated indication.

• Dostarlimab, an Anti-PD-1 Monoclonal Antibody, for Mismatch Repair-Deficient (dMMR) Advanced Solid Tumors. Dostarlimab-gxly (Jemperli®, GlaxoSmithKline LLC) received accelerated approval for the treatment of patients with dMMR recurrent or advanced solid tumors who have progressed on or after receiving prior treatment, and have no satisfactory alternative treatment options. The Ventana MMR RxDx panel (Roche AG), a companion diagnostic test for the detection of dMMR solid tumors, was simultaneously approved. The efficacy of dostarlimab was evaluated in the multicenter, open-label, single-arm, multi-cohort, phase I GARNET trial. In 209 patients with dMMR recurrent or advanced solid tumors who received dostarlimab, the overall response rate (ORR) was 41.6% with 9.1% complete response (CR). The median duration of response was 34.7 months, with 95% of patients experiencing a DoR of ≥6 months.

• Belzutifan, a Hypoxia-Inducible Factor (HIF) Inhibitor for Cancers Associated With Von Hippel-Landau (VHL) Disease. VHL disease is an inherited condition caused by a mutation in the VHL gene that can cause tumors to develop in various organs. Belzutifan (Welireg^TM, Merck) is the first oral HIF-2 alpha inhibitor approved for the treatment of patients with VHL disease who require treatment for associated renal cell carcinoma (RCC), central nervous system (CNS) hemangioblastomas, or pancreatic neuroendocrine tumors (pNET). The approval is based on results from the ongoing, open-label, phase II study, in which 61 patients with VHL-associated clear cell RCC (ccRCC), diagnosed based on a VHL germline alteration and with at least one measurable solid tumor localized to the kidney, received belzutifan. The updated ORR was 49%, and median DoR was not reached; 56% of responders had a DoR of ≥12 months and a median time to response of 8 months. In patients with other VHL tumors, including CNS hemangioblastomas or pNET, the ORR was 63% and 83%, respectively, and median DoR was not reached.

• Lenvatinib and Pembrolizumab Combo for Advanced RCC. Approval was granted for the combination of lenvatinib (Lenvima®, Eisai Co., Ltd.) plus pembrolizumab (Keytruda®, Merck) for the first-line treatment of patients with advanced RCC. Results from the multicenter, open-label, randomized, phase III CLEAR trial supported the approval. Patients with advanced ccRCC were randomized, regardless of PD-L1 tumor expression status, to receive either lenvatinib plus pembrolizumab (n=355) or single-agent sunitinib (n=357). The median PFS for patients who received the combination was more than doubled compared with patients who received sunitinib (23.9 versus 9.2 months; HR, 0.39; P<0.0001). Median OS was not reached in either arm (HR, 0.66; P=0.0049). The ORR was 71% for the combination versus 36% for sunitinib (P<0.0001) with 16% and 4% complete responses, respectively.

• Third COVID-19 Vaccine Dose for Cancer Patients. The FDA amended the emergency use authorizations for the Pfizer-BioNTech and Moderna COVID-19 vaccines to allow for the use of an additional vaccine dose in some immunocompromised patients, including patients who have been receiving active cancer treatment for solid tumors or hematologic cancers, according to the clinical recommendations of the Centers for Disease Control and Prevention (CDC). The dose is to be administered at least 28 days following the two-dose regimen of the same vaccine.