During the last 3 months, from August to October, 2020, the US FDA granted new approvals or extended indications to seven cancer therapies, and approved two next-generation sequencing (NGS) companion diagnostic tools.

Pralsetinib, a New Option for Patients with Metastatic RET Fusion-Positive NSCLC.

Accelerated approval wasgranted for the highly potent, selective RET kinase inhibitor pralsetinib (Gavreto™, Blueprint Medicines Corporation) for patients with metastatic RET fusion-positive NSCLC, as detected by the FDA’s simultaneously approved Oncomine Dx Target (ODxT) test (Life Technologies Corporation). This approval is based on the results from the open-label phase I/II ARROW trial that demonstrated high and durable clinical responses. In 87 previously treated patients with advanced RET fusion-positive NSCLC, treatment with pralsetinib yielded an overall response rate (ORR) of 57%, with 80% of responding patients maintaining the response for ≥6 months. In 27 treatment-naïve patients, the ORR was 70%, and 58% of responding patients had responses lasting ≥6 months. The latest update from this study was presented at the ASCO 2020 virtual meeting. The recommended pralsetinib dose is 400 mg orally once daily. The most common adverse reactions (≥25%) were fatigue, constipation, musculoskeletal pain, and increased blood pressure (hypertension). 

Nivolumab plus Ipilimumab, a New Frontline Treatment for Patients with Unresectable Malignant Pleural Mesothelioma.

An extended indication for the combination of nivolumab and ipilimumab (Opdivo® and Yervoy®, Bristol Myers Squibb Co.) was approved for first-line treatment of patients with unresectable, malignant pleural mesothelioma. It is the first drug regimen to be approved for mesothelioma in 16 years. Approval was based on overall survival (OS) data from the randomized, open-label, phase III CHECKMATE-743 trial, in which more than 600 patients were randomized to receive either the combination of nivolumab plus ipilimumab for up to 2 years, or 6 cycles of combination chemotherapy with cisplatin or carboplatin plus pemetrexed. Median OS was significantly improved with the immunotherapy combination compared with chemotherapy (18.1 months versus 14.1 months; hazard ratio [HR], 0.74; P=0.002); the 2-year OS rate was 40.8% versus 27.0%. OS benefit was seen in patients with epithelioid and non-epithelioid histology.

Pembrolizumab for Relapsed/Refractory Classical Hodgkin’s Lymphoma.

An extended approval was granted for pembrolizumab (Keytruda®, Merck Sharp & Dohme Corp.) for adult patients with relapsed or refractory classical Hodgkin lymphoma (cHL) and for pediatric patients with refractory cHL, or cHL that has relapsed after two or more lines of therapy. Approval was based on results from the randomized, open-label, phase III KEYNOTE-204 trial that enrolled 304 adult patients who relapsed after or are ineligible for autologous stem cell transplant and failed at least one prior therapy line. Patients received either pembrolizumab or brentuximab vedotin (BV). Median PFS, the primary endpoint, was statistically significantly longer in the pembrolizumab arm (13.2 versus 8.3 months; HR, 0.65; P=0.0027).

Belantamab Mafodotin, a Novel Therapy for Heavily Pretreated Patients with Relapsed or Refractory (R/R) Multiple Myeloma.

Accelerated approval was granted to belantamab mafodotin-blmf (Blenrep®, GlaxoSmithKline), a first-in-class, anti-B-cell maturation antigen (anti-BCMA) immunoconjugate for patients with R/R multiple myeloma who have received at least four prior therapies, including an anti-CD38 monoclonal antibody, a proteasome inhibitor, and an immunomodulatory agent. The approval was based on efficacy results from the open-label, multicenter, phase II DREAMM-2 trial that enrolled 196 patients. Patients received belantamab mafodotin at a dose of either 2.5 mg/kg or 3.4 mg/kg intravenously, once every 3 weeks. The ORR was 31% and 34% in patients who received 2.5 mg/kg and 3.4 mg/kg, respectively; 71% of patients who received the lower dose had response durations ≥6 months. The most common grade 3–4 adverse events were keratopathy, thrombocytopenia, and anemia. Because of the risks of ocular toxicity, belantamab mafodotin-blmf is only available through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS), called the BLENREP REMS.

Carfilzomib’s Combination with Daratumumab and Dexamethasone for Patients with R/R Multiple Myeloma.

Expandedindication was granted to carfilzomib (Kyprolis®, Onyx Pharmaceuticals, Inc.) in combination with daratumumab (Darzalex®, Janssen Biotech, Inc.) and dexamethasone (DKd) for patients with R/R multiple myeloma who have received one to three prior lines of therapy. Efficacy results from two clinical trials supported the approval. The open-label, multicenter, phase III CANDOR trial randomized 466 patients to receive either the DKd combination, or carfilzomib with dexamethasone only (Kd). The primary endpoint, median PFS, was not reached in the DKd arm versus 15.8 months in the Kd arm (HR, 0.63; P=0.0027). The toxicity profiles were consistent with those seen with monotherapy use. In the open-label phase Ib, multicohort EQUULEUS study, in which 85 patients received the DKd combination, the ORR was 81% with a response duration of 27.5 months. The safety profiles were similar across both treatment groups. Updated data from the trial were published recently in Blood.

Oral Azacitadine for Patients with Acute Myeloid Leukemia (AML).

Approval was granted for azacitadine tablets (Onureg®, Celgene Corporation) for continued treatment of patients with AML who have achieved first complete remission (CR) or CR with incomplete blood count recovery (CRi) following intensive induction chemotherapy, and who are unable to complete intensive curative therapy. The approval was based on efficacy results from the multicenter, randomized, double-blind, placebo-controlled phase III QUAZAR trial that enrolled 472 patients who had achieved CR or CRi with induction chemotherapy, with or without receiving consolidation therapy. Patients received either azacitadine (300 mg) or placebo tablets on day 1–14 of each 28-day cycle, in addition to best supportive care. OS, the primary endpoint, was 24.7 months in the azacitadine arm versus 14.8 months in the placebo arm (HR, 0.69; P=0.0009); a subgroup analysis showed a consistent OS benefit in patients who were in either CR or CRi.

Venetoclax in Combination with Azacitidine, Decitabine, or Low-Dose Cytarabine (LDAC) for Untreated AML.

Venetoclax (Venclexta®, AbbVie Inc. and Genentech Inc.) in combination with azacitidine, decitabine or LDAC was granted full approval for the treatment of newly-diagnosed AML in patients aged 75 years or older, or patients with comorbidities that preclude intensive induction chemotherapy. Accelerated approval for this indication was given in November, 2018. Efficacy data from the phase III randomized, double-blind, placebo-controlled trials, VIALE-A and VIALE-C supported the full approval based on clinically meaningful improvements in OS and a tolerable and manageable safety profile.

Two Next-Generation Sequencing (NGS)-Based FoundationOne CDx Tests.

Approval was granted for NGS companion diagnostic (CDx) tests: one for blood-based testing and another for tissue-based testing (Foundation Medicine, Inc.). The liquid-biopsy CDx was approved to identify mutations in BRCA1 and BRCA2 genes in cell-free DNA isolated from plasma specimens from patients with metastatic castration-resistance prostate cancer (mCRPC) eligible for treatment with rucaparib (Rubraca®, Clovis Oncology, Inc.). Rucaparib was granted accelerated approval in May, 2020. The tissue-biopsy CDx was approved to identify fusions in neurotrophic receptor tyrosine kinase (NTRK) genes, NTRK1, NTRK2, and NTRK3, in DNA isolated from tissue specimens from patients with solid tumors eligible for treatment with larotrectinib (Vitrakvi®, Bayer Healthcare Pharmaceuticals, Inc.). Larotrectinib was approved in November, 2018 for the treatment of patients with solid tumors with an NTRK gene fusion. This approval was based on retrospective testing with the FoundationOne CDx assay of available tumor tissue samples from patients enrolled in three clinical trials that supported the accelerated approval of larotrectinib.