Last month, there was an impressive number of new cancer treatments approved in the United States (US) by the Food and Drug Administration (FDA).

Additional Dosing Regimen for Pembrolizumab. 

The FDA granted accelerated approval to a new dosing regimen of 400 mg every 6 weeks for pembrolizumab (Keytruda®, Merck) across all currently approved adult indications, including monotherapy and combination therapy. This dosing regimen is now available in addition to the current dose of 200 mg every 3 weeks. It is already approved in Europe and some other countries. The approval was based on pharmacokinetic modeling data, which were supported by exposure-response analyses across the pembrolizumab development program. These data were further validated in an interim data analysis of cohort B from the phase I KEYNOTE-555 trial that evaluated 400 mg of pembrolizumab every 6 weeks in patients with metastatic melanoma; the results were presented at the 2020 AACR virtual meeting. The overall response rate (ORR), which was the primary endpoint of this study, was comparable to the ORR in previous pembrolizumab studies in metastatic melanoma, indicating similar efficacy between the 6-week and 3-week dosing regimens. Furthermore, the safety of the 6-week dosing regimen was comparable to the safety profile of pembrolizumab observed in several tumor types. 

Sacituzumab Govitecan-hziy for Patients with Metastatic Triple-Negative Breast Cancer. 

The antibody drug conjugate, sacituzumab govitecan-hziy (Trodelvy™, Immunomedics, Inc), was granted accelerated approval by the FDA for the treatment of patients with metastatic triple-negative breast cancer (mTNBC) who have received ≥ 2 prior therapies for metastatic disease. The approval was based on results from a phase I/II, single arm clinical trial that included 108 heavily pretreated patients with mTNBC. Among treated patients, the ORR was 33.3%, the median duration of response (DOR) was 7.7 months, the median progression free survival (PFS) was 5.5 months, and overall survival (OS) was 13.0 months. The prescribing information includes a boxed warning on the risk of severe neutropenia and diarrhea. Further clinical trials are required to verify and describe sacituzumab govitecan-hziy’s clinical benefit.

Tucatinib for Patients with HER2-Positive Metastatic Breast Cancer. 

The highly selective, oral HER2 tyrosine kinase inhibitor tucatinib (Tukysa™, Seattle Genetics, Inc.) was approved in combination with trastuzumab and capecitabine for patients with advanced unresectable or metastatic HER2-positive breast cancer, including patients with brain metastases, who have received ≥ 1 prior anti-HER2-based regimens in the metastatic setting. Approval was based on efficacy data from the randomized, double blind HER2CLIMB trial that included 612 patients. In patients with previously treated HER2-positive breast cancer, the addition of tucatinib to trastuzumab and capecitabine resulted in significant and clinically meaningful improvement in PFS and OS compared to the additon of placebo. The median PFS in patients receiving the tucatinib combination was 7.8 months versus 5.6 months for patients receiving the placebo combination (HR 0.54; P < 0.001). The PFS benefit with tucatinib was also seen in patients with brain metastases (HR 0.48; P < 0.001). Importantly, the additon of tucatinib prolonged median OS by 4.5 months (HR 0.66, P = 0.005). Of note, tucatinib is associated with an increased risk of diarrhea and hepatotoxicity.

Pemigatinib, the First Targeted Treatment for Patients with Cholangiocarcinoma.

The FDA granted accelerated approval to a selective fibroblast growth factor receptor (FGFR) inhibitor, pemigatinib (Pemazyre™, Incyte Corp.) for the treatment of patients with previously treated, unresectable locally advanced or metastatic cholangiocarcinoma with a FGFR2 fusion or other rearrangement as detected by an FDA-approved test (FoundationOne® CDX, Foundation Medicine, Inc). Approval was based on the ORR and duration of response from a multicenter, single arm, phase II FIGHT-202 clinical trial that included 107 patients with locally advanced or metastatic cholangiocarcinoma with an FGFR2 fusion or rearrangement, who had progressed on or after ≥ 1 prior treatment. The ORR was 36% including a complete response (CR) in 2.8% of patients. Among the 38 patients who had a response, 24 patients (63%) had a response lasting ≥ 6 months and 7 patients (18%) had a response lasting ≥ 12 months. Pemigatinib may cause serious side effects, including hyperphosphatemia and ocular toxicity (retinal pigment epithelial detachment). Continued approval for this indication is dependent on additional efficacy data from a confirmatory trial. 

Mitomycin Gel for Treatment of Low-Grade Upper Tract Urothelial Cancer.

The FDA approved mitomycin gel (Jelmyto™, UroGen Pharma) for patients with low-grade upper tract urothelial cancer (LG-UTUC). This is the first non-surgical treatment for patients with LG-UTUC. Hydrogel-based formulation of mitomycin instilled via ureteral catheter or nephrostomy tube enables longer exposure of the urinary tract tissue to treatment. Approval was based on efficacy data from 71 patients with treatment naïve or recurrent non-invasive LG-UTUC enrolled in the pivotal, single arm, phase III OLYMPUS trial. Patients were treated with mitomycin gel instillations once a week for 6 weeks. The major efficacy outcome measures were CR and CR durability. Forty-one patients (58%) achieved a CR three months following treatment initiation and were continued in follow-up. The median response duration had not been reached (range: 0 – 18.8+ months). The updated results from this study were recently published in Lancet Oncology.

Encorafenib in Combination with Cetuximab for BRAF-mutant Metastatic Colorectal Cancer. 

The FDA granted approval for doublet targeted therapy of BRAF inhibitor encorafenib (Braftovi®, Array BioPharma Inc.) in combination with EGFR inhibitor cetuximab for the treatment of patients with metastatic colorectal cancer (CRC) with a BRAF V600E mutation, detected by an FDA-approved test, after progression on prior therapy. Approval was based on efficacy data from the randomized phase III BEACON trial that compared encorafenib plus cetuximab with or without binimetinib, with standard therapy in previously treated BRAF-positive metastatic CRC. In comparison to standard therapy, both doublet and triplet targeted therapy combinations were associated with improvements in key efficacy outcome measures, including OS, PFS, ORR and DOR. Median OS was 8.4 months in the encorafenib and cetuximab arm and was 9. 0 months with encorafenib, cetuximab and binimetinib compared with 5.4 months in the control arm (HR 0.60; P < 0.001 and HR 0.52;   P < 0.001). However, at median follow up of nearly 13 months, updated OS results presented at the 2020 Gastrointestinal Symposium showed no additional benefit with the triplet targeted therapy. Median OS was 9.3 months with either the doublet or triplet combination compared with 5.9 months with standard therapy. Quality of life was also similarly improved.

Niraparib for First-Line Maintenance Therapy in Advanced Ovarian Cancer. 

The PARP inhibitor niraparib (Zejula®, GlaxoSmithKline) was approved for the maintenance treatment of patients with advanced epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in CR or partial response (PR) to first-line platinum-based chemotherapy. Approval was based on results from the PRIMA trial, a double-blind, placebo-controlled trial that randomized 733 patients to receive niraparib or matched placebo. The trial demonstrated a statistically significant improvement in PFS for patients randomized to niraparib compared with placebo in the homologous recombination deficient and overall population. Median PFS in the homologous recombination deficient population was 21.9 months for patients receiving niraparib compared with 10.4 months for those receiving placebo (HR 0.43; P  < 0.0001). Median PFS in the overall population was 13.8 months for patients receiving niraparib compared with 8.2 months for those receiving placebo (HR 0.62; P < 0.001). 

Ibrutinib Plus Rituximab in Chronic Lymphocytic Leukemia. 

The FDA expanded the indication of ibrutinib (Imbruvica®, Pharmacyclics LLC) to include combination with rituximab for the initial treatment of adult patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL). Approval was based on the E1912 trial, a phase III randomized, multicenter, open-label, actively controlled trial of ibrutinib plus rituximab compared to fludarabine, cyclophosphamide, and rituximab (FCR) in 529 patients ≤ 70 years old with previously untreated CLL or SLL requiring systemic therapy. Ibrutinib was administered at a daily dose of 420 mg until disease progression or unacceptable toxicity. The trial demonstrated a statistically significant improvement in PFS for patients receiving ibrutinib plus rituximab compared with those receiving FCR (89.4% versus 72.9% at 3 years; HR 0.35;  P < 0.001). Median PFS was not reached in either arm after a median follow-up duration of 37 months. The results of the analysis of OS also favored ibrutinib plus rituximab over FCR (98.8% vs. 91.5% at 3 years; HR 0.17; P < 0.001).

Selumetinib for Neurofibromatosis Type 1 in Pediatric Patients.

The FDA also gave a green light for an oral selective MEK inhibitor selumetinib (Koselugo®, AstraZeneca) for pediatric patients ≥ 2 years old with neurofibromatosis type 1 (NF1) who have symptomatic, inoperable plexiform neurofibromas (PN). Approval was based on response data in 50 pediatric patients with NF1 included in the phase II, single arm SPRINT trial. Patients were required to have at least one significant morbidity related to the target PN. Among 50 children, 35 responded (70%), all confirmed responses were partial responses. Responses were sustained in the majority of patients and treatment provided clinically meaningful benefit. No irreversible or cumulative toxic effects were noted.