FDA NEWS: June 30, 2021, and July 26, 2021

TOP - September 2021 Vol 14, No 5 - FDA Updates

This section provides a brief overview of new cancer drugs and new indications approved by the FDA between June 30, 2021, and July 26, 2021.

NEW DRUGS

FDA Approves Rezurock for the Treatment of Chronic Graft-versus-Host Disease

On July 16, 2021, the FDA approved belumosudil (Rezurock; Kadmon Holdings), a kinase inhibitor, for the treatment of patients aged ≥12 years with chronic graft-versus-host disease (GVHD) after failure of ≥2 previous lines of systemic therapy. The FDA granted belumosudil breakthrough therapy designation and priority review for this indication.

“Rezurock represents a new treatment paradigm for thousands of [patients with chronic GVHD], including those with difficult-to-treat manifestations like fibrosis,” said Corey S. Cutler, MD, MPH, FRCPC, Associate Professor of Medicine, Harvard Medical School, and Medical Director, Adult Stem Cell Transplantation Program, Dana-Farber Cancer Institute, Boston, MA, in a press release. “Rezurock has shown robust and durable responses across the spectrum of chronic GVHD and is safe and well-tolerated, allowing patients to stay on therapy and achieve meaningful benefit from treatment.”

The FDA approved belumosudil based on results of the randomized, open-label ROCKstar trial of 65 patients with chronic GVHD who had received 2 to 5 previous lines of therapy. All patients received 200 mg belumosudil orally once daily. The primary end point was overall response rate.

The overall response rate was 75% (95% confidence interval [CI], 63%-85%) through cycle 7, day 1 of treatment, with 6% of patients achieving a complete response and 69% achieving a partial response. Median time to first response was 1.8 months, and median duration of response was 1.9 months. Nearly two-thirds of patients (62%) did not require new systemic therapy for at least 12 months after achieving response.

The most common (≥20%) adverse reactions, including laboratory abnormalities, were infections, hypertension, asthenia, nausea, diarrhea, dyspnea, cough, edema, hemorrhage, abdominal pain, musculoskeletal pain, headache, decreased lymphocytes and phosphate, and increased gamma-glutamyl transferase.

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Rylaze FDA Approved as Part of a Treatment Regimen for Leukemia or Lymphoma

On June 30, 2021, the FDA accelerated the approval of asparaginase erwinia chrysanthemi (recombinant)-rywn (Rylaze; Jazz Pharmaceuticals), an asparagine-specific enzyme, as a component of a multidrug chemotherapy regimen for the treatment of acute lymphoblastic leukemia (ALL) and lymphoblastic lymphoma (LBL) in patients aged ≥1 months with hypersensitivity to Escherichia coli–derived asparaginase. The FDA granted asparaginase erwinia a fast-track review and an orphan drug designation for this indication.

“It is extremely disconcerting to patients, families and providers when there is a lack of access to critical drugs for treatment of a life-threatening, but often curable cancer, due to supply issues,” said Gregory Reaman, MD, Associate Director of Pediatric Oncology in the FDA’s Oncology Center of Excellence. “Today’s approval may provide a consistently sourced alternative to a pivotal component of potentially curative therapy for children and adults with this type of leukemia.”

The FDA approved erwinia chrysanthemi based on results of the JZP458-201 study, an open-label, multicohort, multicenter clinical trial of 102 patients (median age, 10 years; range, 1-24 years) with ALL or LBL and hypersensitivity to asparaginase caused by E coli infection, as part of a multidrug chemotherapy regimen. Erwinia chrysanthemi was administered intramuscularly, at various dosages.

The primary end point was achievement and maintenance of nadir serum asparaginase activity >0.1 U/mL. The results of modeling and simulations showed that for a dosage of 25 mg/m2 administered every 48 hours, the proportion of patients maintaining nadir serum asparaginase activity ≥0.1 U/mL at 48 hours after a dose of erwinia chrysanthemi was 93.6% (95% CI, 92.6%-94.6%).

The most common (>20%) adverse reactions were abnormal liver test, nausea, musculoskeletal pain, fatigue, infection, headache, pyrexia, drug hypersensitivity, febrile neutropenia, decreased appetite, stomatitis, bleeding, and hyperglycemia.

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NEW INDICATIONS

FDA Approves Keytruda for High-Risk, Early-Stage Triple-Negative Breast Cancer

On July 26, 2021, the FDA accelerated the approval of a new indication for the PD-1 inhibitor pembrolizumab (Keytruda; Merck), for the treatment of patients with high-risk, early-stage triple-negative breast cancer (TNBC) in combination with chemotherapy as a neoadjuvant treatment, and then continued as a single agent as adjuvant treatment after surgery.

“Even when TNBC is diagnosed early, 30% to 40% of patients will suffer cancer recurrence after standard neoadjuvant chemotherapy and surgery,” said Joyce O’Shaughnessy, MD, Chair, Breast Cancer Prevention Research, Baylor University Medical Center Texas Oncology/US Oncology Network, Dallas, in a press release. “Therefore, there is a high unmet need for new treatment options. [This] approval is very welcome news and has the potential to change the treatment paradigm by now including an immunotherapy as part of the regimen for patients with high-risk early-stage TNBC.”

This new indication is based on results of the randomized, multicenter, phase 3 KEYNOTE-522 trial, which included 1174 patients with newly diagnosed, previously untreated, high-risk, early-stage TNBC. Patients were randomized in a 2:1 ratio to pembrolizumab plus chemotherapy (N = 784) or placebo plus chemotherapy (N = 390).

The primary end points were pathologic complete response rate and event-free survival. Secondary end points included overall survival, efficacy in the subset of patients with PD-L1–positive disease, and safety. The pathologic complete response rate was 63% (95% CI, 59.5%-66.4%) for patients in the pembrolizumab plus chemotherapy arm versus 56% (95% CI, 50.6%-60.6%) for those in the chemotherapy-alone arm. The number of patients who experienced an event-free survival was 123 (16%) and 93 (24%), respectively.

The most common (≥20%) adverse reactions were fatigue (70%), nausea (67%), alopecia (61%), rash (52%), constipation (42%), diarrhea and peripheral neuropathy (41% each), stomatitis (34%), vomiting (31%), headache (30%), arthralgia (29%), pyrexia (28%), cough (26%), abdominal pain (24%), decreased appetite (23%), insomnia (21%), and myalgia (20%).

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FDA Approves Darzalex Faspro plus Pomalyst and Dexamethasone for Patients with Multiple Myeloma

On July 9, 2021, the FDA accelerated the approval of a new indication for daratumumab and hyaluronidase-fihj (Darzalex Faspro; Janssen Biotech), in combination with pomalidomide (Pomalyst; Bristol Myers Squibb) and dexamethasone, for the treatment of adults with multiple myeloma who have received ≥1 previous lines of therapy, including lenalidomide (Revlimid) or a proteasome inhibitor. Daratumumab and hyaluronidase, as well as pomalidomide, are each already approved for the treatment of patients with multiple myeloma, alone or in combination with other drugs.

This new indication was based on the results of the APOLLO study, an open-label, active-controlled clinical trial of 304 patients who were randomized in a 1:1 ratio to daratumumab and hyaluronidase plus pomalidomide and dexamethasone or to pomalidomide and dexamethasone alone.

“With this approval, we are now able to combine pomalidomide and dexamethasone with a daratumumab subcutaneous option that can be administered in minutes rather than the hours needed for intravenous administration,” said Meletios A. Dimopoulos, MD, Professor and Chairman of the Department of Clinical Therapeutics at the National and Kapodistrian University of Athens School of Medicine, Athens, Greece, and the study’s principal investigator.

The primary end point was progression-free survival. The median progression-free survival was 12.4 months in the daratumumab and hyaluronidase plus pomalidomide and dexamethasone arm versus 6.9 months with pomalidomide and dexamethasone alone (hazard ratio, 0.63; 95% CI, 0.47-0.85; P = .0018), a 37% risk reduction for disease progression or death with the 3-drug versus the 2-drug combination.

The most common (≥20%) adverse reactions with the 3-drug combination were fatigue, pneumonia, upper respiratory tract infection, and diarrhea.

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REGULAR FULL APPROVALS

Pembrolizumab plus Lenvatinib Combination Receives Regular FDA Approval for Advanced Endometrial Carcinoma

On July 21, 2021, the FDA granted full approval for the PD-1 inhibitor pembrolizumab (Keytruda; Merck), in combination with the kinase inhibitor lenvatinib (Lenvima; Eisai), for the treatment of advanced endometrial carcinoma that is not MSI-H (microsatellite instability-high) or dMMR (mismatch repair-deficient), in patients whose disease progressed after previous systemic therapy in any setting, and who are not candidates for curative surgery or radiation. In September 2019, the FDA granted accelerated approval to the combination of pembrolizumab plus lenvatinib for this indication.

The current regular FDA approval of pembrolizumab plus lenvatinib for this indication was based on the confirmatory results of Study 309/KEYNOTE-775, a multicenter, open-label, randomized, active-controlled clinical trial conducted to confirm the clinical benefit of the previous accelerated approval.

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Padcev Receives Regular FDA Approval for Locally Advanced or Metastatic Urothelial Cancer

On July 9, 2021, the FDA granted full approval to enfortumab vedotin-ejfv (Padcev; Astellas Pharma), a Nectin-4–directed antibody and microtubule inhibitor conjugate, for the treatment of adults with locally advanced or metastatic urothelial cancer who have previously received a PD-1 or PD-L1 inhibitor and platinum-containing chemotherapy, or who are ineligible for cisplatin-containing chemotherapy and have received ≥1 previous lines of therapy. The FDA granted initial accelerated approval to enfortumab vedotin for this indication in December 2019.

The current regular FDA approval of enfortumab vedotin for this indication was based on the results of the EV-301 clinical trial, an open-label, randomized, multicenter study that was conducted to further confirm the clinical benefit of enfortumab vedotin for this indication, as part of the requirements of the initial accelerated approval.

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Last modified: September 8, 2021