FDA News: June 22, 2022, and August 11, 2022.

TOP - September 2022 Vol 15, No 5 - FDA Updates

This section provides a brief overview of new indications for cancer drugs approved by the FDA between June 22, 2022, and August 11, 2022.

NEW INDICATIONS

Enhertu Receives 2 New Indications: HER2 Mutation–Positive NSCLC and HER2-Low Breast Cancer

On August 11, 2022, the FDA accelerated the approval of the antibody–drug conjugate fam-trastuzumab deruxtecan-nxki (Enhertu; Daiichi Sankyo) for the treatment of adult patients with unresectable or metastatic non–small-cell lung cancer (NSCLC) whose tumors have activating HER2 (ERBB2) mutations, as determined by an FDA-approved test, and who have received a previous systemic therapy. The FDA granted trastuzumab deruxtecan a priority review and breakthrough designation for this indication.

Concurrently, FDA approved Life Technologies Corporation’s Oncomine Dx Target tissue test and Guardant Health’s Guardant30 CDx plasma test as companion diagnostics for determining HER2 mutations in this patient population.

Trastuzumab deruxtecan was previously approved for the treatment of patients with unresectable or metastatic HER2-positive breast cancer who have received 2 or more previous anti–HER2-based regimens in the metastatic setting and in patients with locally advanced or metastatic HER2-positive gastric or gastroesophageal junction adenocarcinoma who have received a previous trastuzumab-based regimen.

This new indication was based on an interim efficacy analysis in a prespecified patient cohort of patients in the DESTINY-Lung02 study, a multicenter, multicohort, randomized, blinded, dose-optimization clinical trial. Patients with previously treated unresectable or metastatic nonsquamous HER2 mutation–positive NSCLC received intravenous (IV) trastuzumab deruxtecan 5.4 mg/kg every 3 weeks until unacceptable toxicity or disease progression.

The primary efficacy measures were confirmed objective response rate (ORR) as assessed by blinded independent central review using RECIST version 1.1 and duration of response. An interim efficacy analysis in a prespecified patient cohort showed a confirmed ORR of 57.7% (N = 52; 95% confidence interval [CI], 43.2-71.3). Complete responses were observed in 1.9% of patients and partial responses in 55.8% of patients, with a median duration of response of 8.7 months (95% CI, 7.1-not evaluable).

The most common (≥20%) adverse reactions, including laboratory abnormalities, were nausea, decreased white blood cell count, decreased hemoglobin, decreased neutrophil count, decreased lymphocyte count, decreased platelet count, decreased albumin, increased aspartate aminotransferase, increased alanine aminotransferase, fatigue, constipation, decreased appetite, vomiting, increased alkaline phosphatase, and alopecia.

The prescribing information includes a warning about the risk for interstitial lung disease and embryo-fetal toxicity.

On August 5, 2022, the FDA approved trastuzumab deruxtecan for the treatment of adult patients with unresectable or metastatic HER2-low (immunohistochemistry [IHC] 1+ or IHC 2+/in situ hybridization [ISH]-negative) breast cancer who have received previous chemotherapy in the metastatic setting or had disease recurrence during or within 6 months of completing adjuvant chemotherapy. The FDA granted trastuzumab deruxtecan a priority review and breakthrough designation for this indication.

This new indication was based on efficacy data from the DESTINY-Breast04 study, a randomized, multicenter, open-label clinical trial of 557 patients with unresectable or metastatic HER2-low breast cancer. The trial included 2 cohorts: 494 patients with hormone receptor (HR)-positive disease and 63 patients with HR-negative disease. HER2-low expression was defined as IHC 1+ or IHC 2+/ISH-negative, determined at a central laboratory.

The patients were randomized in a 2:1 ratio to receive trastuzumab deruxtecan 5.4 mg/kg IV (N = 373) every 3 weeks or physician’s chemotherapy choice (N = 184).

The primary efficacy measure was progression-free survival (PFS) in patients with HR-positive breast cancer, assessed by blinded independent central review using RECIST version 1.1. Secondary efficacy measures were PFS in the overall population (all randomized patients with HR-positive and HR-negative disease), overall survival (OS) in HR-positive patients, and OS in the overall population.

Median PFS in the HR-positive cohort was 10.1 months in the trastuzumab deruxtecan arm and 5.4 months in the chemotherapy arm. Median PFS in the overall population was 9.9 months for patients receiving trastuzumab deruxtecan and 5.1 months for those receiving chemotherapy.

In the HR-positive cohort, the median OS was 23.9 months and 17.5 months in the trastuzumab deruxtecan and chemotherapy arms, respectively. In the overall population, median OS was 23.4 months in the trastuzumab deruxtecan arm versus 16.8 months in the chemotherapy arm.

The most common (≥20%) adverse reactions reported with trastuzumab deruxtecan were nausea, fatigue, alopecia, vomiting, anemia, constipation, decreased appetite, diarrhea, and musculoskeletal pain.

Return to Top


Nubeqa Receives a New Indication, in Combination with Docetaxel, for Metastatic Hormone-Sensitive Prostate Cancer

On August 5, 2022, the FDA approved darolutamide (Nubeqa; Bayer) tablets, in combination with docetaxel, for the treatment of adult patients with metastatic hormone-sensitive prostate cancer. The FDA granted this new indication a priority review.

Darolutamide was previously approved for the treatment of patients with nonmetastatic castration-resistant prostate cancer.

The new indication was approved based on the ARASENS study, a randomized, multicenter, double-blind, placebo-controlled clinical trial in 1306 patients with metastatic hormone-sensitive prostate cancer. Patients were randomized to darolutamide 600 mg orally twice daily plus intravenous docetaxel 75 mg/m2 every 3 weeks for up to 6 cycles or docetaxel plus placebo. All patients received a gonadotropin-releasing hormone analog concurrently or had a bilateral orchiectomy.

The primary efficacy measure of the study was overall survival (OS). Time-to-pain progression was an additional efficacy measure. Median OS was not reached in the darolutamide plus docetaxel arm and was 48.9 months in the docetaxel plus placebo arm.

In addition, treatment with darolutamide and docetaxel resulted in a statistically significant delay in time-to-pain progression.

The most common (≥10% with a ≥2% increase over placebo with docetaxel) adverse reactions were constipation, decreased appetite, rash, hemorrhage, increased weight, and hypertension. The most common (≥30%) laboratory test abnormalities were anemia, hyperglycemia, decreased lymphocyte count, decreased neutrophil count, increased aspartate aminotransferase, increased alanine transaminase, and hypocalcemia.

Return to Top


Xalkori Now Approved for Treatment of ALK-Positive Inflammatory Myofibroblastic Tumors

On July 14, 2022, the FDA approved the multikinase inhibitor crizotinib (Xalkori; Pfizer) for the treatment of unresectable, recurrent, or refractory inflammatory myofibroblastic tumors with anaplastic lymphoma kinase (ALK) mutation in patients aged ≥1 years. The FDA granted crizotinib an orphan drug designation for this indication.

Crizotinib was previously approved for the treatment of patients with metastatic non–small-cell lung cancer and ALK or ROS1 mutation, and for young patients aged 1 to 21 years with relapsed or refractory systemic anaplastic large-cell lymphoma and ALK mutation.

This new indication was based on the results of 2 multicenter, single-arm, open-label clinical trials—ADVL0912 and A8081013—that enrolled patients with unresectable, recurrent, or refractory ALK-positive inflammatory myofibroblastic tumors.

The ADVL0912 study included 14 pediatric patients, and 12 of these patients had an objective response to crizotinib, with an overall response rate of 86% (95% confidence interval, 57%-98%).

The A8081013 study enrolled 7 patients, 5 of whom had an objective response.

In the pediatric patients, the most common (≥35%) adverse reactions were vomiting, nausea, diarrhea, abdominal pain, rash, vision disorder, upper respiratory tract infection, cough, pyrexia, musculoskeletal pain, fatigue, edema, constipation, and headache. In the adult patients, the most common (≥35%) adverse reactions were vision disorders, nausea, and edema.

The recommended dose of crizotinib is 250 mg/m2 orally twice daily in adults and 280 mg/m2 orally twice daily in pediatric patients until disease progression or unacceptable toxicity.

Return to Top


Breyanzi Now FDA Approved for Second-Line Treatment of LBCL

On June 24, 2022, the FDA approved the CD19-directed chimeric antigen receptor (CAR) T-cell therapy lisocabtagene maraleucel (Breyanzi; Juno Therapeutics) for the treatment of adults with large B-cell lymphoma (LBCL), including diffuse large B-cell lymphoma (DLBCL) not otherwise specified (including DLBCL arising from indolent lymphoma), high-grade B-cell lymphoma, primary mediastinal LBCL, and grade 3B follicular lymphoma.

The FDA granted lisocabtagene maraleucel regenerative medicine advanced therapy and breakthrough therapy designations for this indication. This approval includes a Risk Evaluation and Mitigation Strategy program, because of the risk for life-threatening or fatal cytokine release syndrome (CRS) and neurologic adverse events. This CAR T-cell therapy is not approved for primary central nervous system lymphoma.

Lisocabtagene maraleucel was previously approved for various subtypes of relapsed or refractory LBCL after ≥2 lines of systemic therapy.

This new indication was based on the results of the TRANSFORM study, a global, randomized, multicenter, open-label clinical trial in 184 adults with primary refractory LBCL or with relapsed LBCL within 12 months of having a complete response. Patients were randomized in a 1:1 ratio to a single infusion of lisocabtagene maraleucel after lymphodepleting chemotherapy or to second-line therapy with 3 cycles of salvage chemotherapy, followed by high-dose therapy and autologous hematopoietic stem-cell transplant in patients who had a partial or complete response.

The primary efficacy measure was event-free survival (EFS). The results showed a significant improvement in EFS with the CAR T-cell therapy versus the standard of care (hazard ratio [HR], 0.34; 95% confidence interval [CI], 0.22-0.52; P <.0001); the 1-year EFS rates were 45% and 24%, respectively. The median EFS was 10.1 months with lisocabtagene maraleucel (95% CI, 6.1-nonevaluable) versus 2.3 months with the standard of care (95% CI, 2.2-4.3).

The median progression-free survival was 14.8 months with lisocabtagene maraleucel and 5.7 months with the standard of care (HR, 0.406; P = .0001).

The majority (86%) of the patients who received lisocabtagene maraleucel achieved a partial or complete response, including 66% complete responses, compared with 48% of patients in the standard-of-care arm achieving partial or complete responses, including 39% complete responses.

Lisocabtagene maraleucel had a manageable safety profile, with 49 patients having any-grade CRS, 1 patient had grade 3 CRS, and no grade 4 or 5 CRS reported. In all, 12% of the patients who received the CAR T-cell therapy had any-grade neurologic events, including 4% grade 3 events.

Return to Top


Tafinlar plus Mekinist First Tumor Agnostic Therapy for Any Unresectable or Metastatic Solid Tumors with BRAF Mutation

On June 22, 2022, the FDA accelerated the approval of dabrafenib (Tafinlar; Novartis), a BRAF mutation inhibitor, in combination with trametinib (Mekinist; GlaxoSmithKline), a MEK inhibitor, for the treatment of unresectable or metastatic solid tumors and BRAF V600E mutation in adults and pediatric patients aged ≥6 years who have had disease progression after receiving previous treatment.

The combination of dabrafenib and trametinib is currently approved for unresectable or metastatic melanoma and BRAF V600E or V600K mutations, melanoma with BRAF V600E or V600K mutations involving lymph node(s), metastatic non–small-cell lung cancer with BRAF V600E mutation, and locally advanced or metastatic anaplastic thyroid cancer with BRAF V600E mutation.

This approval was based on the results of 3 clinical trials that included 131 adults in the first 2 studies, 36 patients in the pediatric study, and a total of 24 types of solid tumors.

The phase 2 Rare Oncology Agnostic Research (ROAR) study was an open-label, single-arm, multicenter study of patients with BRAF V600E–positive solid tumors, including low- or high-grade gliomas, biliary tract cancer, adenocarcinoma of the small intestine, gastrointestinal stromal tumor, and anaplastic thyroid cancer. The patients received dabrafenib 150 mg orally twice daily and trametinib 2 mg orally once daily.

The phase 2 National Cancer Institute Molecular Analysis for Therapy Choice (NCI-MATCH) was a precision medicine clinical trial that included adults with BRAF V600E–positive solid tumors, excluding melanoma, thyroid cancer, and colorectal cancer.

The third study, Study X2101, included pediatric patients with BRAF V600 refractory or recurrent low- or high-grade glioma to evaluate the clinical benefit and safety of dabrafenib plus trametinib in pediatric patients.

The major efficacy end point of these 3 studies was overall response rate (ORR), which was up to 80% in patients with BRAF V600E solid tumors. The highest overall responses were seen in biliary tract cancer (46%) and low- and high-grade gliomas (50% and 33%, respectively). In the 2 studies with 131 adults, 54 (41%) patients had an objective response. In the 36 pediatric patients, the ORR was 25%, with a duration of response of ≥6 months in 78% of patients, and of ≥24 months in 44% of patients.

The most common (≥20%) adverse reactions in adults were pyrexia, fatigue, nausea, rash, chills, headache, hemorrhage, cough, vomiting, constipation, diarrhea, myalgia, arthralgia, and edema. In the pediatric patients, most common (≥20%) adverse reactions were pyrexia, rash, vomiting, fatigue, dry skin, cough, diarrhea, dermatitis acneiform, headache, abdominal pain, nausea, hemorrhage, constipation, and paronychia.

Return to Top


NEW SAFETY WARNING

FDA Issues New Warning for Copiktra About Increased Risks for Serious Side Effects and Mortality

On June 30, 2022, the FDA issued a new boxed warning for duvelisib (Copiktra; Secura Bio) about the increased risk for serious side effects and death with this PI3K inhibitor, based on the results of the DUO clinical trial. Duvelisib is approved for the treatment of relapsed or refractory chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) in adults after at least 2 previous therapies. Prophylaxis for Pneumocystis jirovecii is recommended during treatment with duvelisib.

The DUO trial was a phase 3, randomized study that compared duvelisib and ofatumumab (Kesimpta) in 319 patients with relapsed or refractory CLL or SLL who received at least 1 previous therapy.

At a median follow-up of 63 months, the results showed an increased mortality risk with duvelisib versus with ofatumumab (hazard ratio [HR], 1.09; 95% confidence interval [CI], 0.79-1.51). In patients who received ≥2 previous lines of therapy, the HR for mortality was 1.06 (95% CI, 0.71-1.58). The median overall survival was lower with duvelisib than with ofatumumab (52.3 months vs 63.3 months, respectively).

A safety analysis showed more serious adverse reactions (including grade ≥3), increased treatment modifications resulting from adverse reactions, and a higher incidence of death due to adverse reactions with duvelisib than with ofatumumab.

The FDA continues to evaluate the safety of duvelisib and is planning to discuss the trial findings and whether the drug can continue to be prescribed.

Return to Top

Related Items
FDA News: April 1, 2022, and May 27, 2022
TOP - July 2022 Vol 15, No 4 published on July 20, 2022 in FDA Updates
FDA NEWS: February 28, 2022 to March 31, 2022
TOP - May 2022 Vol 15, No 3 published on May 6, 2022 in FDA Updates
FDA NEWS: January 10, 2022, and January 25, 2022
TOP - March 2022 Vol 15, No 2 published on March 16, 2022 in FDA Updates
FDA NEWS: November 29, 2021, and December 15, 2021
TOP - January 2022 Vol 15, No 1 – Online Only published on January 20, 2022 in FDA Updates
FDA NEWS: August 13, 2021 to September 22, 2021
TOP - November 2021 Vol 14, No 7 published on November 10, 2021 in FDA Updates
FDA Issues Revised Final Guidance on Biosimilar Development and the BPCI Act
TOP - October 2021 Vol 14, No 6 | Biosimilars published on November 5, 2021 in FDA Updates, Biosimilars
FDA NEWS: June 30, 2021, and July 26, 2021
TOP - September 2021 Vol 14, No 5 published on September 7, 2021 in FDA Updates
FDA NEWS: May 5, 2021 to May 28, 2021
TOP - July 2021 Vol 14, No 4 published on July 20, 2021 in FDA Updates
FDA NEWS: April 13, 2021 to April 23, 2021
TOP - May 2021 Vol 14, No 3 published on May 14, 2021 in FDA Updates
FDA NEWS: February 5, 2021 to February 22, 2021
TOP - March 2021 Vol 14, No 2 published on March 11, 2021 in FDA Updates
Last modified: September 16, 2022