This week, the U.S. Food and Drug Administration (FDA) granted Priority Review to brigatinib for the treatment of ALK-positive lung cancer and Breakthrough Therapy designation to a potential first-in-class oral antagonist of inhibitors of apoptosis proteins for the treatment of head and neck cancer. In addition, the agency accepted a supplemental new drug application for niraparib in platinum-responsive advanced ovarian cancer and a supplemental biologics application for a fixed-dose subcutaneous injection of pertuzumab plus trastuzumab in HER2-positive breast cancer, and issued a statement on the use of laparoscopic power morcellators in gynecologic surgery.
Priority Review for Brigatinib as a First-Line Treatment for ALK-Positive Metastatic NSCLC
The FDA has granted Priority Review to a supplemental new drug application to expand the use of brigatinib as a first-line treatment for patients with anaplastic lymphoma kinase (ALK)-positive metastatic non–small cell lung cancer (NSCLC) as detected by an FDA-approved test. Brigatinib is a next-generation tyrosine kinase inhibitor that was designed to target and inhibit ALK genetic alterations.
The application for brigatinib as a first-line treatment is based on results from the phase III ALTA-1L trial, which evaluated the safety and efficacy of brigatinib in patients with ALK-positive locally advanced or metastatic NSCLC who have not received prior treatment with an ALK inhibitor compared to that of crizotinib in the same population. The ALTA-1L trial met its primary endpoint, with brigatinib demonstrating superiority in blinded independent review committee–assessed progression-free survival compared to crizotinib.
Breakthrough Therapy Designation for Debio 1143 in Head and Neck Cancer
The FDA has granted Breakthrough Therapy designation to Debio 1143 for the treatment of patients with previously untreated, unresectable locally advanced squamous cell carcinoma of the head and neck in combination with the current standard of care, cisplatin-based concomitant standard fractionation chemoradiotherapy.
Debio 1143 is a potential first-in-class oral antagonist of inhibitors of apoptosis proteins that sensitizes tumor cells to chemoradiotherapy by promoting programmed cell death and fostering antitumor immunity.
This designation is based on phase II study results presented by Bourhis et al at the European Society for Medical Oncology 2019 Congress, which showed an improved locoregional control rate at 18 months after chemoradiotherapy (21% improvement vs control arm) and a marked progression-free survival benefit vs the chemoradiotherapy/placebo arm after a 2-year follow-up period (hazard ratio = 0.37, P = .007). In addition, the compound showed a predictable and manageable safety profile that did not compromise the full delivery of standard chemoradiotherapy.
Supplemental New Drug Application for Niraparib in Platinum-Responsive Advanced Ovarian Cancer
The FDA accepted a supplemental new drug application seeking approval of the poly (ADP-ribose) polymerase inhibitor niraparib as a maintenance treatment in the first-line setting for women with advanced ovarian cancer who responded to platinum-based chemotherapy, regardless of biomarker status. The FDA is reviewing the application under the Real-Time Oncology Review pilot program, which aims to explore a more efficient review process to ensure safe and effective treatments are available to patients as early as possible.
The application is supported by data from the PRIMA study (ENGOT-OV26/GOG-3012), which demonstrated the benefit of niraparib treatment in the first-line maintenance setting. Results from the PRIMA study were presented at the European Society for Medical Oncology 2019 Congress and simultaneously published in The New England Journal of Medicine. PRIMA enrolled women who responded to first-line treatment with platinum-based chemotherapy, including those at higher risk of disease progression, a population previously underrepresented in first-line ovarian cancer studies.
Biologics License Application Acceptance for Fixed-Dose Subcutaneous Pertuzumab/Trastuzumab in HER2-Positive Breast Cancer
The FDA accepted a biologics license application for the fixed-dose combination of pertuzumab and trastuzumab with hyaluronidase, administered by subcutaneous injection in combination with intravenous (IV) chemotherapy, for the treatment of eligible patients with HER2-positive breast cancer.
Pertuzumab in the fixed-dose combination is the same monoclonal antibody as in intravenous pertuzumab, and trastuzumab in the combination is the same monoclonal antibody as in IV trastuzumab. The mechanisms of action of pertuzumab and trastuzumab are believed to complement each other, as both bind to the HER2 receptor, but in different locations. The combination of the two agents is thought to provide a more comprehensive, dual blockade of the HER-signaling pathways.
Subcutaneous administration of the fixed-dose combination takes approximately 8 minutes for the initial loading dose and approximately 5 minutes for each subsequent maintenance dose—this is compared to approximately 150 minutes for infusion of a loading dose of pertuzumab and trastuzumab using the standard intravenous formulations, and between 60 and 150 minutes for subsequent maintenance infusions of the two medicines.
The application is based on results from the phase III FeDeriCa study, which demonstrated noninferior levels of pertuzumab in the blood and comparable efficacy and safety to standard IV infusions of pertuzumab/trastuzumab and chemotherapy. The safety profile of the fixed-dose combination in combination with chemotherapy was comparable to that of intravenous administration of the combination and chemotherapy, and no new safety signals were identified, including no meaningful difference in cardiac toxicity. The most common adverse events in both arms were alopecia, nausea, diarrhea, and anemia. In previous studies of other subcutaneous formulations, this method of administration has been shown to be strongly preferred by the majority of patients compared to intravenous administration of the same medicine, with the most common reason being that administration required less time in the clinic.
New Steps to Increase the Safety of Laparoscopic Power Morcellators Used in Gynecologic Surgeries
This week, Jeffrey E. Shuren MD, JD, Director of the Center for Devices and Radiological Health at the FDA, issued the following statement:
[W]e are taking several important steps to make the use of laparoscopic power morcellators (LPMs) safer in gynecologic surgeries, including granting marketing authorization for updated labeling of the PneumoLiner containment system (a device that contains tissue to be morcellated during certain gynecologic surgeries), releasing a draft guidance recommending the addition of specific safety information to the product labeling for laparoscopic power morcellators, and issuing a Safety Communication recommending that a laparoscopic power morcellator only be used in certain gynecologic surgeries with a containment system that is compatible with the laparoscopic power morcellator.
Laparoscopic power morcellators are used during minimally invasive surgeries to cut tissue into smaller pieces so the tissue can be removed through a small incision site. These devices can be used in a variety of surgeries, including various gynecologic surgeries, such as a myomectomy, a surgical procedure to remove uterine fibroids from a woman’s uterus. While laparoscopic surgeries are associated with shorter postoperative recovery time and a reduced risk of infection compared to traditional surgery, there are known risks associated with the use of laparoscopic power morcellators, specifically in gynecologic surgeries. For example, current scientific evidence indicates that cancerous tissue may be present in uterine fibroids presumed to be benign. When laparoscopic power morcellators are used in surgeries where unsuspected cancerous tissue is present, there is a risk that morcellation could spread cancerous tissue throughout the body, decreasing a woman’s long-term survival.
In 2016, the FDA authorized the use of a first-of-kind tissue containment system, called the PneumoLiner, for use with certain laparoscopic power morcellators to isolate uterine tissue that is not suspected to contain cancer. The device includes a containment bag where the tissue to be removed is placed in the bag and sealed such that morcellated tissue is not spread throughout the abdominal cavity during the morcellation process. Although the device effectively contains morcellated tissue, to ensure that the benefits of this device continued to outweigh the risks, this device was only authorized for use in specific patient populations, including women without uterine fibroids undergoing hysterectomy and premenopausal women with fibroids who wish to maintain their fertility. We also required specific warnings to be included in the labeling so that both patients and health-care providers were aware of the risks of morcellation during certain gynecologic procedures.
[Now,] we are providing marketing authorization for the PneumoLiner containment system with updated labeling. While the device itself remains unchanged since its prior marketing authorization, [this] clearance updates the labeling for this device to better define the appropriate patient population for the safe and effective use of this device, including stating that the device should only be used in women who have fibroids if they are premenopausal and under 50 years old. The likelihood of unsuspected cancer in women undergoing hysterectomy or myomectomy increases with age such that the benefit/risk profile of using laparoscopic power morcellators is worse in older women when compared to younger women.
In addition to our efforts to ensure these devices are used in the appropriate patient population, we are issuing draft guidance proposing to update our recommendations in the 2014 final guidance concerning the content and format of certain labeling information for laparoscopic power morcellators. Specifically, the FDA is recommending that the labeling of laparoscopic power morcellators include contraindications and warnings highlighting the following information regarding the risks of use of laparoscopic power morcellators in gynecologic surgeries:
- The risk of occult cancer, including uterine sarcoma, increases with age, particularly in women over 50 years of age—this information should be shared with patients when considering surgery with the use of these devices
- Uncontained power morcellation has been associated with the spread of benign uterine tissue, ie, parasitic myomas and disseminated peritoneal leiomyomatosis
- Laparoscopic power morcellators should only be used with a containment system, and the containment system should be compatible with the laparoscopic power morcellator
- Laparoscopic power morcellators are contraindicated in gynecologic surgery in which the tissue to be morcellated is known or suspected to contain malignancy
- Laparoscopic power morcellators are contraindicated for removal of uterine tissue containing suspected fibroids in patients who are postmenopausal or over 50 years of age, or candidates for en bloc tissue removal through the vagina or via a minilaparotomy incision.
Finally, today we are issuing an updated Safety Communication that provides important information to patients and health-care providers on the risks associated with laparoscopic power morcellators when used in certain gynecologic surgeries. This Safety Communication now recommends that a laparoscopic power morcellator only be used in certain surgeries with a containment system that is compatible with the device. This communication also contains recommendations for patients and health-care providers if they are considering using laparoscopic power morcellators for gynecologic surgery—such as discussing the risks and benefits of all available treatments options to determine whether morcellation is appropriate—and provides specific questions that patients can use to start a dialogue with their physician.
