Durvalumab Approved for Locally Advanced or Metastatic Biliary Tract Cancer
The FDA approved durvalumab in combination with gemcitabine and cisplatin for adult patients with locally advanced or metastatic biliary tract cancer (BTC). Efficacy was evaluated in TOPAZ-1 (NCT03875235), a randomized, double-blind, placebo-controlled, multiregional trial that enrolled 685 patients with histologically confirmed, locally advanced unresectable or metastatic BTC who had not previously received systemic therapy for advanced disease.
Trial demographics were as follows: 56 percent Asian, 37 percent White, 2 percent Black, and 4 percent other race; 7 percent Hispanic or Latino; 50 percent male and 50 percent female; median age was 64 years (range 20-85) and 47 percent were 65 years or older. Fifty-six percent had intrahepatic cholangiocarcinoma, 25 percent had gallbladder cancer, and 19 percent had extrahepatic cholangiocarcinoma.
Patients were randomized 1:1 to receive the following: durvalumab 1,500 mg on Day 1+ gemcitabine 1,000 mg/m2 and cisplatin 25 mg/m2 on Days 1 and 8 of each 21-day cycle up to 8 cycles, followed by durvalumab 1,500 mg every 4 weeks, or placebo on Day 1+ gemcitabine 1,000 mg/m2 and cisplatin 25 mg/m2 on Days 1 and 8 of each 21-day cycle up to 8 cycles, followed by placebo every 4 weeks.
Durvalumab or placebo was continued until disease progression or unacceptable toxicity. Treatment was permitted beyond disease progression if the patient was clinically stable and deriving clinical benefit, as determined by the investigator.
The major efficacy outcome measure was overall survival (OS). Tumor assessments were conducted every 6 weeks for the first 24 weeks, then every 8 weeks until confirmed objective disease progression. A statistically significant improvement in OS was demonstrated in patients randomized to receive durvalumab with gemcitabine and cisplatin compared to those randomized to receive placebo with gemcitabine and cisplatin. Median OS was 12.8 months (95% CI: 11.1, 14) and 11.5 months (95% CI: 10.1, 12.5) in the durvalumab and placebo arms, respectively (HR 0.80; 95% CI: 0.66, 0.97, p=0.021). The median progression-free survival was 7.2 months (95% CI: 6.7, 7.4) and 5.7 months (95% CI: 5.6, 6.7) in the durvalumab and placebo arms, respectively. Investigator-assessed overall response rate was 27 percent (95% CI: 22-32%) and 19 percent (95% CI: 15-23%) in the durvalumab and placebo arms, respectively. The most common (>=20%) adverse reactions occurring in patients were fatigue, nausea, constipation, decreased appetite, abdominal pain, rash, and pyrexia.
The recommended durvalumab dose is 1,500 mg every 3 weeks for patients with a body weight >=30 kg when given with gemcitabine and cisplatin, followed by 1,500 mg every 4 weeks as a single agent until disease progression or unacceptable toxicity. For patients with a body weight <30 kg, the recommended dose is 20 mg/kg every 3 weeks with gemcitabine and cisplatin followed by 20 mg/kg every 4 weeks until disease progression or unacceptable toxicity.
Safety Alert for Squamous Cell Carcinoma & Various Lymphomas in Scar Tissue
The FDA issued a safety communication informing patients and providers about reports of squamous cell carcinoma (SCC) and various lymphomas located in the capsule or scar tissue around breast implants. "After an initial extensive review, we currently believe that the risk of SCC and other lymphomas occurring in the tissue around breast implants is rare. However, in this case, and when safety risks with medical devices are identified, we wanted to provide clear and understandable information to the public as quickly as possible."
In some reported cases, patients were diagnosed years after having breast implants and presented with findings such as swelling, pain, lumps, or skin changes. These emerging reports of lymphoma in scar tissue are different from breast implant-associated anaplastic large cell lymphoma, which the FDA began communicating about as a potential risk more than a decade ago.
The FDA's work in the area of patient-centered risk communication for these devices has accelerated in recent years, including convening stakeholders to share perspectives that have informed the FDA's regulatory oversight and implementation of new requirements for manufacturers. "We continue to engage top cancer experts and are consulting with our Oncology Center of Excellence to ensure a coordinated approach informed by leaders in the field." Additionally, the agency continues to closely monitor various data sources, such as the scientific literature and adverse event reports submitted to the agency. It also is soliciting information from manufacturers regarding any reports they may have regarding SCC and other lymphomas related to the tissue around an implant.
"We know that breast implants are not lifetime devices, and that the longer a patient has breast implants, the more likely they will need to be removed or replaced," the FDA noted. "We also understand that information regarding breast implant risks can be overwhelming for a patient. For this reason, we encourage review of our website with attention to patient labeling, which has easy to understand information in the patient brochure.
"Right now, we do not have enough information to say whether breast implants cause these cancers or if some implants pose higher risk than others. For this reason, instances of SCC, lymphoma, and any cancer located in the scar tissue around breast implants should be reported to the FDA. Our collective understanding has advanced significantly because of the efforts to study, communicate, and act when needed. As the agency moves further into adopting modernized approaches to our regulatory responsibilities to promote faster science-based decision-making, accurate data is crucial."
If a patient with breast implants experiences a problem, or there is a case of SCC, lymphoma, or any other cancer of the breast implant capsule identified, the FDA strongly encourages reporting this through MedWatch, the FDA Safety Information and Adverse Event Reporting program. This safety communication underscores the FDA's commitment to sharing the information...so that patients may fully consider and thoughtfully discuss implant risks with their doctors. "We will continue to collaborate with other regulatory authorities, clinical and scientific experts, breast implant registries, and patients as a part of our commitment to educate and enhance evidence generation on these potential new risks," the agency noted.
Looking ahead, the FDA will soon complete a thorough literature review and continue partnership with the American Society of Plastic Surgeons to identify ways to collect more detailed information regarding patient cases where cancer in the breast implant capsule has been reported. As more is learned about these cases, the agency hopes to better understand the patient risk and communicate findings to the public.
New Drug Application for Motixafortide in Stem Cell Mobilization for Multiple Myeloma
A New Drug Application (NDA) was submitted to the FDA for motixafortide in stem cell mobilization for autologous bone marrow transplantation for multiple myeloma patients. The NDA submission is based on the overwhelmingly positive top-line results from the GENESIS Phase III trial of motixafortide on top of G-CSF (versus placebo on top of G-CSF) in stem cell mobilization for autologous bone marrow transplantation in multiple myeloma patients. The study met all primary and secondary endpoints with a very high degree of statistical significance (p<0.0001). The combination was also found to be safe and well-tolerated.
The FDA's decision on acceptance of the NDA filing is expected in November. Assuming the filing is accepted, the potential PDUFA date would be in Q2 2023 (under a priority review process, if applicable) or Q3 2023 (under a standard review process).