FDA Updates Highlighting the Latest Cancer Treatments

Orphan Drug Designation of NUV-422 for (mCRC) or squamous cell carcinoma of the head and neck (SCCHN). Malignant Gliomas This approval provides for a biweekly dosage regimen ­option in The FDA has granted Orphan Drug Designation to NUV-422, a cyclin- ­addition to the previously approved weekly dosage regimen for the dependent kinase (CDK) 2/4/6 inhibitor, for the treatment of patients approved indications when cetuximab is used as a single agent or in with malignant gliomas. combination with chemotherapy. Patient enrollment and dosing is ongoing in the Phase I/II study The approval was based on population pharmacokinetic (PK) of NUV-422 in adult patients with recurrent or refractory high-grade modeling analyses that compared the predicted exposures of cetux- gliomas, including glioblastoma multiforme. The Phase I dose-esca- imab 500 mg Q2W to observed cetuximab exposures in patients who lation part of the study is designed to evaluate safety and tolerability, received cetuximab 250 mg weekly. The application was also supported as well as determine a recommended Phase II dose based on the toler- by pooled analyses of overall response rates, progression-free survival, ability profile and pharmacokinetic properties of NUV-422. The Phase and overall survival (OS) from published literature in patients with II dose expansion part of the study is expected to initially focus on CRC and SCCHN, and OS analyses using real-world data in patients patients with high-grade gliomas, and it is designed to evaluate overall with mCRC who received either the weekly cetuximab or Q2W regi- response rate, duration of response, and survival. Data from the Phase mens. In these exploratory analyses, the observed efficacy results were I portion of this study is expected in 2022. consistent across dosage regimens and supported the results of the NUV-422 is a selective small molecule resulting from a cyclin-depen- population PK modeling analyses. dent kinase (CDK) inhibitor program. CDK4/6 inhibitors are known The most common adverse reactions (incidence ≥25%) to cetux- clinical entities with proven efficacy, but cancer cells can evade these imab are cutaneous adverse reactions (including rash, pruritus, and treatments by increasing signaling through CDK2. Inhibition of CDK2 nail changes), headache, diarrhea, and infection. in addition to CDK4/6 cuts off the tumor’s natural escape route. NUV- 422 is a potent inhibitor of CDK 2, 4, and 6. Preclinical studies have Approval of Sacituzumab Govitecan for shown that NUV-422 has favorable blood-brain barrier penetration. Triple-Negative Breast Cancer The FDA Office of Orphan Drug Development grants Orphan The FDA granted regular approval to sacituzumab govitecan for pa- Drug Designation to support drug candidates in development for un- tients with unresectable locally advanced or metastatic triple-negative derserved patient populations or rare disorders that affect fewer than breast cancer (mTNBC) who have received two or more prior systemic 200,000 people in the U.S. The designation qualifies a candidate for therapies, at least one of them for metastatic disease. various development incentives, including tax credits for eligible clini- In April 2020, sacituzumab govitecan received accelerated approval cal trials, waiver of application fees, and market exclusivity for 7 years for patients with mTNBC who have received at least two prior thera- upon FDA approval. pies for metastatic disease. The following trial was the confirmatory trial for the accelerated approval. Approval of Isatuximab-Irfc for Multiple Efficacy and safety were evaluated in a multicenter, open-label, Myeloma randomized trial (ASCENT; NCT02574455) conducted in 529 pa- The FDA approved isatuximab-irfc in combination with carfilzomib and tients with unresectable locally advanced or mTNBC who had re- dexamethasone for the treatment of adult patients with relapsed or re- lapsed after at least two prior chemotherapies, one of which could fractory multiple myeloma who have received 1-3 prior lines of therapy. be in the neoadjuvant or adjuvant setting, if progression occurred The efficacy and safety of isatuximab-irfc in combination with carfil- within 12 months. Patients were randomized (1:1) to receive saci- zomib and dexamethasone was evaluated in IKEMA (NCT03275285), tuzumab govitecan, 10 mg/kg as an intravenous infusion, on days 1 a multicenter, multinational, randomized, open-label, two-arm, Phase and 8 of a 21-day (n=267) cycle or physician’s choice of single-agent III trial in patients with relapsed and/or refractory multiple myeloma chemotherapy (n=262). who had received 1-3 prior lines of therapy. The trial randomized 302 The primary efficacy endpoint was progression-free survival (PFS) patients (3:2) to receive isatuximab-irfc with carfilzomib and dexa- in patients without brain metastases at baseline as measured by a methasone (Isa-Kd) or carfilzomib and dexamethasone (Kd). blinded, independent, centralized review assessed using RECIST 1.1 The main efficacy outcome measure was progression-free survival criteria. Additional efficacy endpoints included PFS for the full popu- (PFS), assessed by an independent response committee based on central lation (with and without brain metastases) and overall survival (OS). laboratory data for M-protein and central radiologic imaging review us- Among all randomized patients (with and without brain metasta- ing International Myeloma Working Group criteria. Median PFS was ses), median PFS for patients receiving sacituzumab govitecan was 4.8 not reached in the Isa-Kd arm and was 20.27 months (95% CI: 15.77- months (95% CI: 4.1, 5.8) compared with 1.7 months (95% CI: 1.5, NR) in the Kd arm (HR 0.548; 95% CI: 0.366-0.822; p=0.0032), repre- 2.5) in those receiving chemotherapy (HR 0.43; 95% CI: 0.35, 0.54; senting a 45 percent reduction in the risk of disease progression or death p<0.0001). Median OS was 11.8 months (95% CI: 10.5, 13.8) and 6.9 in patients treated with Isa-Kd compared to those treated with Kd. months (95% CI: 5.9, 7.6), respectively (HR 0.51; 95% CI: 0.41, 0.62; The most common adverse reactions (≥20%) in patients receiving p<0.0001). isatuximab with carfilzomib and dexamethasone were upper respiratory Most common adverse reactions (incidence >25%) in patients re- tract infection, infusion-related reactions, fatigue, hypertension, diar- ceiving sacituzumab govitecan were nausea, neutropenia, diarrhea, rhea, pneumonia, dyspnea, insomnia, bronchitis, cough, and back pain. fatigue, alopecia, anemia, vomiting, constipation, rash, decreased ap- The most common hematology laboratory abnormalities (≥80%) were petite, and abdominal pain. decreased hemoglobin, decreased lymphocytes, and decreased platelets. The recommended sacituzumab govitecan dose is 10 mg/kg once The recommended isatuximab-irfc dose with carfilzomib and weekly on days 1 and 8 of 21-day treatment cycles until disease pro- dexamethasone is 10 mg/kg as an intravenous infusion every week gression or unacceptable toxicity. for 4 weeks followed by every 2 weeks until disease progression or un­ acceptable toxicity. Breakthrough Therapy Designation to Futibatinib for Advanced Cholangiocarcinoma A New Dosing Regimen for Cetuximab The FDA granted Breakthrough Therapy Designation for futi- The FDA approved a new dosage regimen of 500 mg/m2 as a batinib (TAS-120), a covalently binding FGFR inhibitor, for the 120-­minute intravenous infusion every 2 weeks (Q2W) for cetuximab treatment of patients with previously treated locally advanced or for patients with KRAS wild-type, EGFR-expressing colorectal cancer metastatic cholangiocarcinoma harboring FGFR2 gene rearrange-

36 Oncology Times May 5, 2021 ments, including gene fusions. Futibatinib is an investigational cancer is the integration of leading-edge technologies into gastroen- therapy and has not been approved by any regulatory authority for terology practices to increase detection rates,” said James Weber, MD, use in patients. a gastroenterologist and Chief Executive Officer of the GI Alliance. The designation is based on efficacy and safety results from the “Detection of adenomas during colonoscopy is an important qual- Phase II FOENIX-CCA2 study. In May 2018, the FDA Office of ity metric. The addition of AI can increase the quality of colonosco- Orphan Drug Development granted futibatinib orphan drug status pies, potentially improving diagnosis and outcomes for colon cancer for the treatment of cholangiocarcinoma. Futibatinib is an investiga- patients.” tional, oral, potent, selective, and irreversible small molecule inhibitor “Colonoscopies allow highly skilled gastroenterologists to identify of FGFR1, 2, 3 and 4 being studied as a potential treatment for pa- polyps and lesions that might develop into cancer. With GI Genius, tients with advanced solid tumors with FGFR1-4 genetic aberrations, we can tap into the potential of artificial intelligence approaches to including cholangiocarcinoma, who were previously treated with che- increase detection rates. This important new development helps us motherapy or other therapies. Futibatinib selectively and irreversibly in our mission to detect colon cancer early and to improve patient binds to the ATP binding pocket of FGFR1-4, resulting in the inhi- outcomes,” said Michael Sapienza, Chief Executive Officer of the bition of FGFR-mediated signal transduction pathways, reduced tu- Colorectal Cancer Alliance. mor cell proliferation, and increased tumor cell death in tumors with The detection system uses advanced AI to highlight the presence FGFR1-4 genetic aberrations. of precancerous lesions with a visual marker in real-time—serving as an ever vigilant second observer. It processes images using advanced Fast Track Designation for Annamycin in the algorithms that can identify and mark abnormalities consistent with Treatment of Sarcoma Lung Metastases polyps, including small flat polyps that might otherwise go undetected The FDA approved a Fast Track Designation request for the drug, by the human eye. Studies have shown that having a second observer annamycin, for the treatment of soft tissue sarcoma (STS) lung can increase polyp detection rates and every 1 percent increase in ad- metastases. enoma detection rate (ADR) reduces the risk of colorectal cancer by 3 Once metastasized to the lungs, if tumors cannot be surgically percent. Use of the GI Genius module has demonstrated a 14 percent removed, the primary chemotherapy regimen is the anthracycline absolute increase in ADR compared to colonoscopy alone for both flat doxorubicin. While 10-30 percent of patients with sarcoma lung (42% increase) and polyploid (36% increase) lesions, thus increasing metastases may initially respond to doxorubicin, most will relapse accuracy and reducing the rise of interval cancers which can occur leaving the majority of these patients without an alternative chemo- between colonoscopies. OT therapy. Treatment options are further limited because of the inher- ent cardiotoxicity of currently approved anthracyclines, including doxorubicin, which limits the amount of anthracycline that can be given to patients. Annamycin is a next-generation anthracycline that has recently been shown in animal models to accumulate in the lungs at up to Get the latest cancer 30-fold the level of doxorubicin. Importantly, annamycin has also demonstrated a lack of cardiotoxicity in recently conducted human related news from clinical trials for the treatment of acute myeloid leukemia, so research- ers believe that the use of annamycin may not face the same usage limitations imposed on doxorubicin. the Food and Drug

Eftilagimod Alpha Receives Fast Track Designation for Recurrent/Metastatic Head Administration & Neck Cancer Eftilagimod alpha (efti or IMP321), a soluble LAG-3 protein, has received FDA Fast Track designation in first-line recurrent or meta- static head and neck squamous cell carcinoma (HNSCC). It has been granted for the development program of efti for first-line treatment of recurrent or metastatic HNSCC due to its potential to address an unmet medical need, as evidenced by encouraging data indicating a positive risk-benefit ratio. The data package evaluated by the FDA included promising results from Part C of the Phase II TACTI-002 trial evaluating efti in com- bination with pembrolizumab second-line PD-X naive HNSCC, and its plans for a trial in first-line HNSCC (TACTI-003). Interim clinical data from the study was presented at the Society for Immunotherapy of Cancer (SITC) in November 2020. The overall response rate re- ported at SITC was approximately 36 percent (approximately 44% in evaluable patients) for 28 patients receiving efti in combination with pembrolizumab. Access the FDA Actions FDA Grants Clearance for First & Only Artificial Intelligence System for Colonoscopy & Updates Blog online The FDA granted de novo clearance for GI Genius intelligent endos- copy module in the U.S., which is the first and only commercially at Oncology-times.com available computer-aided detection (CADe) system using artificial in- telligence (AI) to identify colorectal polyps. The module, compatible with any colonoscope video, provides physicians with a powerful new solution in the fight against colorectal cancer—the third most com- mon form of cancer globally. 7-Q887 “More than 19 million screening colonoscopies are performed in the United States each year. A key factor in the prevention of colorectal

oncology-times.com Oncology Times 37