Oncology Regulatory Review
Highlights of 2022
The OCE collaborates with the three FDA product centers reviewing drugs, biologic therapies, and devices to develop and execute an integrated regulatory approach to enhance the cross-center coordination of oncology product clinical review.
Drugs and Biologic Therapies (CDER)
The Office of Oncologic Diseases (OOD) in the Center for Drug Evaluation and Research (CDER) approved several new immunotherapeutics and molecularly targeted drugs in 2022 for the treatment of multiple cancer types, including lymphoma, leukemia, multiple myeloma, melanoma, prostate cancer, hepatocellular carcinoma, and cholangiocarcinoma. These included 11 approvals of new drugs or biologic agents, along with 29 labeling expansions.
The OCE led the development of FDA guidance in 2022, Tissue Agnostic Drug Development in Oncology, and established an Associate Director position to facilitate consistency and policy with respect to tissue agnostic development programs. Notable tissue agnostic approvals included:
- Dabrafenib and trametinib for BRAF positive solid tumors.
- Selpercatinib for locally advanced or metastatic RET fusion-positive solid tumors.
Other notable approvals included:
- Fam-trastuzumab deruxtecan-nxki, for unresectable or metastatic HER2-low breast cancer. This is the first approved therapy for patients with the HER2-low breast cancer subtype, a newly defined subset of HER2-negative breast cancer.
- Teclistamab-cqyv for relapsed or refractory multiple myeloma. Tecvayli is the first bispecific therapy directed at both the B-cell maturation antigen protein and cluster of differentiation 3 protein complex and T cell co-receptor.
- Mosunetuzumab, a bispecific CD20-directed CD3 T-cell engager for relapsed or refractory follicular lymphoma.
- Mirvetuximab soravtansine-gynx for patients with FRα positive, platinum-resistant epithelial ovarian, fallopian tube, or primary peritoneal cancer, who have received one to three prior systemic treatment regimens.
- Lutetium LU 177 vipivotide tetraxetan, for patients with prostate-specific membrane antigen-positive metastatic castration-resistant prostate cancer who have received at least two specific lines of therapy. Pluvicto is the first PSMA-targeted radiopharmaceutical.
- Sodium thiosulfate injection to treat ototoxicity associated with cisplatin in pediatric patients.
- Tebentafusp-tebn for unresectable or metastatic uveal melanoma, a new medical entity (NME) and first approval for this rare cancer.
- Relatlimab and nivolumab fixed-dose combination, an NME for adult and pediatric patients 12 years of age or older with unresectable or metastatic melanoma.
- Nivolumab in combination with chemotherapy or in combination with ipilimumab for the first-line treatment of esophageal squamous carcinoma.
- Crizotinib for the treatment of ALK-positive inflammatory myofibroblastic tumors, the first approval for this tumor.
- Durvalumab in combination with chemotherapy, the first immunotherapy for the treatment of biliary tract cancer.
- Futibatinib, an NME for patients with previously treated, unresectable, locally advanced or metastatic intrahepatic cholangiocarcinoma harboring fibroblast growth factor receptor 2 gene fusions or other rearrangements.
- Tremelimumab in combination with durvalumab, an NME for the treatment of patients with hepatocellular cancer.
Cellular Cancer Therapies (CBER)
The Center for Biologics Evaluation and Research (CBER) reviews and regulates cellular cancer therapies in partnership with OCE.
In 2022, CBER and OCE approved two original cell therapies and three supplemental indications.
- Ciltacabtagene autoleucel (Carvykti), for relapsed or refractory multiple myeloma after four or more prior lines of therapy, including a proteasome inhibitor, an immunomodulatory agent, and an anti-CD38 monoclonal antibody.
- Adofaragene firadenovec (Adstiladrin) for high-risk Bacillus Calmette-Guérin unresponsive non-muscle invasive bladder cancer with carcinoma in situ with or without papillary tumors.
- Axicabtagene ciloleucel (Yescarta), for large B-cell lymphoma that is refractory to first-line chemoimmunotherapy or that relapses within 12 months of first-line chemoimmunotherapy.
- Tisagenlecleucel (Kymriah), granted accelerated approval for adult patients with relapsed or refractory follicular lymphoma after two or more lines of systemic therapy.
- Lisocabtagene maraleucel (Breyanzi) for large B-cell lymphoma (LBCL) refractory to first-line chemoimmunotherapy or relapse within 12 months of first-line chemoimmunotherapy; or refractory disease to first-line chemoimmunotherapy or relapse after first-line chemoimmunotherapy and are not eligible for hematopoietic stem cell transplantation due to comorbidities or age.
Visit Oncology (Cancer) / Hematologic Malignancies Approval Notifications for further information on drug and biologics approvals.
The Center for Devices and Radiological Health (CDRH) reviews and regulates oncology devices, including in vitro diagnostics (IVDs), in partnership with OCE. In 2022, CDRH in collaboration with OCE authorized 54 oncology-related devices including 18 IVDs, 12 of which were companion diagnostic approvals, 33 radiation oncology and diagnostic imaging, breast cancer sentinel lymph node, and orthopedic devices. Some highlights of these approvals included:
- Two new tumor agnostic companion diagnostic indications, including the first tumor agnostic next-generation sequencing companion diagnostic for the detection of Microsatellite Instability High status in patients with solid tumors.
- A third companion diagnostic group indication for patients with non-small cell lung cancer to detect specific EGFR variants for the selection of tyrosine kinase inhibitors.
- The first circulating tumor cell (CTC) enrichment device to enrich CTCs from peripheral blood of cancer patients for subsequent in vitro diagnostic testing.
- Computer Aided detection software cleared for identification of prostate and breast cancer, providing diagnostic information such as likelihood of malignancy.
- Radiation software planning systems using artificial intelligence and machine learning algorithms, radiation therapy systems including contouring and patient tracking/positioning, as well as MRI-Linear accelerator combination to allow for MRI-image guided radiation therapy.
- A novel device-drug combination product using magnetic detection to identify sentinel lymph nodes was approved as part of a sentinel lymph node biopsy procedure in patients with breast cancer undergoing a lumpectomy for peritumoral injection.
In addition, CDRH held a panel meeting to discuss skin lesion analyzer technology and its application to detecting skin cancers in various patient care settings. The Center also issued a safety communication informing the public about reports of cancers, including squamous cell carcinoma (SCC) and various lymphomas, in the scar tissue (capsule) that forms around breast implants.
Visit Oncology Therapeutic and Diagnostic Devices for further information on CDRH approvals.
2022 Oncology Approvals*
|NMEs/Original BLA||12 (4 NDAs CDER, 6 BLAs CDER, 2 BLAs CBER) (5 Regular CDER, 5 AA CDER) (4 RTOR, 11 AAid)|
|Supplements (new indication)||44 (41 CDER, 3 CBER) (39 Regular, 5 AA) (11 RTOR, 36 AAid)|
|Supplements (new population)||5|
|Oncology-Related Devices (total, CDRH)
|Breakthrough Designation||17 (13 CDER, 4 CBER)|
|Breakthrough Device Designation||14 (CDRH)|
|Fast Track||7 (6 CDER, 1 CBER)|
|Priority Review||39 (35 CDER, 4 CBER)|
AA: Accelerated Approval; AAid: Assessment Aid; BLA: Biologics License Application; NME: new molecular entity; PMA: Premarket Approval; RTOR: Real-Time Oncology Review.
OCE’s Project Orbis provides a framework for concurrent submission and review of oncology products among international partners. FDA approved the following drug-indication combinations through Project Orbis in 2021. Visit Oncology (Cancer) / Hematologic Malignancies Approval Notifications for further information on these approvals.
|Approval Date||Product Name(s)||Indication||Orbis #||AAid||RTOR|
|1/25/2022||Kimmtrak1 (tebentafusp-tebn)||Uveal Melanoma||45||Y||Y|
|3/4/2022||Opdivo (nivolumab)||neoadjuvant NSCLC||66||Y||Y|
|3/11/2022||Lynparza (olaparib)||Adjuvant hi-risk EBC||63||Y||N|
|3/18/2022||Opdualag1 (nivolumab & relatlimab)||1L metastatic melanoma||51||Y||Y|
|3/23/2022||Pluvicto1,4 (lutetium (177Lu) vipivotide tetraxetan)||PSMA-positive mHSPC||52||Y||N|
|5/4/2022||Enhertu2 (fam-trastuzumab)||unresectable or met HER2+ BC||62||Y||Y|
|5/27/2022||Opdivo2 (nivolumab) and Yervoy2 (ipilimumab)||1L ESCC||55||Y||Y|
|6/22/2022||Tafinlar2,3,4,5 (dabrafenib and Mekinist2, 3, 4 (trametinib)||adult & pediatric locally advanced or metastatic solid tumors w/ BRAF V600E mutation||64||Y||N|
|8/5/2022||Enhertu (fam-trastuzumab deruxtecan-nxki)||HER2 low (IHC 1+ or IHC 2+/ISH) breast cancer||75||Y||Y|
|8/10/2022||Tabrecta (capmatinib)5||metastatic NSCLC MET exon 14 skipping||79||Y||N|
|9/30/2022||Lytgobi (futibatinib)1,3||FGFR2 intrahepatic cholangiocarcinoma||74||Y||Y|
|10/25/2022||Tecvayli (teclistamab)1,3||R/R Multiple myeloma||71||Y||N|
|11/18/2022||Rylaze (asparaginase erwinia chrysanthemi (recombinant)-rywn)||additional recommended RYLAZE dosage for ALL & LBL||76||N||Y|
2Two or more separate applications associated with approval
3Accelerated Approval (AA)
4Type C Orbis – share unredacted FDA reviews, minimal collaboration if any
The OCE Pediatric Oncology Program promotes the development of safe and effective new drugs and biologics to treat cancer in children and adolescents. To do this, we attempt to maximize the authority available through the Pediatric Research Equity Act to increase the number and timeliness of molecularly targeted pediatric cancer investigations for certain new targeted therapies under development for treatment of adult cancers. We also aim to leverage the authority under the Best Pharmaceuticals for Children Act to encourage voluntary conduct of pediatric trials of appropriate new drugs developed for adult cancers much earlier in the development timeline by issuing Written Requests for these studies.
2022 Pediatric Oncology Approvals
|Approval Date||Product Name||Indication|
|3/18/2022||Opdualag (nivolumab and relatlimab-rmbw)||Treatment of adult and pediatric patients 12 years of age or older with unresectable or metastatic melanoma|
|5/20/2022||Vidaza (azacitidine)||Treatment of pediatric patients aged 1 month and older with newly diagnosed Juvenile Myelomonocytic Leukemia (JMML)|
|6/22/2022||Tafinlar (dabrafenib)||In combination with trametinib, for the treatment of adult and pediatric patients 6 years of age and older with unresectable or metastatic solid tumors with BRAF V600E mutation who have progressed following prior treatment and have no satisfactory alternative treatment options|
|6/22/2022||Mekinist (trametinib)||In combination with dabrafenib, for the treatment of adult and pediatric patients 6 years of age and older with unresectable or metastatic solid tumors with BRAF V600E mutation who have progressed following prior treatment and have no satisfactory alternative treatment options|
|7/14/2022||Xalkori (crizotinib)||Treatment of adult and pediatric patients 1 year of age and older with unresectable, recurrent, or refractory inflammatory myofibroblastic tumor (IMT) that is ALK-positive|
|11/10/2022||Adcetris (brentuximab vedotin)||Treatment of pediatric patients 2 years and older with previously untreated high risk classical Hodgkin lymphoma (cHL), in combination with doxorubicin, vincristine, etoposide, prednisone, and cyclophosphamide|
|12/9/2022||Tecentriq (atezolizumab)||As a single agent for the treatment of adult and pediatric patients 2 years of age and older with unresectable or metastatic alveolar soft part sarcoma (ASPS)|
|Initial Pediatric Study Plans (iPSPs)||118|
|Amended Agreed iPSPs||8|
|Proposed Pediatric Study Requests||13|
|Written Requests (WRs)||1|
|Type F Meetings||6|
Launched in late 2021, the mission of the Rare Cancers Program is to leverage OCE’s ongoing initiatives to promote development of safe and effective new drugs and biologics to treat patients with rare cancers.
In 2022, the program launched a webpage to highlight how the Rare Cancers Program works in conjunction with other FDA initiatives to proactively address challenges that are common to rare cancer drug development as a whole as well as those that are specific to each rare cancer type.
Notable 2022 FDA approvals of original marketing applications for drugs or biologics for rare cancers or other rare diseases include the approval of tebentafusp-tebn (Kimmtrak) for adult patients with unresectable or metastatic uveal melanoma, alpelisib (Vijoice) for the treatment of adult and pediatric patients with severe manifestations of PIK3CA-related overgrowth spectrum (PROS), and ibrutinib (Imbruvica) oral suspension for the treatment of adult and pediatric patients with chronic graft-versus-host disease.
Outreach activities in 2022 included participation in a Project Community’s Quarterly Advocacy Meeting with a group of patients with rare cancers and in sessions related to rare cancer drug development during FDA Rare Disease Day. The OCE Rare Cancers program also initiated and plans ongoing collaborative engagement with investigator/scientists at the National Cancer Institute to identify ways to accelerate drug development for rare cancers.
Project Confirm, begun in October 2021, is an OCE initiative to increase the transparency of outcomes related to Accelerated Approval for oncology indications. The cornerstone of Project Confirm is the searchable public database listing all accelerated approvals granted in oncology since 1992. The database is divided into separate pages that list accelerated approvals that are ongoing, those that have verified clinical benefit and have been granted traditional approval, and those that have been withdrawn. Project Confirm participated in a Twitter campaign to provide public education on the accelerated approval program as well as the project. Information from the database has been used to respond to internal FDA, public, and government stakeholder inquiries on the use of accelerated approval in oncology.
Project Confirm has also supported a series of OCE mini-symposia, external presentations, and academic publications. Looking to the year ahead, the project aims to continue to facilitate evaluation of ongoing accelerated approvals and to continue efforts to increase public awareness of the program and its outcomes.
The Oncology Labeling Program provides critical support and labeling expertise for several OCE programs including Project Renewal, Project Optimus, Project Equity, and Pediatric Oncology.
- The program served as the core team to develop the FDA guidance, Cross Labeling Oncology Drugs in Combination Regimens, and provided expert advice on the FDA guidance Characterizing, Collecting, and Reporting Immune-Mediated Adverse Reactions in Cancer Immunotherapeutic Clinical Trials, as well as other guidances currently in clearance.
- The team advanced oncology labeling awareness through engagement with the external community, hosting mini-symposia on communicating overall survival results, and by presenting on dose optimization in FDA-approved labeling.
- The team collaborated across FDA Centers where devices for patient selection, drug promotion, safe use and drug administration, and patient information intersect with oncology product labeling.
Project Renewal is a public health initiative to update long-standing, off-patent oncology drug labeling while providing an opportunity to engage with the oncology community. Since its inception in 2018, Project Renewal has continued to assemble multi-disciplinary teams of oncologists, clinical fellows in training, and other scientific experts to review the accumulated publicly available data informing the safe and effective use of older oncology drugs. This engagement culminates in an independent FDA review of available data to ensure revised labeling provides adequate directions for contemporary use.
On December 14, 2022, Project Renewal completed the review and approval of updated product labeling for Xeloda, the first oncology drug to be approved under this initiative. Other labeling updates are in the process of being prepared for formal FDA review.
Project Renewal reached additional milestone achievements in 2022. These included:
- Completing a process to reformat older labeling into contemporary PLR/PLLR format,
- Developed a video to promote awareness and educate prescribers about FDA drug labeling,
- Evaluated 14 existing cancer indications and potential off-label uses for two oncology drugs.
Eleven academic oncologists and 4 fellows from 11 institutions across the U.S. participated in labeling evaluation as part of our on-going effort to improve awareness and education of FDA and product labeling. To date, 10 oncologists and fellows who participated in Project Renewal also have participated in additional OCE educational efforts including the FDA-AACR fellowship program.
Project Protect formed a uniquely structured safety team organized by drug class to provide consistent advice and review of safety signals in the pre-and post-market setting, supporting CDER and CBER reviewers. In 2022, Project Protect provided support for 37 drug applications.
Project Protect engaged external stakeholders to develop safety data standards across CBER and CDER to expedite regulatory review and research. Project Protect is also engaged in FDA’s continued efforts to digitalize premarket safety reporting.
The project also helped develop a Safety Analysis Generator tool customized to oncology-specific applications that since its launch in March 2021, has aided the efficient review of applications and provided individual data analysis support for reviewers. Project Protect continues to build a team of data analysts to assist with review data analytics and regulatory research to further the OCE’s mission. Project Protect has also engaged with Project Data Sphere on several workstreams including imaging endpoints and research related to immune mediated adverse reactions.