Highlights of FDA Oncology Approvals in 2022: Tissue-Agnostic Indications, Dosage Optimization, and Diversity in Drug Development

This year, the FDA approved several molecularly targeted therapies and immunotherapies for oncologic indications, and development continued to grow in radiopharmaceuticals and cell therapies. Collaborations across FDA centers, including the Center for Drug Evaluation and Research (CDER), the Center for Biologics Evaluation and Research (CBER), and the Center for Devices and Radiological Health (CDRH), were critical to these approvals. International collaboration was robust, with more than 10 products reviewed under the Oncology Center of Excellence (OCE) Project Orbis (1), a framework for concurrent submission and review of oncology products among international partners.

Diversity remains a key area of focus, and the OCE's Project Equity (2) aims to ensure that clinical trial participants adequately reflect the demographic representation of patients for whom the medical products are intended (3). Notably, in the clinical trial data supporting new molecular entities approved in 2022, there continued to be a lack of adequate racial and ethnic representation, with the majority of enrolled patients self-identifying as white. The FDA issued postmarketing commitments to further characterize the safety and efficacy of several drugs in racial and ethnic minorities.

With the establishment of the new OCE Rare Cancers Program (4), the FDA continues to engage with stakeholders to identify opportunities to decrease obstacles, better harness scientific knowledge, and strengthen coordination to facilitate efficient drug development for patients with rare cancers. Several products approved this year were for rare cancers, including two new tissue-agnostic indications for molecularly targeted agents (5).

Highlights of the original New Drug Applications/Biologics Licensing Applications approved through November 4, 2022, are summarized in Table 1. CDER approved six new molecular entities/new biological products as of this date, including lutetium (¹⁷⁷Lu) vipivotide tetraxetan, a first-in-class radioligand therapeutic agent indicated for the treatment of adult patients with prostate-specific membrane antigen (PSMA)–positive metastatic castration-resistant pros­tate cancer who have been treated with androgen receptor pathway inhibition and taxane-based chemotherapy. On the day of the drug approval, CDER also approved gallium Ga 68 gozetotide, a radioactive diagnostic agent indicated for positron emission tomography of PSMA-positive lesions in men with prostate cancer, including the selection of patients with metastatic prostate cancer for whom lutetium (¹⁷⁷Lu) vipivotide tetraxetan PSMA-directed therapy is indicated. Although this was the first radioactive diagnostic agent specifically approved for patient selection in the use of a radioligand therapeutic agent, several other molecularly targeted agents had companion diagnostics approved this year. Other original approvals included a novel combination product, nivolumab and relatlimab-rmbw [programmed death receptor-1 (PD-1) blocking antibody and lymphocyte activation gene-3 (LAG-3) blocking antibody, respectively] for the treatment of adult and pediatric patients 12 years of age or older with unresectable or metastatic melanoma. Tebentafusp-tebn, a bispecific gp100 peptide-HLA–directed CD3 T-cell engager, was approved for HLA-A*02:01–positive adult patients with unresectable or metastatic uveal melanoma—the first therapy approved for this indication. Futibatinib, a kinase inhibitor, received accelerated approval for the treatment of adult patients with previously treated, unresectable, locally advanced or metastatic intrahepatic cholangiocarcinoma harboring fibroblast growth factor receptor 2 (FGFR2) gene fusions or other rearrangements. Tremelimumab-actl, a cytotoxic T-lymphocyte–associated antigen 4 (CTLA-4) blocking antibody, received its first indication, in combination with durvalumab for the treatment of adult patients with unresectable hepatocellular carcinoma. Teclistamab-cqyv, the first bispecific B-cell maturation antigen (BCMA)–directed CD3 T-cell engager, received accelerated approval for the treatment of adult patients with relapsed or refractory multiple myeloma who have received at least four prior lines of therapy, including a proteasome inhibitor, an immunomodulatory agent, and an anti-CD38 monoclonal antibody.

CBER approved an original cell therapy, ciltacabtagene autoleucel, a BCMA-directed genetically modified autologous T-cell immunotherapy, for the treatment of adult patients with 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.

Several original approvals included pediatric patients and were the first treatment for their respective indications. Substantial evidence of effectiveness for the accelerated approval of alpelisib to treat adult and pediatric patients 2 years of age and older with severe manifestations of PIK3CA-related overgrowth spectrum (PROS) who require systemic therapy was established using real-world data, and radiographic evidence was collected within the clinical study from participating clinical sites as part of an expanded access program for compassionate use. Data submitted in response to a pediatric written request issued by the FDA led to the approval of a new oral suspension formulation and extension of the indication for ibrutinib, a Bruton's tyrosine kinase inhibitor, to include pediatric patients age 1 year and older with chronic graft-versus-host disease after the failure of one or more lines of systemic therapy. FDA also approved sodium thiosulfate as supportive care to reduce the risk of ototoxicity associated with cisplatin in pediatric patients one month of age and older with localized, nonmetastatic solid tumors.

FDA approved two new biosimilars to the vascular endothelial growth factor inhibitor Avastin (bevacizumab), and new dosage forms or formulations of carmustine, pemetrexed, bortezomib, paclitaxel, and acalabrutinib.

Of the efficacy supplements approved through November 4, 2022, key highlights include accelerated approvals for two new tissue-agnostic indications for molecularly targeted therapies: (i) 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 and (ii) selpercatinib for the treatment of adult patients with locally advanced or metastatic solid tumors with a rearranged during transfection (RET) gene fusion who have progressed on or following prior systemic treatment or who have no satisfactory alternative treatment options. Both tissue-agnostic indications were based on durable response rate data observed across multiple tumor types in the setting of a genetically based biological rationale and supported by existing evidence from prior approvals in other tumor types [e.g., selpercatinib in 41 patients with RET fusion–positive solid tumors, in the context of 343 patients with RET fusion–positive non–small cell lung cancer (NSCLC) and thyroid cancer, which formed the basis of prior approvals].

The antibody–drug conjugate fam-trastuzumab deruxtecan-nxki received three new indications this year. For unresectable or metastatic breast cancer, it was approved for HER2-positive tumors after a prior anti-HER2–based regimen (an earlier line of therapy than previously approved), as well as for HER2-low (IHC 1⁺ or IHC 2⁺/ISH⁻) tumors (the first therapy for this indication). Subsequently, the PATHWAY anti-HER2/neu (4B5) Rabbit Monoclonal Primary Antibody assay was approved as a companion diagnostic device for fam-trastuzumab deruxtecan-nxki for assessment of “HER2-low” status. Fam-trastuzumab deruxtecan-nxki also received accelerated approval for patients with unresectable or metastatic HER2-mutant NSCLC who have received a prior systemic therapy. The latter indication was supported by evidence from a dose randomization study conducted in order to identify the optimal dosage for the given patient population based on principles of OCE's Project Optimus (6, 7).

One year after the initiation of Project Confirm (8), the OCE continues to provide information through a public-facing website on the current status of outcomes related to accelerated approvals for oncology indications. The goal is to highlight the balance of access and verification of benefit for therapies made available through the accelerated approval pathway to treat patients with cancer (9). To date, eight products received accelerated approval this year. Five drugs previously granted accelerated approval had clinical benefit verified and were granted regular approval: fam-trastuzumab deruxtecan-nxki for metastatic HER2-positive breast cancer, capmatinib for MET exon 14 skipping mutated NSCLC, selpercatinib for RET fusion–positive NSCLC, clofarabine for pediatric patients 1 to 21 years old with relapsed or refractory acute lymphoblastic leukemia after at least two prior regimens, and asciminib for Philadelphia chromosome–positive chronic myeloid leukemia in chronic phase previously treated with two or more tyrosine kinase inhibitors. In addition, three drugs were voluntarily withdrawn by the drug company due to a lack of verification of benefit in confirmatory trials. All three withdrawals were PARP inhibitors for patients with advanced ovarian cancer: rucaparib after two or more prior lines of chemotherapy, and niraparib and olaparib after three or more prior lines of chemotherapy.

New efficacy supplements for immune-checkpoint inhibitors included nivolumab in combination with platinum-doublet chemotherapy for patients with resectable NSCLC in the neoadjuvant setting—the first FDA-approved treatment in this disease setting; nivolumab in combination with ipilimumab for the first-line treatment of patients with unresectable advanced or metastatic esophageal squamous cell carcinoma; pembrolizumab for advanced endometrial carcinoma that is microsatellite instability–high or mismatch repair–deficient who have disease progression following prior systemic therapy; and durvalumab in combination with chemotherapy for advanced biliary tract cancer—the first immunotherapy regimen approved for the treatment of cholangiocarcinoma.

Three previously approved CD19-directed genetically modified autologous T-cell immunotherapies received new indications: axicabtagene ciloleucel for adult patients with large B-cell lymphoma (LBCL) that is refractory to first-line chemoimmunotherapy or relapses within 12 months of first-line chemoimmunotherapy; tisagenlecleucel for adult patients with relapsed or refractory follicular lymphoma after two or more lines of systemic therapy; and lisocabtagene maraleucel for adult patients with LBCL in two new indications: (i) refractory disease to first-line chemoimmunotherapy or relapse within 12 months of first-line chemoimmunotherapy and (ii) refractory disease to first-line chemoimmunotherapy or relapse after first-line chemoimmunotherapy and not eligible for hematopoietic stem cell transplantation due to comorbidities or age.

The FDA approved new indications for several molecularly targeted therapies, including the first available therapy for the following indications: crizotinib for adult and pediatric patients 1 year of age and older with unresectable, recurrent, or refractory inflammatory myofibroblastic tumor that is ALK-positive and azacitidine for pediatric patients ages 1 month and older with newly diagnosed juvenile myelomonocytic leukemia. Other notable new indications include darolutamide in combination with docetaxel for patients with metastatic hormone-sensitive prostate cancer, olaparib for germline BRCA-mutant HER2-negative high-risk early breast cancer who completed definitive local treatment and neoadjuvant or adjuvant chemotherapy, pemigatinib for adults with relapsed or refractory myeloid/lymphoid neoplasms with FGFR1 rearrangement, and ivosidenib in combination with azacitidine or as monotherapy for the treatment of newly diagnosed acute myeloid leukemia with a susceptible isocitrate dehydrogenase-1 (IDH1) mutation in adults 75 years or older or who have comorbidities that preclude use of intensive induction chemotherapy.

Amidst a busy year of oncology drug approvals, the FDA OCE continues to promote patient-centered regulatory decision-making through innovation and collaboration. As reflected in the oncology approvals of 2022, active efforts are ongoing to optimize medical product dosing, safety, and efficacy for all patients throughout all stages of drug development.

No disclosures were reported.