FDA Drug Approvals, Hematology and Oncology — 2022 Midyear Review

August 24, 2022

Kimmtrak (tebentafusp)

Tebentafusp is the first drug approved for treatment of HLA-A*02:01-positive adults with unresectable or metastatic uveal melanoma (mUM). It is a first-in-class bispecific protein comprising a soluble T-cell receptor (TCR) fused to an anti-CD3 immune-effector function that specifically targets gp100, a lineage antigen expressed in melanocytes and melanoma. Immune-mobilizing monoclonal TCRs against cancer (ImmTAC) molecules bind cells that present a peptide derived from an antigen of interest, and they recruit T-cells to lyse the target cells.

Approval of tebentafusp was based on the results of the phase 3 IMCgp100-202 clinical trial, which evaluated overall survival (OS) of tebentafusp compared to investigator’s choice (either pembrolizumab, ipilimumab, or dacarbazine) in patients with previously untreated mUM. The trial randomized 378 patients in a 2:1 ratio to either tebentafusp or investigator’s choice. Results demonstrated that OS was 73% in the tebentafusp group compared to 59% in the investigator’s-choice group (82% pembrolizumab; 13% ipilimumab; 6% dacarbazine) at 1 year (P<0.001). Progression-free survival was also significantly higher in the tebentafusp group than in the control group (31% vs. 19% at 6 months; P=0.01). N Engl J Med. 2021 Sep 23;385(13):1196-1206

Carvykti (ciltacabtagene autoleucel)

Ciltacabtagene autoleucel is a B-cell maturation antigen (BCMA)-directed, genetically modified autologous chimeric antigen receptor T-cell (CAR-T) therapy. The patient’s own T-cells are reprogrammed with a transgene encoding CAR that identifies and eliminates cells that express BCMA, which are highly expressed on myeloma cells. It is indicated for adults with relapsed or refractory multiple myeloma, after at least 4 prior lines of therapy, including a proteasome inhibitor, an immunomodulatory agent, and an anti-CD38 monoclonal antibody.

Approval was based on the findings from the open-label, single-arm, phase 1b/2 CARTITUDE-1 study, which enrolled patients who had received a median of 6 prior treatment regimens. Treated patients had a 98% overall response rate. Stringent complete response rates were 78% (95% CI, 68.8-86.1) at 18-month follow-up and 83% at 22-month follow-up. At a median of 18 months follow-up, median duration of response was 21.8 months. CARTITUDE-1 data presented at 64th ASH Annual Meeting. December 12, 2021

Opdualag (nivolumab/relatlimab)

The fixed-dose combination of nivolumab/relatlimab is indicated for treatment of adults and pediatric patients aged 12 years and older with unresectable or metastatic melanoma. Nivolumab is a programmed death receptor-1 (PD-1) blocking antibody, and relatlimab is a lymphocyte activation gene-3 (LAG-3) blocking antibody. The combination results in increased T-cell activation compared to activity of either antibody alone.

Approval in March 2022 was based on the RELATIVITY-047 phase 2/3 global trial, which found a median progression-free survival (PFS) of 10.1 months in 355 patients randomly assigned to the combination therapy, compared to 4.6 months in 359 patients who received nivolumab alone (HR, 0.75; P=0.0055). N Engl J Med. 2022 Jan 6;386(1):24-34

Pluvicto (lutetium Lu 177 vipivotide tetraxetan)

Lutetium Lu 177 vipivotide tetraxetan is indicated for the treatment of men with prostate-specific membrane antigen (PSMA)-positive, metastatic castration-resistant prostate cancer (mCRPC) who have been treated with androgen receptor (AR) pathway inhibition and taxane-based chemotherapy.

Approval was based on the phase 3 VISION trial. Patients who received lutetium Lu 177 vipivotide tetraxetan plus standard of care (SOC) (n = 581), compared to those who received standard care alone (n = 196), showed significantly prolonged imaging-based progression-free survival (median, 8.7 vs. 3.4 months; P<0.001) and overall survival (15.3 vs. 11.3 months; P<0.001). N Engl J Med. 2021 Sep 16;384(12):1091-1103

Vonjo (pacritinib)

Pacritinib is indicated for adults with intermediate or high-risk primary or secondary (post-polycythemia vera or post-essential thrombocythemia) myelofibrosis (MF) with a platelet count <50 x 109/L. Pacritinib is a Janus kinase (JAK) inhibitor with activity against wild-type JAK2. JAK2 contributes to signaling of cytokines and growth factors that are important for hematopoiesis and immune function. MF is often associated with dysregulated JAK2 signaling.

Approval was based on the PERSIST-1 and PERSIST-2 phase 3 trials and the phase 2 PAC203 trial. The PERSIST-1 trial randomized 327 patients to receive pacritinib or the best available therapy (BAT) until disease progression or unacceptable toxicity. At week 24, 19% of the pacritinib-treated arm achieved the primary endpoint of spleen volume reduction (SVR) of 35% or more, as compared to 5% in the BAT arm. Lancet Haematol. 2017 May;4(5)

PERSIST-1 led to PERSIST-2, which randomized 311 patients with myelofibrosis and a platelet count ≤100 × 109/L to receive pacritinib 400 mg once daily, pacritinib 200 mg BID, or BAT (including ruxolitinib). Pacritinib at either dosage was more effective for SVR ≥35% than BAT (18% vs 3%), but twice-daily pacritinib was also significantly more effective for producing a ≥50% reduction in total symptom score (TSS) compared to BAT. JAMA Oncol 2018 May;4(5):651-659

Pyrukynd (mitapivat)

Mitapivat is the first-in-class disease-modifying therapy approved for hemolytic anemia in adults with pyruvate kinase (PK) deficiency. Mitapivat is a PK activator that acts by allosterically binding to pyruvate kinase tetramer and increasing PK activity. The ACTIVATE and ACTIVATE-T clinical trials demonstrated improved hemoglobin response and reduced transfusion burden in patients. Blood 2021;138(suppl1):848

Enjaymo (sutimlimab)

Sutimlimab is an immunoglobulin G (IgG), subclass 4 (IgG4) monoclonal antibody (mAb) that selectively targets and inhibits complement protein component 1, s subcomponent (C1s), a serine protease. C1s cleaves C4, which is the first step in activating the classical complement pathway. It is indicated to decrease the need for RBC transfusion because of hemolysis in adults with cold agglutinin disease (CAD).

Approval was based on the CARDINAL clinical trial (n = 24), an open-label, single-arm study. The primary end point was a normalization of Hgb level to at least 12 g/dL or an increased Hgb of 2 g/dL or more from baseline, without red-cell transfusion or medications prohibited by the protocol. Fifteen patients (63%) achieved a hemoglobin of 12 g/dL or higher, or an increase of at least 2 g/dL. Seventeen patients (71%) remained transfusion-free after week 5. Twenty-two patients (92%) did not use other CAD-related treatments. N Engl J Med. 2021 Apr 8;384(14):1323-1334

Other hematology-oncology approvals

Yescarta (axicabtagene ciloleucel) – Indication for large B-cell lymphoma (LBCL) expanded to include LBCL that is refractory to first-line chemoimmunotherapy or relapses within 12 months of first-line chemoimmunotherapy.

Breyanzi (lisocabtagene maraleucel) – Use for CAR T-cell therapy approved for second-line therapy following refractory or refractory diffuse large B-cell lymphoma (DLBCL) to first-line chemoimmunotherapy.

von Willebrand factor, recombinant (Vonvendi) – Indicated for routine prophylaxis to reduce bleeding episode frequency in patients with severe type 3 von Willebrand disease (VWD) receiving on-demand therapy.

Lynparza (olaparib) – New indication for adjuvant treatment of deleterious or suspected deleterious gBRCAm human epidermal growth factor receptor 2 (HER2)-negative high-risk early breast cancer in adults previously treated with neoadjuvant or adjuvant chemotherapy.

Keytruda (pembrolizumab) – New indication as monotherapy for advanced endometrial carcinoma that is microsatellite instability-high (MSH-H) or mismatch repair deficient (dMMR), in patients who have disease progression after prior systemic therapy in any setting and are not candidates for curative surgery or radiation (already approved in combination with lenvatinib for MSI-H or dMMR endometrial cancer).

Tibsovo (ivosidenib) – Indicated in combination with azacitidine or as monotherapy for newly diagnosed acute myeloid leukemia with a susceptible IDH1 mutation in adults aged 75 years and older, or who have comorbidities that preclude use of intensive induction chemotherapy.

Enhertu (trastuzumab deruxtecan) – Expanded indication for unresectable or metastatic HER2-positive breast cancer in patients who have received a prior anti-HER2-based regimen in the metastatic setting, or in the neoadjuvant or adjuvant setting and have developed disease recurrence during or within 6 months of completing therapy.

Mekinist (trametinib) in combination with Tafinlar (dabrafenib) – Granted accelerated approval for adults and children aged 6 years and older with unresectable/metastatic solid tumors with BRAF V600E mutation who have progressed following prior treatment and have no satisfactory alternative treatment options.

Xalkori (crizotinib) – New indication for adults and children aged 1 year and older with unresectable, recurrent, or refractory inflammatory anaplastic lymphoma kinase (ALK)-positive myofibroblastic tumors (IMT).

Opdivo (nivolumab)

  • New indication for neoadjuvant treatment in combination with platinum-doublet chemotherapy for resectable (tumors 4 cm or greater, or node positive) early-stage non-small cell lung cancer.

  • New indication for first-line treatment for unresectable advanced or metastatic esophageal squamous cell cancer in combination with fluoropyrimidine- and platinum-containing chemotherapy, or in combination with ipilimumab.

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