Amtagvi (lifileucel) in Melanoma – Iovance Biotherapeutics ($IOVA)
Amtagvi received FDA accelerated approval in February 2024 for metastatic melanoma in the 2L+. Amtagvi was approved based on the C-144-01 Phase II study that showed an overall response rate (ORR) of 31.5% (n=73). At a later 4-year analysis Amtagvi demonstrated a median overall survival (OS) of 13.9 months [1]. Amtagvi’s label carries a black box warning for treatment-related mortality, prolonged cytopenia, severe infections, and cardiopulmonary and renal impairment.
Amtagvi broke new ground as the first tumor-infiltrating lymphocyte (TIL) cell therapy to be approved. Furthermore, it showed good durability, creating a new treatment choice in the 2L+ post-immune checkpoint inhibitor (ICI) setting. GlobalData analysts previously estimated Amtagvi’s peak sales at $846M by 2029 [2].
Vyloy (zolbetuximab-clzb) in Gastric Cancer – Astellas ($ALPMY)
Vyloy, a CLDN18.2-directed antibody received FDA approval in October 2024 in combination with chemotherapy for the treatment of 1L HER2-negative, CLDN18.2 positive gastric or gastroesophageal junction (GEJ) adenocarcinoma. The pivotal Phase III trials GLOW (N=507) and SPOTLIGHT (n=565) demonstrated an improvement in both OS and progression-free survival (PFS) over the chemotherapy controls. The discontinuation rate due to adverse events (AE) was 20%.
Vyloy marks an important addition to the treatment of gastric cancer as a biomarker-driven agent and as the first-in-class anti-CLDN18.2 agent. The success of targeting CLDN18.2 has led to a race of investment into this target, including other modalities such as antibody-drug conjugates (ADC), making it into one of the most popular targets in oncology [3].
Anktiva (nogapendekin alfa inbakicept-pmln) in Bladder Cancer – ImmunityBio ($IBRX)
Anktiva is a first-in-class IL-15 agonist that received FDA approval in April 2024 in combination with the Bacillus Calmette-Guérin (BCG) vaccine for adult patients with BCG-unresponsive non-muscle invasive bladder cancer (NMIBC) with carcinoma in situ with or without papillary tumors [4]. Anktiva was approved on the basis of the Phase II/III QUILT-3.032 trial which showed a complete response (CR) rate of 62% (n=77). The regimen was relatively well-tolerated with a 7% discontinuation rate.
This approval is not only an enhancement to the treatment paradigm of NMIBC, but also marks the first success in many years for the troubled class of cytokines, which is likely to bring back some interest and R&D resources to the field. ImmunityBio is developing Anktiva further in the BCG-responsive setting, as well as in lung cancer.
Imdelltra (tarlatamab-dlle) in Small-Cell Lung Cancer (SCLC) – Amgen ($AMGN)
Imdelltra is a bispecific DLL3/CD3 mAb that received accelerated FDA approval in May 2024 for 2L+ extensive-stage SCLC. In the Phase II DeLLphi-301 study (n=99), the ORR was 40% and the median duration of response (DOR) was 9.7 months. The treatment discontinuation rate was 7%, however, the label includes a black box warning for serious or life-threatening cytokine release syndrome (CRS) and neurologic toxicity, including immune effector cell-associated neurotoxicity syndrome (ICANS).
As a first-in-class and first-to-market DLL3/CD3 bispecific, Imdelltra validated DLL3 as a lung cancer target, and also added a new MOA to the physician’s armamentarium, potentially extending the lines of therapy available to patients after they have been treated with ICIs and chemotherapy. Previously William Blair analysts estimated its peak sales potential at $842M by 2028 [5].
Tecelra (afamitresgene autoleucel) in Synovial Sarcoma – Adaptimmune ($ADAP)
Tecelra is a TCR modified cell therapy targeting the MAGE-A4 antigen. Tecelra received accelerated FDA approval in August 2024. for adults with unresectable or metastatic 2L+ synovial sarcoma who are HLA-A*02:01P, -A*02:02P, -A*02:03P, or -A*02:06P positive and whose tumor expresses the MAGE-A4 antigen as determined by FDA-approved companion diagnostics. The approval was based on the Phase II SPEARHEAD-1 (Cohort 1) trial, with 44 patients, where Tecelra showed a 43% overall response rate (ORR) and a median duration of response of 6 months. The median overall survival (OS) in the synovial sarcoma population was not reached. The FDA label includes a black box warning for serious or fatal CRS.
Tecelra became the first approved TCR cell therapy and created a new option for synovial sarcoma patients who progressed on 1L regimens. Previously these patients would have been treated with a different chemotherapy regimen such as Johnson & Johnson’s/PharmaMar’s Yondelis (trabectedin) or tyrosine kinase inhibitors (TKI), including Novartis’ Votrient (pazopanib) and Bayer’s Stivarga (regorafenib). Unfortunately due to the intricacies of the treatment setting, only a subset of eligible patients will benefit from the treatment [6].
By Sakis Paliouras, PhD
References
- https://jitc.bmj.com/content/11/Suppl_1/A873
- https://www.globaldata.com/media/pharma/iovances-amtagvi-gain-major-share-melanoma-treatment-first-market-advantage-says-globaldata/
- https://www.biochempeg.com/article/345.html
- https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-nogapendekin-alfa-inbakicept-pmln-bcg-unresponsive-non-muscle-invasive-bladder-cancer
- https://www.biopharmadive.com/news/amgen-imdelltra-fda-approval-tarlatamab-lung-cancer/716450/?utm_source=chatgpt.com
- https://www.celeritasinsights.com/build/articles/2024-09-02_tecelras-approval-for-synovial-sarcoma-will-benefit-few-patients
