2021 Oncology FDA Approvals: Small Molecules Deep Dive

together with Dr. Jennifer Huen, Saumil Patel, and Dr. Naveed Yasin

In 2021, the FDA approved 9 non-radiological novel small molecule drugs for oncology. Excluding melphalan flufenamide, which has already been withdrawn, the remaining FDA-approved novel small molecule oncology drugs of 2021 are:

  • umbralisib (PI3Kδ and CK1ε inhibitor)
  • sotorasib (KRASG12C inhibitor)
  • infigratinib (FGFR1/2/3 inhibitor)
  • tepotinib (MET kinase inhibitor)
  • asciminib (allosteric BCR-ABL1 kinase inhibitor)
  • mobocertinib (EGFR exon 20 insertion kinase inhibitor)
  • tivozanib (pan-VEGFR kinase inhibitor)
  • trilaciclib (CDK4/6 kinase inhibitor)

2021 FDA Novel Small Molecule Drug Approvals

In this article, we explore each of these novel small molecule drug approvals in oncology in greater detail, including their mechanisms of action, what separates them from previous generations of molecules, the clinical data, the originators, and more.

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asciminib (Scemblix)

Asciminib is an oral, ABL/BCR-ABL1 allosteric kinase inhibitor approved for adults with Philadelphia chromosome-positive chronic myeloid leukemia (CML) who were previously treated with at least two tyrosine kinase inhibitors.

It was derived from one of the compounds identified through a phenotypic, differential cytotoxicity screen, confirming with NMR and XRD. Asciminib binds to native ABL1 and BCR-ABL1 tumor kinase in a unique and non-competitive manner. It is the sixth BCR-ABL inhibitor (imatinib, dasatinib, nilotinib, ponatinib, bosutinib), but the first allosteric inhibitor.

Chimeric BCR-ABL1 fusions are the cause of 95% of CML cases and are generated by failed DNA damage repair resulting in a shortened chromosome 22, or Philadelphia chromosome. The chimeric protein is constitutively active as it is missing the myristoylation autoregulatory element and drives uncontrolled hematopoietic stem cell proliferation.

But because BCR-ABL1 retains the myristate binding site, kinase activity can still be inhibited through asciminib binding to the allosteric myristate site without affecting other kinases. This was shown using an activity screen of 335 protein kinases in which the presence of asciminib did not have any substantial effect on off-target kinase activities.

These results suggest that asciminib treatment may produce fewer side-effects than classical kinase inhibitors. In addition, because a large portion of resistant tumors are due to mutations in the ATP-binding pocket, of which T315I is the most difficult to treat, asciminib is potentially better at treating cancers that are resistant to competitive kinase inhibitors.

In a Phase III active-controlled trial, significantly more patients on asciminib (25%) were found to reach a major molecular response and complete cytogenetic response compared to treatment with the current first-line TKI for CML, bosutinib (13%), making it a potential best-in-class drug. A Phase I study is currently investigating the safety of asciminib in combination with other kinase inhibitors in CML patients with the T315I mutation. An 80 mg dose is usually given and those with T315I mutation are given 200 mg.

The molecule was patented by Novartis AG (US8829195B2).

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