[3-D model of adagrasib molecule from PubChem]

The risk of cancer deaths has fallen steadily in recent years. Before the pandemic, the risk of death from cancer fell roughly 2% annually from 2015 to 2019. In the 1990s, the risk of cancer death fell approximately 1% each year, according to the American Cancer Society. In addition to improved screening and diagnosis, cancer survival rates have fallen as a result of therapeutic breakthroughs.

In this feature, we round up a variety of oncology drug candidates that may prove to be promising cancer therapeutics in the coming years.

1. Adagrasib

Adagrasib from Mirati Therapeutics is a KRASG12C inhibitor. In 2021, the drug candidate won Breakthrough Therapy Designation for patients with advanced non-small cell lung cancer (NSCLC) with the KRASG12C mutation. The KRAS protein inhibitor has been the subject of 14 trials to date, including a Phase 3 study focused on colorectal cancer. Adagrisib was the focus of a July 14, 2022 NEJM article, which concluded that adagrasib showed clinical efficacy in patients with previously treated KRASG12C-mutated NSCLC without any new safety signals. In February, Mirati announced that FDA had accepted the New Drug Application (NDA) for adagrasib for small cell lung cancer (NSCLC) with the KRASG12C mutation. The potential indication would cover patients who had received at least one prior systemic therapy. The Prescription Drug User Fee Action (PDUFA) date for the compound is December 14, 2022.

2. Elacestrant


[3-D model of Elacestrant from PubChem]

Elecestrant is an oral selective estrogen receptor degrader. Discovered by Eisai (TYO:4523), Criterium and Radius Health are developing the drug candidate. FDA granted Priority Review to elacestrant for ER+/HER2- advanced metastatic breast cancer. The former company was recently acquired by Gurnet Point Capital and Patient Square Capital. In late 2021, The American Association for Cancer Research (AACR) released a statement noting that elacestrant appeared to outcomes in patients with metastatic breast cancers that had progressed on prior endocrine therapy in Phase 3 study involving postmenopausal patients with estrogen receptor (ER)-positive/HER2-negative metastatic breast cancers that progressed on prior endocrine and targeted therapies. AACR announced that elacestrant  is the first oral selective estrogen receptor degrader to demonstrate superiority over standard of care in a Phase 3 study for that patient population.

3. Elranatamab

Elranatamab from Pfizer (NYSE:PFE) is B-cell maturation antigen (BCMA) CD3-targeted bispecific antibody. Elranatamab has won Orphan Drug Designations from the FDA and the European Medicines Agency (EMA) for the treatment of multiple myeloma. The FDA has also granted elranatamab Fast Track Designation and for patients with MM who are refractory to at least one proteasome inhibitor, one immunomodulatory drug and one anti-CD38 antibody.

4. Magrolimab

Magrolimab from Gilead Sciences (Nasdaq:GILD) is a potential therapy for lymphoma and multiple myeloma (MM). Earlier this year, FDA lifted a partial clinical hold on magrolimab studies after reviewing safety data from a magrolimab lymphoma study. FDA granted magrolimab Breakthrough Therapy designation for treating newly diagnosed myelodysplastic syndrome (MDS) in 2020. Gilead is also developing the drug for acute myeloid leukemia (AML) and several hematologic cancers and solid tumor malignancies. Magrolimab was featured in a 2021 roundup of antibodies to watch from the peer-reviewed journal mAbs 

5. Orelabrutinib


[3-D model of Orelabrutinib from PubChem]

Orelabrutinib from Asia-based InnoCare (HKG:9969) is a small molecule inhibitor of Bruton’s tyrosine kinase (BTK; Bruton agammaglobulinemia tyrosine kinase) that may have antineoplastic activity. The drug candidate won breakthrough therapy designation from the FDA in 2021. Orelabrutinib binds to and inhibits the activity of BTK. The mode of action blocks the activation of the B-cell antigen receptor signaling pathway and BTK-mediated activation of downstream survival pathways. It thus inhibits the growth of malignant B cells that overexpress BTK. China approved orelabrutinib in late 2020 to treat patients with relapsed/refractory chronic lymphocytic leukemia, small lymphocytic lymphoma and relapsed/refractory mantle cell lymphoma.

6. Patritumab deruxtecan


[2-D model of deruxtecan from Pubchem]

In late 2021, FDA recognized patritumab deruxtecan (HER3-DXd) from Daiichi Sankyo (OTCMKTS:DSNKY) as a promising oncology drug candidate by granting it Breakthrough Therapy Designation. The drug candidate would be a first-in-class HER3 directed antibody drug conjugate (ADC) for patients with metastatic or locally advanced EGFR-mutated non-small cell lung cancer (NSCLC). Daiichi Sankyo is pursuing an indication for the drug to treat NSCLC with disease progression on or after treatment with a third-generation tyrosine kinase inhibitor (TKI) and platinum-based therapies.

7. Pirtobrutinib

Pirtobrutinib (LOXO-305) from Loxo Oncology and Lilly (NYSE:LLY) is an investigational, oral, highly selective, reversible (noncovalent) Bruton tyrosine kinase (BTK) inhibitor. The drug candidate has shown promise in preclinical studies to reversibly bind BTK. Investigators are investigating pirtobrutinib (LOXO-305) in clinical trials focused on chronic lymphocytic leukemia/small lymphocytic lymphoma, mantle cell lymphoma and non-Hodgkin’s lymphoma.

8. Poziotinib


[3-D model of poziotinib image courtesy of Pubchem]

Earlier this year, FDA agreed to review a new drug application for poziotinib from Spectrum Therapeutics for previously treated locally advanced or metastatic non–small cell lung cancer (NSCLC) with HER2exon 20 insertion mutations. Hanmi Pharmaceutical and Luye Pharma are assisting in the development of the drug. Paziotinib has activity against mutations of HER1, HER2 and HER4.

9. Tislelizumab

Tislelizumab originally developed by BeiGene, is a humanized monoclonal antibody directed against PD-1. Novartis (NYSE:NVS) has licensed the drug in most major markets. In June, Novartis  announced that the antibody plus chemotherapy improved overall survival as a first-line treatment for adult patients with unresectable, locally advanced or metastatic esophageal squamous cell carcinoma (ESCC) in the Phase 3 RATIONALE 306 study. Novartis noticed that, in the Phase 3 study, investigators saw benefits in patients regardless of PD-L1 status.

10. Ublituximab

The immunomodulator ublituximab from TG Therapeutics is an experimental glycoengineered monoclonal antibody targeting an epitope on CD20-expressing B-cells. TG Therapeutics is pursuing indications for the drug for lymphoma and leukemia. The drug candidate also fared well in relapsing multiple sclerosis studies, including the Phase 3 ULTIMATE I (NCT03277261) and II (NCT03277248) trials. The drug was recently profiled in The New England Journal of Medicine.