Novel Mechanisms of Action Open Door for New Drugs in Non–Small Cell Lung Cancer

Several new mechanisms of action could describe potential new treatment areas for non–small cell lung cancer (NSCLC) with drugs in phase 2 and 3 clinical trials, according to a poster presented at the American Society of Health-System Pharmacists (ASHP) 2022 Midyear Clinical Meeting.

Lung cancer is a leading cause of death in the United States, with 25% of annual overall cancer deaths attributed to the disease. Of those, 84% of cases are NSCLC, representing significant opportunities for novel development. There are currently several mechanisms of action for drugs treating NSCLC and many new mechanisms of action are being investigated.

“We were really interested because sotorasib has just recently been approved. It’s the first drug to be approved for treating non–small cell lung cancer, and for the longest time, it was thought that this area that it’s targeting was undruggable,” said researcher Daniel Edi, in an interview with Pharmacy Times. “So given that it was the first one to be approved, it’s now setting the framework for many other drugs, because once we know that one drug is effective, it opens the door to many other drugs that can literally be revolutionary.”

To investigate this further, students from the Rutgers University Ernest Mario School of Pharmacy performed a systematic literature review of different types of mechanisms of action for NSCLC in both phase 2 and 3 trials. The review included literature published between 2000 and 2022. Clinicaltrials.gov was used to discover investigative treatments currently in phase 2 and 3 trials, and PubMed, Embase, and Medline were used to analyze the results and understand the mechanisms of action.

The researchers found more than 3000 citations, which were narrowed down to several articles and 3 key mechanisms of action that were the most represented. These included sotorasib, a tyrosine kinase inhibitor (TKI) targeting the KRAS gene; apatinib and anlotinib, TKIs targeting the VEGFR gene; and atezolizumab, which involves the antitumor activity of programmed death-ligand 1 (PD-L1).

Sotorasib targets the KRAS viral oncogene homolog gene and is a derivative of the RAS signaling pathway, which plays a role in cancer cell growth. It was approved by the FDA in May 2021.

Similarly, the mechanism of action for apatinib involves a TKI and is being investigated in combination with radiotherapy. However, it targets the intracellular domain of the receptors on the VEGFR2 gene and blocks signal transduction. The clinical trial for apatinib is currently enrolling by invitation.

Anlotinib acts as a receptor tyrosine kinase (RTK) inhibitor targeting the VEGFR1, VEGFR2/KDR, VEGFR3, c-Kit, and PDGFR-α receptors. It inhibits angiogenesis and tumor cell growth and is currently undergoing multiple phase 2 and 3 trials in combination with other treatments.

Finally, the mechanism of action for atezolizumab involves the PD-L1 protein, which can be expressed on tumor cells and tumor-infiltrating immune cells. According to the poster, binding PD-L1 to its inhibitory receptors programmed cell death protein 1 (PD-1) and B7.1 on T cells can suppress cytotoxic T-cell activation.

Based on the findings in the literature review, the investigators concluded that these various mechanisms of action could have significant potential in NSCLC moving forward. Future research should investigate which therapies with new mechanisms of action add incremental benefit to existing treatment regimens, according to the researchers.

“It was very interesting to see how many different drugs and mechanisms there are that are currently in trials,” Edi said. “It’s a very exciting time, because treating lung cancer is where we want to be and there’s amazing technology, and it’s very, very exciting.”

REFERENCE

Asad A, Edi D, Toscani M. Non­–Small Cell Lung Cancer (NSCLC) Systematic Literature Review of New Mechanisms of Action in Phase II and III Clinical Trials. Poster. Presented at American Society of Health-System Pharmacists (ASHP) 2022 Midyear Clinical Meeting. December 5, 2022.