The Pharmacology of Cutting-Edge Non-Small Cell Lung Cancer Therapies in 2021

Non–small cell lung cancer (NSCLC) has become the most heterogeneous, molecularly driven cancer in therapeutics, explained R. Donald Harvey, PharmD, BCOP, FCCP, during a session at the virtual 2021 American Society of Clinical Oncology Annual Meeting. The agents that have been evaluated and approved, and those that are coming in the pipeline, make for an exciting time to consider directed therapies in NSCLC.

"Oral MET, RET, and KRAS inhibitors certainly have unique pharmacologic principles that we need to think of when these agents are selected for use, and certainly during and after use as well, as we consider mechanisms of resistance and other aspects of adverse events (AEs), drug interactions, etc," Harvey said during the session.

Before 2020, significant expansion occurred in the field of non–small cell small molecule therapeutics around the agents being used in clinics today, Harvey explained. Epidermal growth factor receptor (EGFR) inhibition, anaplastic lymphoma kinase (ALK) inhibition, and others provided the foundation for the start to the molecularly derived and molecularly selected population of patients who may be able to be treated with small molecules.

Harvey explained that in this space, over 2020 and 2021, there were FDA approvals of 3 RET inhibitors and 2 MET inhibitors, with more potentially on the horizon in the second half of 2021. Similarly, the first KRAS G12C inhibitor was submitted to the FDA for a new drug application in late 2020, with more potentially to follow.

In terms of the clinical pharmacology characteristics of some of the small molecules, Harvey explained that it is important to note certain valuable points for both patients and practitioners to understand around these agents. For example, in the case of MET skipping variants in the exon 14 region, capmatinib (Tabrecta; Novartis) has some areas worth considering for patients and practitioners alike.

"First, it's a twice-daily agent with or without food. It has no food effects for absorption. It is a [cytochrome P450 family 3 subfamily A (CYP3A) member 4] and P-glycoprotein substrate, and so should patients be on agents that inhibit those pathways? You need to consider capmatinib exposure and, ideally, avoid moderate and strong inducers of CYP3A as well," Harvey said during the session.

Additionally, there are some AEs associated with capmatinib. Although it is generally well tolerated, Harvey explained that there can be some rare and serious pneumonitis and transaminitis. Although these are issues that should be monitored closely, pneumonitis and transaminitis are not considered overt or common AEs for capmatinib.

"Each of these agents does have a dose reduction and discontinuation rate. I think it's important, when we counsel patients and think about therapy initiations, that we consider this in the background, that we may have to dose reduce in certain areas," Harvey said during the session. "Only about 1 out of 5 patients needed to discontinue these agents within the licensing trials submitted for approval. Specifically, with capmatinib, there's no effect o age or weight on pharmacokinetics, and so the dose and exposure are linearly related within each of those areas."

Additionally, Harvey noted that with tepotinib (Tepmetko, EMD Serono), an important drug interaction that practitioners should stay aware of is with dabigatran (Pradaxa; Boehringer Ingelheim), which is a P-glycoprotein substrate. Since tepotinib is a strong P-glycoprotein inhibitor, it has the potential to significantly increase dabigatran's Cmax value, Harvey explained. Specifically, clinicians would preferably avoid concurrent use of dabigatran with tepotinib for this reason.

In the RET inhibition space, selpercatinib (Retevmo; Eli Lilly and Company) is the first agent that was approved in this class. For dosing, although selpercatinib has weight-based dosing as an option, most adults will be dosed at 160 milligrams. Additionally, although it is a CYP3A4 substrate, it may also have other CYP and transport protein substrate and interacting potential as well.

For patients treated with selpercatinib, acid-reducing agents should be avoided, Harvey noted. However, if, for example, a proton pump inhibitor is unavoidable, then selpercatinib can be taken by patients with food at least 2 hours before other antacids, outside proton pump inhibitors.

Additionally, selpercatinib has a good tolerability profile in terms of AEs. Although there are some rare but serious occurrences of transaminitis and hemorrhage, overall, the AE profile is reasonable and manageable.

Both selpercatinib and the RET inhibitor pralsetinib (Gavreto; Blueprint Medicines and Genentech) should be held for at least 7 days before elective surgery, and for about 2 weeks after surgery, so healing can occur. This healing period is necessary since RET fusion inhibitors can impair wound healing for many patients, Harvey explained.

For the RET inhibitor pralsetinib, the dosing for patients should be 400 milligrams on an empty stomach. Pralsetinib is also a CYP3A4 substrate with a good tolerability profile and low discontinuation rates. However, approximately 1 in 3 patients were found to need a dose reduction during the licensing trials that were conducted.

For the first KRAS G12C inhibitor sotorasib (Lumakras; Amgen), there is currently not much known, Harvey explained. However, it is known based on the data available that the recommended phase 2 dose and the licensing dose is 960 milligrams.

“It comes in 120 milligram sizes and so it’s 8 tablets that need to be used within that,” Harvey said. “There are ongoing questions of dosing of 240 mg vs 960 mg in a comparison trial that’s been recommended by FDA to be performed.”

For sotorasib, AEs such as diarrhea, fatigue, and nausea are known to occur, with a discontinuation rate of 7%. However, dose reduction data have not been reported.

Additionally, Harvey noted that there are resistance mechanisms that should be considered for patients who are receiving small molecule inhibitors. One resistance mechanism is within the kinase domain itself, whether that be RET, MET, or other aspects of the kinase, while another is the activation of escape alternative pathways.

“When we look specifically at MET, there’s laboratory data suggesting that EGFR activation and/or PI3 kinase upregulation may be responsible for those who develop resistance to the MET inhibitors that are approved,” Harvey said during the session. “RET inhibition, as well, has resistance pathways that need to be considered. There may be new RET mutations within the domain of the gene itself, and there may be MET gene amplifications or KRAS mutations that may lead to RET resistance clinically.”

The occurrence of KRAS G12C resistance shows how these agents work, Harvey explained. The active G12C binding of the KRAS compound to an overarching tumor cell demonstrates the active proliferation and conversion of GDP to GTP, which can go unchecked. With the addition of an inhibitor of the G12C molecule, inhibition of KRAS G12C can lead to growth arrest and subsequent cell death as the GDP-bound cells go into quiescence.

“One mechanism of resistance that’s been identified is that KRAS G12C cells may then undergo an increase in epidermal growth factor, as well as aurora kinase A expression,” Harvey said during the session. “Though those pathways may reactivate in an escape mechanism, the G12C can become once again GTP-bound, rather than GDP-bound, and allow for proliferation to occur. This is one mechanism of resistance that’s been identified and there may be others that come forward.”

REFERENCE

Harvey RD. TKIs, MAbs, PROTACs, and more: the pharmacology of cutting-edge cancer therapies. Presented at: ASCO 2021 Annual Meeting; June 12, 2021. Accessed July 20, 2021. https://meetinglibrary.asco.org/record/193789/video