Selective RET Inhibitors for RET Fusion-Positive Non-Small Cell Lung Cancer

The shift from nonspecific treatments to targeted therapies has led to exciting advances in cancer care in recent years; among these developments, the selective RET inhibitors pralsetinib and selpercatinib received accelerated approval in 2020 and 2022, respectively, by the US Food and Drug Administration (FDA) for adult patients with metastatic RET fusion-positive NSCLC.^1,2 While clinical trials are still ongoing, these new agents may offer greater efficacy when compared with traditional treatment approaches.
 
Raja Mudad, MD, FACP, is a thoracic medical oncologist at the Sylvester Comprehensive Cancer Center at the University of Miami Miller School of Medicine in Florida with expertise in novel therapies. In this article, Dr Mudad shares details regarding the mechanisms and benefits of selective RET inhibitors in RET fusion-positive NSCLC, their associated side effects, the risks of acquired resistance, and emerging next-generation therapies in this drug class.

The drug approvals of pralsetinib and selpercatinib have resulted in a paradigm shift in cancer treatment from an organ- and histology-specific strategy to a biomarker-guided approach. What are the implications of this for patients with RET fusion-positive NSCLC?

The recent advances and research in the field of oncology have changed our approach to the treatment of cancer, which has shifted dramatically in the past several years. While initially our treatment approaches were organ-specific and histology-specific, we have now learned that various cancers share a common oncogenic pathway.
 
We now know that an event that happens early in the cell cycle becomes a driver for malignant growth — an oncogenic driver. This event is usually an alteration in the DNA of that cell; this can be in the form of a mutation, fusion, or other alteration. Once the cell follows that pathway, it grows out of control and becomes malignant.
 
With the development of specific inhibitors for that oncogenic driver, we can now use this approach to treat all cancers that share the same driver pathway.³ This has certainly improved treatments, in that they are more specific to the cause of cancer, rather than treating a growing tumor nonspecifically.
 
This approach has opened the door for the treatment of multiple cancers with the same therapeutic approach and has increased the options available for patients with a variety of cancers. In the case of RET-altered cancers, the early event in the cell cycle is either a fusion or a mutation affecting the activity of this gene. The result is a new protein inside the cell that causes the cells to become malignant. These new RET-inhibitors target this specific protein and achieve growth arrest in that cell.

In terms of efficacy and key outcomes, how do the selective RET inhibitors compare to the traditional treatment approaches in this patient population?

Traditional treatment approaches for cancer have always been based on the theory that cancer cells grow rapidly, usually faster than normal cells. By inhibiting cell division, traditional treatments like chemotherapy and radiation therapy are not able to differentiate a growing cancerous cell from a growing normal cell; this results in the side effects that are usually associated with these forms of therapies. In addition, the traditional approach seems very nonspecific and only differentiates normal cells from cancer cells based on the rate of growth. Organs associated with rapid regeneration like the mucosa, bone marrow, gastrointestinal tract lining, and hair are typically affected the most with this nonspecific approach, which is why we tend to see side effects from this treatment like hair loss, low blood counts, and gastrointestinal symptoms.

Given that the new treatment inhibits the root cause of the malignant process, it is better able to differentiate normal cells from malignant cells. Normal cells do not contain the new oncogenic protein, while cancer cells do; this makes the treatment very specific to cancer cells and subsequently produces better responses and fewer side effects. Consequently, patients treated with the specific RET inhibitors do not suffer from hair loss, reduction in blood counts, or suppression of the immune system.

However, this treatment is not without side effects, which tend to differ from the side effects seen in traditional treatments. In general, side effects include skin rash, elevated blood pressure, potential damage to the liver, and slow wound healing.^4,5 Even though these inhibitors are very specific, they may affect other normal receptors and interfere with their normal function, but not to the extent that chemotherapy does.

What is the risk of acquired resistance during treatment with pralsetinib and selpercatinib? What are the involved mechanisms, and what are treatment strategies for patients who develop resistance to these therapies?

Treatment of cancer is generally associated with eventual failure in patients who are not cured. Failure of a specific therapy is usually due to resistance of the tumor cells to the treatment, and there are several mechanisms by which cancer cells become resistant — we call them escape mechanisms. In general, these result from the development of alterations at the molecular level in the DNA of the cancer cells, making them unresponsive to the current treatment.
 
The mechanisms of tumor cell resistance are dependent on the original oncogenic driver alterations. These resistance mechanisms can affect the original molecular alteration, or they can be independent of that initial event. In the case of RET inhibitors, acquired resistance mutations can occur in the RET oncogene in a manner that alters the specific DNA sequence in the target of the inhibitor. Acquired resistance then produces a protein that is not inhibited by the current treatment. Therefore, the cells eventually start growing and the tumor progresses clinically.^3,5
 
Other mechanisms of resistance are RET-independent; that means other escape mechanisms are activated that will bypass the inhibited pathway and allow tumor cells to proliferate, even in the presence of the inhibitor. However, data on the mechanisms of resistance to RET inhibitors is limited due to the short period of time these new drugs have been in use. In a limited series of clinically resistant patients, it was found that most of the resistance comes from RET-independent pathways such as MET amplifications and KRAS amplifications, for example.⁶
 
Strategies to overcome resistance include the development of molecules that can target the resistance mutation, or the escape pathway; an example of this would be a RET inhibitor that also targets MET or KRAS alterations. These types of drugs tend to be the focus of drug development research and are usually considered next-generation inhibitors that can be used when resistance develops. While these types of drugs are not yet available, we hope they will be soon.

Can you discuss the safety profile of selective RET inhibition in patients with RET fusion-positive lung cancer? How are some of the adverse effects of these therapies managed in practice?

Although targeted therapies in general tend to have less side effects than traditional chemotherapy, they are not without side effects. The safety profile of the 2 approved RET inhibitors tends to be similar, but with a varying frequency of events. With pralsetinib, there is a 7% rate of discontinuation due to treatment-related adverse events (TRAE); with selpercatinib, this rate is 2%. The rate of TRAEs is around 94% with pralsetinib and 91% with selpercatinib. In pralsetinib, the most common grade 3 to grade 4 TRAEs were neutropenia (20.2%), anemia (12.4%), and hypertension (12%); with selpercatinib, the most common grade 3 or worse TRAEs were hypertension (9%), increased alanine aminotransferase (9%), and increased aspartate aminotransferase (6%).^7,8
 
Common adverse events for both drugs include liver toxicity, hypertension, and delayed wound healing. In clinical practice, when patients are initiated on these therapies, it is recommended to monitor liver function tests every 2 weeks for the first 3 months. In addition, patients with hypertension need to have their blood pressure optimized before starting treatment and monitored throughout therapy. Patients who develop hypertension should be started on antihypertensives. Patients scheduled for an elective surgery need to have this medication withheld for a week prior and 2 weeks after surgery to prevent it from having an effect on wound healing.^4,9

What are the potential benefits of combining RET-selective inhibitors with other therapies to improve outcomes in this patient population? What other agents can be used in these combination regimens?

In general, combining targeted agents has not been a common approach in clinical practice because toxicities tend to prohibit this combination. In addition, very few patients carry more than 1 targetable mutation requiring 2 targeted agents.
 
Chemotherapy is usually reserved for salvage treatment after the failure of targeted agents. Occasionally, in certain situations, chemotherapy may be added to the targeted agents once clinical progression is established and if there is a lack of development of a second driver alteration.
 
Data on immunotherapy in patients with targetable mutations is derived from subgroup analyses and retrospective reviews, most of which suggest that immune checkpoint inhibitors (ICIs) are not usually beneficial in patients with an epidermal growth factor receptor (EGFR)-mutated cancer.¹⁰ Consequently, in clinical practice, we never offer ICIs to these patients as front-line therapy.
 
In second line and beyond, these agents may be used in combination with chemotherapy; ICIs were used mostly beyond first line. In conclusion, at this point, it is not recommended to combine targeted agents with another therapy outside of a clinical trial, except for EGFR mutations.¹¹

Can you discuss the next-generation RET-selective inhibitors that are currently being tested in clinical trials? What are the anticipated benefits of these therapies over the currently available therapies?

There are some new molecules currently in development that are designed to overcome resistance in tumors with a RET alteration. One such molecule is TPX-0046, which is a structurally different inhibitor that is potent against a range of RET fusions and mutations. TPX-0046 has shown activity in vitro and in vivo on patient-derived xenograft tumor models. This molecule also inhibits the SRC oncogene and is currently being studied in a phase 1/2 trial (ClinicalTrials.gov identifier: NCT04161391).
 
The advantage of this molecule is that it can both overcome resistance to a first-line drug and also be active upfront. This will be considered the next-generation inhibitor and may eventually replace the first-generation inhibitors once activity is confirmed in clinical trials.
 
A second molecule in clinical development is BOS172738, a potent selective oral RET kinase inhibitor. This next-generation inhibitor was designed with increased potency against RET and high selectivity against vascular endothelial growth factor receptor 2 (VEGFR-2). This drug has completed a phase 1 clinical trial (ClinicalTrials.gov identifier: NCT03780517) and exhibited a favorable safety profile for long-term administration, with most adverse events classified as grade 2 or below.¹²
 
BOS172738 demonstrated an overall response of 33% in NSCLC and 44% in medullary thyroid cancer; patients with brain metastases also responded to this treatment.¹² The benefits of this agent are its increased specificity to the target and its ability to cover a variety of alterations.

Can you comment on the role of serial biopsy and next-generation sequencing in the context of sequential therapy in RET fusion-positive NSCLC?

In general, performing serial biopsies in everyday routine practice is not feasible; however, scientifically, it would be ideal to repeat next-generation sequencing at every progression. With the advent of blood-based DNA sequencing, one is able to detect possible resistance mutations in some patients; consequently, it has been a common practice to perform a blood-based DNA analysis at every progression in patients with an altered oncogene at presentation.
 
In the case of RET fusion-positive NSCLC, because one of the mechanisms of resistance involves a new mutation, sequential testing will be important to detect this abnormality. However, at this point, we do not have a specific inhibitor for the resistance mutation, making it unfeasible to perform this practice in everyday clinical work. The other 2 mechanisms of resistance include amplifications, which are usually detected on tissue biopsy, but may also be detected occasionally by liquid biopsy. With the development of specific inhibitors targeting resistance mutations or other alterations, serial testing will most likely become favored and will become the standard of care.

This Q&A was edited for clarity and length.

References

1. FDA approves pralsetinib for lung cancer with RET gene fusions. News release. US Food and Drug Administration. September 8, 2020. Accessed January 22, 2023. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-pralsetinib-lung-cancer-ret-gene-fusions
 
2. FDA D.I.S.C.O. Burst Edition: FDA approvals of Retevmo (selpercatinib) for adult patients with locally advanced or metastatic RET fusion-positive solid tumors, and Retevmo (selpercatinib) for adult patients with locally advanced or metastatic RET fusion-positive non-small cell lung cancer. News release. US Food and Drug Administration. November 7, 2022. Accessed January 22, 2023. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-disco-burst-edition-fda-approvals-retevmo-selpercatinib-adult-patients-locally-advanced-or
 
3. Tan AC, Tan DSW. Targeted therapies for lung cancer patients with oncogenic driver molecular alterations. J Clin Oncol. 2022;40(6):611-625. doi:10.1200/JCO.21.01626
 
4. Gavreto®. Prescribing information. Genentech, Inc. Accessed March 7, 2023. https://www.gene.com/download/pdf/gavreto_prescribing.pdf
 
5. Shen Z, Qiu B, Li L, Yang B, Li G. Targeted therapy of RET fusion-positive non-small cell lung cancer. Front Oncol. 2022;12:1033484. doi:10.3389/fonc.2022.1033484
 
6. Lin JJ, Liu SV, McCoach CE, et al. Mechanisms of resistance to selective RET tyrosine kinase inhibitors in RET fusion-positive non-small-cell lung cancer. Ann Oncol. 2020;31(12):1725-1733. doi:10.1016/j.annonc.2020.09.015
 
7. Griesinger F, Curigliano G, Thomas M, et al. Safety and efficacy of pralsetinib in RET fusion-positive non-small-cell lung cancer including as first-line therapy: update from the ARROW trial. Ann Oncol. 2022;33(11):1168-1178. doi:10.1016/j.annonc.2022.08.002
 
8. Drilon A, Oxnard GR, Tan DSW, et al. Efficacy of selpercatinib in RET fusion-positive non-small-cell lung cancer. N Engl J Med. 2020;383(9):813-824. doi:10.1056/NEJMoa2005653
 
9. Retemvo®. Prescribing information. Eli Lilly and Company. Accessed March 7, 2023.  https://pi.lilly.com/us/retevmo-uspi.pdf
 
10. Yang F, Wang Y, Tang L, et al. Efficacy of immune checkpoint inhibitors in non-small cell lung cancer: A systematic review and meta-analysis. Front Oncol. 2022;12:955440. doi:10.3389/fonc.2022.955440
 
11. Mazieres J, Drilon A, Lusque A, et al. Immune checkpoint inhibitors for patients with advanced lung cancer and oncogenic driver alterations: results from the IMMUNOTARGET registry. Ann Oncol. 2019;30(8):1321-1328. doi:10.1093/annonc/mdz167
 
12. Schoffski P, Cho BC, Italiano A, et al. BOS172738, a highly potent and selective RET inhibitor, for the treatment of RET-altered tumors including RET-fusion+ NSCLC and RET-mutant MTC: phase 1 study results. J Clin Oncol. 2021;36(suppl 15):3008. American Society of Clinical Oncology (ASCO) Annual Meeting I abstract 3008.

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