Introduction/History FDA

A defining feature of the past decade of cancer drug development has been the rapid expansion of tyrosine kinase inhibitors (TKIs) available on the market, with over 30 agents approved between 2010 and 2019 for at least one cancer indication.¹ The FDA, undeterred by the COVID-19 pandemic, approved five new TKIs during 2021 and seven new TKIs during 2020, including the first TKI that primarily targets rearranged during transfection (RET) kinase.² On May 8, 2020, the FDA granted Retevmo (selpercatinib) accelerated approval for the treatment of RET fusion-positive metastatic non–small cell lung cancer (NSCLC) and thyroid cancer, as well as RET-mutant thyroid cancer.²

RET is a proto-oncogene that encodes a receptor tyrosine kinase that has been shown to activate several signaling pathways commonly associated with cellular proliferation, including RAS, ERK, and PI3K/AKT.³ RET alterations, including gene fusions and rearrangements, can be found in around 1%–2% of NSCLCs and 70% of all medullary thyroid cancers.⁴ Preclinical studies have shown that mutations in RET can lead to constitutive activation of the encoded kinase and subsequent oncogenesis, making RET a potentially attractive target for the management of malignancies with RET alterations.³ Although previously approved multikinase inhibitors with RET inhibition cause a variety of off-target toxicities, selpercatinib was designed with an enhanced specificity toward RET with the goal of reducing adverse effects and enhancing efficacy.⁵

Trial Overview^4,6

The FDA approval of selpercatinib mentioned earlier was based on the findings of LIBRETTO-001, a phase I/II trial evaluating the safety and preliminary efficacy of selpercatinib in RET-altered NSCLC and thyroid cancer. The two parts of the study had a combined total of 306 patients, including 162 patients with thyroid cancer and 144 patients with NSCLC. The primary end point for both study groups was the objective response rate as determined by an independent review committee.

In the NSCLC portion of the study, patients were divided into two groups for analysis: patients with (n=105) or without (n=39) prior treatment with platinum-based chemotherapy. Patients with prior platinum-based chemotherapy treatment had an objective response rate of 64% (95% CI, 54%–73%), and those without prior treatment had an objective response rate of 85% (95% CI, 70%–94%).

In patients with medullary thyroid cancer, there were three subgroups: medullary thyroid cancer with RET mutations (1) with or (2) without previous treatment with cabozantinib or vandetanib and (3) previously treated RET fusion-positive thyroid cancer. In patients with previously treated medullary thyroid cancer (n=55), previously untreated medullary thyroid cancer (n=88), and previously treated RET fusion-positive thyroid cancer (n=19), the objective response rates were 69% (95% CI, 55%–81%), 73% (95% CI, 62%–82%), and 79% (95% CI, 54%–94%), respectively. Although investigators calculated the median duration of response and 1-year progression-free survival, these metrics have limited usefulness, given the uncontrolled design and the limited duration of the study.

Among all study participants, around 40% had Common Terminology Criteria for Adverse Events (CTCAE) grade 3 or 4 treatment-related adverse events. The most common grade 3/4 events were hypertension (11.4%, n=35) and increased AST or ALT (20.9%, n=64).

Given the drug’s response rate and duration, selpercatinib was granted FDA approval through an accelerated approval pathway, in addition to receiving priority review and breakthrough therapy statuses.^1,2 These programs allow for expedited approval of novel medications that address unmet medical needs in the treatment of serious or rare diseases in an effort to make these therapies rapidly available to patients directly after the completion of phase II trials with promising safety and efficacy results.¹ Selpercatinib qualified for these approval pathways on the basis of its preliminary evidence of substantial improvement over other available therapies for RET-altered cancers, indication for treatment of a rare condition, and ability to provide significant improvements in safety and efficacy, as shown by phase I/II studies.² Maintaining FDA approval depends on continuing clinical trials for additional safety testing.

Clinical Factors

Selpercatinib is available as a 40- or 80-mg oral capsule. Dosing is weight based for all patients and is approved for use in patients 12 years and older. Patients weighing 50 kg or more should receive 160 mg twice daily and those weighing less than 50 kg should receive 120 mg twice daily. Proper dose adjustment has not been determined for patients with severe renal impairment (CrCl less than 30 mL/minute), though the package insert contains some dosing recommendations for patients with impaired hepatic function. Selpercatinib is predominantly metabolized by CYP3A4 enzymes, warranting avoidance or dose adjustment of moderate-strong CYP3A inhibitors and inducers in combination with selpercatinib. As an inhibitor of CYP2C8 (moderate) and CYP3A (weak), coadministration of selpercatinib with substrates of these enzymes should be avoided. Use of selpercatinib with acid-reducing agents or in pregnant or lactating women should also be avoided.⁴ The most common adverse events include dry mouth (39%), diarrhea (37%), fatigue (35%), QT interval prolongation (17%), hypertension (35%), and elevated liver enzymes (AST and ALT) (51% and 45%, respectively).^4,6-8 Selpercatinib may require dose adjustment or discontinuation depending on the severity of adverse events (CTCAE grade 3 or 4).⁷ The package insert recommends monitoring the QT interval, electrolytes (potassium, calcium, magnesium), TSH, LFTs, and blood pressure at baseline and periodically throughout therapy.⁷

Summary

With the recent approval of selpercatinib, RET kinase can be added to the list of druggable targets in cancer medicine because it is the first TKI approved with RET as its primary target. In addition to lung and thyroid cancers, changes in RET expression levels or structural RET alterations have been found in other solid tumors, including breast and pancreatic cancers. Whether the potential benefit of selpercatinib in lung and thyroid cancers is translatable to these malignancies is not yet clear.

It is important to temper this optimism with the current limitations present in the clinical data regarding selpercatinib. To date, there is no evidence that selpercatinib improves patient-centered outcomes (either overall survival or quality of life) in RET-altered cancers compared with the current standard of care, and it is imperative that the clinical response witnessed in LIBRETTO-001 be further assessed in randomized controlled phase III/IV studies compared with the current standard of care in these malignancies.

Overall, the continued addition of new druggable targets in cancer medicine means that we are “on the RET track” regarding the drug discovery pipeline. However, further data are needed to confirm that medications aimed at these new targets prolong or improve the lives of patients with cancer.

References

1. U.S Food and Drug Administration (FDA). New Drugs at FDA: CDER’s New Molecular Entities and New Therapeutic Biological Products [report]. FDA, January 10, 2020. Available at https://www.fda.gov/drugs/development-approval-process-drugs/new-drugs-fda-cders-new-molecular-entities-and-new-therapeutic-biological-products.

2. U.S. Food and Drug Administration (FDA). FDA Approves Selpercatinib for Lung and Thyroid Cancers with RET Gene Mutations or Fusions [press release]. FDA, May 11, 2020. Available at https://www.fda.gov/drugs/drug-approvals-and-databases/fda-approves-selpercatinib-lung-and-thyroid-cancers-ret-gene-mutations-or-fusions.

3. Li AY, McCusker MG, Russo A, et al. RET fusions in solid tumors. Cancer Treat Rev 2019;81:101911.

4. 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;383:813-24.

6. Kurzrock R. Selpercatinib aimed at RET-altered cancers. N Engl J Med 2020;383:868-9.
7. Wirth LJ, Sherman E, Robinson B, et al. Efficacy of selpercatinib in RET-altered thyroid cancers. N Engl J Med 2020;383:825-35.

7. DailyMed. RETEMVO – Selpercatinib Capsule. National Library of Medicine, 2020. Available at https://dailymed.nlm.nih.gov.

8. UpToDate. Selpercatinib: Drug Information. In: Post TW, ed. UpToDate. Available at www.uptodate.com.