Evolving Treatment Strategies in RET+ Lung Cancer Leave Unanswered Questions

Vivek Subbiah, MD

Vivek Subbiah, MD

Next-generation highly selective RET inhibitors are among the modern strategies used for the treatment of patients withRET-dependent cancers, including non—small cell lung cancer (NSCLC) that is driven byRETfusions. However, multi-kinase inhibitors (MKIs) like cabozantinib (Cabometyx) and vandetanib (Caprelsa) are still used even though they have shown modest clinical efficacy in clinical trials, often lead to resistance, and cause unacceptable toxicity. Oncologists are left with questions of how to deal with resistance mechanisms for MKIs and selective RET inhibitors, and how efficacy is impacted when they combine 2 or more such drugs into a treatment regimen.

In a paper published in theJournal of Clinical Oncology, researchers led by Vivek Subbiah, MD, an associate professor in the Investigational Cancer Therapeutics Department at The University of Texas MD Anderson Cancer Center, reviewed the information that is currently know aboutRETalterations and the modern treatment strategies forRET-altered cancers.¹

“Lung cancer has become the poster child for precision oncology.RETfusions are oncogenic drivers in 1-2% of NSCLCs and have derived only limited benefit from MKIs that were re-purposed as RET inhibitors. Development of highly selective, potent RET inhibitors is poised to change this paradigm. In this review, we seek focus on the impact of selective RET therapeutic targeting. Data from 2 early clinical trials using selective RET inhibitors demonstrate that specific targeting of activatedRETin NSCLC, has fewer off-target side effects, and is associated with remarkable responses opening up a new era of precision oncology inRET-positive NSCLC,” Subbiah toldTargeted Oncology.

Understanding RET

Discovered in 1985 by Takashi et al,²theRETgene conceals an immense receptor tyrosine kinase (RTK) that encompasses an extracellular domain, a transmembrane domain, and an intracellular tyrosine kinase domain. After early studies revealed the isoforms ofRET, it was also discovered thatRET51is more prominent in tumors than RET9, and it more efficiently promotes cell proliferation, migration, and anchorage-independent growth.

Chromosomal rearrangements can activateRETthrough the generation of fusion genes containing the kinase domain of RETand gain-of-function missense mutations in both the extracellular and cytoplasmic areas of theRETprotein, the authors noted. High expression of wild-type RET has alsobeen linked to the pathogenesis of several cancer types.³

In the paper, Subbiah et al extensively described the mutational categories ofRETand how they are activated. These categories include germline and somatic mutations. GermlineRETmutations are more commonly associated with thyroid and breast cancers, whereas somatic mutations have been observed across multiple solid tumors. Although, researchers still seek further clarity on the functional effect ofRETmutations on tumorigenesis in these tumors.

Targeted Therapies forRET-Positive Lung Cancer

MKIs that have shown activity inRET-positive cancers include cabozantinib, lenvatinib (Lenvima), sorafenib (Nexavar), vandetanib, ponatinib (Iclusig), sunitinib (Sutent), and alectinib (Alecensa), the authors noted based on prior research from Drilon et al,³and Wells et al.⁴

Data from multiple studies show that MKI treatment ofRET-rearranged NSCLC elicit lower response and survival rates than in other oncogene-driven NSCLCs. The examples provided by Subbiah et al include a phase II study of cabozantinib (NCT01639508), the phase III LURET trial, the phase II GLORY trial, and others.¹

First, 2016 results from a phase II study of cabozantinib inRET-rearranged NSCLC showed that treatment with cabozantinib elicited an overall response rate (ORR) of 28%, a median progression-free survival (PFS) of 5.5 months, and a median overall survival (OS) of 9.9 months.⁵

The same year, better efficacy was demonstrated with vandetanib according to results from the LURET trial.⁶The ORR was 53% (95% CI, 28%-77%), the median PFS was 4.7 months (95% CI, 2.8-8.5), and the median OS was 11.1 months (95% CI, 9.4 to not reached [NR]). A phase II South Korean study demonstrated comparable survival to the LURET trial with a median PFS of 4.5 months and an OS of 11.6 months, even though the ORR was slightly lower at 18%.⁷Together, these 2 studies validate the efficacy of vandetanib inRET-positive NSCLC.

Other data show that MKIs can have mixed efficacy in patients withRET-rearranged NSCLC. In a phase II study of lenvatinib, results from 2016 showed that the agent yielded a low ORR of 16% and a higher median PFS of 7.3 months (95% CI, 3.6-10.2), and the median OS was not evaluable (NE; 95% CI, 5.8 to NE).⁸Data from a registry of patients withRET-rearranged NSCLC treated with MKIs corroborate the objective response and survival results of cabozantinib, vandetanib, and sunitinib, which demonstrated ORRs of 37%, 18%, and 22%, respectively.⁹Median PFS and OS in the registry were 2.3 months and 6.8 months, respectively.

In a more recent study, a 19% ORR was yielded with the investigational agent RXDX-105.¹⁰Subbiah et al noted that this efficacy was only in non-KIF5B upstream partners and other trials involving RXDX-105 had even less favorable clinical outcomes in patients withRETfusion—positive cancers. Additionally, they recommended further investigation to address the small sample sizes and gaps in clinical outcomes between patients with RETfusions and those with other RETrearrangements.¹

One con recognized with the use of MKIs is that is other kinases are also targeted, which may lead to inferior inhibition of RET and increase the probability of treatment-related toxicities. When this occurs, physicians may have to decrease the treatment dose or discontinue a patient’s treatment altogether. A second con is that MKIs may demonstrate different efficacy results for different types ofRETalterations. The final down point noted in the paper is that acquired genomic changes in other genes can still occur and lead to drug resistance to MKIs.¹

Selective RET inhibitors offer higher potency and less toxicity for patients withRET-positive cancers. For NSCLC, in a recent phase I/II study (ARROW, NCT03037385), treatment with pralsetinib (BLU-667) led to an ORR of 58%.¹¹Additionally, in thephase I/II LIBRETTO-001 trial (NCT03157128), an ORR of 68% was observed with selpercatinib(LOXO-292)in patients withRETfusion—positive NSCLC.¹²These studies showed favorable safety, as most adverse events were grades 1 and 2 in severity, however data are still preliminary.

Newer selective RET inhibitors like BOS172738, TPX-0046, and TAS0953/HM06 are also in the early stages of development.

In terms of treatment strategy, oncologists who treat patients withRET-rearranged NSCLC have ongoing uncertainty about the long-term efficacy of the selective RET inhibitors as these are newer treatments.¹

As a start to finding answers to ongoing questions, further research is also focused on resistance mechanisms related to selective RET inhibitors along with other mechanisms for acquired resistance to MKIs. How efficacy is impacted when these drugs are combined in treatment regimens is also an ongoing area of exploration in NSCLC.

References

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2. Takahashi M, Buma Y, Iwamoto T, et al. Cloning and expression of the ret proto-oncogene encoding a tyrosine kinase with two potential transmembrane domains.Oncogene, 1988:3(5);571-578.
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4. Wells SA Jr. Advances in the management of MEN2: From improved surgical and medical treatment to novel kinase inhibitors.Endocr Relat Cancer. 2018:25(2):T1-T13. doi: 10.1530/ERC-17-0325.
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9. Gautschi O, Milia J, Filleron T, et al. Targeting RET in patients with RET-rearranged lung cancers: Results from the Global, Multicenter RET Registry.J Clin Oncol.2017:35(13);1403-1410. doi: 10.1200/JCO.2016.70.9352
10. Drilon A, Fu S, Patel MR, et al. A phase I/Ib trial of the VEGFR-sparing multikinase RET inhibitor RXDX-105.Cancer Discov. 2019:9(3);384-395. doi: 10.1158/2159-8290.CD-18-0839.
11. Gainor JF, Lee DH, Curigliano G, et al. Clinical activity and tolerability of BLU-667, a highly potent and selective RET inhibitor, in patients (pts) with advanced RET-fusion+ non-small cell lung cancer (NSCLC).J Clin Oncol. 2019;37(suppl; abstr 9008). doi: 10.1200/JCO.2019.37.15_suppl.9008
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