Lung Cancer

Advances in the treatment of RET-fusion-positive lung cancer
Georg Pall a,*, Oliver Gautschi b
a University Hospital of Innsbruck, Anichstraße 35, 6020, Innsbruck, Austria
b Cantonal Hospital of Lucerne, Spitalstrasse, 6004, Lucerne, Switzerland

A R T I C L E I N F O

Keywords: NSCLC
RET-fusion RET-inhibitors

A B S T R A C T

Ten years ago, RET-fusions were discovered as oncogenic drivers and potential drug targets in approximately 1% of metastatic lung adenocarcinomas. Several multikinase inhibitors were tested in clinical trials, however, their antitumor activity was limited. Recently, two selective and potent RET-inhibitors were approved for the treat- ment of patients with metastatic RET-fusion-positive lung cancer (RET-NSCLC). Here, we discuss the two RET- inhibitors selpercatinib and pralsetinib, and the management of patients with RET-fusion positive NSCLC.

1. Molecular biology
The RET (rearranged during transfection) gene located on chromo- some 10 was discovered in 1985 [1]. It encodes the RET transmembrane receptor kinase, that is required for normal neuronal and genitourinary development. The RET receptor kinase is activated by glial-derived neurotrophic factor (GDNF) family ligands (GFL), and forms a hetero- complex with GDNF-family receptor alpha (GFRA1). In mice, knockout of RET, GDNF or GFRA1 leads to renal agenesis and perinatal death. The activated RET-GFRA1-heterocomplex triggers the MAP-kinase pathway for cell proliferation, and the PI3K-AKT pathway for cell survival.

Genomic RET alterations are involved in various human diseases [2]. For example, germline loss of function RET mutations cause Hirsch- sprung disease (intestinal aganglionosis, HSCR), and congential anom- alies of kidney and urinary tract (CAKUT). Gain of function RET point-mutations are associated with multiple endocrine neoplasia (MEN) syndromes. Sporadic RET point-mutations and fusions are com- mon in medullary and papillary thyroid cancers, respectively. Activating RET-mutations also occur in other solid tumors, and in chronic myeloid leukemia. In lung cancer, RET fusions were discovered by four inde- pendent research groups in 2012 [3–6]. These groups found RET fusions in approximately 1–2 % of lung adenocarcinomas, primarily in tumors without any other driver mutations and in non-smokers. The most frequent fusion partner of the RET gene in lung cancer is KIF5B, but at least 14 other fusion partners have been identified so far, including CCDC6 and NCOA4 [7]. Dimerization of fusion products resulted in constitutive activation, and had tumorigenic activity in animal models. Inhibition of RET kinase with small molecules had antitumor activity in xenograft models. These seminal discoveries spurred clinical studies investigating the role of targeted therapies for patients with metastatic RET-NSCLC.

2. Diagnosis
RET-fusions are detected via different molecular methods in tissue biopsies, fine-needle aspirates, and even in liquid biopsies [8]. Immu- nohistochemistry (or immunocytochemistry) is not yet recommended for RET-fusion detection, although potential antibodies exist [9]. Fluorescence-in-situ-hybridization (FISH) using a specific break-apart probe for RET detects different variants and fusions, is reliable, fast, and KIF5B-RET fusions can be validated using a probe for KIF5B [10]. FISH works well on tissue or cytology smears, but is not established for circulating tumor cells. Many laboratories use RET-FISH, because they have experience with ALK-FISH and ROS1-FISH. Because false-positive FISH results may occur, validation of positive results by NGS is recom- mended if possible. Real-time PCR and next generation sequencing require trained laboratory staff and sufficient tumor DNA (or RNA). NGS has the advantage of parallel testing for other driver mutations, and is considered cost-effective by the European Society of Medical Oncology (ESMO) for metastatic lung adenocarcinoma [11]. Moreover, NGS can detect RET-fusions in liquid biopsies, which makes it suitable for serial analysis, primarily in research projects [12].

3. Conventional systemic therapies
Chemotherapy remains a reasonable choice for the treatment of metatastic lung adenocarcinomas with driver mutations, including RET- fusions. In a retrospective clinical study, platinum and pemetrexed was

* Corresponding author at: University Hospital Innsbruck, Department for Internal Medicine V (Hematology/Oncology), Anichstraße 35, 6020, Innsbruck, Austria.
E-mail addresses: [email protected] (G. Pall), [email protected] (O. Gautschi).
https://doi.org/10.1016/j.lungcan.2021.04.017 Received 15 April 2021; Accepted 18 April 2021
Available online 24 April 2021
0169-5002/© 2021 Elsevier B.V. All rights reserved. very effective in (ALK, ROS1, RET) fusion-positive lung adenocar- inomas, compared with KRAS-mutant NSCLC [13].

Therefore, the standard chemotherapy for RET-NSCLC remains platinum and pemetrexed. Immunotherapy (alone or in combination with chemotherapy) is approved for first line therapy, except for EGFR- and ALK-NSCLC. NSCLC with ALK, ROS1 or RET fusions, however, are associated with poor response to checkpoint inhibitors. In the global IMMUNOTARGET registry, 551 patients with single-agent checkpoint inhibitor therapy and known driver mutations were analyzed [14]. PD-L1 expression levels were relatively high in the 16 RET-fusion positive cases compared with other genomic subtypes. Nevertheless, only 1 patient had an objective response, and the median progression free survival was 2.1 months. A second study from the MD Anderson Cancer Center showed similar results [15]. In analogy to ALK-NSCLC or ROS1-NSCLC, broad use of immunotherapy alone or in combination with chemotherapy for RET-NSCLC cannot be recommended, regardless of the PD-L1 expression level of the tumor.

Multikinase inhibitors (MKIs) targeting RET and other kinases showed encouraging activity in preliminary reports [16,17]. However, prospective trials revealed inferior activity for MKIs in RET-NSCLC, compared with EGFR or ALK inhibitors for EGFR/ALK mutant NSCLC [18]. As expected from the inhibition of KDR/VEGF, toxicity of these MKIs was relevant. Responses were achieved with cabozantinib, lenva- tinib and vandetanib [19–22]. Most patients were heavily pretreated, and median progression free survival was relatively short. While the results of the European ALERT trial are pending, the ALL-RET trial showed no relevant clinical activity of alectinib against RET-NSCLC [23]. These results were confirmed by the global registry GLORY, which included 50 patients with RET-NSCLC treated with 8 different MKIs [24]. In a separate analysis, RET-NSCLC was shown to frequently metastasize into the brain, and MKIs had suboptimal intracerebral ac- tivity [25]. These findings called for better RET-inhibitors in terms of potency, selectivity and intracerebral activity.

4. Selective RET-inhibitors
4.1. Selpercatinib
Selpercatinib (formerly known as LOXO-292) has been developed as a selective, ATP-competitive RET-inhibitor. Data on its preclinical characterization and activity was published in 2018 [26]. Besides high efficacy in RET-inhibition (also overcoming V804M-mediated resis- tance), the drug showed favorable properties with regard to target-specificity, tolerability and intracranial efficacy. Based on this background the Libretto-001-study was designed. In the initial phase I –part of this trial [27] 82 RET-driven cancers of different origin were treated with increasing doses of selpercatinib, ranging from 20 mg daily to 260 mg BID. The maximum tolerated dose was not reached and only two treatment related adverse events of grade 3 were observed (tumor lysis syndrom, ALT increase). The response-rate in patients with NSCLC, who were heavily pretreated, reached 77 % and was independent of the respective RET-fusion-partner and MTK-inhibitor pretreatment. All 3 patients with pretreatment brain-metastases showed intracranial tumor-shrinkage. Following these data, 160 mg BID was determined as the recommended phase II-dose and and expansion cohort was opened [28]. This cohort then comprised of 105 patients with RET-fusion positive (determined by local certified laboratories) metastatic NSCLC, an ECOG performance-status of 0–2 and pretreatment with at least a platium-based chemotherapy. CNS-involvement (pretreated or treatment-naive) was allowed, as long as it did not cause any neurological symptoms.

Overall response (determined by independent radiological review) was defined as the primary endpoint. In 64 % of patients a RECIST- response was observed (CR 2%, PR 62 %). This, by far, exceeded the response rates of the last previous treatment [29]. Disease stabilization was reached in 29 % of the participants and only 4% showed primary progression. Effiacay was independent from previous treatment mo- dalities like immunotherapy or MTKʾs and RET-fusion-partners. Overall, responses were durable with a median duration of response of 17,5 months (95 % CI, 12,0 to NE). This efficacy led to a median progression free survival (PFS) of 16,5 months (95 % CI, 13,7 to NE). Among 11 patients with measurable CNS-metastases, an intracranial response was documented in 91 %.

In addition 39 patients with previously untreated metastatic RET- fusion positive NSCLC were treated within Libretto-001. In this cohort the response rate was 85 % (95 % CI, 70 94. Median duration of response and median progression free survival were not reached at the time of analysis.
In general, selpercatinib-treatment was well tolerated. In 30 % of the cases doses reductions due to adverse events were necessary. Dry mouth (36 %), diarrhea (25 %), elevated hepatic transaminases (20–22%), hypertension (17 %), peripheral edema (13 %), rash (12 %), QTc- prolongation (10 %) and thrombocytopenia (10 %) were the most prevalent treatment related toxicities (any grade). G3/4 side effects were infrequent with hypertension (9%) and elevated transaminases (5–8 %) being the most numerous. From a practical clinical perspective close monitoring of hepatic transaminases, blood pressure and QTc- interval have to be recommended. Rare side effects with clinical rele- vance are bleeding events (2–3 %) and impaired wound-healing (stop- ping of selpercatinib 7 days before elective surgery is recommended). A symptom-complex of fever, rash, arthralgia, myalgia, thrombocyto- penia, elevated transaminases, tachycardia, decreased blood pressure and sometimes creatinine increase has been described as hypersensitivity-reaction. Its overall frequency was 7,6% (G3/4 6,7%) with prior immune-checkpointinhibitor-treatment being a significant risk-factor [30]. Selpercatinib was approved by the FDA in 2020 for the treatment of RET-fusion-positive metastatic NSCLC in first and later lines. In 2021, selpercatinib was approved by EMA and Swissmedic for second or later lines.

4.2. Pralsetinib
Initially known as BLU-667, pralsetinib is the second selective RET- inhibitor in clinical development. Its preclinical efficacy was demon- strated in an initial publication in 2018 [31]. High target-specificity and strong evidence of preclinical in vivo tumor-shrinking properties were reported. This also extended to models with V804 L or V804 M resis- tance mutations.
In phase I testing [32] pralsetinib showed favorable tolerability. A maximum tolerated dose could not be determined. Constipation, elevation of hepatic transaminases, hypertension, diarrhea, fatigue, increased creatinine and leukopenia were the most frequent reported side-effects (mostly G1/2). A once daily dose of 400 mg was chosen as the recommended phase-II-dose and based on promising response rates of 83 % in different RET-driven cancers an expansion phase of the trial was initiated.

The most recent update of these data has been presented at the ASCO annual meeting 2020 [33]. The study population comprised of 132 pa- tients with metastatic RET-fusion positive NSCLC (92 prio platinum-chemotherapy, 29 treatment naive). Most patients (95 %) were in good performance-status. In the response-evaluable population (n 116), the overall response rate achieved was 65 % (61 % in platinum-pretreated pateints, 73 % in treatment-naive patients). 28 % reached disease-stabilization, 7% were determined as primary pro- gressors. The median duration of response was not reached (95 % CI, 11,3 months vs. not reached). Of 9 patients with measurable CNS-metastases, all showed some degree of intracranial tumor-shrinkage (intracranial response rate 56 %, intracranial CR 33%).Regarding safety, 4% of the study participants discontinued treat- ment due to toxicity, data on dose-reductions were not reported.

Elevated hepatic transaminases (31 %, 21 %), anemia (22 %), con- stipation (21 %), hypertension (20 %), diarrhea (14 %) were the most frequent side effects of all grades. Hypertension (10 %), neutropenia (10
%) and anemia (8%) showed up as the most relevant toxicities with G3/
4. Pralsetinib was approved treatment of RET-fusion positive metastatic NSCLC.
5. Acquired resistance to selective RET-inhibtors

The ocurrence of secondary mutations, leading to sterically hinder- ing of target binding, is a known mechanism of resistance against different targeted agents used in the treatment of genetically driven NSCLC. For patients progressing during selpercatinib-treatment, such G810-mutations have been described in a limited number of samples (ctDNA and tissue-rebiopsies) [34]. In serial measurements, these mu- tations occurred several months in advance to clinical disease-progression. Biopsies taken post mortem revealed different subtypes of G810-mutations in different metastatic lesions proofing significant intratumor-heterogeneity. This specific type of mutation was also reproduced in preclinical models and determined as the resistance-mediating event.

In another series [35] of 18 patients treated with selective RET-inhibitors (selpercatinib and pralsetinib) RET G810-mutations were also detected in 10 % of patients. Other singular genetic events like KRAS- or FGFR-amplification have been described in specimen from tumor-sites taken at the time of acquired resistance, however their mechanistic role remains to be established. Histologic transformation, a known mechanism of resistance in EGFR-driven NSCLC has not been described for RET-TKI-treated NSCLC so far. Interestingly, in this patient cohort MET-amplification emerged as an alternative off-target resis- tance mechanism in 15 % of the patients analyzed. Additional data [36] strengthened this observation with preclinical evidence for MET-signalling being the driver of resistance. When treated with a combination of selpercatinib and the MET-inhibitor crizotinib, some of these patients showed at least transient responses.

6. Next generation RET-inhibitors
With the aim of overcoming acquired resistance and therefore improving treatment-results next generation RET-TKIʾs are being developed. TPX-0046 has shown preclinial activity against RET-WT and RET-G810-mutated isoforms [37]. However, its inhibitory-activity
seems to be low against the V804M-gatekeeper mutation. A phase I/II trial is ongoing to better characterize toxicity and efficacy of this com- pound (ClinicalTrials.gov Identifier: NCT04161391). With BOS172738, another candidate has entered phase I-testing (ClinicalTrials.gov Iden- tifier: NCT03780517). LOX-18228 and LOX-19260 are in preclinical development.

7. Conclusions

Based on the available preclinical and clinical evidence it is fair to state, that RET-fusions can now be considered an established therapeutic target in NSCLC. Accordingly, testing for RET-fusions should be included in the standard molecular work-up of metastatic non-squamous NSCLC. Selpercatinib and pralsetinib represent the currently most effective treatment options for patients with metastatic RET-fusion positive NSCLC. With results from randomized trials still lacking, their definitive place within the treatment algorithms, however, remains uncertain. Two first line studies, comparing selpercatinib (Libretto-431) and pral- setinib (AcceleRET) to platinum/pemetrexed /- immunotherapy are currently recruiting.
To better understand and finally overcome acquired resistance to selective RET-inhibitors can be considered one of the most important challenges for the near future.

Finally, we have to ask whether treatment with RET-inhibitors might
also improve survival in early-stage RET-fusion positive NSCLC. Despite the relative rarity of this patient subgroup, global trial efforts should be capable of answering this important question.

Disclosures
OG reported consultant roles for AMGEN, LILLY and BAYER; and advisory boards for NOVARTIS, BAYER, LILLY, and TAKEDA.
GP reported consultant roles for ROCHE, LILLY, EISAI; and advisory boards for ROCHE, LILLY, EISAI.
CRediT authorship contribution statement
Oliver Gautschi: Conceptualization, Writing, Project administra- tion. Georg Pall: Conceptualization, Writing, Project administration.

Funding
This research did not revieve any specific grant form funding agencies in the public, commercial, or not-for-profit sectors.
Declaration of Competing Interest
Oliver Gautschi reported consultant roles for AMGEN, LILLY and BAYER; and advisory boards for NOVARTIS, BAYER, LILLY, and TAKEDA.
Georg Pall reported consultant roles for ROCHE, LILLY, EISAI; and advisory boards for ROCHE, LILLY, EISAI.

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