RET Fusion mutation drugs – lung cancer

This post was written by marc on September 22, 2016
Posted Under: Letters to the Editor

Activated RET and ROS: two new driver mutations in lung adenocarcinoma

http://tlcr.amegroups.com/article/view/1031/1683

RET Inhibitors

Vandetanib

In April 2011 the FDA approved vandetanib, a RET, VEGF 2, VEGF 3 and EGF receptor tyrosine kinase inhibitor for the treatment of patients with metastatic MTC who were ineligible for surgery and had progressive or symptomatic disease. The approval followed the results from an open label single arm phase II study testing vandetanib in patients with hereditary MTC. This phase II study conducted by Wells et al.showed that 83% of the patients treated with vandetanib had a reduction in tumor size at their first assessment and 11 out of 30 patients responded with an initial decrease in tumor size ≥30% of which 6 (20%) had confirmed partial responses (PR) according to RECIST. Disease control rate at 24 weeks was 78% and the duration of response in patients with confirmed PR was durable with a median of 10.2 months (33). Following the phase II data a large phase III trial was initiated showing a significantly improved efficacy and prolongation of PFS for vandetanib compared to placebo in patients with sporadic and hereditary MTC with a hazard ratio of 0.46 (95% CI, 0.31-0.69; P<0.001) (34). Preclinical studies suggest that vandetanib has superior activity in MEN2B cell lines compared to cabozantinib (29). The predominant mutation in MEN2B is the activating M918T point mutation in the RET kinase domain, which is also the most frequent mutation in sporadic MTC (35). Vandetanib also showed activity against RET/PCT in vitro and in vivo (36).

Cabozantinib

Cabozantinib, a potent inhibitor of RET, VEGFR2 and MET tyrosine kinases, received FDA approval for its use in MTC in November 2012. Early signals of activity in MTC were seen in a phase I dose escalation trial, which led to the testing of cabozantinib in patients with MTC in an expansion cohort of the phase I study. Of the 35 patients with MTC and measurable disease included into the study 17 patients (49%) experienced a 30% or greater reduction in the sum of tumor diameters at first assessment. Disease control of at least 6 months was present in 68% of the patients (37). Following the positive data from the phase II study a large phase III study was started, which tests cabozantinibvs. placebo in patients with progressive, unresectable, locally advanced or metastatic MTC. First data were presented at ASCO 2012, which showed that the primary objective of significant PFS prolongation was met (HR 0.28 95% CI, 0.19-0.40; P<0.0001) (38).

In July 2012 a phase II study testing cabozantinib in KIF5B/RET positive NSCLC patients has been initiated at Memorial Sloan-Kettering Cancer Center (NCT01639508) and is thus to our knowledge the first study investigating a personalized treatment approach for this newly defined subgroup of NSCLC. Interestingly, in vitro studies showed a greater activity of cabozantinib compared to vandetanib in cell lines harboring the RET/PTC1 fusion gene, which also has been found in NSCLC (29).

Sorafenib

Sorafenib is a multi-tyrosine kinase inhibitor targeting VEGFR1, VEGFR2, KIT, RET, BRAF and CRAF (39). In vitro sorafenib was shown to inhibit RET in the low nanomolar range and exerted anti-tumor activity in RET-driven xenografts (40). Sorafenib has been tested in several phase II studies in patients with DTC, anaplastic thyroid carcinoma and MTC (4143). In an open-label phase II study of 41 patients with PTC, 6 patients (15%) showed a PR and 23 (56%) patients had a stable disease for longer than 6 months. The PRs seen in the patients were durable with a median duration of 7.5 months. The authors concluded that sorafenib is an active drug in metastatic PTC. Genetic testing was included into the trial and the great majority of PTCs harbored an activating BRAF mutation whereas none was positive for RET/PTC1 or RET/PTC3. These observations render translation into the RET driven NSCLC setting difficult (43). In another phase II study sorafenib was tested in locally advanced or metastatic MTC. Of 15 evaluable patients with sporadic MTC, one patient had a PR and more than 50% of the patients had SD ≥15 months. The majority of tumors in the tested population had activating mutations in the RET gene (42) The phase II study from Gupta-Abramson et al. demonstrated in 30 (27 out of 30 being DTC) patients with metastatic, iodine-refractory thyroid carcinoma a PR rate of 23% (7 patients). The median PFS was stated with 19.75 months. Data of specific genetic testing were not presented in this paper. Given the PR rate of 23% and the PFS of 19.25 months the sorafenib treatment may be considered superior to chemotherapy in these patients (41).

Sunitinib

Sunitinib is a multi-tyrosine kinase inhibitor targeting VEGFR, Flt-3, c-Kit and RET (40) and has proven to be a potent inhibitor of RET/PTC oncoproteins in vitro and in vivo (36). In a phase II study in iodine refractory DTC and MTC from 33 evaluable patients one patient showed a complete response (3%), ten patients had a PR (28%) and 16 patients demonstrated stable disease (46%). There was also a significant association seen between decreased 18FDG-PET uptake and RECIST response (44). Intermediate results of two studies testing sunitinib in patients with thyroid carcinoma were presented at ASCO 2008 (45,46). The study of Cohen et al. presented data of 31 evaluable patients with DTC treated for at least two cycles with sunitinib. Of these patients 13% showed a PR and 65% of patients a SD. In MTC there have been no PRs reported, but a SD rate of 85% (45) In a mixed patient cohort with MTC, DTC and anaplastic thyroid carcinoma Ravaud et al.demonstrated in 15 evaluable patients a PR rate of 7% (n=1) and a SD rate of 80% (n=12) (46). In addition two case reports have been published, one reporting a PR in a patient with MTC and one in a patient with PTC treated with sunitinib (47,48).

Motesanib

The multi-tyrosine kinase inhibitor motesanib inhibits VEGFR, PDGFR, Kit and RET and demonstrated activity in TT tumor cell xenografts expressing the RET C634W protein (49). But there have also been reports indicating the ineffectiveness of motesanib in inhibiting the C634W mutant form of RET and being only active in wild type RET (50). Motesanib was tested in two phase II studies involving patients with thyroid cancer. One study which included 93 patients with confirmed locally advanced metastatic DTC or MTC yielded a 14% PR rate and a 68% SD rate. However none of the patients genetically analyzed showed a RET mutation or RET rearrangement in their tumor (51). Another phase II trial studying motesanib in MTC included 91 patients. In this trial only 2% of the patients were reported to have achieved a PR and 81% of the patients had a SD. The objective response rate for RET-mutation negative (n=10) and for RET-mutation positive (n=28) was 10% and 0%, respectively (50).

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