Potent RET Kinase Inhibitor Research Articles

Selpercatinib in non-MTC, RET-mutated tumors: Efficacy in MEN-associated and other tumors.

3150 Background: Selpercatinib, a first-in-class highly selective and potent RET kinase inhibitor with CNS activity, is approved in multiple countries for the treatment of RET-activated cancers. Current indications for RET mutant disease are limited to MTC. This analysis examined if selpercatinib was effective in non-MTC, RET mutation positive tumors and whether certain RET mutations demonstrated better activity (n=23; data cut-off: 13Jan2023). Methods: The phase 1/2 LIBRETTO-001 trial (NCT03157128) enrolled pts with locally advanced/metastatic RET-altered solid tumors, including pts with RET mutations in tumors other than MTC. Mutations must be known to be activating based on activity in MTC or other published evidence. Primary endpoint was objective response rate (ORR) by independent review committee (IRC). Secondary endpoints included ORR by investigator (INV), duration of response (DoR), progression-free survival (PFS), and safety. Results: Fourteen different tumor types were identified among the 23 pts with non-MTC RET-mutated tumors. This included 8 tumors from the Multiple Endocrine Neoplasia (MEN) syndrome spectrum; adrenal (pheochromocytoma; n=5), paraganglioma (n=2), neuroendocrine (n=1) (Table). Most of the mutations were located in extracellular cysteine-rich domain (CRD) and in the tyrosine kinase domain (TKD) of RET. In 23 efficacy-evaluable pts, confirmed ORR by IRC was 21.7% (5/23, 95% CI: 7.5, 43.7). ORR by IRC for pts with MEN-associated tumors (n=8) was 37.5% while five of these pts (62.5%) had stable disease lasting at least 16 weeks (SD16+). ORR by IRC for the sub-population with pheochromocytoma (n=5) was 40.0% and for pts with tumors manifesting RET extracellular cysteine mutations (n=5) was 60.0%. Of the 15 pts with non-MEN-associated tumors, 2 pts (8.7%; mutation in TKD) had a partial response (both with NSCLC adenocarcinoma, of which one had co-existent MTC). For the overall pts, the median DoR was 12.2 months (95% CI: 3.8, NE) and median PFS was 5.5 months (95% CI: 1.8, 19.4). No new safety signals were identified compared to previous reports. One grade 5 AE, general physical health deterioration, was observed and deemed by INV as not related to selpercatinib. Conclusions: This study suggests that RET-mutated, MEN-associated cancers (adrenal, paraganglioma, neuroendocrine) may benefit from selpercatinib treatment, which could be mediated through mutations in the extracellular CRD. The non-MTC RET-mutated tumor types appear not to derive benefit from selpercatinib. Clinical trial information: NCT03157128 . [Table: see text]

Durable efficacy of selpercatinib in patients with RET fusion+ solid tumors, with a focus on GI tumors: LIBRETTO-001.

746 Background: Selpercatinib, a first-in-class highly selective and potent RET kinase inhibitor with CNS activity, is approved in multiple countries for the treatment of RET-activated cancers. This update includes more patients (pts, n=52) and 16 months (mo) longer follow-up (data cut-off: 13Jan2023) in RET fusion+ solid tumors other than lung/thyroid with a focus on GI histologies. Methods: The phase 1/2 LIBRETTO-001 trial (NCT03157128) enrolled pts with locally advanced/metastatic RET fusion+ solid tumors. 51/52 pts received the recommended dose of 160 mg orally. The efficacy analysis set consisted of pts enrolled ≥6 months prior to the cut-off date. Primary endpoint was objective response rate (ORR) by independent review committee (IRC). Secondary endpoints included ORR by investigator (INV), duration of response (DoR), progression-free survival (PFS), and safety. Results: Of the 52 pts with RET-activated solid tumors other than lung or thyroid, 51.9% were female with a median age of 54.0 years. The majority (31/52) of patients had GI RET fusion+ tumor types, with pancreatic (N=13) and colorectal (N=13) as the most common (Table). 47 pts received prior systemic therapy (median prior lines: 2, range 0-9); 28.8% received ≥3 lines. In 52 efficacy-evaluable pts, confirmed ORR by IRC was 44.2% (23/52, 95% CI: 30.5, 58.7). ORR by IRC for pts with pancreatic tumors was 53.8% and for colorectal tumors was 30.8%. Clinical benefit (complete response + partial response + stable disease ≥16 weeks) was observed in 67.3% (35/52) of pts. Median DoR was 37.2 mo (95% CI: 13.3, NE) for overall pts (Table). No new safety signals were identified compared to previous reports. 4 grade 5 AEs were observed (unrelated to treatment by INV), and 2 pts discontinued due to treatment-related AEs per INV. Conclusions: Selpercatinib continued to demonstrate durable antitumor activity and tolerable safety in pts with RET fusion+ cancers across multiple tumor types and fusion partners, including difficult-to-treat GI cancers with poor results in standard-of-care options, such as pancreatic and colorectal. These results emphasize the importance of comprehensive genomic profiling across all tumor types in order to identify actionable oncogenic drivers, including RET fusions. Clinical trial information: NCT03157128 .[Table: see text]

1656P Durable efficacy of selpercatinib in patients (pts) with medullary thyroid cancer (MTC): Update of the LIBRETTO-001 trial

Selpercatinib, a first-in-class highly selective and potent RET kinase inhibitor with CNS activity, is approved in multiple countries for the treatment of RET-mutant MTC and RET fusion-positive thyroid and lung cancers. In the previous report, duration of response (DoR) and progression free survival (PFS) follow-up (f/u) was limited.

Tumor agnostic efficacy of selpercatinib in patients with RET fusion+ solid tumors: A global, multicenter, registrational trial update (LIBRETTO-001).

3094 Background: Selpercatinib, a first-in-class highly selective and potent RET kinase inhibitor, is approved in multiple countries for the treatment of lung and thyroid cancer with RET fusions and medullary thyroid cancer with RET mutations. We provide an efficacy and safety update with more patients (pts) and longer follow-up (data cut-off: 24Sep2021) in RET fusion+ solid tumors with histologies other than lung/thyroid. Methods: The phase 1/2 LIBRETTO-001 trial (NCT03157128) enrolled pts with locally advanced/metastatic RET fusion+ solid tumors. Following dose escalation, pts received the recommended dose of 160 mg orally twice daily. The efficacy analysis set consisted of pts enrolled ≥6 months (mo) prior to the cut-off date. If a pt achieved response, an additional ≥6 mo follow-up from the initial response was required. There was no additional follow-up required for non-responders. Response was assessed per RECIST 1.1. Primary endpoint was objective response rate (ORR) by independent review committee (IRC). Secondary endpoints included ORR by investigator (INV), duration of response (DoR), progression-free survival (PFS), time to response (TTR), and safety. Results: Forty-five pts with 14 unique RET fusion+ tumor types received ≥1 dose of selpercatinib: 12 pancreatic, 10 colon, 4 salivary, 3 unknown primary, 3 sarcoma, 2 each of breast, carcinoma of the skin, xanthogranuloma, and cholangiocarcinoma, and 1 each of lung carcinoid, rectal neuroendocrine, small intestine, ovarian, and pulmonary carcinosarcoma. Median age was 53 years (range 21-85). Forty-one pts received prior systemic therapy (median prior lines: 2, range 0-9); 31% received ≥3 lines. In 41 efficacy-evaluable pts, confirmed ORR by IRC was 44% (18/41, 95% CI: 29-60). Clinical benefit was observed in 63% (26/41) of pts: 2 complete responses (breast, small intestine), 16 partial responses, and stable disease ≥16 weeks in 8 pts by IRC. Responses were observed across a variety of fusion partners. Median TTR was 1.9 mo by IRC. Median DoR was 24.5 mo (95% CI: 9.2-NE) with 50% (9/18) of responses ongoing at a median follow-up of 14.9 mo by IRC. Median PFS by IRC was 13.2 mo (95% CI: 7.4-26.2), with 34.1% alive and progression-free at a median follow-up of 16.4 mo. No new safety signals were identified in this cohort compared to broader safety database. Three grade 5 AEs were observed (unrelated to treatment by INV), and 4 pts discontinued treatment due to AEs (1 deemed related to treatment by INV). Conclusions: Selpercatinib continued to demonstrate durable antitumor activity in pts with RET fusion+ cancers across multiple tumor types. No new safety signals were identified. These results emphasize the importance of comprehensive genomic profiling to identify actionable oncogenic drivers, including RET fusions. The LIBRETTO-001 study continues to enroll pts. Clinical trial information: NCT03157128.

Abstract CT011: Efficacy and safety of selpercatinib in RET fusion-positive cancers other than lung or thyroid cancers

Abstract Introduction: Selpercatinib, a first-in-class highly selective and potent RET kinase inhibitor, is approved in multiple countries for the treatment of RET fusion-positive lung or thyroid cancers. RET fusions are also implicated in the pathogenesis of other cancers. Selpercatinib's efficacy and safety were thus explored in patients (pts) with RET fusion-positive non-lung/non-thyroid cancers in a global, multicenter, registrational trial. Methods: Adults with locally advanced or metastatic RET fusion-positive non-lung/non-thyroid solid tumors enrolled in the phase 1/2 LIBRETTO-001 trial (NCT03157128) were included in this analysis (data cut-off: 19 March 2021). Following dose escalation, pts received the recommended dose of 160 mg orally, twice daily. Pts enrolled long enough to allow 6-month follow-up from their first dose comprised the efficacy-evaluable population. Response was assessed (RECIST 1.1) by investigators. The primary endpoint was objective response rate (ORR). Secondary endpoints included duration of response (DoR), time to response, and safety. Results: Thirty-two pts with RET fusion-positive non-lung/non-thyroid cancers included 12 unique tumor types: 9 pancreatic, 9 colon, 2 each of breast, salivary, sarcoma, and unknown primary, and 1 each of carcinoid, rectal neuroendocrine, small intestine, xanthogranuloma, ovarian, and pulmonary carcinosarcoma. The median age was 48 years (range 22-85). Twenty-nine pts received prior systemic therapy (median prior lines: 2, range 0-9). The ORR was 47% (N=15/32, 95% CI: 29-65). Objective responses were observed in 9 unique cancer types including colon, pancreatic, carcinoid, small intestine, salivary, xanthogranuloma, breast, ovarian, and sarcoma, and 5 additional patients had stable disease lasting ≥ 16 weeks. Median time to response was 1.9 months (range 0.7-7.3). Median DoR was not reached (median follow-up time of 13 months). Responses were ongoing in 73% (11/15) of pts. Safety among this population was consistent with the overall selpercatinib safety database. No patients in this cohort discontinued due to treatment-related AEs. Conclusion: Selpercatinib demonstrated promising antitumor activity in RET fusion-positive non-lung/non-thyroid cancers, including multiple treatment-refractory GI malignancies. Broad-based genomic profiling is essential to identify actionable oncogenic drivers, including RET fusions. The safety and efficacy of selpercatinib will continue to be explored in pts with these cancers in the ongoing LIBRETTO-001 study. Citation Format: Vivek Subbiah, Bhavana Konda, Todd Bauer, Caroline McCoach, Gerald Falchook, Masayuki Takeda, Jyoti Patel, Jared Weiss, Nir Peled, Lyudmila Bazhenova, Victoria Soldatenkova, Pearl French, Nora Drove, Oliver Gautschi, Alexander Drilon. Efficacy and safety of selpercatinib in RET fusion-positive cancers other than lung or thyroid cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr CT011.

Efficacy of selpercatinib after prior systemic therapy in patients with RET mutant medullary thyroid cancer.

6074 Background: Selpercatinib is a first-in-class, CNS active, highly selective, and potent RET kinase inhibitor which has demonstrated durable antitumor activity in patients (pts) with RET altered thyroid cancer and is approved in multiple countries for the treatment of RET fusion+ lung or thyroid cancers. As response rates to cancer therapy usually decline on subsequent lines of therapy, the efficacy of selpercatinib was examined in the context of the last prior therapy received before trial enrollment. Methods: Pts with RET mutant medullary thyroid cancer (MTC) previously treated with multikinase inhibitors (cabozantinib and/or vandetanib) were enrolled in the global LIBRETTO-001 trial (NCT03157128). This post-hoc exploratory intrapatient analysis, based on March 30, 2020 data cutoff date, was performed to compare the retrospective physician-reported objective response rate (ORR) from the last systemic therapy prior to enrollment, as reported in pts case reports, to ORR by independent review committee per RECIST 1.1 with selpercatinib treatment, with each patient serving as his/her own control. Results: Efficacy-evaluable pts, 64% male, 90% white with a median age of 58 years, received prior therapy for MTC (n = 143). Pts had a median of 2 (range 1-8) prior systemic regimens. The ORR on selpercatinib (69%) was markedly higher than for the last prior therapy (10%) received before enrollment. ORR improvements with selpercatinib were observed regardless of prior therapy: cabozantinib (66% vs 14%) or vandetanib (71% vs 12%). Fewer pts had progressive disease as their best overall response with selpercatinib (2/143; 1.4%) compared to last prior therapy (33/143; 23.1%). Notably selpercatinib achieved 62% ORR in pts that did not respond to their previous line of therapy prior to enrolment. This shift from non-responder to responder on selpercatinib therapy was consistent regardless of prior cabozantinib or vandetanib treatment, where pts achieved 57% and 61% ORR respectively when subsequently treated with selpercatinib. In contrast, only 3% of patients did not respond to selpercatinib after a previous response to the immediate prior therapy. Similarly, 5% and 2% of patients were non-responders on selpercatinib after a prior response with cabozantinib and vandetanib therapy respectively. Conclusions: Prior to selpercatinib, response with previous multikinase therapy was rare. By contrast, selpercatinib demonstrated robust efficacy regardless of response to or specific prior therapy in pts with RET mutant MTC. Clinical trial information: NCT03157128.

Identification of nicotinamide aminonaphthyridine compounds as potent RET kinase inhibitors and antitumor activities against RET rearranged lung adenocarcinoma

RET rearrangement is a recently identified oncogenic mutation in lung adenocarcinoma (LADC) that accounts for approximately 2% of all NSCLCs. More than six fusion partners have been identified in NSCLC, such as KIF5B, CCDC6, NCOA4, TRIM33, CLIP1 and ERC1. Many RET inhibitors have been reported and some have progressed to the clinic. Similar to most kinase inhibitors, patients often respond to current RET inhibitors but relapse can occur due to the emergence of mutant RET kinases, such as RET (S904F) and (V804L/M), which are resistant to inhibition. Our group previously reported that the benzamide aminonaphthyridine HSN356, a multikinase inhibitor, also inhibited RET. In this study, we prepared various nicotinamide analogs of HSN356 and investigated RET inhibition to uncover the salient moieties on HSN356 that are important for kinase inhibition and to also evaluate if HSN356 and analogs thereof could inhibit mutant RET kinases, such as RET (S904F) and (V804L/M). Compound 3 (HSN608), the nicotinamide analog of HSN356, inhibits RET and mutant forms better than reported RET inhibitors such as Alectinib, Sorafenib, Vandetanib and Apatinib, and comparable to BLU667. HSN608 inhibited the growth of CCDC6-RET driven LC-2/ad cell line with IC50 of ~3 nM. Under similar conditions, BLU667 and vandetanib (two drugs being evaluated against RET-driven cancers in the clinic) inhibited the growth of LC-2/ad with IC50 values of ~10 and 328 nM respectively.

The discovery of 2-substituted phenol quinazolines as potent RET kinase inhibitors with improved KDR selectivity

Deregulation of the receptor tyrosine kinase RET has been implicated in medullary thyroid cancer, a small percentage of lung adenocarcinomas, endocrine-resistant breast cancer and pancreatic cancer. There are several clinically approved multi-kinase inhibitors that target RET as a secondary pharmacology but additional activities, most notably inhibition of KDR, lead to dose-limiting toxicities. There is, therefore, a clinical need for more specific RET kinase inhibitors. Herein we report our efforts towards identifying a potent and selective RET inhibitor using vandetanib 1 as the starting point for structure-based drug design. Phenolic anilinoquinazolines exemplified by 6 showed improved affinities towards RET but, unsurprisingly, suffered from high metabolic clearance. Efforts to mitigate the metabolic liability of the phenol led to the discovery that a flanking substituent not only improved the hepatocyte stability, but could also impart a significant gain in selectivity. This culminated in the identification of 36; a potent RET inhibitor with much improved selectivity against KDR.

Abstract 4761: Glial cell derived neurotrophic factor (GDNF)-RET signaling as a target in aromatase inhibitor resistant ER-positive breast cancers.

Abstract The majority of breast cancers are estrogen receptor (ER)-positive and depend on estrogen for growth and survival. Blockade of estrogen biosynthesis by aromatase inhibitors (AIs) is the first-line endocrine therapy for post-menopausal women with ER-positive breast cancers. Despite providing substantial improvements in patient outcome, resistance to such therapy remains a major clinical challenge. We previously showed that GDNF-RET signaling plays an important role in ER-positive breast tumors and in the response to tamoxifen treatment. Resistance to this therapy is often associated with estrogen-independent activation of ER mediated by cell surface growth factor receptors, such as RET. Here, a multidisciplinary strategy was used to address the impact of GDNF-RET signaling in the response to AI treatment. First, using 2D and 3D in vitro approaches we show that GDNF-mediated RET signaling is enhanced in a model of AI resistance. Further, GDNF-RET signaling promotes the survival of AI-resistant cells and increases resistance in AI-sensitive cells, effects that are selectively reverted by a potent RET kinase inhibitor. Second, we generated a proliferation-independent GDNF-response gene set, identified from gene expression profiling in ER-positive breast cancer cells, and demonstrated this to be an independent prognostic marker of poor patient outcome and, importantly, to be predictive of poor response to AI treatment and development of resistance. Finally, the relevance of these findings was validated by demonstrating increased RET protein expression levels in an independent cohort of AI resistant patient samples. Together these preclinical and clinical models identify GDNF-RET signaling as a key determinant of response and resistance to AIs in ER-positive breast cancers. As a consequence, RET inhibition may be of use in the clinical setting either in combination with an AI to prevent and delay the onset of resistance, or to prolong the efficacy of the AI in the recurrent and/or metastatic setting. Citation Format: Andrea Morandi, Lesley-Ann Martin, Qiong Gao, Alan Mackay, David Robertson, Marketa Zvelebil, Mitch Dowsett, Ivan Plaza-Menacho, Clare M. Isacke. Glial cell derived neurotrophic factor (GDNF)-RET signaling as a target in aromatase inhibitor resistant ER-positive breast cancers. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4761. doi:10.1158/1538-7445.AM2013-4761

ChemInform Abstract: The Discovery of Substituted 4‐(3‐Hydroxyanilino)‐quinolines as Potent RET Kinase Inhibitors.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

The discovery of substituted 4-(3-hydroxyanilino)-quinolines as potent RET kinase inhibitors

Substituted 4-(3-hydroxyanilino)-quinoline compounds, initially identified as small-molecule inhibitors of src family kinases, have been evaluated as potential inhibitors of RET kinase. Three compounds, 38, 31, and 40, had K i’s of 3, 25, and 50 nM in an in vitro kinase assay; while a cell based kinase assay showed K i’s of 300, 100, and 45 nM, respectively. These compounds represent potential new leads for the treatment of medullary and papillary thyroid cancer.