Selective RET Inhibitors Research Articles

Abstract CT160: Safety of selpercatinib for RET-altered advanced solid tumors: a post hoc analysis of LIBRETTO-001

Abstract Introduction: Selpercatinib, approved by FDA in May 2020 is a highly selective and potent RET inhibitor which has demonstrated antitumor activity in patients (pts) with RET-altered non-small-cell lung cancer and thyroid cancer. To further characterize clinical safety, we analyzed the timing of selected treatment-emergent adverse events (TEAEs) as well as long-term use of selpercatinib. Methods: Pts with RET-fusion positive or RET-mutant tumors who received at least 1 dose of selpercatinib, as part of the LIBRETTO-001 study, were included in this analysis (data-cut off 19 Dec 2019; NCT 03157128). Median time to onset, dose reduction, and discontinuation due to TEAEs were evaluated for relevant common TEAEs (≥25% of pts) and TEAEs of special interest. TEAE data were also analyzed according to time exposed to treatment at cutoff (<12 or ≥12 months). Results: A total of 702 pts were included in the analysis and 99% experienced ≥1 TEAE (any grade). At cutoff, median time on treatment was 8.7 mo, with 78% continuing to receive selpercatinib. Common TEAEs and TEAEs of interest are summarized (median time to onset, dose reduction, and discontinuation due to TEAEs) in the table. 466 (66.4%) pts received treatment for <12 months, whereas 236 (33.6%) pts received treatment for ≥12 months. Similar rates of grade ≥3 TEAEs were observed across the two exposure groups, 271 (58.2%) pts and 145 (61.4%) pts on treatment for <12 months and ≥12 months, respectively. 138 (29.6%) pts on treatment <12 months and 81 (34.3%) pts on treatment ≥12 months underwent dose reductions due to TEAEs. 32 (6.9%) pts on treatment <12 months and 5 (2.1%) pts on treatment ≥12 months discontinued treatment due to TEAEs. Conclusion: Most TEAEs had a median onset within the first month of treatment, with TEAEs minimally impacting a patient's ability to receive selpercatinib. In these analyses, no new safety concerns were identified in patients on treatment for <12 months or ≥12 months. Relevant TEAEs of interest by decreasing frequency in any grade in ≥25% of patients and TEAEs of interest (N = 702)TEAE(consolidated terms)Any Grade TEAEn (%)Median time (weeks) to first occurrence (range)Leading to dose reductionn (%)Leading to drug discontinuationn (%)Dry Mouth273 (38.9)2.9 (0.1-107.9)5 (0.7)0 (0.0)Diarrhea257 (36.6)8.0 (0.1-99.9)11 (1.6)0 (0.0)Hypertension252 (35.9)History of hypertension114 (39.4)2.5 (0.1-83.0)5 (1.7)0 (0.0)No history of hypertension138 (33.4)2.2 (0.1-60.0)4 (1.0)0 (0.0)AST increased210 (29.9)4.1 (0.1-111.1)39 (5.6)2 (0.3)ALT increased201 (28.6)4.1 (0.1-79.7)45 (6.4)3 (0.4)Constipation178 (25.4)4.4 (0.1-90.4)2 (0.3)0 (0.0)QTc Prolongation118 (16.8)3.5 (0.1-92.0)16 (2.3)0 (0.0)Hypersensitivity30 (4.3)1.7 (0.9-77.0)20 (2.8)3 (0.4)Rash191 (27.2)9.3 (0.1-110.4)15 (2.1)1 (0.1)Edema242 (34.5)9.8 (0.1-109.9)7 (1.0)0 (0.0)Fatigue246 (35.0)5.4 (0.1-9918 (2.6)2 (0.3)N, number of subjects in the population; n, number of subjects in the specified category; TEAE, treatment-emergent adverse event. AST, aspartate transaminase; ALT, alanine aminotransferase; QTc, corrected QT. Citation Format: Todd M Bauer, Benjamin Besse, Herbert H F Loong, Bruce Robinson, Victoria Soldatenkova, Catherine Elizabeth Muehlenbein, Bente Frimodt-Moller, Caroline E McCoach. Safety of selpercatinib for RET-altered advanced solid tumors: a post hoc analysis of LIBRETTO-001 [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 CT160.

Pralsetinib for patients with advanced or metastatic RET-altered thyroid cancer (ARROW): a multi-cohort, open-label, registrational, phase 1/2 study

Oncogenic alterations in RET represent important therapeutic targets in thyroid cancer. We aimed to assess the safety and antitumour activity of pralsetinib, a highly potent, selective RET inhibitor, in patients with RET-altered thyroid cancers. ARROW, a phase 1/2, open-label study done in 13 countries across 71 sites in community and hospital settings, enrolled patients 18 years or older with RET-altered locally advanced or metastatic solid tumours, including RET-mutant medullary thyroid and RET fusion-positive thyroid cancers, and an Eastern Co-operative Oncology Group performance status of 0-2 (later limited to 0-1 in a protocol amendment). Phase 2 primary endpoints assessed for patients who received 400 mg once-daily oral pralsetinib until disease progression, intolerance, withdrawal of consent, or investigator decision, were overall response rate (Response Evaluation Criteria in Solid Tumours version 1.1; masked independent central review) and safety. Tumour response was assessed for patients with RET-mutant medullary thyroid cancer who had received previous cabozantinib or vandetanib, or both, or were ineligible for standard therapy and patients with previously treated RET fusion-positive thyroid cancer; safety was assessed for all patients with RET-altered thyroid cancer. This ongoing study is registered with clinicaltrials.gov, NCT03037385, and enrolment of patients with RET fusion-positive thyroid cancer was ongoing at the time of this interim analysis. Between Mar 17, 2017, and May 22, 2020, 122 patients with RET-mutant medullary and 20 with RET fusion-positive thyroid cancers were enrolled. Among patients with baseline measurable disease who received pralsetinib by July 11, 2019 (enrolment cutoff for efficacy analysis), overall response rates were 15 (71%) of 21 (95% CI 48-89) in patients with treatment-naive RET-mutant medullary thyroid cancer and 33 (60%) of 55 (95% CI 46-73) in patients who had previously received cabozantinib or vandetanib, or both, and eight (89%) of nine (95% CI 52-100) in patients with RET fusion-positive thyroid cancer (all responses confirmed for each group). Common (≥10%) grade 3 and above treatment-related adverse events among patients with RET-altered thyroid cancer enrolled by May 22, 2020, were hypertension (24 patients [17%] of 142), neutropenia (19 [13%]), lymphopenia (17 [12%]), and anaemia (14 [10%]). Serious treatment-related adverse events were reported in 21 patients (15%), the most frequent (≥2%) of which was pneumonitis (five patients [4%]). Five patients [4%] discontinued owing to treatment-related events. One (1%) patient died owing to a treatment-related adverse event. Pralsetinib is a new, well-tolerated, potent once-daily oral treatment option for patients with RET-altered thyroid cancer. Blueprint Medicines.

Clinical activity and safety of the RET inhibitor pralsetinib in patients with RET fusion-positive solid tumors: Update from the ARROW trial.

3079 Background: RET fusions are targetable oncogenic drivers in multiple solid tumor types. ARROW study (NCT03037385) data supported the US FDA approval of pralsetinib, a once-daily (QD) oral highly potent and selective RET inhibitor, for RET-altered metastatic non-small cell lung cancer (NSCLC) and advanced/metastatic thyroid cancer. Here we provide an update on the clinical activity of pralsetinib in patients (pts) with advanced RET fusion-positive solid tumors other than NSCLC and thyroid cancer (“other” RET fusion–positive solid tumors). Methods: The global ongoing ARROW study (84 sites in 13 countries) includes phase 1 dose-escalation (30–600 mg [QD or twice daily]) and phase 2 expansion cohorts (400 mg QD) defined by tumor type and RET alteration status. Primary objectives are overall response rate (ORR; blinded independent central review per RECIST v1.1) and safety. Results: Updated analyses were completed as of Nov 6, 2020 (data cut-off) for 21 pts with other RET fusion–positive solid tumors enrolled by May 22, 2020 (enrollment cut-off) (lung other than NSCLC, n = 4; pancreatic, n = 3; colon, n = 3; cholangiocarcinoma, n = 3; unknown primary [UP], n = 2; other, n = 6). Overall, 11 (52%) pts received ≥2 prior lines of therapy for metastatic disease. The most common RET fusion partners were CCDC6 and KIF5B (24% each), NCOA4 (19%), other (10%), and unknown (24%). Two pts with colon cancer were excluded from efficacy analyses due to other driver mutations ( KRAS, PIK3CB). In 19 evaluable pts, ORR was 53% (95% CI, 29–76) with 2 (11%) complete responses (CR) and 8 (42%) partial responses (PR). Responses occurred across multiple tumor types including 3/3 pts with pancreatic cancer (including a CR ongoing at 20.8 months on treatment), 2/2 pts with UP, 2/3 pts with cholangiocarcinoma, and in pts with mesenchymal, salivary duct, and lung carcinoid tumors. Median duration of response was 19.0 months (95% CI, 5.5–not estimable). Clinical benefit rate (proportion with CR, PR, or stable disease persisting ≥16 weeks) was 68% (95% CI, 43–87). Tumor shrinkage was observed in 89% of 18 evaluable pts with post-baseline tumor assessment. In all pts enrolled in ARROW who received pralsetinib 400 mg QD irrespective of tumor type (n = 471) the most common (≥25%) treatment-related adverse events (TRAEs) were increased aspartate aminotransferase (39%), anemia (35%), increased alanine aminotransferase (28%), constipation (26%), and hypertension (25%). Overall, 6% of pts discontinued treatment due to TRAEs. Conclusions: Pralsetinib showed robust, durable antitumor activity in patients with multiple RET fusion‒positive, heavily pre-treated, advanced solid tumors, and was well tolerated. These data highlight the need for broad RET testing to identify candidates who could benefit from treatment with pralsetinib. Enrollment of patients with other RET fusion–positive solid tumors in ARROW is ongoing. Clinical trial information: NCT03037385.

Prognostic factors in RET dependent cancers treateded with RET inhibitors in early phase clinical trials.

3117 Background: Activation of the RET proto-oncogene has been identified in multiple cancer types, for example, gene rearrangements in non-small cell lung cancer (NSCLC) and papillary thyroid cancer (PTC) and activating mutations in medullary thyroid cancer (MTC), amongst others. The recent FDA approval of two highly selective RET inhibitors, selpercatinib and pralsetinib has changed the treatment paradigm of RET-driven cancers, but the significance of historical prognostic factors is unknown. Herein, we analyzed the outcomes of patients with RET-altered cancers enrolled in phase I trials and assess the utility of prognostic scores. Methods: A retrospective analysis was performed of patients treated with selective RET inhibitors at the MD Anderson Cancer Center (MDACC). Baseline clinical factors and survival data were assessed. Overall and progression free survival (OS and PFS) were estimated using the Kaplan-Meier method and multivariable Cox models were constructed. For all a p-value of < 0.05 was consider significant. Results: Among 126 patients, median age was 58 years (range, 15-82), most with ECOG 0-1 (n = 124). RET-mutant MTC was most frequent (n = 81), followed by RET fusion-positive NSCLC (n = 30) and RET fusion positive thyroid cancer (n = 9). RET fusion partners were KIF5B (n = 17), CCD6 (n = 12) and NCOA4 (n = 7). RET M918T mutation was the most frequent (n = 50, 63%). Most patients were treated in the relapsed/refractory (R/R) setting (n = 85) and received a median of 1 prior line of therapy (range, 0-11). Median follow up was 20 months (range, 1-43). The estimated median PFS and OS were 24 and 35 months, respectively. Overall objective response rate was 64% (81/126), 2 complete response, 79 partial response, 32 had stable disease (25%) and 13 had progressive disease (PD). The following were associated with shorter PFS and OS: age ≥50 years (p < 0.05), albumin < 4 g/dL (p < 0.01), brain metastases (p < 0.0001), hemoglobin < 12 g/dL ( < 0.05), LDH > normal (p < 0.05), WBC ≥8 (p < 0.01), PD (p < 0.0001) and NSCLC (p < 0.01). The M918T mutation and ECOG > 0 were associated with shorter OS but not PFS (p < 0.05). > 3 metastatic sites and R/R disease were associated with inferior PFS (p = 0.04 and p = 0.01, respectively) but not OS. The Royal Marsden Hospital (RMH) and MDACC prognostic scores were significantly associated with PFS and OS (p < 0.01). In multivariable models including all variables significantly associated with PFS and OS (excluding LDH as this was only tested in 58 patients) albumin < 4 (HR 6.10, p = 0.013), brain metastases (HR 4.90, p = 0.027) and WBC ≥8 (HR 4.67, p = 0.031) were associated with inferior OS. NSCLC was significantly associated with inferior PFS (HR 5.45, p = 0.02). Conclusions: The RMH and MDACC prognostic scores predict OS in RET-aberrant cancers treated on early phase trials. Low albumin, WBC > 8 and brain metastases are significantly associated with inferior survival.

Addition of selpercatinib to overcome osimertinib resistance in non-small cell lung cancer (NSCLC) with acquired RET fusion detected in ctDNA at very low allele frequency.

3046 Background: Osimertinib, a highly selective third generation EGFR tyrosine kinase inhibitor (TKI) became the standard front-line therapy for EGFR-mutant NSCLC. However, therapeutic options are limited for TKI resistance which commonly occurs. Therefore, overcoming acquired resistance to osimertinib remains an important high unmet need in the field of precision oncology. Herein, we present the first case of advanced adenocarcinoma of the lung that showed notable response with the addition of selpercatinib after acquired resistance to osimertinib monotherapy. Methods: Case presentation. Results: A 37-year-old woman with stage IVB adenocarcinoma of lung with osseous, hepatic and brain metastases initially received one cycle of carboplatin, pemetrexed and pembrolizumab. Based on the EGFR exon19 deletion detected from ctDNA NGS assay (Guardant 360) [variant allele frequency (VAF) 62.7%], the treatment regimen was changed to osimertinib monotherapy (80mg PO daily). Bevacizumab was empirically added given CNS involvement. She maintained overall stable disease for 10 months before subsequent CT showed disease progression. The treatment regimen was switched to atezolizumab, bevacizumab, paclitaxel and carboplatin combination therapy. She tolerated 6 cycles of the regimen in 4 month before a subsequent brain MRI revealed progression of the metastatic brain disease with new leptomeningeal disease. Whole brain radiotherapy was performed and decision was made to start combination TKI treatment of selpercatinib (120mg BID) added to the osimertinib (80mg daily) monotherapy based on her repeat ctDNA NGS assay result showing concurrent acquired CCDC6RET fusion (VAF 0.05%) and EGFR exon 19 deletion (VAF 10.0%). The 6 week follow-up CT demonstrated significant decrease in the largest lung mass (33.95*24.22mm->32.50*16.07mm). Repeat ctDNA NGS assay at one week after selpercatinib use showed disappearance of RET fusion and significant decrease in EGFR clone (VAF 10.0% to 0.05%). Conclusions: It has been reported that co-occurring RET fusions in NSCLC patients with EGFR mutations may contribute to acquired resistance to EGFR inhibitors. Several successful cases of cabozantinib, a non-selective RET inhibitor, or pralsetinib, a selective RET inhibitor combined with EGFR inhibitor, have been reported to aid in overcoming the acquired resistance to EGFR inhibitors. To date, there has been no report of clinical benefit in adding a RET inhibitor based on ctDNA detection of RET fusion with minute variant allele frequency. We for the first time report the case of overcoming acquired resistance to osimertinib by adding selpercatinib, a selective RET inhibitor in NSCLC patients with acquired RET fusion detected in ctDNA at VAF of 0.05%.

Safety and efficacy of pralsetinib in patients with advanced RET fusion-positive non-small cell lung cancer: Update from the ARROW trial.

9089 Background: RET fusions are targetable oncogenic drivers in 1–2% of non-small cell lung cancer (NSCLC). ARROW (NCT03037385) supported the US FDA approval of pralsetinib, a highly potent oral selective RET inhibitor for RET-altered NSCLC and thyroid cancer. Here, we present updated results for a larger population of patients with RET fusion–positive NSCLC enrolled in ARROW. Methods: ARROW is a phase 1/2 open-label study conducted at 84 sites in 13 countries. Phase 2 expansion cohorts included patients with RET fusion–positive NSCLC. Initially, all treatment-naïve patients were not candidates for platinum-based therapy, a requirement removed by protocol amendment in July 2019. Primary objectives are overall response rate (ORR; blinded independent central review [BICR] per RECIST v1.1), assessed for patients with baseline measurable disease, and safety. Results: Updated analyses were completed as of Nov 6, 2020 (data cut-off), for patients who initiated pralsetinib 400 mg QD by May 22, 2020 (enrollment cut-off). Efficacy results, including analyses for treatment-naïve patients enrolled after eligibility criteria were revised to allow candidates for platinum-based therapy, are shown in the Table. Conclusions: Pralsetinib showed rapid, potent, and durable clinical activity in patients with RET fusion-positive NSCLC (regardless of prior therapies), including poor prognosis patients not eligible for platinum-based therapy. Overall, pralsetinib was well-tolerated. These data highlight the need for RET testing early in the course of disease to identify candidates who may benefit from treatment with pralsetinib. Clinical trial information: NCT03037385. [Table: see text]

A pooled analysis of response to selective RET inhibitors among patients with medullary thyroid cancer with M918T versus non-M918T RET mutations.

6078 Background: Medullary thyroid cancer (MTC) accounts for 1 to 2% of thyroid cancers in the United States; RET alterations occur in >95% of hereditary and 50% of sporadic forms. Up to 80% of patients with sporadic MTC have somatic M918T RET mutations, which is associated with poor prognosis (1). The tyrosine kinase inhibitors (TKIs) cabozantinib and vandetanib are approved to treat patients with MTC regardless of RET status; however, retrospective analyses have suggested that there may be greater benefit in patients with M918T mutations (1,2). Newly approved therapies selpercatinib and pralsetinib, developed for patients with RET mutations, have demonstrated higher response rates than previous first line therapies. In this analysis, we examine the differences in overall response rate (ORR) between patients with MTC with RET M918T non- RET M918T mutations. Methods: An analysis of ORR in patients with MTC with RET M918T mutations with non-M918T mutations was conducted using the efficacy populations used to support the approvals of pralsetinib and selpercatinib using the following groups: Patients who received prior cabozantinib or vandetanib (referred to as “previously treated”). Patients with no prior cabozantinib or vandetanib (“TKI naïve”). All patients regardless of prior therapy. Results: Exploratory analysis of ORR of pooled population of Selpercatinib and Pralsetinib in patients with MTC with RET M918T mutations and non-M918T mutations. 1 Prior vandetanib or cabozantinib. 2 No prior vandetanib or cabozantinib. Two groups of patients were analyzed ( RET M918T mutation and RET non-M918T mutation), with subgroups with respect to prior treatment. Among all patients regardless of prior therapy, the ORR was similar between M918T non-M918T groups. Among previously treated patients, the ORR was lower in the M918T group vs. the non-M918T group, while in the TKI naïve group the ORR was higher in the M918T groups vs the non-M918T group although the 95% CIs overlap in both comparisons. Conclusions: There were no major differences in ORR among mutational subtypes in patients with MTC treated with RET inhibitors, regardless of prior therapy. ORR was similar between patients with M918T and non-M918T mutations. Additional experience in ongoing clinical studies may provide additional data regarding responses across specific mutation types.

Clinical Activity of Selpercatinib in RET Mutant Pheochromocytoma-Case Reports

Activating RET gene alterations have been reported in solid tumors including the rare cancer, pheochromocytoma (PHEO) found sporadically and in familial multiple endocrine neoplasia type 2 (MEN2) syndromes. Selpercatinib is a highly selective and potent small molecule RET kinase inhibitor that has demonstrated marked and durable anti-tumor activity in diverse RET-altered solid tumors. Described are the initial 3 PHEO patients treated with selpercatinib (LIBRETTO-001/NCT03157128). Case 1: 70-year-old white male with MEN2A and a history of medullary thyroid cancer (MTC) and PHEO s/p thyroidectomy and adrenalectomy, received MIBG in 1991 and 2016 due to symptom reoccurrence. Progressive metastatic disease associated with severe hypertension was treated with Lutate in 2017 and germline RET mutation p.Cys634Phe was confirmed. After developing severe back pain due to a T6 vertebral metastasis, he began selpercatinib treatment. As of Mar 2020, he has a partial response (PR) as assessed by investigator; his back pain resolved, normetanephrine and metanephrine levels decreased, and has ceased alpha and beta blockers. He remains on treatment with only grade 1-2 adverse events, none requiring interruption or dose modification. Case 2: 51-year-old white female with MEN2A and history of MTC and PHEO s/p thyroidectomy and adrenalectomy in 2010. She developed metastatic PHEO in 2013, with multiple bone, omentum, lung, liver, and spleen metastases. Between 2013 and 2018 she was treated with multiple courses of radiation and, additional surgical resections; a PR with sunitinib lasted 13 months followed by temozolomide/capecitabine treatment. A bone lesion biopsy in 2018 confirmed RET C618S mutation and with her disease progression and uncontrolled bone pain, she began selpercatinib treatment, experiencing a PR. After 5.5 months in the study, she discontinued treatment due to disease progression. Case 3: 45-year-old African American female diagnosed with sporadic PHEO in 1996, s/p multiple surgical resections. She received 2 cycles of cyclophosphamide/vincristine/dacarbazine without clinical benefit. I-131-MIBG therapy with autologous stem cell rescue in 2017 improved blood pressure, palpitations, and flushing but without tumor shrinkage while abdominal pain persisted. Somatic M918T RET-mutation was confirmed, and she began selpercatinib treatment in 2018 with symptom resolution and improved plasma metanephrine levels. She required dose reduction for grade 3 palmar-plantar erthrodysesthesia and had stable disease for 22 months until a new bone metastasis was identified. Due to ongoing clinical benefit, she remains on treatment despite disease progression. Conclusion: These are the initial reports of RET-mutant PHEO patients treated with selpercatinib adding to the diversity of RET-altered tumor types that may benefit from a selective RET inhibitor.

Paraneoplastic Eosinophilia (PNE): A Rare Finding in a Patient With Metastatic Medullary Thyroid Carcinoma

Abstract Introduction: Medullary thyroid cancer (MTC) is a rare tumor of neuroendocrine origin that co-secretes various peptides leading to diarrhea and vasodilation. Ectopic Cushing syndrome due to production of adrenocorticotropic or corticotrophin-releasing hormone is a well-recognized but uncommon paraneoplastic manifestation of advanced MTC. We report an extremely rare presentation of eosinophilia in a patient with MTC that correlated with disease progression. Case: A 58-year-old woman with sporadic metastatic MTC harboring somatic RET M918T mutation developed metastatic disease to the liver, lung and bones 2 years after surgery for locally advanced disease. Calcitonin (Ctn) was 123 pg/ml and CEA was 2575 ng/ml. At that time, leukocytosis [WBC 30.8 K/ul (4-11k/ul)] and eosinophilia [eosinophil count 16.01 k/ul (0.04-0.40 k/ul)] were noted. She was asymptomatic. Extensive evaluation of hypereosinophilia ruled out hematological or infectious causes. The patient initiated vandetanib with a partial response (PR) with decrease in lung and liver metastases and a significant improvement of the paraneoplastic eosinophilia [eosinophil count 2.39 k/ul] after 10 weeks of treatment. After a year on treatment, there was progressive disease (PD) with increasing hilar and abdominal lymphadenopathy associated with increased eosinophilia of 4.34 K/ul. Vandetanib was discontinued. She was enrolled on a clinical trial with a highly potent and selective RET inhibitor. The patient achieved PR to study drug by the 2nd month on treatment and durable response for 30 months. The eosinophil count normalized [0.32 k/ul] 4 weeks after starting the new treatment. She developed PD in liver metastases associated with recurrent leukocytosis (WBC 58.6 K/ul) and eosinophilia of 28.13 K/ul. Ctn was 1646 pg/ml. CEA was 8722 ng/ml. Her bone marrow biopsy showed marked eosinophilia, focal MTC metastatic infiltrate, no increased blasts, and was negative for the BCR-ABL1 translocation and the FIP1L1-PDGFRA fusion. She was switched to a different RET Inhibitor but passed away 1 month after starting the new protocol. Discussion: Paraneoplastic eosinophilia should be considered after excluding other causes (e.g. infections, allergy, collagen, vascular or malignant hematopoietic diseases). Thyroid tumors producing colony-stimulating factors, associated with neutrophilia and/or eosinophilia have been described almost exclusively in patients with anaplastic thyroid cancer. This patient had a poorly differentiated MTC as evidenced by the disproportionally high CEA relative to Ctn. The course of the eosinophilia paralleled the clinical behavior of her disease. To our knowledge, this is only the 2nd report of eosinophil trends corresponding with MTC disease course, consistent with a paraneoplastic process. Conclusion: PNE is very rare in MTC and its presence suggests a poor prognosis.

An early look at selective RET inhibitor resistance: new challenges and opportunities.

Two RET inhibitors, selpercatinib and pralsetinib, recently received approval for the treatment of advanced RET fusion-positive lung cancer. Acquired resistance to these inhibitors will be a major challenge. We have shown that resistance can emerge due to recurrent RET kinase domain mutations and, in most cases, due to RET-independent mechanisms.

Chasing the Target: New Phenomena of Resistance to Novel Selective RET Inhibitors in Lung Cancer. Updated Evidence and Future Perspectives

Simple SummaryREarranged during Transfection (RET) is an emerging target for several types of cancer, including non-small cell lung cancer (NSCLC). The recent U.S. FDA approval of pralsetinib and selpercatinib raises issues regarding the emergence of secondary mutations and amplifications involved in parallel signaling pathways and receptors, liable for resistance mechanisms. The aim of this review is to explore recent knowledge on RET resistance in NSCLC in pre-clinic and in clinical settings and accordingly, the state-of-the-art in new drugs or combination of drugs development.The potent, RET-selective tyrosine kinase inhibitors (TKIs) pralsetinib and selpercatinib, are effective against the RET V804L/M gatekeeper mutants, however, adaptive mutations that cause resistance at the solvent front RET G810 residue have been found, pointing to the need for the development of the next-generation of RET-specific TKIs. Also, as seen in EGFR- and ALK-driven NSCLC, the rising of the co-occurring amplifications of KRAS and MET could represent other escaping mechanisms from direct inhibition. In this review, we summarize actual knowledge on RET fusions, focusing on those involved in NSCLC, the results of main clinical trials of approved RET-inhibition drugs, with particular attention on recent published results of selective TKIs, and finally, pre-clinical evidence regarding resistance mechanisms and suggestion on hypothetical and feasible drugs combinations and strategies viable in the near future.

P87.04 Chemotherapy and Immunotherapy Outcomes of RET-Rearranged Lung Cancers: A Case Series

RET rearrangement is detected in 1% to 2% of lung adenocarcinomas. RET fusions correlate with adenocarcinoma histologic subtype, never-smoking status, younger age, more advanced disease stage. Prior studies have reported potential higher chemosensitivity and low response to immunotherapy. Given the rarity of these tumors, the natural history, and the role of chemotherapy and immunotherapy in the context of new selective RET inhibitors is still being defined. We performed a retrospective review of RET-rearranged lung cancer cases treated at the University of Miami from 2013 to 2020. RET rearrangements were identified using targeted next-generation sequencing of DNA (FoundationOne or Caris). Clinicopathologic characteristics and response to chemotherapy and immunotherapy were analyzed. PFS was defined as the time from therapy initiation to radiologic progression or death. Overall survival (OS) was defined as time from diagnosis of metastatic disease to death. For PFS, and OS analyses, Kaplan-Meier curves were compared using the Mantel-Cox log-rank test. A total of 15 patients with a median age of 64 (range 50-83) were identified in a cohort of 617 sequenced lung cancers (representing a prevalence of 2.4%). There were 9 women; 11 never smokers; 1 light smoker (<1pack/day) and 3 former smokers (>1pack/day). The patients came from a diverse background (7 Non-Hispanic whites, 5 Hispanics, 1 Asian, 2 African Americans). The majority of cases had adenocarcinoma histology and KIF5B-RET fusions (n=14)). In 10 patients with sufficient tissue for PD-L1testing, PD-L1 expression was 0%, low (1-49%), and high (50% or greater) in 50% (n=5 of 10), 10% (n=1 of 10), and 40% (n=4 of 10) of cases, respectively. Twelve patients (80%) presented with metastatic disease and three (20%) with locally advanced disease. The most common sites of metastases were lung (15), followed by bone (10), brain (6), malignant pleural effusion (6), and liver (3). The median overall survival was 33 months (range 6 to 87). Five out of six patients with malignant pleural effusion had prolonged survival greater than 32 months. Eleven patients received platinum-based chemotherapy and 7 patients received immunotherapy during their course of treatment. Nine patients who received platinum-pemetrexed chemotherapy in the first line setting had prolonged responses with a median PFS of 19 months (range 5-53 mos), while those who received immunotherapy (n=6) had lower median PFS of 9 months (range 4-13 mos). Three patients with tumors that showed high PDL1 expression responded to immunotherapy for an average of 10 months. RET-rearranged lung cancer in our series presented with adenocarcinoma, never smoking status, younger age and advanced disease. PFS after treatment with pemetrexed based chemotherapy in RET cases was longer than after immunotherapy. However, no patients in this series received combination chemotherapy and immunotherapy which is currently a standard of care. Unlike prior reports, patients with RET arranged lung cancers and high PDL1 expression responded to immunotherapy in this series. More data is needed to define the role of chemotherapy and immunotherapy in the context of new selective RET inhibitors.

FP14.07 Combination Osimertinib plus Selpercatinib for EGFR-mutant Non-Small Cell Lung Cancer (NSCLC) with Acquired RET fusions

Selpercatinib is a highly selective and potent FDA-approved RET inhibitor that has demonstrated marked and durable efficacy in RET fusion-positive NSCLC. While RET fusions are the primary oncogenic driver in ∼2% of NSCLC, RET fusions have also been identified as acquired resistance alterations following treatment with EGFR inhibitors, including osimertinib, in EGFR-mutant NSCLC. We sought to evaluate the safety and preliminary efficacy of the combination of osimertinib and selpercatinib in patients progressing on osimertinib. Patients received selpercatinib in combination with osimertinib across three selpercatinib compassionate access programs: single patient protocols (SPP), named patient programs (NPPs), and an expanded access program (EAP). All patients had advanced EGFR-mutated NSCLC with a RET fusion detected from tissue or plasma following osimertinib therapy. Clinicopathologic and outcomes data were collected retrospectively. Across 12 patients identified, 11 had an EGFR exon 19 deletion (92%) and one had an EGFR L858R mutation (8%). The most common emergent RET fusion was CCDC6-RET (five patients, 42%), followed by NCOA4-RET (four patients, 33%), KIF5B-RET (two patients, 17%), and RUFY2-RET (one patient, 8%). All patients had received prior osimertinib and seven (58%) had also received a 1st or 2nd generation EGFR TKI. Most patients received selpercatinib at 80 mg BID (92%, range 100 mg QD - 120 mg BID) and osimertinib at 80 mg daily (75%, range 40 mg QD - 80 mg BID). Of twelve identified patients, 10 were evaluable for response per RECIST 1.1. Among RECIST evaluable patients five had a response (50%, four confirmed partial responses, one unconfirmed partial response). One patient, unevaluable per RECIST for non-measurable disease at baseline, demonstrated sustained clinical radiographic improvement ongoing at 8.2 months. The second unevaluable patient discontinued treatment prior to reassessment for unrelated clinical events preventing oral medication administration. The median duration of combination treatment across all 12 identified patients was 7.4 months (range 0.6 – 16.7+ months). For patients who achieved a RECIST response, the median treatment duration was 11 months (range 7.4 – 16.7+ months). Treatment was discontinued due to disease progression in seven patients, one patient discontinued for toxicity (grade 2 pneumonitis), one patient for intolerance to oral medication administration, and three patients remained on therapy at data cut-off. In one patient with a response lasting 10 months, plasma sequencing at resistance revealed persistence of EGFR 19del (22% AF) and RET fusion (0.4% AF) plus newly detected second-site resistance mutations in both EGFR (C797S, 0.1%) and RET (G810S, 0.8%), providing additional confirmation of the biologic relevance of the acquired RET fusion. For patients with EGFR-mutant NSCLC with an acquired RET fusion as a mechanism of EGFR inhibitor resistance, the addition of selpercatinib to osimertinib was feasible, with evidence of radiographic responses and durable benefit. These findings support future investigation of this combination, which will be evaluated prospectively as an arm of the phase 2 ORCHARD platform study (NCT03944772). The availability of active combination targeted therapy strategies highlights the need for assessment for genomic mechanisms of resistance following initial EGFR targeted therapy in NSCLC.

Molecular-Driven Therapy in Advanced Thyroid Cancer.

With a growing understanding of the biologic drivers of different thyroid cancers, there is an ongoing revolution in the treatment of aggressive and advanced disease variants. This includes matching patients with specific point mutations or gene fusions to targeted therapies (e.g., selective RET inhibitors), delineating patients who are likely to respond to immune checkpoint inhibition (i.e., PD-L1-positive tumors) and even priming responses to traditional therapies such as radioactive iodine (via concomitant MAPK pathway inhibition). There is also a growing role for genomics in the prognostication of thyroid tumors to aid the adjudication of appropriate treatments. Taking stock of the current state of the field, recent successes should be celebrated, but there still remains a long road ahead to improve outcomes for patients, particularly for radioactive-iodine refractory differentiated thyroid cancer and anaplastic thyroid cancer. In this review, we summarize findings from recent clinical trials and highlight promising preclinical data supporting molecular-driven therapy in advanced thyroid cancer. Ultimately, enrollment in clinical trials remains paramount to the advancement of thyroid cancer care.

Clinical activity of the RET inhibitor pralsetinib (BLU-667) in patients with RET fusion–positive solid tumors.

467 Background: Recent tumor-agnostic drug approvals have resulted in a paradigm shift in cancer treatment away from organ/histology specific indications to biomarker-guided tumor-agnostic approaches. Pralsetinib is a potent and selective RET inhibitor, which has recently been approved by the U.S. Food and Drug Administration (FDA) for the treatment of adults with metastatic RET fusion–positive non-small cell lung cancer (NSCLC) and is under New Drug Application review for RET mutant thyroid cancers by the FDA. RET fusions occur in up to approximately 7‒8% of patients with gastrointestinal malignancies, including pancreatic, liver, and colorectal cancers. There are currently no approved selective RET inhibitors for patients with RET fusion–positive solid tumors other than NSCLC and thyroid cancer. Here, we present data on the clinical activity of pralsetinib in patients with RET fusion–positive solid tumor types other than NSCLC enrolled in the Phase I/II ARROW study (NCT03037385). Methods: ARROW consists of a phase I dose escalation (30–600 mg once [QD] or twice daily) followed by a phase II expansion (400 mg QD) in patients with advanced RET-altered solid tumors. Primary objectives are overall response rate (ORR), per RECICT v1.1 and safety. Results: A total of 13 patients with RET fusion–positive thyroid cancer (12 papillary, 1 poorly differentiated; enrollment cutoff July 11, 2019) and 14 patients with RET fusion–positive solid tumors other than NSCLC and thyroid (3 pancreatic, 3 colon, 2 cholangiocarcinoma, 6 other; enrollment cutoff November 19, 2019) were enrolled in ARROW and received pralsetinib. At the February 13, 2020, data cutoff, the ORR (blinded central review) in response-evaluable patients with RET fusion–positive thyroid cancer was 91% (10/11; 95% CI: 59‒100) and disease control rate was 100% (95% CI: 72‒100). Treatment was ongoing in 7 of 11 patients. In RET fusion–positive solid tumors other than NSCLC and thyroid, ORR (investigator’s assessment) was 50% (6/12; 95% CI: 21‒79) and responses were observed in all patients with pancreatic cancer (3/3) and cholangiocarcinoma (2/2). Treatment was ongoing in 6 of 12 patients, including 2 of 3 patients with pancreatic cancer and 1 of 2 patients with cholangiocarcinoma. Responses were observed across multiple fusion genotypes. In the 27 patients with RET fusion–positive tumors other than NSCLC, most frequent treatment-related adverse events (TRAEs) were grade 1–2, and included anemia (33%), increased aspartate aminotransferase (33%), decreased white blood cell count (33%), hypertension (30%), increased alanine aminotransferase (26%), hyperphosphatemia (19%), and neutropenia (19%). No patients discontinued due to TRAEs. Conclusions: Pralsetinib demonstrated broad and durable antitumor activity across multiple advanced solid tumor types, regardless of RET fusion genotype, and was well tolerated. The study is ongoing. Clinical trial information: NCT03037385.

Characteristics and outcomes of patients with RET-fusion positive non-small lung cancer in real-world practice in the United States

BackgroundContradictory and limited data are available about the presentation and outcomes of patients with RET-fusion positive metastatic NSCLC as compared to patients without RET fusions. This observational study utilizing a linked electronic health records (EHR) database to genomics testing results was designed to compare characteristics, tumor response, progression-free (PFS) and overall survival (OS) outcomes by RET fusion status among patients with metastatic NSCLC treated with standard therapies.MethodsAdult patients with metastatic NSCLC with linked EHR and genomics data were eligible who received systemic anti-cancer therapy on or after January 1, 2011. Adjusted, using all available baseline covariates, and unadjusted analyses were conducted to compare tumor response, PFS and OS between patients with RET-fusion positive and RET-fusion negative disease as detected by next-generation sequencing. Tumor response outcomes were analysed using Fisher’s exact test, and time-to-event analyses were conducted using Cox proportional hazards model.ResultsThere were 5807 eligible patients identified (RET+ cohort, N = 46; RET- cohort, N = 5761). Patients with RET fusions were younger, more likely to have non-squamous disease and be non-smokers and had better performance status (all p < 0.01). In unadjusted analyses, there were no significant differences in tumor response (p = 0.17) or PFS (p = 0.06) but OS was significantly different by RET status (hazard ratio, HR = 1.91, 95% CI:1.22–3.0, p = 0.005). There were no statistically significant differences by RET fusion status in adjusted analyses of either PFS or OS (PFS HR = 1.24, 95% CI:0.86–1.78, p = 0.25; OS HR = 1.52, 95% CI: 0.95–2.43, p = 0.08).ConclusionsPatients with RET fusions have different baseline characteristics that contribute to favorable OS in unadjusted analysis. However, after adjusting for baseline covariates, there were no significant differences in either OS or PFS by RET status among patients treated with standard therapy prior to the availability of selective RET inhibitors.

PUL01.02 AcceleRET Lung: A Phase 3 Study of First-Line Pralsetinib in Patients with RET-Fusion+ Advanced/Metastatic NSCLC

RET gene fusions have been identified as oncogenic drivers in multiple tumor types, including 1–2% of non-small cell lung cancer (NSCLC). The investigational oral RET inhibitor, pralsetinib, potently and selectively targets oncogenic RET alterations, including those that confer resistance to multi-kinase inhibitors. In the registration-enabling phase 1/2 study (ARROW; NCT03037385), patients with RET-fusion+ NSCLC treated with pralsetinib 400 mg once daily (QD) after platinum-based chemotherapy (n=80) achieved an overall response rate (ORR) of 61% (95% CI 50, 72; two responses pending confirmation) per independent central review. In addition, an ORR of 73% (all centrally confirmed responses) was attained in the systemic treatment naïve cohort (n=26). Most treatment-related adverse events were grade 1–2 across the entire safety population treated with pralsetinib 400 mg QD (N=354). AcceleRET Lung, an international, open-label, randomized, phase 3 study, will evaluate the efficacy and safety of pralsetinib versus standard of care (SOC) in first-line treatment of advanced/metastatic RET fusion+ NSCLC (NCT04222972). This abstract was previously submitted to and presented at the American Society of Clinical Oncology 2020 annual meeting (May 29 to June 2, 2020). Approximately 250 patients with advanced/metastatic RET-fusion+ NSCLC will be randomized 1:1 to pralsetinib 400 mg QD or SOC (non-squamous histology: platinum/pemetrexed ± pembrolizumab followed by maintenance pemetrexed ± pembrolizumab; squamous histology: platinum/gemcitabine). Stratification factors include intended use of pembrolizumab, history of brain metastases, and Eastern Cooperative Oncology Group Performance Status 0 vs 1. Key eligibility criteria include no prior systemic treatment for advanced/metastatic NSCLC; RET-fusion+ tumor by local or central assessment, no additional actionable oncogenic drivers, no prior treatment with a selective RET inhibitor, and measurable disease per RECIST v1.1. Cross-over to receive pralsetinib upon disease progression will be permitted for patients randomized to SOC. The primary endpoint is progression-free survival (blinded independent central review; RECIST v1.1). Secondary endpoints include ORR, overall survival, duration of response, disease control rate, clinical benefit rate, time to intracranial progression, intracranial ORR, safety/tolerability, and quality of life. Recruitment has begun with sites (active or planned) in North America, Europe, Asia, and Australia.

Selpercatinib in RET fusion-positive non-small-cell lung cancer (SIREN): a retrospective analysis of patients treated through an access program.

Introduction:Rearranged during transfection (RET) gene fusions are rare genetic drivers in non-small cell lung cancer (NSCLC). Selective RET-inhibitors such as selpercatinib have shown therapeutic activity in early clinical trials; however, their efficacy in the real-world setting is unknown.Methods:A retrospective efficacy and safety analysis was performed on data from RET fusion-positive NSCLC patients who participated in a selpercatinib access program (named patient protocol) between August 2019 and January 2021.Results:Data from 50 patients with RET fusion-positive advanced NSCLC treated with selpercatinib at 27 centers in 12 countries was analyzed. Most patients were Non-Asian (90%), female (60%), never-smokers (74%), with a median age of 65 years (range, 38–89). 32% of the patients had known brain metastasis at the time of selpercatinib treatment. Overall, 13 patients were treatment-naïve, while 37 were pretreated with a median of three lines of therapy (range, 1–8). The objective response rate (ORR) was 68% [95% confidence interval (CI), 53–81] in the overall population. The disease control rate was 92%. The median progression-free survival was 15.6 months (95% CI, 8.8–22.4) after a median follow-up of 9 months. In patients with measurable brain metastases (n = 8) intracranial ORR reached 100%. In total, 88% of patients experienced treatment-related adverse events (TRAEs), a large majority of them being grade 1 or 2. The most common grade ⩾ 3 TRAEs were increased liver enzyme levels (in 10% of patients), prolonged QTc time (4%), abdominal pain (4%), hypertension (4%), and fatigue/asthenia (4%). None of patients discontinued selpercatinib treatment for safety reasons. No new safety concerns were observed, nor where there any treatment-related death.Conclusions:In this real-world setting, the selective RET-inhibitor selpercatinib demonstrated durable systemic and intracranial antitumor activity in RET fusion-positive NSCLC and was well tolerated.

Determination of selpercatinib, a RET kinase inhibitor, in rat plasma and its application to a pharmacokinetic study.

Selpercatinib (LOXO-292) is a selective and potent RET inhibitor. A highly sensitive, rapid and specific high-performance liquid chromatography with tandem mass spectrometry (LC-MS/MS) method for quantification of selpercatinib in rat plasma is reported. The method was validated in terms of selectivity, linearity, accuracy and precision, extraction recovery and matrix effect, stability and carryover as per the US Food and Drug Administration guidelines for bioanalytical method validation. Selpercatinib was detected by an electrospray ionization interface under selective reaction monitoring conditions in the positive ion mode. The calibration curve was linear over the concentration range from 1 to 2000 ng/ml with r2 = 0.9951. The intra- and inter-batch accuracy values ranged from 97.45 to 100.97% and from 98.70 to 100.74% with coefficients of variation of 2.45-6.99% and 5.89-7.99%, respectively. The extraction recovery and IS-normalized matrix factor were acceptable for the bioanalysis of selpercatinib. Additionally, selpercatinib was found to be stable under the detected conditions. It showed linear pharmacokinetic characteristics following oral administration to rats at 2.0-18.0 mg/kg. The results showed that the novel method for detecting selpercatinib in rat plasma could be successfully applied for quantification of selpercatinib in biosamples from nonclinical studies.

Decade in review: a new era for RET-rearranged lung cancers

Targeted therapy has become the standard of care for non-small cell lung cancers with a range of targetable alterations, including ALK and ROS1 kinase fusions. RET fusions drive the oncogenesis of 1–2% of NSCLCs and represent a substantial global burden of disease. Although these fusions were first identified more than thirty years ago, targeted therapy for RET fusion-positive lung cancers was only explored in the last decade. Whereas repurposed multikinase inhibitors were initially tested, selective inhibitors RET inhibitors have dramatically improved outcomes for patients whose tumors harbor these alterations. In 2020, the US Food and Drug Administration approved selpercatinib, a selective RET inhibitor, for adults with lung and thyroid cancers with RET rearrangements or mutations, making it the first targeted therapy to be approved for RET-altered cancers. While resistance to selective RET inhibition has been described, next-generation RET inhibitors are already being explored for patients who progress on prior RET kinase inhibitors.