Fusion-positive Non-small Cell Lung Cancer Research Articles

72P Pan-tumor survey of RET fusions as detected by next-generation RNA sequencing identified RET+ colorectal carcinoma as a unique molecular subset of CRC

Two selective RET tyrosine kinase inhibitors have been approved to treat RET fusion-positive (RET+) non-small cell lung cancer and well-differentiated thyroid cancer. However, RET fusions have been reported in other solid tumors.

105P Pan-tumor survey of ROS1 fusions detected by next-generation RNA sequencing

Two ROS1 tyrosine kinase inhibitors have been approved for ROS1 fusion-positive (ROS1+) non-small cell lung cancer (NSCLC). We performed a pan-tumor analysis of the incidence and characteristics of ROS1 fusions across all solid tumors.

Safety and efficacy of pralsetinib in RET fusion–positive non-small-cell lung cancer including as first-line therapy: update from the ARROW trial

RET fusions are present in 1%-2% of non-small-cell lung cancer (NSCLC). Pralsetinib, a highly potent, oral, central nervous system-penetrant, selective RET inhibitor, previously demonstrated clinical activity in patients with RET fusion-positive NSCLC in the phase I/II ARROW study, including among treatment-naive patients. We report an updated analysis from the ARROW study. ARROW is a multi-cohort, open-label, phase I/II study. Eligible patients were ≥18 years of age with locally advanced or metastatic solid tumours and an Eastern Cooperative Oncology Group performance status of 0-2 (later 0-1). Patients initiated pralsetinib at the recommended phase II dose of 400 mg once daily until disease progression, intolerance, consent withdrawal, or investigator's decision. The co-primary endpoints (phase II) were overall response rate (ORR) by blinded independent central review and safety. Between 17 March 2017 and 6 November 2020 (data cut-off), 281 patients with RET fusion-positive NSCLC were enrolled. The ORR was 72% [54/75; 95% confidence interval (CI) 60% to 82%] for treatment-naive patients and 59% (80/136; 95% CI 50% to 67%) for patients with prior platinum-based chemotherapy (enrolment cut-off for efficacy analysis: 22 May 2020); median duration of response was not reached for treatment-naive patients and 22.3 months for prior platinum-based chemotherapy patients. Tumour shrinkage was observed in all treatment-naive patients and in 97% of patients with prior platinum-based chemotherapy; median progression-free survival was 13.0 and 16.5 months, respectively. In patients with measurable intracranial metastases, the intracranial response rate was 70% (7/10; 95% CI 35% to 93%); all had received prior systemic treatment. In treatment-naive patients with RET fusion-positive NSCLC who initiated pralsetinib by the data cut-off (n= 116), the most common grade 3-4 treatment-related adverse events (TRAEs) were neutropenia (18%), hypertension (10%), increased blood creatine phosphokinase (9%), and lymphopenia (9%). Overall, 7% (20/281) discontinued due to TRAEs. Pralsetinib treatment produced robust efficacy and was generally well tolerated in treatment-naive patients with advanced RET fusion-positive NSCLC. Results from the confirmatory phase III AcceleRET Lung study (NCT04222972) of pralsetinib versus standard of care in the first-line setting are pending.

LIBRETTO-432, a phase III study of adjuvant selpercatinib or placebo in stage IB-IIIA RET fusion-positive non-small-cell lung cancer.

Selpercatinib, a first-in-class, highly selective and potent central nervous system-active RET kinase inhibitor demonstrated clinically meaningful activity with manageable toxicity in pretreated and treatment-naive advanced/metastatic RET fusion-positive non-small-cell lung cancer (NSCLC). LIBRETTO-432 is a global, randomized, double-blind, phase III trial evaluating selpercatinib versus placebo in stage IB-IIIA, RET fusion-positive NSCLC, previously treated with definitive surgery or radiation; participants must have undergone available anti-cancer therapy (including chemotherapy or durvalumab) or not be suitable for it, per investigator's discretion. The primary end point is investigator-assessed event-free survival (EFS) in the primary analysis population (stage II-IIIA RET fusion-positive NSCLC). Key secondary end points include EFS in the overall population, overall survival, and time to distant disease recurrence in the central nervous system.

Selective RET inhibitors shift the treatment pattern of RET fusion-positive NSCLC and improve survival outcomes

PurposeRearranged during transfection (RET) fusions are important genetic drivers in non-small cell lung cancer (NSCLC). Selective RET inhibitors are setting a new paradigm in RET-driven NSCLC. However, the real-world treatment patterns, outcomes and toxicity remain largely unknown.MethodsData from RET fusion-positive NSCLC patients treated in our centre were retrospectively analysed. Of them, patients diagnosed before and after August 2018 were included in analysis of treatment patterns; and patients received selective RET inhibitors were eligible for analysis of adverse events (AEs).ResultsPatients diagnosed before August 2018 (n = 30) predominantly received chemotherapy and immunotherapy (83%) as initial therapy, while patients diagnosed after August 2018 (n = 39) mainly received selective RET inhibitors (38.5% at first-line; 50.0% at second-line). In the total 69 patients, overall survival (OS) was prolonged in patients treated with selective RET inhibitors versus untreated patients (median 34.3 versus 17.5 months; p = 0.002) during a median follow-up of 28.7 months. But there was no difference between patients treated with immunotherapy versus untreated patients. In the 38 patients received selective RET inhibition, median progression-free survival (PFS) was 11.9 months. AEs ≥ grade 3 occurred in 42.1% patients and were not associated with PFS (p = 0.63) or OS (p = 0.60). Haematological toxicity ≥ grade 3 occurred in 31.6% patients and was the leading cause of drug discontinuation.ConclusionSelective RET inhibitors are increasingly being adopted into clinical practice and are associated with improved OS. However, treatment-related ≥ grade 3 AEs, especially haematologic AEs, occur frequently in real-world setting.

Selpercatinib in RET-fusion positive metastatic non-small cell lung cancer: achievements and gray areas

ABSTRACT Introduction Selpercatinib is a RET selective tyrosine kinase inhibitor with nanomolar potency against diverse RET alterations, including fusions, activating point mutations, and acquired resistance mutations. Rearranged during transfection (RET) gene is a validated target in non-small-cell lung cancer (NSCLC). Selpercatinib is currently approved for adult patients with metastatic RET fusion-positive NSCLC. Areas covered This review summarizes the efficacy and safety data of selpercatinib in the treatment landscape of RET fusion-positive NSCLC. Expert opinion Globally considered, selpercatinib is an optimal treatment choice, in terms of both (systemic and intracranial) efficacy and safety, in patients affected by advanced NSCLC harboring RET fusions as a driver mechanism. Future challenges include the identification of the most appropriate placement for selpercatinib in the treatment algorithm of RET fusion-positive NSCLC (including early stages), the clarification of resistance mechanisms, as well as of its role in EGFR-mutant NSCLC undergoing progression during osimertinib driven by RET alterations.

Abstract 403: Analysis of RET solvent front mutations shows an effect on protein activity in tumor cells

Abstract The rearranged during transfection (RET) gene encodes a receptor tyrosine kinase that is involved in the activation of several signal transduction pathways. Various RET fusions and point mutations were shown to play a role as oncogene drivers in different cancers. In 2020, two selective RET tyrosine kinase inhibitors (TKIs), pralsetinib and selpercatinib, were approved by the FDA for treatment of RET fusion-positive non-small cell lung cancer, RET-mutant medullary thyroid cancer and RET fusion-positive thyroid cancer. These drugs demonstrate a significant advance in efficacy and safety over previous, multi-targeted TKIs for the treatment of RET-positive patients. However, development of acquired resistance to these agents has been observed through the appearance of on-target secondary solvent front mutations in the RET G810 residue. Moreover, 5 different types of amino acid changes - G810A/C/R/S/V have been identified in this position, of which G810C, G810R and G810S are better characterized but their effect on protein activity is lacking. We used a high-throughput functional assay, in which the mutated protein is expressed together with a fluorescently labeled reporter in a cell-based assay. Using this system, we systematically assessed the activity of different combinations of RET fusions or oncogenic point mutations with one of three different common solvent front mutations and compared them to the activity of the individual mutations. Our results show that when a solvent front mutation is expressed on a RET oncogenic point mutation background, the solvent front mutation consistently decreases the oncogenic protein activity. This is supported by our observation that the individual solvent front mutations expressed on a RET WT background show an activity that is lower than that of the RET WT protein. On a RET fusion background the effect of solvent front mutations is more variable, with some RET fusion-solvent front mutation combinations showing a decreased activity and some not affecting the activity of the fusion protein. Across all mutations and fusions tested, the G810R and G810C mutations had a larger effect on RET activity than that of the G810S mutation. We also compared the effect of drug treatment (pralsetinib and selpercatinib) on RET oncogenic activity in the presence of the different solvent front mutations and observed that on all mutational backgrounds tested, the solvent front mutations have an effect on the response dynamics to the drug, and that the extent of the effect depends on the type of solvent front mutation, with G810R and G810C decreasing sensitivity to drug treatment to a larger extent compared to G810S. Together, our findings provide a better understanding of the differential effects of solvent front mutations on RET activity under different oncogenic contexts. Citation Format: Shay Rotkopf, DIkla Haham, Lea Birnbaum, Zohar Barbash, Gabi Tarcic. Analysis of RET solvent front mutations shows an effect on protein activity in tumor cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 403.

Abstract 1100: miR205 mediates acquired resistance to ALK inhibition via targeting Mig6 expression and enhancing EGFR signaling

Abstract Complete responses to ALK tyrosine kinase inhibitors (TKIs) are rare and resistance eventually develops in ALK fusion-positive non-small cell lung cancer patients. To overcome resistance and improve therapeutic outcomes, it is crucial to understand the molecular mechanisms contributing to resistance. Our lab has previously shown EGFR signaling mediates adaptive resistance to ALK inhibitors. We demonstrated that RNA and protein levels of Mig6, an endogenous protein inhibitor of EGFR, were suppressed rapidly following ALK inhibition, thus unlocking EGFR from inhibition to support cell survival. In this study, we asked whether EGFR signaling activation and Mig6 suppression persist once acquired resistance is established. An EML4-ALK cell line, H3122, was continuously exposed to a fixed dose of the ALK inhibitor crizotinib to generate three resistant lines (H3122-CR1, -2, and -3). All H3122-CR lines lacked ALK kinase mutations and were also cross-resistant to other ALK TKIs including ceritinib and alectinib. We found phosphorylation and total EGFR were upregulated while Mig6 protein was attenuated across all resistant lines compared to their parental counterpart. Afatinib, a pan-ERBB family inhibitor, or Mig6 overexpression, was able to re-sensitize those resistant cells to ALK inhibition. Interestingly, we did not find Mig6 overexpression altered phosphorylation of EGFR. Previously reported data suggest that Mig6 competes with Shc1, a critical signaling adapter shared by ALK and EGFR, for the same substrate-binding cleft on EGFR. We then hypothesized Mig6 could block EGFR-Shc1 binding and downstream signaling transduction without directly impacting EGFR phosphorylation. Indeed, the co-immunoprecipitation assay showed Mig6 knockdown in H3122 cells enhanced Shc1 binding to EGFR without altering phosphorylation of EGFR itself, suggesting a novel mechanism in regulating EGFR signaling by impairing the signaling adapter binding. We then investigated the mechanism responsible for Mig6 protein attenuation in resistant lines. By examining the RNA-seq data for all the CR lines compared to the parental H3122, we found MIR205HG was substantially upregulated in resistant cells. MIR205HG is the host gene for miR-205, which was known to target ERRFI1 gene that encodes Mig6. Stem-loop RT-qPCR confirmed that miR-205 was increased ~5 fold in all CR lines. Overexpressing miR-205 in H3122 cells could downregulate Mig6 expression in a dose-dependent manner. Herein we presented a novel resistance mechanism to ALK inhibition by which miR205 upregulation attenuates Mig6 expression, releasing EGFR-Shc1 signaling transduction from inhibition to support cell survival. This study also provides additional support for targeting EGFR signaling to overcome ALK TKI resistance to improve patient survival. Citation Format: Nan Chen, Robert C. Doebele. miR205 mediates acquired resistance to ALK inhibition via targeting Mig6 expression and enhancing EGFR signaling [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1100.

Abstract 5351: LTK mutations responsible for resistance to lorlatinib in non-small cell lung cancer harboring CLIP1-LTK fusion

Abstract Background: CLIP1-LTK was recently discovered as a novel oncogenic gene fusion in non-small cell lung cancer (NSCLC). Lorlatinib, an ALK/ROS1 inhibitor, can inhibit CLIP1-LTK constitutive kinase activity, and showed dramatic and promising efficacy in a patient with NSCLC harboring CLIP1-LTK fusion. However, acquired resistance to lorlatinib will be inevitably developed, especially by mutations in LTK gene, as 50-60% of oncogenic driver-positive NSCLC develop resistance to kinase inhibitors by acquired mutations in the target gene. The aim of this study is to identify the LTK mutations responsible for resistance to lorlatinib in CLIP1-LTK fusion positive NSCLC, and to explore compounds that can overcome resistance. Methods: As LTK and ALK share nearly 80% protein sequence identity in their respective kinase domains, we established Ba/F3 cells expressing CLIP1-LTK (Ba/F3-CLIP1-LTK) with six different LTK mutations (I565N, F568C, L590M, L592F, G596R, and G663A), all of which are analogous to reported ALK mutations responsible for resistance to lorlatinib. Ba/F3 cells expressing CLIP1-LTK with these different LTK mutations, as well as CLIP1-LTK-wild type (WT) were treated with several concentrations of lorlatinib. Then, the efficacy of other compounds including crizotinib, alectinib, ceritinib, brigatinib, entrectinib, giltertinib, repotorectinib was assessed to detect which compounds can overcome lorlatinib resistance. Results: All LTK mutations tested showed resistance to lorlatinib, with IC50s of lorlatinib ranging 2.7 to 31.3 nM, which were higher than that in Ba/F3-CLIP-LTK-WT (1.0 nM) in cell viability assay. An IC50 of giltertinib in Ba/F3-CLIP1-LTK-F568C was lower than that of lorlatinib (0.9 vs 2.7 nM). Moreover, an IC50 of giltertinib in Ba/F3-CLIP1-LTK-G663A was lower than that of lorlatinib (2.7 vs 19.4 nM). Ba/F3-CLIP1-LTK-L592F was rather sensitive to crizotinib compared with Ba/F3-CLIP1-LTK-WT (IC50, <0.1 vs 16.5 nM). Similarly, Ba/F3-CLIP1-LTK-G596R was similar to repotorectinib compared with WT (IC50, 10.4 vs 11.3 nM). The results of western blotting assay evaluating phosphorylation of CLIP1-LTK were in accordance with that obtained cell viability assay. Conclusion: We identified that several LTK mutations, analogous to ALK resistant mutations, were responsible for lorlatinib resistance, some of which can be overcome by existing compounds. Further validation and exploration are warranted to establish resistance mechanism-based precision medicine following lorlatinib treatment in CLIP1-LTK fusion-positive NSCLC. Citation Format: Shunta Mori, Hiroki Izumi, Jie Liu, Kosuke Tanaka, Shogo Kumagai, Takuma Hayashida, Yosuke Kagawa, Yuji Shibata, Shingo Matumoto, Koichi Goto, Susumu Kobayashi. LTK mutations responsible for resistance to lorlatinib in non-small cell lung cancer harboring CLIP1-LTK fusion [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5351.

Abstract 5239: Switching inhibitor class overcomes crizotinib resistance in a MET fusion-positive NSCLC with a novel acquired MET G1090A mutation

Abstract Purpose: MET fusions are oncogenic drivers of multiple cancers including non-small cell lung cancer (NSCLC). While MET fusion-positive tumors can be sensitive to MET tyrosine kinase inhibitors (TKI), to date no mechanisms of TKI resistance have been identified or characterized for MET fusion-positive disease. Experimental Design: Serial targeted genomic sequencing (MSK-IMPACT) was performed in clinical samples from a MET fusion-positive NSCLC treated with the type Ia MET TKI crizotinib. Structural modeling and in vitro kinase assays were used to characterize crizotinib resistance and to test the activity of MET inhibitors with alternative binding modes. Results: A novel MET G1090A resistance mutation was identified in a patient with a CD47-MET-rearranged NSCLC after crizotinib progression. In silico structural modeling and simulations indicated that the 2,6-dichloro-3-fluorophenyl moiety present on crizotinib directly binds to the side chain of the Y1230 residue in the activation loop of the MET wild type (WT) kinase. In the MET G1090A mutant kinase, the position of the Y1230 residue is predicted to be flipped roughly 180°. As a result, the interaction between crizotinib and Y1230 is compromised; this in turn is predicted to reduce crizotinib’s binding affinity for the mutant kinase. Similar results were obtained when MET WT and G1090A mutant kinases were modeled in complex with selective type Ib MET TKI (i.e., capmatinib, savolitinib and tepotinib). Conversely, we found that type II agents (i.e., cabozantinib and foretinib) were not predicted to interact with Y1230. Therefore, their binding affinity to the mutant MET kinase was predicted to be retained. In vitro kinase assays performed using titrations of crizotinib and capmatinib (representative type I agents) and of cabozantinib (representative type II agent) showed that all three TKI were active against the MET WT kinase (calculated IC50 of 2.5nM, 3.89nM and 1.59nM, respectively). However, the calculated IC50 for crizotinib and capmatinib were 6.04- and 48.4-fold higher than the calculated IC50 for cabozantinib against the MET G1090A mutant kinase. Consistent with the prediction of type II inhibitor activity, the patient was transitioned to cabozantinib. A marked clinical, radiographic, and metabolic response was observed. Conclusions: In MET fusion-positive cancers, the novel MET G1090A resistance mutation drives resistance to type I MET kinase inhibition. Drug binding mode switching to type II MET inhibition overcomes preclinical and clinical resistance, highlighting the need for further rational type II inhibitor development. Citation Format: Yonina R. Murciano-Goroff, Srinivasaraghavan Kannan, Jason C. Chang, Ryma Benayed, Ilya Blokhin, Natasha Rekhtman, Ann Elizabeth Sisk, Jaime Gibson, Lia Judka, Lauren Kaplanis, Madeline Merrill, Erica Sgroe, Chandra S. Verma, Alexander Drilon, Emiliano Cocco. Switching inhibitor class overcomes crizotinib resistance in a MET fusion-positive NSCLC with a novel acquired MET G1090A mutation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5239.

LIBRETTO-001 cohort 7: A single-arm, phase 2 study of neoadjuvant selpercatinib in patients with resectable stage IB-IIIA RET fusion-positive NSCLC.

TPS8594 Background: Despite definitive surgery and perioperative chemotherapy, many patients with locoregional non-small cell lung cancer (NSCLC) continue to experience recurrent disease and limited survival. Although targeted therapies are standard treatment for metastatic NSCLC with genomic alterations, their use in the early-stage setting is still being characterized. Initial studies examining targeted therapy in neoadjuvant setting for early-stage epidermal growth factor receptor positive NSCLC has shown promise. Selpercatinib is a highly selective, potent, and central nervous system active rearranged during transfection (RET) inhibitor with demonstrated robust and sustained antitumor activity and manageable toxicity in patients with RET fusion-positive advanced NSCLC. Cohort 7 of the Phase 2, open-label, single arm LIBRETTO-001 study evaluates efficacy and safety of neoadjuvant selpercatinib in patients with resectable stage IB-IIIA RET fusion-positive NSCLC (NCT03157128). Methods: Key eligibility criteria include age ≥18 years; histologically confirmed stage IB–IIIA NSCLC (AJCC, version 8); presence of RET fusion in tumor (by PCR or NGS) or blood (by NGS) (pre-treatment biopsy confirmed); resectable and operable tumor; measurable disease (RECIST 1.1); and ECOG performance status 0-1. Key exclusion criteria include presence of other known oncogenic drivers; and concurrent investigational anticancer therapy. Eligible patients will undergo full staging including radiographic tumor measurements using CT, PET, and brain MRI at baseline and after two 28-day cycles of neoadjuvant selpercatinib, followed by surgery. Dosing regimen is 160 mg twice daily. Resected tumor specimens will be sent to an Independent Pathology Review Committee (IPRC) for evaluation. Patients may then be treated with stage-appropriate adjuvant therapy/surveillance, based on the treating physician’s decision, followed by selpercatinib until disease recurrence, unacceptable toxicity, withdrawal, or death, for a maximum treatment duration of 3 years. The primary endpoint is to determine the rate of major pathologic response (MPR) by IPRC, defined as ≤ 10% residual viable tumor cells in the surgically resected specimen. Efficacy based on the MPR will be assessed using the Simon's 2-stage design. In Stage I, 9 patients will be enrolled; if ≤1 patient achieves an MPR, the study will be stopped. Otherwise, at least 10 additional patients will be enrolled, with a total of 19 patients undergoing surgery. The rate of pathologic complete response (pCR) by IPRC, disease-free survival, and overall survival will be assessed as secondary endpoints. pCR rate will be determined at the time of surgery, indicating no remaining viable tumor cells. Safety of peri-operative treatment will be assessed, including 30- and 90-day post-operative readmission and mortality rates. Clinical trial information: NCT03157128.

Central nervous system (CNS) outcomes and progression patterns in patients with RET fusion-positive lung cancers treated with selpercatinib.

3109 Background: Selpercatinib, a potent/selective RET inhibitor, is approved for the treatment of RET fusion-positive non-small cell lung cancers. While the drug is known to have substantial intracranial activity (intracranial ORR 82%) in patients with existing brain metastases, (1) central nervous system (CNS) outcomes in patients without brain metastases and (2) CNS progression patterns in patients with brain metastases have not been explored. Methods: Patients with advanced RET fusion-positive lung cancers were prospectively treated with selpercatinib on the registrational LIBRETTO-001 trial (NCT03157128) or the LIBRETTO-201 multi-center expanded access program (EAP, NCT03906331). Key overall and CNS eligibility criteria were previously presented. Patients with and without pre-selpercatinib brain metastases who underwent serial CNS and extracranial imaging were eligible for analysis. The data cutoff was November 24, 2020. Cumulative incidence rates (CIRs) were calculated using a competing risk model with systemic progression of disease (PD) or death as competing risks; patients with simultaneous CNS and systemic PD were treated as having had CNS PD. Results: Sixty-two patients (48 LIBRETTO-001, 14 EAP) were identified. Median age was 64. Thirty-two (52%) were female and 47 (76%) were never smokers. The most common 5’ fusion partner was KIF5B (68%). The median number of prior therapies was 2 (range 1-11); 34% received prior multikinase inhibitor therapy. The median time on treatment was 21.8 months. Thirty-one (50%) patients had no baseline brain metastases. In these patients, the CIR of CNS metastasis was 0% at 6 months and 12 months; none of these patients developed CNS metastasis during selpercatinib treatment. The 9 patients that progressed did so extracranially. Of the 31 patients with baseline brain metastases, 12 (39%) had prior CNS radiation and 3 (10%) had prior CNS surgery. At the time of data cut-off, 23 patients had some evidence of progression, including 8 in both the CNS and systemically, 6 only in the CNS, and 9 only systemically. Overall, 17 of the 31 patients with baseline brain metastasis did not develop evidence of CNS progression as of the data cut. Among patients with baseline brain metastasis, the CIR for evidence of CNS PD was 6.7% at 6 months and 27.4% at 12 months. Conclusions: In patients with RET fusion-positive lung cancers without baseline brain metastases, new CNS metastases were not observed during selpercatinib therapy. Among patients with baseline brain metastasis, a substantial number did not experience progression in the CNS on treatment.

TRUST-II: A global phase II study for taletrectinib in ROS1 fusion–positive lung cancer and other solid tumors.

TPS8601 Background: Taletrectinib (AB-106/DS-6051b) is a next-generation, brain-penetrant, ROS1/ NTRK tyrosine kinase inhibitor (TKI) and has shown clinically meaningful effect and safety profile in ROS1+ Non-Small Cell Lung Cancer (NSCLC) patients in phase 1 studies (Fujiwara et al, Oncotarget 2018; 9(34): 23729-23737; Ou et al, JTO Clin Res Rep. 2020 Oct 21;2(1):100108). Taletrectinib has also demonstrated activity against ROS1 G2032R resistance mutation and CNS metastases in the ongoing phase 2 TRUST study (NCT04395677) in China. Also, taletrectinib has shown preliminary efficacy against NTRK positive solid tumors in an ongoing phase 2 study (NCT04617054). Methods: TRUST-II study (NCT04919811) is a phase 2, global, multicenter, open-label, single-arm multi-cohort study evaluating the efficacy and safety of taletrectinib for ROS1 fusion-positive advanced metastatic NSCLC and other solid tumors. Taletrectinib will be given at 600 mg once daily in 21-day cycle. The patients with ROS1 fusions detected by local tests are eligible to enroll with retrospective confirmation by a central laboratory. The study consists of four cohorts: cohort 1: systemic chemotherapy naïve or ≤ one prior line and ROS1 TKI naïve NSCLC (N = 53); cohort 2: previously treated with one ROS1 TKI (crizotinib or entrectinib) and with progression who are either chemotherapy naïve or ≤ one line of platinum and/or pemetrexed based therapy for NSCLC (N = 46); cohort 3: ≤ 2 prior ROS1 TKIs and with progression who are either chemotherapy naïve or ≤ 2 lines of platinum and/or pemetrexed based therapy for NSCLC (N = 10); and cohort 4: systemic chemotherapy naïve or ≤ 2 prior lines of chemotherapy, but ROS1-TKI naïve ROS1 positive solid tumor other than NSCLC (N = 10). The primary endpoint is objective response rate (ORR) (RECIST v1.1) by independent review committee (IRC) assessment for cohorts 1 and 2. Key secondary endpoints include IRC-assessed duration of response, IRC-assessed intra-cranial ORR, progression free survival (PFS), overall survival (OS), and safety. This study is currently recruiting in Japan, Republic of Korea, and USA. Additional accrual is planned in Canada, China, and European Union. Clinical trial information: NCT04919811.

AcceleRET Lung: A phase 3 study of first-line pralsetinib in patients with RET fusion–positive advanced/metastatic NSCLC.

TPS9159 Background: RET gene fusions have been identified as oncogenic drivers in multiple tumor types, including 1–2% of non-small cell lung cancer (NSCLC). Pralsetinib is a potent, selective RET inhibitor, approved in the US and EU for the treatment of metastatic RET fusion–positive NSCLC based on the phase 1/2 ARROW study (NCT03037385). In the ARROW study (data cutoff: Nov 6, 2020), patients who initiated 400 mg once daily (QD) of pralsetinib after platinum-based chemotherapy achieved an overall response rate (ORR) of 62%, per independent central review. In the treatment-naïve group, the ORR was 79%. Most treatment-related adverse events were grade 1–2 across the entire safety population treated at 400 mg QD (n=471). AcceleRET Lung, an international, open-label, randomized, phase 3 study (NCT04222972), will evaluate the efficacy and safety of pralsetinib versus standard of care (SOC) for first-line treatment of advanced/metastatic RET fusion–positive NSCLC. Abstracts for this study were previously submitted to the European Lung Cancer Congress 2020, the American Society of Clinical Oncology 2020 annual meeting, and 2020 World Conference on Lung Cancer. Methods: Approximately 226 patients with metastatic RET fusion–positive NSCLC will be randomized 1:1 to oral pralsetinib (400 mg QD) or SOC (non-squamous histology: platinum/pemetrexed ± pembrolizumab followed by maintenance pemetrexed ± pembrolizumab [at investigator’s discretion]; squamous histology: platinum/gemcitabine or platinum + pembrolizumab + paclitaxel/nab-paclitaxel followed by maintenance pembrolizumab). Stratification factors include intended use of pembrolizumab, history of brain metastases, and Eastern Cooperative Oncology Group Performance Status. Key eligibility criteria include no prior systemic treatment for advanced/metastatic NSCLC; RET fusion–positive tumor by local or central assessment; no additional actionable oncogenic drivers; no prior selective RET inhibitor; measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. Patients with central nervous system metastases were permitted if asymptomatic and on a stable dose of corticosteroids. 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 evaluations. Identification of potential biomarkers of antineoplastic activity and resistance was an exploratory endpoint. Recruitment has begun with sites (active or planned) in North America, Central America, Europe and Asia. Clinical trial information: NCT04222972.

Selpercatinib (Retevmo)


 CADTH recommends that Retevmo be reimbursed by public drug plans for the treatment of adult patients with metastatic rearranged during transfection (RET) fusion-positive non-small cell lung cancer (NSCLC), if certain conditions are met.
 Retevmo should only be covered to treat adult patients 18 years and older with metastatic RET fusion-positive NSCLC who had never received any cancer treatment or who had prior cancer treatment.
 Retevmo should only be reimbursed if prescribed by a clinician with expertise in the management of NSCLC and if the cost of Retevmo is reduced. Retevmo should not be given or reimbursed in combination with cancer treatment.

Pralsetinib: A Review in Advanced RET Fusion-Positive NSCLC.

Activating mutations in the proto-oncogene RET have been identified as an oncogenic driver of non-small cell lung cancer (NSCLC) in a small subset of patients. Pralsetinib (Gavreto®) is an orally-administered, next-generation, small-molecule selective RET inhibitor that is approved for the treatment of RET fusion-positive metastatic NSCLC. In the pivotal phase I/II ARROW trial, pralsetinib demonstrated rapid and durable anti-tumour activity in patients with advanced RET fusion-positive NSCLC who were previously treated with platinum-based chemotherapy or were treatment-naïve. Pralsetinib also showed clinical activity against intracranial metastases arising from NSCLC. Pralsetinib had a manageable tolerability profile, with the most common grade 3 treatment-related adverse events being neutropenia, hypertension, anaemia and decreased white blood cell count. Currently available data indicate that pralsetinib is a promising new targeted treatment option for patients with advanced RET fusion-positive NSCLC.

Pralsetinib: chemical and therapeutic development with FDA authorization for the management of RET fusion-positive non-small-cell lung cancers.

Pralsetinib (PRL) is a selective Rearranged during Transfection (RET) inhibitor, developed by Blueprint Medicines Corporation for the treatment of RET fusion non-small-cell lung cancer (NSCLC), papillary thyroid cancer (PTC), and medullary thyroid carcinoma (MTC). RET is a known proto-oncogene found in NSCLC, PTC, and MTC. PRL was recently granted accelerated USFDA approval with the brand name GAVRETO™ on 4 September 2020 to treat metastatic RET fusion-positive NSCLC and was updated on 1 December 2020 with the addition of advanced and metastatic RET-altered MTC and PTC in the USA. On 19 November 2021, the European Commission granted conditional marketing authorization to PRL for use as a single agent in adult patients with RET fusion-positive advanced NSCLC. They were not previously treated with an RET inhibitor. This review article summarizes the milestones in the development of PRL, chemistry, chemical (synthesis) research and development, characterization and identification of PRL-resistant RET mutants, the structural basis of resistance to PRL, mechanism of action, pharmacokinetics, pharmacodynamic, adverse effects, and regulatory status, including ongoing clinical trial of PRL and other potential drug candidates, leading to this first approval of PRL for the treatment of various solid tumors (RET fusion NSCLC, MTC, and PTC).

Novel HIVEP1-ALK fusion in a patient with lung adenocarcinoma demonstrating sensitivity to alectinib: a case report

BackgroundAnaplastic lymphoma kinase (ALK) fusion is an important oncogenic driver in non-small cell lung cancer (NSCLC). Reports on the intergenic region (IGR) as an ALK fusion partner are rare. Here, we report the case of a patient with advanced NSCLC harboring a human immunodeficiency virus type I enhancer binding protein 1 (HIVEP1)-ALK fusion that responded effectively to alectinib.Case DescriptionA 60-year-old non-smoking male was referred with a 3-month history of productive cough secondary to lung adenocarcinoma metastatic to mediastinal lymph nodes, brain, liver, and bone (T2N3M1c, stage IVB). Next-generation sequencing identified an IGR (upstream HIVEP1-) ALK fusion, and immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH) results were consistent with an ALK-positive tumor. The patient was subsequently started on alectinib, with no obvious adverse reaction. After 1 month of therapy, the patient achieved significantly remission of the clinical symptoms and had led to an ongoing partial response (PR) lasting >33 months.ConclusionsOur experience highlights the efficacy of alectinib in a patient with HIVEP1-ALK fusion positive NSCLC with multiple metastases including brain disease, and the need for multiple genetic testing methods to verify the oncogenicity of ALK fusions prior to treatment. It could provide useful guidance for the treatment of similar cases in the future.

77TiP TRUST-II: A global phase II study for taletrectinib in ROS1 fusion-positive lung cancer and other solid tumors

Taletrectinib (AB-106/DS-6051b) is a next-generation, brain-penetrant, ROS1/ NTRK tyrosine kinase inhibitor (TKI) and has shown clinically meaningful effect and safety profile in ROS1+ Non-Small Cell Lung Cancer (NSCLC) patients in phase 1 studies (Fujiwara et al, Oncotarget 2018; 9(34): 23729-23737; Ou et al, JTO Clin Res Rep. 2020 Oct 21;2(1):100108). Taletrectinib has also demonstrated activity against ROS1 G2032R resistance mutation and CNS metastases in the ongoing phase 2 TRUST study (NCT04395677) in China. Also, taletrectinib has shown preliminary efficacy against NTRK-positive solid tumors in an ongoing phase 2 study (NCT04617054). TRUST-II study (NCT04919811) is a phase 2, global, multicenter, open-label, single-arm multi-cohort study evaluating the efficacy and safety of taletrectinib for ROS1 fusion-positive advanced metastatic NSCLC and other solid tumors. Taletrectinib will be given at 600 mg once daily in 21-day cycle. The patients with ROS1 fusions detected by local tests are eligible to enroll with retrospective confirmation by a central laboratory. The study consists of four cohorts: cohort 1: systemic chemotherapy naïve or ≤ one prior line and ROS1 TKI naïve NSCLC (N=53); cohort 2: previously treated with one ROS1 TKI (crizotinib or entrectinib) and with progression who are either chemotherapy naïve or ≤ one line of platinum and/or pemetrexed based therapy for NSCLC (N=46); cohort 3: ≤ 2 prior ROS1 TKIs and with progression who are either chemotherapy naïve or ≤ 2 lines of platinum and/or pemetrexed based therapy for NSCLC (N=10); and cohort 4: systemic chemotherapy naïve or ≤ 2 prior lines of chemotherapy, but ROS1-TKI naïve ROS1-positive solid tumor other than NSCLC ( N=10). The primary endpoint is objective response rate (ORR) (RECIST v1.1) by independent review committee (IRC) assessment for cohorts 1 and 2. Key secondary endpoints include IRC-assessed duration of response, IRC-assessed intra-cranial ORR, progression free survival (PFS), overall survival (OS), and safety. This study is currently recruiting in Japan, Republic of Korea, and USA. Additional accrual is planned in Canada, China, and European Union. NCT04919811. The authors.

Case Report: Adjuvant Crizotinib Therapy Exerted Favorable Survival Benefit in a Resectable Stage IIIA NSCLC Patient With Novel LDLR–ROS1 Fusion

Novel adjuvant strategies are needed to optimize outcomes after complete surgical resection in patients with early-stage non-small-cell lung cancer (NSCLC). The adjuvant treatment of ROS Proto-Oncogene 1 (ROS1) fusion-positive resected NSCLC is challenging because there is no curative confirmed randomized controlled trial. Next-generation sequencing (NGS) and immunohistochemistry (IHC) staining were performed on the biopsy sample. In this case, we identified a novel LDLR–ROS1 fusion in a resectable stage IIIA NSCLC patient. The patient received crizotinib as adjuvant treatment and achieved recurrence-free survival (RFS) for 29 months, without significant symptoms of toxicity. In this case, we report a novel LDLR–ROS1 fusion responding to crizotinib in a patient with lung adenocarcinoma, supporting the use of adjuvant treatment with the ROS1 inhibitor exerting clinical survival benefit in ROS1 fusion-positive resected NSCLC.