Fusion-positive Non-small Cell Lung Cancer Research Articles

Exploring the Impact of Hepatic Impairment on Pralsetinib Pharmacokinetics.

Pralsetinib is a kinase inhibitor indicated for the treatment of metastatic rearranged during transfection (RET) fusion-positive non-small cell lung cancer. Pralsetinib is primarily eliminated by the liver and hence hepatic impairment (HI) is likely alter its pharmacokinetics (PK). Mild HI has been shown to have minimal impact on the PK of pralsetinib. This hepatic impairment study aimed to determine the pralsetinib PK, safety and tolerability in subjects with moderate and severe HI, as defined by the Child-Pugh and National Cancer Institute Organ Dysfunction Working Group (NCI-ODWG) classification systems, in comparison to subjects with normal hepatic function. Based on the Child-Pugh classification, subjects with moderate and severe HI had similar systemic exposure (area under the plasma concentration time curve from time 0 to infinity [AUC0-∞]) to pralsetinib, with AUC0-∞ geometric mean ratios (GMR) of 1.12 and 0.858, respectively, compared to subjects with normal hepatic function. Results based on the NCI-ODWG classification criteria were comparable; the AUC0-∞ GMR were 1.22 and 0.858, respectively, for subjects with moderate and severe HI per NCI-ODWG versus those with normal hepatic function. These results suggested that moderate and severe hepatic impairment did not have a meaningful impact on the exposure to pralsetinib, thus not warranting a dose adjustment in this population.

Entrectinib as first-line vs. second-line therapy in ROS1 fusion-positive non-small cell lung cancer: a cost-effectiveness analysis.

The concept of cost-effectiveness is crucial for the optimal allocation of scarce healthcare resources. However, the cost-effectiveness of entrectinib in ROS1 fusion-positive non-small cell lung cancer (NSCLC) has not been evaluated. We aim to evaluate the cost-effectiveness of entrectinib as a first-line treatment compared to its reservation for second-line therapy or the exclusive use of chemotherapy in ROS1 fusion-positive advanced NSCLC. A Markov model was created to assess the clinical outcomes and healthcare costs associated with these three treatment approaches. Cost and utility values were obtained from established literature and cost databases. To test model robustness, probabilistic and univariate sensitivity analyses were conducted. In the first-line setting, where entrectinib was administered as the initial therapy, it yielded an extra 0.07 quality-adjusted life years (QALYs) at an incremental cost of $73,453, leading to an incremental cost-effectiveness ratio (ICER) of $1,090,594.30 per QALY compared to chemotherapy. Conversely, in the second-line setting, when entrectinib was used as a second-line therapy following chemotherapy, it provided an extra 0.11 QALYs at an incremental cost of $53,480, resulting in an ICER of $494,290.39 per QALY compared to chemotherapy. Furthermore, the analysis revealed that the cost of entrectinib and utility values of progressed disease were the most influential factors for the ICER. Considering the current pricing of entrectinib, it is not deemed cost-effective as a first-line or second-line therapy for patients with ROS1 fusion-positive advanced NSCLC when compared to chemotherapy. Alternatively, reserving entrectinib exclusively for second-line therapy might strike a balance between healthcare expenditures and patient outcomes.

Abstract 5839: Identification of low-dose ligand dependent drug-resistance in ALK/ROS1 positive NSCLC via CRISPR library screening

Abstract Tyrosine kinase inhibitor (TKI) therapy has displayed significant effectiveness in treating patients with anaplastic lymphoma kinase (ALK) and ROS proto-oncogene 1 (ROS1)-positive non-small cell lung cancer (NSCLC). Nonetheless, the emergence of acquired resistance in most patients presents a major challenge. Drug-tolerant persister (DTP) cells have recently gained attention as potential sources of resistance, highlighting the need for a deeper understanding of drug resistance mechanisms. To address this issue, a comprehensive genome-wide CRISPR-Cas9 knockout screening was conducted using an ALK-positive NSCLC cell line derived from pleural effusion in a patient who had not been exposed to ALK-TKI treatment. Following a 9-day ALK-TKI treatment, sequencing analysis was performed to identify sgRNAs in DTP cells. Notably, this analysis detected the involvement of tumor suppressor genes, including NF2, BAX, and ERRFI1.NF2 depletion was found to induce a substantial resistance to ALK-TKIs, and a combination therapy involving mTOR inhibitors showed promise in partially overcoming this resistance. Moreover, knockout of ERRFI1 or BAX led to an increase in DTP cells, drawing particular attention to ERRFI1, also known as MIG6, which is known for negatively regulating EGFR signaling. One intriguing discovery was that the loss of MIG6 induced resistance to ALK-TKIs when exposed to a relatively low dose of EGF, comparable to concentrations in plasma of healthy adults. This resistance was attributed to the upregulation of the MAPK and PI3K/Akt/mTOR pathways. Similar to ALK-rearranged NSCLC, ROS1 fusion-positive NSCLC cell lines also showed resistance by MIG6 knockout. Interestingly, some cell lines with reduced MIG6 expression tended to develop resistance with low-dose EGF, even without prior treatment, and overexpression of MIG6 restored sensitivity to TKIs. We further explored the potential of combination therapy, combining ALK-TKIs with anti-EGFR antibodies, and this approach effectively addressed acquired resistance in both in vivo and in vitro models. Furthermore, an analysis of clinical samples revealed that individuals resistant to ALK-TKIs displayed decreased mRNA MIG6 levels in comparison to their sensitive counterparts. Investigating the mechanisms behind MIG6 expression, we confirmed that ALK-TKI therapy suppressed MIG6 expression levels, while factors such as corticosteroid usage or exposure to hypoxia induced the upregulation of MIG6, potentially influencing the formation of DTP cells. In conclusion, this research has unveiled a novel factor contributing to resistance in ALK and ROS1-TKI therapies by activating the EGFR pathway through exposure to low-dose ligands, shedding light on potential therapeutic strategies to combat acquired resistance. Citation Format: Nobuyuki Kondo, Takahiro Utsumi, Ken Uchibori, Yasunari Miyazaki, Ryohei Katayama. Identification of low-dose ligand dependent drug-resistance in ALK/ROS1 positive NSCLC via CRISPR library screening [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5839.

Abstract 1958: EGFR and mTOR signaling facilitate RET-independent resistance to selective RET-TKIs

Abstract RET fusions are an oncogenic driver mutation occurring in 1-2% non-small cell lung cancer (NSCLC). Currently, RET-selective tyrosine kinase inhibitors (TKIs) selpercatinib and pralsetinib are approved for this patient population, demonstrating favorable antitumor activity and safety profiles in advanced RET fusion-positive NSCLC. However, tumors eventually become refractory to selective RET inhibitor monotherapy. We sought to identify signaling pathways which mediate RET-independent acquired resistance to RET inhibitors and effective therapeutic combinations to overcome resistance. Using LC-2/ad (CCDC6-RET) NSCLC cells, we assessed the expression and activation of critical signaling pathways at a proteomic level following RET knockdown using reverse-phase protein array. RET knockdown resulted in rapidly increased adaptive upregulation of EGFR, HER2, MET, mTOR and MEK pathway signaling; observations were confirmed by Western Blotting. To determine whether EGFR or MET signaling facilitate RET inhibitor resistance, LC-2/ad and NCCE-TH1101 (KIF5B-RET) NSCLC cells were treated with increasing concentrations of selpercatinib or pralsetinib with or without ligands for these receptors, EGF or HGF respectively, and after five days cell viability was measured by CellTiter Glo. EGFR and MET signaling promoted RET TKI resistance in both cell lines. Next, to evaluate whether blockade of EGFR or MET signaling could enhance the activity of RET inhibitors, we treated LC-2/ad and NCCE-TH1101 cells with RET TKIs alone or in combination with the EGFR TKI erlotinib or poziotinib, or the MET inhibitor SU11274. We observed an additive effect with EGFR but not MET inhibitors when combined with RET TKIs. Western blot analysis revealed that EGFR signaling could reactivate mTOR and MAPK signaling after RET TKI treatment. Therefore, we next tested whether inhibition of these downstream pathways might enhance RET TKI sensitivity. We observed that treatment of LC-2/ad and NCCE-TH1101 cells with an mTOR inhibitor (everolimus) or a MEK inhibitor (trametinib) in combination with RET TKIs increased the anti-tumor activity or RET inhibitors. Finally, we established cells with acquired resistance to selpercatinib and pralsetinib. RET TKI resistant cells did not harbor secondary RET fusion mutations but underwent epithelial to mesenchymal transition and exhibited pan-RET inhibitor resistance. Moreover, RET TKI resistant cells showed increased cell surface expression of EGFR and MET by flow cytometry. RET TKI resistant cells were sensitive to mTOR or MEK inhibitors in combination with RET TKIs. Collectively, our findings indicate that in RET-fusion positive NSCLC tumor cells, activation of bypass pathways including the EGFR, MAPK, mTOR pathways may facilitate RET inhibitor resistance and that blockade of bypass pathways may enhance the efficacy of selective RET inhibitors and overcome acquired RET TKI resistance. Citation Format: Tomohiro Takehara, Monique B. Nilsson, Ximeng Liu, Hibiki Udagawa, Naoto Morikawa, Alissa Poteete, Junqin He, Xiaoxing Yu, Thiru Arumugam, Koichi Goto, John V. Heymach. EGFR and mTOR signaling facilitate RET-independent resistance to selective RET-TKIs [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1958.

Abstract 4998: Pralsetinib induces opportunistic infection in RET fusion-positive NSCLC patients via inhibition of IL-2 production by blocking Jak3-Stat5 activation

Abstract Background: Oncogenic alteration in RET, representing 1-2% of non-small cell lung cancer (NSCLC), is one of the important targets. Pralsetinib is a selective RET inhibitor that targets RET fusions. We present a case series on opportunistic infections and the mechanism of immunosuppression. Methods: From October 2021 to March 2022, we administered pralsetinib to a total of 15 patients with NSCLC harboring RET fusion. We retrospectively analyzed the clinical efficacy and adverse event related to pralsetinib. To investigate the potential impact of pralsetinib on T-cells, we examined cytokine release from Jurkat T (JT) cells after pralsetinib treatment. To test if Stat5 bind to IL-2 promotor, we conducted Chromatin Immunoprecipitation (ChIP). Results: Out of a total of 18 patients with measurable disease, 14 patients (93%) achieved a partial response. With the median follow-up duration of 8.7 months, four cases of opportunistic infections were occurred. Notably, three patients (16.6%) experienced invasive pulmonary aspergillosis, and one patient (5.5%) experienced cytomegalovirus pneumonia. To mimic conditions akin to activated T cells, we treated JT cells with PMA and ionomycin, inducing IL-2 release through the binding of NFAT, AP-1, and NF-κB to the IL-2 promoter. Following approximately two weeks of pralsetinib treatment, a decrease of IL-2 releases, the inhibition of Jak3 and the reduced-expression of JunB and c-Jun was observed. Additionally, to investigate the direct correlation between Jak3 and IL-2 release, JT cells were treated with ritlecitinib, the Jak3-selective inhibitor, for approximately two weeks. Like pralsetinib, a reduction in IL-2 release was observed. Furthermore, based on the evidence that Stat5 inhibition leads to reduced IL-2 release, we also showed that the transcription factor Stat5, a direct downstream signaling component of Jak3, binds to the IL-2 promoter during the activation of Jurkat T cells. Conclusion: Pralsetinib inhibits additional IL-2 production by blocking Jak3/Stat5 activation triggered by IL-2 released during early T cell activation. As a result, the Jak3 inhibition induced by pralsetinib leads to a decrease in JunB/c-Jun expression and blocking Stat5 activation by reducing IL-2 release. Consequently, Pralsetinib-related opportunistic infections may be caused by inhibition of the JAK3 pathway and IL-2 release. Citation Format: Shinkyo Yoon, Hyun-Min Ryu, Sang-We Kim, Kang-Seo Park, Dae Ho Lee. Pralsetinib induces opportunistic infection in RET fusion-positive NSCLC patients via inhibition of IL-2 production by blocking Jak3-Stat5 activation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4998.

Abstract 5833: Genomic mechanisms of RET inhibitor resistance in RET-fusion positive NSCLC

Abstract RET fusions are a driver oncogene detected in 1-2% of non-small cell lung cancer (NSCLC) cases. Currently, two selective RET inhibitors (RETi), selpercatinib and pralsetinib have received FDA approval for RET fusion-positive NSCLC. However, RET fusions are highly heterogeneous and the impact of specific fusion partners and breakpoints on RETi sensitivity is not well understood. Moreover, most patients eventually develop resistance to RETi, and secondary RET mutations are thought to be a key mechanism of acquired resistance. Thus, we aimed to identify RET-dependent mechanism of RETi resistance in effort to improve treatment options and clinical outcomes. We engineered a panel of Ba/F3 cells expressing various RET fusion partners and breakpoints observed in clinical cases of NSCLC and evaluated their drug sensitivity profile against a panel of RETi including selpercatinib, pralsetinib, TPX-0046, lovatinib, zeteletinib and ponatinib. We determined that individual RET fusions impart distinct sensitivities to RETi. For example, cells expressing KIF-RET (K22, R12) were sensitive to selpercatinib and pralsetinib but less sensitive to ponatinib, whereas cells expressing KIF-RET (K15, R12) were highly sensitive to selpercatinib, pralsetinib, and ponatinib. Moreover, using RET-fusion positive NSCLCs, we observed that the RETi sensitivity profile of human cell lines was similar to that observed using Ba/F3 models. To identify potential resistance mutations, we utilized the LentiMutate approach. In KIF5B-RET (K15, R12) expressing cells, we identified G810S as being associated with resistance to both selpercatinib and pralsetinib, a finding consistent with previous reports and clinical observations. In addition, we identified Y806H/N, V804M/E, and M918T as being associtated with selpercatinib-resistance and L730I/V, E732K, and Y806H/N as being associated with pralsetinib-resistance. We next constructed Ba/F3 cells expressing KIF5B-RET in combination with each secondary mutation and evaluated RETi sensitivity. G810S and Y806N conferred resistance to selpercatinib and pralsetinib, as well as to RET-targeting multi-kinase inhibitors. V804M/E mutations conferred resistance to selpercatinib but not pralsetinib, whereas L730I/V and E732K mutations conferred resistance to pralsetinib but not selpercatinib, demonstrating RETi-specific resistance mutations. Cells expressing G810S secondary mutations were resistant to selpercatinib and pralsetinib, but sensitive to zeteletinib. Collectively, we show that individual RET fusion variants have distinct drug sensitivity profiles and that secondary resistance mutations are non-overlapping between RETi. The comprehensive characterization of RET-dependent mechanisms of resistance to RETi may provide therapeutic guidance for treating RET-fusion driven NSCLC and provide structural insights that can guide the development of new therapeutic regimens. Citation Format: Ximeng Liu, Monique Nilsson, Tomohiro Takehara, Junqin He, Xiaofang Huo, Ashwani Kumar, John Heymach, Ralf Kittler. Genomic mechanisms of RET inhibitor resistance in RET-fusion positive NSCLC [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5833.

Targeting RET alterations in non-small cell lung cancer

Rearranged during transfection (RET) alterations, which lead to aberrant activation of the RET proto-oncogene, have been identified in various cancers. In non-small cell lung cancer (NSCLC), RET mutations often manifest as RET fusion genes and are observed in 1–2 % of patients with NSCLC. In recent years, selective RET inhibitors such as selpercatinib and pralsetinib, approved by the Food and Drug Administration (FDA) in 2020, have been part of the revolutionary changes in the treatment landscape for non-small cell lung cancer. While first-generation RET inhibitors have become part of the standard of care for RET-fusion positive NSCLC, a new challenge has emerged: acquired resistance to RET inhibitors. RET resistance is a complex phenomenon that can manifest as either on-target or off-target resistance. Numerous studies have been conducted to identify the mechanisms behind this resistance. This review provides an overview of the biology of RET in NSCLC, methods of RET testing, and a comprehensive analysis of the clinical outcomes associated with multikinase and selective RET inhibitors for NSCLC. Additionally, we will explore future perspectives for RET fusion-positive NSCLC, including ongoing trials and the challenges involved in overcoming resistance to RET inhibitors.

Mechanisms of Resistance to Tyrosine Kinase Inhibitors in ROS1 Fusion-Positive Nonsmall Cell Lung Cancer.

ROS1 fusion-positive (ROS1+) nonsmall cell lung cancer (NSCLC) patients are highly sensitive to tyrosine kinase inhibitor (TKI) treatments. However, acquired TKI resistance remains the major hurdle preventing patients from experiencing prolonged benefits. 107 advanced or metastatic ROS1+ NSCLC patients who progressed on crizotinib and lorlatinib were recruited. Tissue and plasma samples were collected at baseline (N = 50), postcrizotinib (N = 91), and postlorlatinib (N = 21), which were all subject to the 139-gene targeted next-generation DNA sequencing. Molecular dynamics modeling was performed to investigate the effects of ROS1 mutations on binding to different TKIs. In patients with postcrizotinib and postlorlatinib samples, an accumulation of on- and off-target resistance alterations after multiple TKI treatments was observed. ROS1 G2032R and MET amplification were the most common on-target and off-target alterations, respectively. Patients with CD74-ROS1 and SLC34A2-ROS1 had longer progression-free survival (PFS) (P < 0.001) and higher rates of resistance mutations (on-target, P = 0.001; off-target, P = 0.077) than other ROS1 fusion variants following crizotinib treatment. Ten distinct on-target resistance mutations were detected after TKI therapies, of which 4 were previously unreported (ROS1 L2010M, G1957A, D1988N, L1982V). Molecular dynamics simulations showed that all 4 mutations were refractory to crizotinib, while G1957A, D1988N, and L1982V were potentially sensitive to lorlatinib and entrectinib. This study provided a comprehensive portrait of TKI-resistance mechanisms in ROS1+ NSCLC patients. Using in silico simulations of TKI activity, novel secondary mutations that may confer TKI resistance were identified and may support clinical therapeutic decision-making.

[China expert recommendations on anaplastic lymphoma kinase-tyrosine kinase inhibitors treatment for advanced non-small cell lung cancer (2024 edition)].

Anaplastic lymphoma kinase (ALK) fusion represents one of pivotal driver genes within the realm of non-small cell lung cancer (NSCLC). ALK-tyrosine kinase inhibitors (ALK-TKI) have demonstrated remarkable therapeutic efficacy for patients afflicted with ALK-positive NSCLC. As of June 27, 2023, seven ALK-TKI, including crizotinib, ceritinib, alectinib, ensartinib, brigatinib, lorlatinib, and iruplinalkib, have garnered approval from the China National Medical Products Administration (NMPA)(ranking according to the approval time for marketing by NMPA), providing individualized treatment modalities for ALK-positive NSCLC patients. To standardize the application of ALK-TKI, the Chinese Association for Clinical Oncologists and the Medical Oncology Branch of China International Exchange and Promotive Association for Medical and Health Care has organized experts to compile the " China expert recommendations on anaplastic lymphoma kinase-tyrosine kinase inhibitors treatment for advanced non-small cell lung cancer (2024 edition)". This treatment expert recommendation provides recommendations in four aspects, encompassing ALK fusion testing, ALK-TKI targeted therapy, ALK-TKI adverse events management, and patient post-treatment follow-up, thus serving as a valuable reference for the standardized treatment of Chinese advanced ALK fusion-positive NSCLC.

Response to immune checkpoint inhibitor combination therapy in metastatic RET-mutated lung cancer from real-world retrospective data

BackgroundThe impact of immune checkpoint inhibitors (ICIs) based treatments on non-small cell lung cancers (NSCLCs) with RET fusions remains poorly understood.MethodsWe screened patients with RET fusions at the First Affiliated Hospital of Zhengzhou University and included those who were treated with ICIs based regimens for further analysis. We evaluated clinical indicators including objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), and overall survival (OS).ResultsA total of 232 patients with RET fusions were included in the study. Of these, 129 patients had their programmed death-ligand 1 (PDL1) expression levels tested, with 22 patients (17.8%) having a PDL1 level greater than or equal to 50%. Additionally, tumor mutational burden (TMB) status was evaluated in 35 patients, with the majority (30/35, 85.8%) having a TMB of less than 10 mutations per megabase. Out of the 38 patients treated with ICI based regimens, the median PFS was 5 months (95% confidence interval [CI]: 2.4–7.6 months) and the median OS was 19 months (95% CI: 9.7–28.3 months) at the time of data analysis. Stratification based on treatment lines did not show any significant differences in OS (18 vs. 19 months, p = 0.63) and PFS (6 vs. 5 months, p = 0.86). The ORR for patients treated with ICIs was 26.3%. Furthermore, no significant differences were found for PFS (p = 0.27) and OS (p = 0.75) between patients with positive and negative PDL1 expression. Additionally, there was no significant difference in PD-L1 levels (p = 0.10) between patients who achieved objective response and those who did not.ConclusionsPatients with RET fusion positive NSCLCs may not benefit from ICI based regimens and therefore should not be treated with ICIs in clinical practice.

Economic Evaluation of Targeted Therapies for Anaplastic Lymphoma Kinase- and ROS1 Fusion-Positive Non-Small Cell Lung Cancer in India.

Targeted therapies, such as crizotinib and ceritinib, have shown promising results in treating non-small cell lung cancer (NSCLC) with specific oncogenic drivers like anaplastic lymphoma kinase (ALK), c-ros (ROS1) oncogene, etc. This study aims to assess the cost-effectiveness of these therapies for patients with NSCLC in India. The Markov model consisted of three health states: progression-free survival, progressive disease, and death. Lifetime costs and consequences were estimated for three treatment arms: crizotinib, ceritinib, and chemotherapy for patients with ALK- and ROS1-positive NSCLC. Incremental cost per quality-adjusted life-year (QALY) gained with crizotinib and ceritinib was compared to chemotherapy and assessed using a willingness-to-pay threshold of one-time per capita gross domestic product in India. The total lifetime cost per patient for ALK-positive NSCLC was ₹332,456 ($4,054 US dollars [USD]), ₹1,284,100 ($15,659 USD), and ₹2,337,779 ($28,509 USD) in the chemotherapy, crizotinib, and ceritinib arms, respectively. The mean QALYs lived per patient were 1.20, 2.21, and 3.34, respectively. For patients with ROS1-positive NSCLC, the total cost was ₹323,011 ($3,939 USD) and ₹1,763,541 ($21,507 USD) for chemotherapy and crizotinib, with mean QALYs lived per patient of 1.16 and 2.73, respectively. Nearly 92% and 81% reduction in the price of ceritinib and crizotinib is required to make it a cost-effective treatment option for ALK- and ROS1-positive NSCLC, respectively. Our study findings suggest that the prices of ceritinib and crizotinib need to be reduced significantly to justify their value for inclusion in India's publicly financed health insurance scheme for treatment of patients with locally advanced/metastatic ALK- and ROS1-positive NSCLC, respectively.

Repotrectinib in ROS1 Fusion–Positive Non–Small-Cell Lung Cancer

BackgroundThe early-generation ROS1 tyrosine kinase inhibitors (TKIs) that are approved for the treatment of ROS1 fusion–positive non–small-cell lung cancer (NSCLC) have antitumor activity, but resistance develops in tumors, and intracranial activity is suboptimal. Repotrectinib is a next-generation ROS1 TKI with preclinical activity against ROS1 fusion–positive cancers, including those with resistance mutations such as ROS1 G2032R.MethodsIn this registrational phase 1–2 trial, we assessed the efficacy and safety of repotrectinib in patients with advanced solid tumors, including ROS1 fusion–positive NSCLC. The primary efficacy end point in the phase 2 trial was confirmed objective response; efficacy analyses included patients from phase 1 and phase 2. Duration of response, progression-free survival, and safety were secondary end points in phase 2.ResultsOn the basis of results from the phase 1 trial, the recommended phase 2 dose of repotrectinib was 160 mg daily for 14 days, followed by 160 mg twice daily. Response occurred in 56 of the 71 patients (79%; 95% confidence interval [CI], 68 to 88) with ROS1 fusion–positive NSCLC who had not previously received a ROS1 TKI; the median duration of response was 34.1 months (95% CI, 25.6 to could not be estimated), and median progression-free survival was 35.7 months (95% CI, 27.4 to could not be estimated). Response occurred in 21 of the 56 patients (38%; 95% CI, 25 to 52) with ROS1 fusion–positive NSCLC who had previously received one ROS1 TKI and had never received chemotherapy; the median duration of response was 14.8 months (95% CI, 7.6 to could not be estimated), and median progression-free survival was 9.0 months (95% CI, 6.8 to 19.6). Ten of the 17 patients (59%; 95% CI, 33 to 82) with the ROS1 G2032R mutation had a response. A total of 426 patients received the phase 2 dose; the most common treatment-related adverse events were dizziness (in 58% of the patients), dysgeusia (in 50%), and paresthesia (in 30%), and 3% discontinued repotrectinib owing to treatment-related adverse events.ConclusionsRepotrectinib had durable clinical activity in patients with ROS1 fusion–positive NSCLC, regardless of whether they had previously received a ROS1 TKI. Adverse events were mainly of low grade and compatible with long-term administration. (Funded by Turning Point Therapeutics, a wholly owned subsidiary of Bristol Myers Squibb; TRIDENT-1 ClinicalTrials.gov number, NCT03093116.)

An Anaplastic Lymphoma Kinase-positive Inflammatory Myofibroblastic Tumor with Rapidly Acquired Resistance to First-line Anaplastic Lymphoma Kinase Inhibitor: A Case and Literature Review

Abstract Inflammatory myofibroblastic tumors (IMTs) are soft-tissue neoplasms with rare metastatic potential. Approximately half of IMTs are positive for an anaplastic lymphoma kinase (ALK) gene rearrangement which causes aberrant expression. Early phase clinical trials have demonstrated the efficacy of ALK inhibitors in the treatment of IMTs. However, there is no definite conclusion on which ALK inhibitor performs best, and data regarding subsequent therapy after first-line ALK inhibitor failure are scarce. Here, we report a case of ALK+ metastatic IMT that demonstrated a dramatic response to first-line alectinib but resulted in rapidly acquired resistance. Repeated biopsy and next-generation sequencing (NGS) showed ALK:c.3604G&gt;A; p.(Gly1202Arg), which is a common mechanism of drug resistance in ALK fusion-positive non-small cell lung cancer. We also report subsequent treatment choices and responses in this patient and perform a literature review regarding similar cases as this rare tumor.

[Chinese expert consensus on the diagnosis and treatment of advanced RET fusion-positive non-small cell lung cancer (2023 edition)].

Lung cancer is the most common cancer and the leading cause of cancer death in China. Non-small cell lung cancer (NSCLC) is the most common histological type of lung cancer. Mutations of driver genes have major impacts on incidence and progression of lung cancer. Advances in molecular biology research and clinical research have promoted the discovery of rare tumor driver genes, as well as the development and application of new targeted drugs. Nearly 1% to 2% of NSCLCs harbor RET fusions, and this patient population may not respond well to traditional treatments like chemotherapy or radiation therapy. After the new highly selective RET inhibitors pralsetinib (BLU-667) and selpercatinib (LOXO-292) entered clinical application, the diagnosis and treatment of RET fusion positive NSCLC has made breakthrough progress. At present, there is a lack of guiding consensus on the standardized diagnosis and treatment of RET fusion-positive NSCLC in China. The Society of Cancer Precision of Chinese Anti-Cancer Association and Lung Cancer Expert Group of Chinese Medical Journal, invited 38 experts form respiratory medicine, medical oncology, oncology radiotherapy and pathology to form a consensus development group. Based on the existing research evidence, combined with China's clinical practice experience, a standardized process for the diagnosis and treatment of advanced RET fusion-positive NSCLC is proposed, including suitable populations and methods for RET gene fusion, treatment drug selection, treatment of resistance to highly selective RET inhibitors, and management of adverse reactions to treatment, with a view to providing guidance for clinicians.

Updated efficacy and safety of entrectinib in NTRK fusion-positive non-small cell lung cancer

ObjectivesNTRK fusions result in constitutively active oncogenic TRK proteins responsible for ∼ 0.2 % of non-small cell lung cancer (NSCLC) cases. Approximately 40 % of patients with advanced NSCLC develop CNS metastases; therefore, treatments with intracranial (IC) efficacy are needed. In an integrated analysis of three phase I/II studies (ALKA-372–001: EudraCT 2012–000148–88; STARTRK-1: NCT02097810; STARTRK-2: NCT02568267), entrectinib, a potent, CNS-active, TRK inhibitor, demonstrated efficacy in patients with NTRK fusion-positive (fp) NSCLC (objective response rate [ORR]: 64.5 %; 2 August 2021 data cut-off). We present updated data for this cohort. Materials and methodsEligible patients were ≥ 18 years with locally advanced/metastatic, NTRK-fp NSCLC with ≥ 12 months of follow-up. Tumor responses were assessed by blinded independent central review (BICR) per RECIST v1.1 at Week 4 and every eight weeks thereafter. Co-primary endpoints: ORR; duration of response (DoR). Secondary endpoints included progression-free survival (PFS); overall survival (OS); IC efficacy; safety. Enrolment cut-off: 2 July 2021; data cut-off: 2 August 2022. ResultsThe efficacy-evaluable population included 51 patients with NTRK-fp NSCLC. Median age was 60.0 years (range 22–88); 20 patients (39.2 %) had investigator-assessed baseline CNS metastases. Median survival follow–up was 26.3 months (95 % CI 21.0–34.1). ORR was 62.7 % (95 % CI 48.1–75.9), with six complete and 26 partial responses. Median DoR and PFS were 27.3 months (95 % CI 19.9–30.9) and 28.0 months (95 % CI 15.7–30.4), respectively. Median OS was 41.5 months. In patients with BICR-assessed baseline CNS metastases, IC-ORR was 64.3 % (n = 9/14; 95 % CI 35.1–87.2), including seven complete responders, and IC-DoR was 55.7 months. In the safety–evaluable population (n = 55), most treatment-related adverse events were grade 1/2; no treatment-related deaths were reported. ConclusionEntrectinib has continued to demonstrate deep and durable systemic and IC responses in patients with NTRK-fp NSCLC.

Abstract PR003: Repotrectinib in patients with ROS1 fusion-positive (ROS1+) non-small cell lung cancer (NSCLC): Update from the pivotal phase 1/2 TRIDENT-1 trial

Abstract Introduction: Repotrectinib, a next-generation ROS1 tyrosine kinase inhibitor (TKI), has demonstrated durable activity and manageable safety in patients (pts) with locally advanced/metastatic ROS1+ NSCLC in the pivotal phase 1/2 TRIDENT-1 trial (NCT03093116). We report efficacy with a minimum follow-up of 14 months (mo) from start of treatment in two ROS1+ NSCLC primary efficacy cohorts and safety in all pts treated at the recommended phase 2 dose (RP2D). Methods: Pts with ROS1+ NSCLC were assigned to 4 cohorts by treatment history: TKI-naïve, 1 TKI and no chemo, 1 TKI and 1 platinum-based chemo, and 2 TKIs and no chemo. Repotrectinib RP2D was 160 mg once daily for 14 days, then 160 mg twice daily. Phase 2 primary endpoint was confirmed objective response rate (cORR) by Blinded Independent Central Review per RECIST v1.1. Secondary endpoints included duration of response (DOR), progression-free survival (PFS), intracranial ORR, cORR in TKI-pretreated pts with ROS1 G2032R NSCLC, and safety. Efficacy analyses included pts with ≥14 mo follow-up. Safety assessments included pts treated at RP2D across all study cohorts. Results: At data cutoff (December 19, 2022), median (range) follow-up in the primary efficacy cohorts was 24.0 (14.2–66.6) mo in the TKI-naïve cohort (n=71) and 21.5 (14.2–58.6) mo in the 1 prior TKI and no chemo cohort (n=56). In the TKI-naïve cohort, cORR was 79% (95% CI, 68–88). Median (95% CI) DOR was 34.1 (25.6–not estimable [NE]) mo; estimated 12- and 18-mo DOR rates were 83% (73–93) and 79% (68–90), respectively. Median PFS (95% CI) was 35.7 (27.4–NE) mo; estimated 12- and 18-mo PFS rates were 77% (66–87) and 70% (59–81), respectively. In the 1 prior TKI and no chemo cohort, cORR was 38% (95% CI, 25–52). Median DOR (95% CI) was 14.8 (7.6–NE) mo; estimated 12-mo DOR rate was 56% (34–77). Median PFS (95% CI) was 9.0 (6.8–19.6) mo; estimated 12-mo PFS rate was 41% (27–56). The median (range) time to response was 1.8 (0.9–5.6) mo in the TKI-naïve cohort and 1.8 (1.6–3.6) mo in the 1 prior TKI and no chemo cohort. Among pts with measurable brain metastasis at baseline, intracranial ORR was 89% (95% CI, 52–100) in the TKI-naïve cohort (n=9), and 38% (95% CI, 14–68) in the 1 prior TKI and no chemo cohort (n=13). In pts with TKI-pretreated ROS1 G2032R NSCLC (n=17), cORR was 59% (33–82). Among pts receiving repotrectinib at RP2D (n=426), treatment-emergent adverse events (TEAEs) occurred in 422 (99%), most commonly dizziness (62%). Grade ≥3 TEAEs occurred in 216 (51%) and were considered treatment-related in 122 (29%). TEAEs led to dose reduction and treatment discontinuation in 38% and 7% of pts, respectively. Additional analysis in CNS efficacy and by subsequent therapies will be presented. Conclusion: With a minimum follow-up of 14 mo in TRIDENT-1, repotrectinib continued to demonstrate durable efficacy in pts with ROS1+ NSCLC, including intracranial activity, in both TKI-naïve and 1 prior TKI and no chemo cohorts. Safety in pts treated at RP2D was manageable, consistent with previous reports in all treated pts. Prior:WCLC(Sep 10). Citation Format: Jessica J Lin, Byoung Chul Cho, D. Ross Camidge, Sang-We Kim, Benjamin Solomon, Rafal Dziadziuszko, Benjamin Besse, Koichi Goto, Adrianus Johannes de Langen, Jürgen Wolf, Ki Hyeong Lee, Sanjay Popat, Christoph Springfeld, Misako Nagasaka, Enriqueta Felip, Nong Yang, Shun Lu, Steven Kao, Vamsidhar Velcheti, Parneet Cheema, Shanna Stopatschinskaja, Minal Mehta, Denise Trone, Felipe Ades, Christophe Y. Calvet, Alexander Drilon. Repotrectinib in patients with ROS1 fusion-positive (ROS1+) non-small cell lung cancer (NSCLC): Update from the pivotal phase 1/2 TRIDENT-1 trial [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr PR003.

Abstract B154: Safety and preliminary activity of the selective ALK inhibitor NVL-655 in patients with ALK fusion-positive solid tumors

Abstract Background: Oncogenic ALK alterations drive diverse tumor types, including ALK fusions in 3-5% of non-small cell lung cancers (NSCLCs). While 3 generations (1G, 2G, 3G) of ALK tyrosine kinase inhibitors (TKIs) are approved globally for ALK fusion-positive (ALK+) NSCLC, they are limited by acquired ALK resistance mutations, CNS relapses, and for the 3G TKI lorlatinib, neurologic adverse events attributed to off-target TRK inhibition. A rationally designed ALK TKI that overcomes these limitations is needed. Preclinically, NVL-655 is a brain-penetrant, ALK-selective, and TRK-sparing TKI that exhibits activity against diverse ALK fusions and resistance mutations, including lorlatinib-refractory compound mutations. Materials and Methods: ALKOVE-1 (NCT05384626) is a global phase 1/2 trial of NVL-655. The ongoing phase 1 dose escalation enrolls patients (pts) with a previously treated ALK+ solid tumor, including NSCLC treated with ≥1 prior 2G or 3G ALK TKI. Primary objectives are to determine the safety/tolerability, recommended phase 2 dose (RP2D), and if applicable, the maximum tolerated dose (MTD). Additional objectives include assessments of pharmacokinetics (PK), pharmacodynamics, and preliminary activity by investigator-assessed tumor response (RECIST v1.1). Data cut: June 12, 2023. Results: 57 pts (54 NSCLC, 3 other solid tumors) received NVL-655 orally at 15-200 mg once daily (QD). Pts previously received a median of 4 (range: 1-8) prior anticancer therapies, including a 2G or 3G ALK TKI (100%); ≥1 2G ALK TKI + lorlatinib (77%); ≥3 ALK TKIs (53%); and chemotherapy (60%). At baseline, 51% had a history of CNS metastases. 47% had known ALK resistance mutations and 32% had compound ALK mutations, as per available local testing or central analyses of baseline circulating tumor DNA (ctDNA). Treatment-related adverse events (TRAEs) were generally mild; most frequent were nausea (12%), transaminase elevation (12%), fatigue (9%), and constipation (7%). Grade ≥3 TRAEs were transaminase elevation (n=2), CPK elevation (n=1), and fatigue (n=1). NVL-655 PK analyses demonstrated dose-proportional exposure. Partial responses (PR) were observed in 45% (15/33; 8 pending confirmation) of efficacy-evaluable pts with ALK+ NSCLC (15-150 mg QD), in 65% (11/17) with baseline ALK resistance mutations, and in 41% (12/29) post-lorlatinib, including cases with compound resistance mutations. CNS activity, including complete resolution of CNS metastases, has been observed. ctDNA analyses showed reductions, including clearance, of ALK fusion and mutation variants. Neither the MTD nor RP2D has been identified; phase 1 continues. Conclusions: NVL-655 has been well-tolerated up to 200 mg daily with favorable PK. Preliminary activity has been demonstrated in heavily pretreated pts with ALK+ NSCLC, including those who previously received 2G ALK TKI(s) + lorlatinib, with brain metastases, or with single/compound ALK resistance mutations. Citation Format: Jessica J Lin, Melissa Johnson, Enriqueta Felip, Sai-Hong Ignatius Ou, Benjamin Besse, Christina Baik, Julien Mazieres, Yasir Elamin, Joshua E. Reuss, Anna Minchom, Aurelie Swalduz, Nick Pavlakis, Geoffrey Liu, Shirish Gadgeel, D. Ross Camidge, Jennifer A Green, Junwu Shen, John Soglia, Yuting Sun, Viola W Zhu, Alexander Drilon. Safety and preliminary activity of the selective ALK inhibitor NVL-655 in patients with ALK fusion-positive solid tumors [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr B154.

Pralsetinib-associated pneumonia in RET fusion-positive non-small cell lung cancer

ObjectiveOncogenic alternation in RET is one of the important targets of non-small cell lung cancer (NSCLC). Pralsetinib has shown great efficacy in RET fusion-positive NSCLC, but a series of adverse reactions will inevitably occur in the meantime. We aimed to explore the clinical characteristics of patients with pneumonia and recognition it in early stage, so patients could longer benefit from pralsetinib.MethodsThis is a multicenter, retrospective study. RET fusion-positive advanced NSCLC patients who developed pneumonia during pralsetinib treatment from January 2020 to December 2022 were included. Clinical data, time to onset of pneumonia, methods of pneumonia diagnosis, treatment with pneumonia, prognosis of pneumonia, and the effect of pneumonia on the efficacy of pralsetinib.ResultsA total of 8 patients with pneumonia were included in the study, most of which were non-smoking female patients and the main fusion gene was KIF5B (87.5%), which was consistent with the general characteristics of RET fusion population. The median occurrence time of pralsetinib-associated pneumonia was 2.15 (range 1.1–6.63) months. All patients were infected by opportunistic pathogens, and the most common pathogen was human herpesviruses and pneumospora yerbii. Fever was always the first symptom, and timely anti-infective treatment including antibiotics, antiviral drugs, and antifungal drugs was effective. Until February 28, 2023, the median follow-up time was 18.7 months, the mean PFS of patients was 17.4 months, and the median PFS was not reached. Fortunately, patients who restarted pralsetinib after infection control continued to benefit.ConclusionsOpportunistic infection may be a unique adverse effect of pralsetinib. During the treatment of pralsetinib, we should be vigilant about the occurrence of pneumonia and achieve early recognition and timely treatment.

596P Repotrectinib in patients (pts) from Asia and China with ROS1 fusion-positive (ROS1+) non-small cell lung cancer (NSCLC): Results from the phase I/II TRIDENT-1 trial

596P Repotrectinib in patients (pts) from Asia and China with ROS1 fusion-positive (ROS1+) non-small cell lung cancer (NSCLC): Results from the phase I/II TRIDENT-1 trial

595P Durable efficacy of zenocutuzumab, a HER2 x HER3 bispecific antibody, in advanced NRG1 fusion-positive (NRG1+) non-small cell lung cancer (NSCLC)

595P Durable efficacy of zenocutuzumab, a HER2 x HER3 bispecific antibody, in advanced NRG1 fusion-positive (NRG1+) non-small cell lung cancer (NSCLC)