Ready, Set, Go: Setting Off on the Mission to Target KRAS in Colorectal Cancer.

Understanding the landscape of KRAS mutations in #CRC is crucial with over 2.8M annual diagnoses worldwide. Explore promising therapies and ongoing challenges in this comprehensive review. #CancerResearch #KRAS #ColorectalCancer.

The evolving landscape of tissue-agnostic therapies in precision oncology.

Tumor-agnostic therapies represent a paradigm shift in oncology by altering the traditional means of characterizing tumors based on their origin or location. Instead, they zero in on specific genetic anomalies responsible for fueling malignant growth. The watershed moment for tumor-agnostic therapies arrived in 2017, with the US Food and Drug Administration's historic approval of pembrolizumab, an immune checkpoint inhibitor. This milestone marked the marriage of genomics and immunology fields, as an immunotherapeutic agent gained approval based on genomic biomarkers, specifically, microsatellite instability-high or mismatch repair deficiency (dMMR). Subsequently, the approval of NTRK inhibitors, designed to combat NTRK gene fusions prevalent in various tumor types, including pediatric cancers and adult solid tumors, further underscored the potential of tumor-agnostic therapies. The US Food and Drug Administration approvals of targeted therapies (BRAF V600E, RET fusion), immunotherapies (tumor mutational burden ≥10 mutations per megabase, dMMR) and an antibody-drug conjugate (Her2-positive-immunohistochemistry 3+ expression) with pan-cancer efficacy have continued, offering newfound hope to patients grappling with advanced solid tumors that harbor particular biomarkers. In this comprehensive review, the authors delve into the expansive landscape of tissue-agnostic targets and drugs, shedding light on the rationale underpinning this approach, the hurdles it faces, presently approved therapies, voices from the patient advocacy perspective, and the tantalizing prospects on the horizon. This is a welcome advance in oncology that transcends the boundaries of histology and location to provide personalized options.

A Vision for Democratizing Next-Generation Oncology Clinical Trials.

SUMMARY: Revolutionary advancements in oncology have transformed lives, but the clinical trials ecosystem encounters challenges, including restricted access to innovative therapies and a lack of diversity in participant representation. A vision emerges for democratized, globally accessible oncology trials, necessitating collaboration among researchers, clinicians, patients, and policymakers to shift from converting complex, exclusive trials into a dynamic, inclusive force against cancer.

The Impact of Prior Single-Gene Testing on Comprehensive Genomic Profiling Results for Patients with Non-Small Cell Lung Cancer.

INTRODUCTION: Tissue-based broad molecular profiling of guideline-recommended biomarkers is advised for the therapeutic management of patients with non-small cell lung cancer (NSCLC). However, practice variation can affect whether all indicated biomarkers are tested. We aimed to evaluate the impact of common single-gene testing (SGT) on subsequent comprehensive genomic profiling (CGP) test outcomes and results in NSCLC. METHODS: Oncologists who ordered SGT for guideline-recommended biomarkers in NSCLC patients were prospectively contacted (May-December 2022) and offered CGP (DNA and RNA sequencing), either following receipt of negative SGT findings, or instead of SGT for each patient. We describe SGT patterns and compare CGP completion rates, turnaround time, and recommended biomarker detection for NSCLC patients with and without prior negative SGT results. RESULTS: Oncologists in > 80 community practices ordered CGP for 561 NSCLC patients; 135 patients (27%) first had negative results from 30 different SGT combinations; 84% included ALK, EGFR and PD-L1, while only 3% of orders included all available SGTs for guideline-recommended genes. Among patients with negative SGT results, CGP was attempted using the same tissue specimen 90% of the time. There were also significantly more CGP order cancellations due to tissue insufficiency (17% vs. 7%), DNA sequencing failures (13% vs. 8%), and turnaround time > 14 days (62% vs. 29%) than among patients who only had CGP. Forty-six percent of patients with negative prior SGT had positive CGP results for recommended biomarkers, including targetable genomic variants in genes beyond ALK and EGFR, such as ERBB2, KRAS (non-G12C), MET (exon 14 skipping), NTRK2/3, and RET . CONCLUSION: For patients with NSCLC, initial use of SGT increases subsequent CGP test cancellations, turnaround time, and the likelihood of incomplete molecular profiling for guideline-recommended biomarkers due to tissue insufficiency.

Patients with non-small cell lung cancer (NSCLC) should have their tumor tissue tested for all recommended biomarkers that can help identify their best treatment options. Traditional tests look at gene biomarkers one by one (single-gene testing), and doctors can order some or all these tests individually or in a group. However, some recommended biomarkers cannot be tested by traditional single-gene tests at all. Newer technology (next-generation sequencing) covers all current recommended treatment biomarkers in one test (comprehensive genomic profiling), but this testing is more expensive and can take more time. Our study shows that NSCLC patients do not get all recommended treatment biomarkers tested when a single-gene testing approach is taken. Single-gene testing also used up some patients' tumor tissue entirely, such that further testing by comprehensive genomic profiling could not be done at all (17% vs. 7% for patients with no prior single-gene tests), resulted in more sequencing failures (13% vs. 8%), and had turnaround time for results greater than 14 days for more patients (62% vs. 29%). When comprehensive genomic profiling was completed, 46% of patients with negative results from prior single-gene testing had positive results for recommended treatment biomarkers that were not included in the initial single-gene tests. To ensure that NSCLC patients receive testing for all recommended biomarkers, comprehensive genomic profiling must be performed first.

Adaptive Darwinian off-target resistance mechanisms to selective RET inhibition in RET driven cancer.

Patients treated with RET protein tyrosine kinase inhibitors (TKIs) selpercatinib or pralsetinib develop RET TKI resistance by secondary RET mutations or alterative oncogenes, of which alterative oncogenes pose a greater challenge for disease management because of multiple potential mechanisms and the unclear tolerability of drug combinations. A patient with metastatic medullary thyroid carcinoma (MTC) harboring a RET activation loop D898_E901del mutation was treated with selpercatinib. Molecular alterations were monitored with tissue biopsies and cfDNA during the treatment. The selpercatinib-responsive MTC progressed with an acquired ETV6::NTRK3 fusion, which was controlled by selpercatinib plus the NTRK inhibitor larotrectinib. Subsequently, tumor progressed with an acquired EML4::ALK fusion. Combination of selpercatinib with the dual NTRK/ALK inhibitor entrectinib reduced the tumor burden, which was followed by appearance of NTRK3 solvent-front G623R mutation. Preclinical experiments validated selpercatinib plus larotrectinib or entrectinib inhibited RET/NTRK3 dependent cells, whereas selpercatinib plus entrectinib was necessary to inhibit cells with RET/NTRK3/ALK triple alterations or a mixture of cell population carrying these genetic alterations. Thus, RET-altered MTC adapted to selpercatinib and larotrectinib with acquisition of ETV6::NTRK3 and EML4::ALK oncogenes can be managed by combination of selpercatinib and entrectinib providing proof-of-concept of urgency of incorporating molecular profiling in real-time and personalized N-of-1 care transcending one-size-fits-all approach.

RAF inhibitor re-challenge therapy in BRAF-aberrant pan-cancers: the RE-RAFFLE study.

Previous studies have shown the clinical benefit of rechallenging the RAF pathway in melanoma patients previously treated with BRAF inhibitors. 44 patients with multiple tumors harboring RAF alterations were rechallenged with a second RAF inhibitor, either as monotherapy or in combination with other therapies, after prior therapy with a first RAF inhibitor. This retrospective observational study results showed that rechallenging with RAFi(s) led to an overall response rate of 18.1% [PR in thyroid (1 anaplastic; 3 papillary), 1 ovarian, 2 melanoma, 1 cholangiocarcinoma, and 1 anaplastic astrocytoma]. The clinical benefit rate was 54.5%; more than 30% of patients had durable responses with PR and SD lasting > 6 months. The median progression-free survival on therapy with second RAF inhibitor in the rechallenge setting either as monotherapy or combination was shorter at 2.7 months (0.9-30.1 m) compared to 8.6 months (6.5-11.5 m) with RAF-1i. However, the median PFS with RAF-2i responders (PFS-2) improved at 12.8 months compared to 11.4 months with RAF-1i responders. The median OS from retreatment with RAF-2i was 15.5 months (11.1-30.8 m). Further prospective studies are needed to validate these results and expand targeted therapy options for RAF-aberrant cancers.

Phase I study of sapanisertib (CB-228/TAK-228/MLN0128) in combination with ziv-aflibercept in patients with advanced solid tumors.

BACKGROUND: Sapanisertib is a potent ATP-competitive, dual inhibitor of mTORC1/2. Ziv-aflibercept is a recombinant fusion protein comprising human VEGF receptor extracellular domains fused to human immunoglobulin G1. HIF-1α inhibition in combination with anti-angiogenic therapy is a promising anti-tumor strategy. This Phase 1 dose-escalation/expansion study assessed safety/ tolerability of sapanisertib in combination with ziv-aflibercept in advanced solid tumors. METHODS: Fifty-five patients with heavily pre-treated advanced metastatic solid tumors resistant or refractory to standard treatment received treatment on a range of dose levels. RESULTS: Fifty-five patients were enrolled and treated across a range of dose levels. Forty were female (73%), median age was 62 (range: 21-79), and ECOG PS was 0 (9, 16%) or 1 (46, 84%). Most common tumor types included ovarian (8), colorectal (8), sarcoma (8), breast (3), cervical (4), and endometrial (4). Median number of prior lines of therapy was 4 (range 2-11). Sapanisertib 4 mg orally 3 days on and 4 days off plus 3 mg/kg ziv-aflibercept IV every 2 weeks on a 28-day cycle was defined as the maximum tolerated dose. Most frequent treatment-related grade ≥2 adverse events included hypertension, fatigue, anorexia, hypertriglyceridemia, diarrhea, nausea, mucositis, and serum lipase increase. There were no grade 5 events. In patients with evaluable disease (n = 50), 37 patients (74%) achieved stable disease (SD) as best response, two patients (4%) achieved a confirmed partial response (PR); disease control rate (DCR) (CR + SD + PR) was 78%. CONCLUSION: The combination of sapanisertib and ziv-aflibercept was generally tolerable and demonstrated anti-tumor activity in heavily pre-treated patients with advanced malignancies.

Targeting All BRAF Alterations: The (Re)-Search Continues.

VivekSubbiah & colleagues delve into the @ASCO #TAPURStudy, shedding light on the importance of targeting ALL #BRAFAlterations, beyond V600E. (Re)-search continues, urging us to push the boundaries and unlock new possibilities in #PrecisionMedicine. #CancerResearch #JCOPO.

Modernize Precision Oncology With Decentralized Trial Tools.

This Viewpoint examines how modern precision oncology clinical trials, bolstered by decentralized trial tools, can enhance access to cancer treatments and reduce the burden of trial participation on clinics and participants.

Tissue-Agnostic Cancer Therapy Approvals.

Tumor-agnostic, or histology-agnostic, cancer therapy marks a groundbreaking evolution in the realm of precision oncology. In stark contrast to conventional cancer treatments that categorize malignancies based on their tissue of origin (eg, breast, lung, renal cell, etc), tumor-agnostic therapies transcend histologic boundaries, honing in on the genetic and molecular attributes of tumors, regardless of their location. This article offers a comprehensive review of the current landscape of tissue-agnostic cancer therapies and provides clinical insights to empower surgical oncologists with a deeper understanding of these innovative therapeutic approaches.

Lurbinectedin in patients with small cell lung cancer with chemotherapy-free interval ≥30 days and without central nervous metastases.

OBJECTIVES: This report focuses on lurbinectedin activity and safety in a subgroup of small cell lung cancer (SCLC) patients from a Basket phase 2 study (Trigo et al. Lancet Oncology 2020;21:645-654) with chemotherapy-free interval (CTFI) ≥ 30 days. This pre-planned analysis was requested for obtaining regulatory approval of lurbinectedin in Switzerland. MATERIALS AND METHODS: Patients with extensive-stage SCLC, no central nervous system (CNS) metastases, and disease progression after platinum-containing therapy were included. Topotecan data from a contemporary, randomized, controlled phase 3 study (ATLANTIS) were used as indirect external control in a matched patient population (n = 98 patients). RESULTS: Lurbinectedin showed a statistically significant higher overall response rate (ORR) by investigator assessment (IA) compared to topotecan subgroup (41.0 % vs. 25.5 %; p = 0.0382); higher ORR by Independent Review Committee (IRC) (33.7 % vs. 25.5 %); longer median duration of response (IA: 5.3 vs. 3.9 months; IRC: 5.1 vs. 4.3 months), and longer median overall survival (10.2 vs. 7.6 months). Grade ≥ 3 hematological abnormalities were remarkably lower with lurbinectedin: anemia 12.0 % vs. 54.1 %; leukopenia 30.1 % vs. 68.4 %; neutropenia 47.0 % vs. 75.5 %, and thrombocytopenia 6.0 % vs. 52.0 %. Febrile neutropenia was observed at a higher incidence with topotecan (6.1 % vs. 2.4 % with lurbinectedin) despite that the use of growth-colony stimulating factors was mandatory with topotecan. CONCLUSION: With the limitations of an indirect comparison, however using recent and comparable SCLC datasets, this post hoc analysis shows that SCLC patients with CTFI ≥ 30 days and no CNS metastases have a positive benefit/risk ratio with lurbinectedin, superior to that observed with topotecan.

Interpreting and integrating genomic tests results in clinical cancer care: Overview and practical guidance.

The last decade has seen rapid progress in the use of genomic tests, including gene panels, whole-exome sequencing, and whole-genome sequencing, in research and clinical cancer care. These advances have created expansive opportunities to characterize the molecular attributes of cancer, revealing a subset of cancer-associated aberrations called driver mutations. The identification of these driver mutations can unearth vulnerabilities of cancer cells to targeted therapeutics, which has led to the development and approval of novel diagnostics and personalized interventions in various malignancies. The applications of this modern approach, often referred to as precision oncology or precision cancer medicine, are already becoming a staple in cancer care and will expand exponentially over the coming years. Although genomic tests can lead to better outcomes by informing cancer risk, prognosis, and therapeutic selection, they remain underutilized in routine cancer care. A contributing factor is a lack of understanding of their clinical utility and the difficulty of results interpretation by the broad oncology community. Practical guidelines on how to interpret and integrate genomic information in the clinical setting, addressed to clinicians without expertise in cancer genomics, are currently limited. Building upon the genomic foundations of cancer and the concept of precision oncology, the authors have developed practical guidance to aid the interpretation of genomic test results that help inform clinical decision making for patients with cancer. They also discuss the challenges that prevent the wider implementation of precision oncology.

Quantitative bias analysis for external control arms using real-world data in clinical trials: a primer for clinical researchers.

Development of medicines in rare oncologic patient populations are growing, but well-powered randomized controlled trials are typically extremely challenging or unethical to conduct in such settings. External control arms using real-world data are increasingly used to supplement clinical trial evidence where no or little control arm data exists. The construction of an external control arm should always aim to match the population, treatment settings and outcome measurements of the corresponding treatment arm. Yet, external real-world data is typically fraught with limitations including missing data, measurement error and the potential for unmeasured confounding given a nonrandomized comparison. Quantitative bias analysis (QBA) comprises a collection of approaches for modelling the magnitude of systematic errors in data which cannot be addressed with conventional statistical adjustment. Their applications can range from simple deterministic equations to complex hierarchical models. QBA applied to external control arm represent an opportunity for evaluating the validity of the corresponding comparative efficacy estimates. We provide a brief overview of available QBA approaches and explore their application in practice. Using a motivating example of a comparison between pralsetinib single-arm trial data versus pembrolizumab alone or combined with chemotherapy real-world data for RET fusion-positive advanced non-small cell lung cancer (aNSCLC) patients (1-2% among all NSCLC), we illustrate how QBA can be applied to external control arms. We illustrate how QBA is used to ascertain robustness of results despite a large proportion of missing data on baseline ECOG performance status and suspicion of unknown confounding. The robustness of findings is illustrated by showing that no meaningful change to the comparative effect was observed across several 'tipping-point' scenario analyses, and by showing that suspicion of unknown confounding was ruled out by use of E-values. Full R code is also provided.

Impact of tissue-agnostic approvals on management of primary brain tumors.

Novel tissue-agnostic therapeutics targeting driver mutations in tumor cells have been recently approved by FDA, driven by basket trials that have demonstrated their efficacy and safety across diverse tumor histology. However, the relative rarity of primary brain tumors (PBTs) has limited their representation in early trials of tissue-agnostic medications. Thus, consensus continues to evolve regarding utility of tissue-agnostic medications in routine practice for PBTs, a diverse group of neoplasms characterized by limited treatment options and unfavorable prognoses. We describe current and potential impact of tissue-agnostic approvals on management of PBTs. We discuss data from clinical trials for PBTs regarding tissue-agnostic targets, including BRAFV600E, neurotrophic tyrosine receptor kinase (NTRK) fusions, microsatellite instability-high (MSI-High), mismatch repair deficiency (dMMR), and high tumor mutational burden (TMB-H), in context of challenges in managing PBTs. Described are additional tissue-agnostic targets that hold promise for benefiting patients with PBTs, including RET fusion, fibroblast growth factor receptor (FGFR), ERBB2/HER2, and KRASG12C, and TP53Y220C.

Circulating Tumor DNA Enables Sensitive Detection of Actionable Gene Fusions and Rearrangements Across Cancer Types.

PURPOSE: Genomic rearrangements can generate potent oncogenic drivers or disrupt tumor suppressor genes. This study examines the landscape of fusions and rearrangements detected by liquid biopsy (LBx) of circulating tumor DNA (ctDNA) across different cancer types. EXPERIMENTAL DESIGN: LBx from 53,842 patients with 66 solid tumor types were profiled using FoundationOneLiquid CDx, a hybrid-capture sequencing platform that queries 324 cancer-related genes. Tissue biopsies (TBx) profiled using FoundationOneCDx were used as a comparator. RESULTS: Among all LBx, 7,377 (14%) had ≥1 pathogenic rearrangement detected. A total of 3,648 (6.8%) LBx had ≥1 gain-of-function (GOF) oncogene rearrangement, and 4,428 (8.2%) LBx had ≥1 loss-of-function rearrangement detected. Cancer types with higher prevalence of GOF rearrangements included those with canonical fusion drivers: prostate cancer (19%), cholangiocarcinoma (6.4%), bladder (5.5%), and non-small cell lung cancer (4.4%). Although the prevalence of driver rearrangements was lower in LBx than TBx overall, the frequency of detection was comparable in LBx with a tumor fraction (TF) ≥1%. Rearrangements in FGFR2, BRAF, RET, and ALK, were detected across cancer types, but tended to be clonal variants in some cancer types and potential acquired resistance variants in others. CONCLUSIONS: In contrast to some prior literature, this study reports detection of a wide variety of rearrangements in ctDNA. The prevalence of driver rearrangements in tissue and LBx was comparable when TF ≥1%. LBx presents a viable alternative when TBx is not available, and there may be less value in confirmatory testing when TF is sufficient.

Revolutionizing cancer drug development: Harnessing the potential of basket trials.

The landscape of cancer therapy has been transformed by advances in clinical next-generation sequencing, genomically targeted therapies, and immunotherapies. Well designed clinical trials and efficient clinical trial conduct are crucial for advancing our understanding of cancer, improving patient outcomes, and identifying personalized treatments. Basket trials have emerged as one of the efficient modern clinical trial designs that evaluate the efficacy of these therapies across multiple cancer types based on specific molecular alterations or biomarkers, irrespective of histology or anatomic location. This review delves into the evolution of basket trials in cancer drug development, highlighting their potential prospects and current obstacles. The design of basket trials involves screening patients for specific molecular alterations or biomarkers and enrolling them in the trial to receive the targeted therapy under investigation. Statistical considerations play a crucial role in the design, analysis, and interpretation of basket trials. Several notable examples of basket trials that have led to US Food and Drug Administration approval for uncommon molecular alterations (e.g., NTRK fusions, BRAF mutations, RET and FGFR1 alterations) are discussed, including LOXO-TRK (ClinicalTrials.gov identifier NCT02122913)/SCOUT (ClinicalTrials.gov identifier NCT02637687)/NAVIGATE (ClinicalTrials.gov identifier NCT02576431)/STARTRK (ClinicalTrials.gov identifiers NT02097810, NT02568267), VE-BASKET (ClinicalTrials.gov identifier NCT01524978), ROAR Basket (ClinicalTrials.gov identifier NCT02034110), LIBRETTO-001 (ClinicalTrials.gov identifier NCT03157128), ARROW (ClinicalTrials.gov identifier NCT03037385), FIGHT-203 (ClinicalTrials.gov identifier NCT03011372), and the National Cancer Institute-Molecular Analysis for Therapy Choice trial (ClinicalTrials.gov identifier NCT02465060). Basket trials have the potential to revolutionize cancer treatment by identifying effective therapies for patients based on specific molecular alterations or biomarkers rather than traditional histology-based approaches. PLAIN LANGUAGE SUMMARY: To gain more knowledge about cancer, improve patient outcomes, and discover personalized treatments, it is crucial to conduct clinical trials efficiently. One effective type of clinical trial is called a basket trial. In basket trials, new treatments are tested on various types of cancer, regardless of their location in the body; instead, researchers focus on specific abnormalities in the cancer cells. Basket trials offer hope that we can find personalized treatments that are more effective for each individual battling cancer.

Transporting Comparative Effectiveness Evidence Between Countries: Considerations for Health Technology Assessments.

Internal validity is often the primary concern for health technology assessment agencies when assessing comparative effectiveness evidence. However, the increasing use of real-world data from countries other than a health technology assessment agency's target population in effectiveness research has increased concerns over the external validity, or "transportability", of this evidence, and has led to a preference for local data. Methods have been developed to enable a lack of transportability to be addressed, for example by accounting for cross-country differences in disease characteristics, but their consideration in health technology assessments is limited. This may be because of limited knowledge of the methods and/or uncertainties in how best to utilise them within existing health technology assessment frameworks. This article aims to provide an introduction to transportability, including a summary of its assumptions and the methods available for identifying and adjusting for a lack of transportability, before discussing important considerations relating to their use in health technology assessment settings, including guidance on the identification of effect modifiers, guidance on the choice of target population, estimand, study sample and methods, and how evaluations of transportability can be integrated into health technology assessment submission and decision processes.

Pralsetinib in Patients with Advanced/Metastatic Rearranged During Transfection (RET)-Altered Thyroid Cancer: Updated Efficacy and Safety Data from the ARROW Study.

Background: Rearranged during transfection (RET) alterations are targetable oncogenic drivers in thyroid cancer. Primary data from the open-label, phase 1/2 ARROW study demonstrated clinical activity and manageable safety with pralsetinib, a selective RET inhibitor, in patients with advanced/metastatic RET-altered thyroid cancer. We present an updated analysis with more patients and longer follow-up. Methods: Adult patients with advanced/metastatic RET-mutant medullary thyroid cancer (MTC) or RET fusion-positive thyroid cancer who initiated oral pralsetinib at 400 mg once daily were included. Primary endpoints were overall response rate (ORR) by blinded independent central review (per RECIST v1.1) and safety. Secondary endpoints included duration of response (DoR), progression-free survival (PFS), and overall survival. Responses were assessed in three cohorts of patients with baseline measurable disease: patients with RET-mutant MTC who had received prior cabozantinib and/or vandetanib (C/V), treatment-naïve patients with RET-mutant MTC, and patients with previously treated RET fusion-positive thyroid cancer. Patient-reported outcomes (PROs) were an exploratory endpoint. Results: As of October 18, 2021, the measurable disease population comprised of 61 patients with RET-mutant MTC and prior C/V, 62 treatment-naïve patients with RET-mutant MTC, and 22 patients with RET fusion-positive thyroid cancer who had received prior systemic therapy, including radioactive iodine. The ORR was 55.7% [confidence interval; 95% CI: 42.4-68.5] in patients with RET-mutant MTC and prior C/V, 77.4% [95% CI: 65.0-87.1] in treatment-naïve patients with RET-mutant MTC, and 90.9% [95% CI: 70.8-98.9] in patients with previously treated RET fusion-positive thyroid cancer. Median DoR and median PFS were both 25.8 months in patients with RET-mutant MTC and prior C/V, not reached in treatment-naïve patients with RET-mutant MTC, and 23.6 and 25.4 months, respectively, in patients with previously treated RET fusion-positive thyroid cancer. In the RET-altered thyroid cancer safety population (N = 175), 97.1% of patients reported a treatment-related adverse event (TRAE); these led to discontinuation in 5.7% and dose reduction in 52.6% of patients. There was one death (0.6%) due to a TRAE. PROs improved or remained stable after pralsetinib treatment. Conclusions: In this updated analysis of the ARROW study, pralsetinib continued to show deep and durable clinical activity and a manageable safety profile in patients with advanced/metastatic RET-altered thyroid cancer. Clinical Trial Registration: NCT03037385.

Pralsetinib in patients with RET fusion-positive non-small-cell lung cancer: A plain language summary of the ARROW study.

WHAT IS THIS SUMMARY ABOUT?: This is a summary of a research study called ARROW, which tested a medicine called pralsetinib in patients with non-small cell lung cancer (NSCLC), thyroid cancer, and other advanced solid tumours caused by a change in a gene called RET. For the purposes of this summary, only patients with NSCLC with a change in RET called fusion (RET fusion+) are highlighted. WHAT WERE THE RESULTS?: In total, 281 patients with RET fusion+ NSCLC had taken part in this study across the USA, Europe, and Asia. Patients were asked to take four pills (adding up to 400 mg) of pralsetinib each day and were checked for any changes in their tumours, as well as for any side effects. After an average of 8 months of treatment with pralsetinib, 72% of previously untreated patients and 59% of patients who had previously received chemotherapy had considerable shrinkage of their tumours. Among 10 patients with tumours which had spread to the brain (all of whom had received previous treatments), 70% had their tumours shrink greatly in the brain after treatment with pralsetinib. On average, patients lived with little to no tumour growth for 16 months. In previously untreated patients, the most common severe side effects that were considered related to pralsetinib treatment were decreased white blood cells (neutrophils and lymphocytes), increased blood pressure, and an increase in a blood protein called creatine phosphokinase. In previously treated patients, the severe side effects were decreased white blood cells (neutrophils, lymphocytes, and leukocytes), increased blood pressure, and low levels of red blood cells. In both untreated and previously treated patients, the most common severe side effects that required hospital attention were lung inflammation/swelling causing shortness of breath (pneumonitis) and lung infection (pneumonia). WHAT DO THE RESULTS MEAN?: Overall, the ARROW study showed that pralsetinib was effective in shrinking tumours in patients with RET fusion+ NSCLC regardless of previous treatment history. The recorded side effects were expected in patients receiving this type of medicine. Clinical Trial Registration: NCT03037385 (ARROW) (ClinicalTrials.gov).