Troubles du système nerveux central sous lorlatinib : comment les détecter et les gérer en pratique? Central nervous system disorders on lorlatinib: How to detect and manage in practice?

The therapeutic arsenal for advanced ALK positive non-small cell lung cancer has been enriched by specific treatments targeting this molecular abnormality, with five molecules available, including lorlatinib, approved since July 2020. This treatment can have side effects common to other tyrosine kinase inhibitors, as well as other less common disorders affecting the central nervous system such as impaired cognitive function, speech or mood. The prevalence of neuro-psychiatric effects under treatment with lorlatinib reported in studies is nearly 40 % with a mild to moderate intensity in most cases. Given the potential impact on patients’ quality of life and even on compliance with treatment, it is essential to include their detection during consultations. The main problem is still to have simple screening tools adapted to clinical practice. A multidisciplinary expert panel (pulmonologist, medical oncologist, psychiatrist, neurologist, pharmacist, nurse) therefore met to propose, based on data from the literature and their clinical experience, elements of management in order to detect these cognitive disorders at an early stage and optimize treatment tolerance. The subjects discussed concern screening and assessment tools, the management of side effects, and their prevention. The use of the practical elements proposed by the group could help optimize the identification and management of central nervous system disorders occurring on lorlatinib. READ ARTICLE

Bulletin du Cancer DOI:10.1016/j.bulcan.2022.01.011

Authors: Vincent Fallet, Pascal Rouby, Guido Ahle, Jennifer Arrondeau, Charles Naltet, Adeline Duflot-Boukobza, Françoise De Crozals, Hervé Lena, Alexis Cortot

P8-133: Clinical course of the patients who survived more than five-years in patients with EGFR mutated OR ALK rearranged advanced non-small cell lung cancer (NSCLC)

Background and Aims: The discovery of driver oncogenes like EGFR mutation and ALK fusion gene, and the development of their specific inhibitors have improved prognosis of NSCLC patients. Because the patients had been followed up to about 5 years in most of the clinical trials, the long-term clinical course especially after 5 years has been undefined. The object is to know clinical course after 5 years from the first chemotherapy, and to investigate factors that lead to long-term survival.
Methods: One hundred seventy-seven patients with EGFR mutated or ALK rearranged advanced NSCLC who received the first chemotherapy between December 2008 and September 2015 were included. Kaplan Meier curves were drawn for the total cohort and for the subgroups of characteristics and metastases.
Results: Median OS in the total cohort was 40.6 months, the 1-year survival rate was 89 %, the 3-year survival rate was 54 %, and the 5-year survival rate was 28 %. “Long tail” in OS curve existed, but most of ..... READ ARTICLE

Respirology DOI:10.1111/resp.14150_645

Authors: Shoko Shimamura, Takehito Shukuya, Tetsuhiko Asao, Daisuke Hayakawa, Kana Kurokawa, Shiting Xu, Yoichiro Mitsuishi, Ken Tajima, Rina Shibayama, Naoko Shimada, Fumiyuki Takahashi, Kazuhisa Takahashi

Conference PaperKirk SmithNovember 19, 2021EGFR, ALK, 5 years+

P8-170: A patient with ALK translocation-positive lung adenocarcinoma in whom an EGFR mutation developed during the treatment with ALK inhibitors

Background: Generally, ALK gene translocation and EGFR gene mutation are mutually exclusive in non-small cell lung cancer (NSCLC). We present a patient with ALK translocation-positive lung adenocarcinoma in whom an EGFR mutation developed during the treatment with an ALK inhibitors.

Case Presentation: A 70-year-old man was diagnosed with Stage IVb (cT2N3M1c) adenocarcinoma of the lung in July 20XX-8. Initial chemotherapy with CDDP+PEM was started in August, and 6 courses were performed with best response of PR. Maintenance therapy was performed for 26 courses. In May 20XX-5, multiple bone metastases emerged and 5 courses of DTX was given as the 2nd-line chemotherapy from July 20XX-5 to May 20XX-4 with the best response of SD until bone metastases developed. A trans-bronchial re-biopsy of the primary tumor in the upper lobe of the right lung revealed the translocation of ALK gene. Crizotinib was started in June as the 3rd-line chemotherapy. In August 20XX-3, multiple brain metastases de..... READ ARTICLE

Respirology DOI:10.1111/resp.14150_682

Authors: Misaki Morishita, Yoshiki Negi, Taiichiro Otsuki, Koji Mikami, Eisuke Shibata, Daisuke Horio, Maiko Niki, Akio Tada, Mayuko Tokuda, Jotaro Kiyota, Toshiyuki Minami, Ryo Takahashi, Takashi Yokoi, Kozo Kuribayashi, Takashi Kijima

Conference PaperKirk SmithNovember 19, 2021ALK and EGFR co-mutation, ALK, EGFR, Co-mutation

1356P Cumulative incidence and baseline imaging patterns of brain metastases in advanced EGFR and ALK positive non-small cell lung cancer (NSCLC)

Background: Up to 40% of NSCLC patients develop brain metastases (mets) during the course of their disease. We explored the impact of histology and EGFR and ALK mutations on cumulative incidence rates of brain mets and influence of brain imaging patterns. Conclusions: Our real-world data confirm a higher cumulative incidence of brain metastases in EGFR+/ALK+ adenocarcinoma compared to WT or SCC and more brain imaging at baseline. Future analyses will focus on treatment-based outcomes (tyrosine kinase inhibitors, different radiation modalities) in EGFR+/ALK+ patients compared to WT adenocarcinoma and SCC. READ ARTICLE

Annals of Oncology DOI:10.1016/j.annonc.2021.08.1956

Authors: M.T. Chowdhury, M. García Pardo de Santayana, S. Schmid, S. Cheng, L.J. Zhan, M.C. Brown, K. Khan, P. Walia, A. Sabouhanian, E. Strom, J. Herman, N. Leighl, P. Bradbury, F.A. Shepherd, A. Sacher, W. Xu, G. Liu, D. Shultz

1196P Pre-existing and acquired mechanisms of resistance to lorlatinib in previously treated patients (pts) with ALK+ advanced non-small cell lung cancer (NSCLC)

Lorlatinib, a potent, brain-penetrant, 3rd-generation (gen) ALK/ROS1 tyrosine kinase inhibitor (TKI) active against most known resistance mutations, showed robust clinical activity in ALK+ or ROS1+ NSCLC in a Ph 1/2 study that enrolled mostly heavily pretreated pts with CNS metastases. We evaluated potential resistance mechanisms, pre-existing or acquired, and efficacy in these settings.Limitations apply to ctDNA analyses, but in this heavily pretreated group of pts with ALK+ NSCLC, presence of TP53 mutations at BL was potentially associated with decreased lorlatinib efficacy, while presence of bypass mechanism aberrations with reduced activity. Upon progression, ALK compound mutations and bypass mechanism aberrations emerged in ∼28% of pts. READ ARTICLE

Annals of Oncology DOI:10.1016/j.annonc.2021.08.1801

Authors: B.J. Solomon, J-F. Martini, A. Bearz, E.H. Tan, R. Soo, B. Besse, T.M. Bauer, D. Shepard, F. Toffalorio, A. Abbattista, E. Felip, A.T. Shaw, S. Viteri, D.R. Camidge, T. Seto, S-H.I. Ou

Conference PaperKirk SmithSeptember 1, 2021Lorlatinib, CROWN trial, crizotinib, CNS, AE

1199P Dose modification for the management of CNS adverse events in the phase III CROWN study of lorlatinib in non-small cell lung cancer (NSCLC)

In the ongoing phase III CROWN study (NCT03052608), lorlatinib, a 3rd-generation inhibitor of anaplastic lymphoma kinase (ALK), improved progression-free survival (PFS) and intracranial response rates vs crizotinib in patients with previously untreated ALK-positive NSCLC. Here we present data on lorlatinib dose modification for the management of CNS adverse events (AEs). CNS AEs spontaneously resolved in 53% of cases, and lorlatinib dose modification was effective in managing CNS AEs without compromising efficacy. READ ARTICLE

Annals of Oncology DOI:10.1016/j.annonc.2021.08.1804

Authors: B.J. Solomon, T.S.K. Mok, H. Hayashi, A. Bearz, K.D. Penkov, Y-L. Wu, O. Arrieta, A.M. Calella, G. Peltz, A. Polli, H. Thurm, T.M. Bauer

Conference PaperKirk SmithSeptember 1, 2021Lorlatinib, CROWN trial, crizotinib, CNS, AE

1197P First-line lorlatinib versus crizotinib in ALK-positive non-small cell lung cancer: Asian subgroup analysis of CROWN

Lorlatinib, a 3rd-generation ALK inhibitor, significantly prolonged progression-free survival (PFS) vs crizotinib in the CROWN trial in patients with untreated ALK-positive non-small cell lung cancer (NSCLC). We report data from the Asian subgroup of CROWN. In the Asian subgroup, a consistent and clinically meaningful improvement in PFS was observed for lorlatinib vs crizotinib. The efficacy and safety of lorlatinib vs crizotinib in the Asian subgroup of CROWN was consistent with the overall population. READ ARTICLE

Annals of Oncology DOI:10.1016/j.annonc.2021.08.1802

Authors: Q. Zhou, H.R. Kim, R. Soo, G-C. Chang, C-H. Chiu, H. Hayashi, S-W. Kim
S. Teraoka, Y. Goto, J. Zhou, V.H.F. Lee, B. Han, J.C.M. Ho, D-W. Kim
C-C. Lin, S. Lu, A. Polli, A.M. Calella, T.S.K. Mok, Y-L. Wu

Conference PaperKirk SmithSeptember 1, 2021Lorlatinib, CROWN trial, crizotinib

Abstract LB043: Efficacy of Lorlatinib in Treatment-Naïve Patients (pts) With ALK-Positive Advanced Non-Small Cell Lung Cancer (NSCLC) in Relation to EML4-ALK Variant Type and ALK Mutations

Conference PaperKirk SmithJuly 1, 2021Lorlatinib, Treatment-Naïve Patients, ALK +, Non-Small Cell Lung Cancer (NSCLC), EML4-ALK Variants, https://cancerres.aacrjournals.org/content/81/13_Supplement/LB043.short

Abstract 1468: NUV-655 (NVL-655) is a selective, brain-penetrant ALK inhibitor with antitumor activity against the lorlatinib-resistant G1202R/L1196M compound mutation

ALK is a proto-oncogene that encodes the receptor tyrosine kinase ALK, which can be aberrantly activated by gene rearrangement or point mutation to drive tumor cell proliferation, survival, and metastasis. In advanced non-small cell lung cancer (NSCLC), ALK rearrangements are detected in about 4% of patients; at the time of diagnosis, 30% to 40% of these patients present with accompanying central nervous system (CNS) metastases. Brain-penetrant tyrosine kinase inhibitors (TKIs) alectinib, brigatinib, ceritinib, and lorlatinib are FDA-approved treatments for ALK-positive NSCLC; however, durability of response to these treatments has been limited in many cases by the emergence of mutations in ALK that confer resistance. A major resistance mutation to alectinib, brigatinib, and ceritinib is the ALK G1202R solvent front mutation. Although patients with tumors harboring the ALK G1202R mutation have responded to lorlatinib, many have subsequently relapsed by emergence of ALK compound mutatio..... READ ARTICLE

Cancer Research DOI:10.1158/1538-7445.AM2021-1468

Authors: Henry E. Pelish, Anupong Tangpeerachaikul, Nancy E. Kohl, James R. Porter, Matthew D. Shair and Joshua C. Horan

Circulating tumor DNA to investigate resistance mechanism and clone evolution of ALK TKI treated lung adenocarcinoma

Conference PaperKirk SmithMay 28, 2021ctDNA, resistance mechanism, ALK, TKI sequence, lung adenocarcinoma

RNA sequencing effectively identifies gene fusions undetected by DNA sequencing in lung adenocarcinomas

Background: Next-generation sequencing of DNA, which can provide valid information for clinical therapeutic decision-making, has been widely used in the management of lung cancer especially adenocarcinoma. However, due to its technical limitations for detecting certain alterations such as gene rearrangement, the DNA-based sequencing (DNA-seq) may miss the actionable alteration in some cases, who would have benefited from targeted therapy. The study aimed to evaluate the capability of RNA sequencing (RNA-seq) in identifying DNA-seq undetectable gene alterations in lung adenocarcinomas. Conclusions: Targeted RNA-seq can effectively identify genomic rearrangements that are undetectable by DNA-seq and provide lung adenocarcinoma patients with more opportunities for targeted therapy. Therefore, it should be recommended for all patients, in whom DNA-seq fails to detect driver alteration. READ ARTICLE

Journal of Clinical Oncology DOI:10.1200/JCO.2021.39.15_suppl.3052

Authors: Ruiying Zhao, Yuchen Han, Chan Xiang, Shengnan Chen, Jikai Zhao, Lianying Guo, Anbo Yu, Jinchen Shao, Lei Zhu, Yue Tian, Fan Yang, Lin Shao, Xuejing Li, Lu Zhang

Conference PaperKirk SmithMay 28, 2021RNA sequencing, DNA sequencing, lung adenocarcinoma

Real-world patterns of biomarker testing and targeted therapy in metastatic non-small cell lung cancer (mNSCLC) in the community oncology setting

Background: National guidelines recommend biomarker testing in mNSCLC, and targeted therapy is associated with improved outcomes. The aim of this study was to understand the real-world biomarker testing and treatment patterns in the community setting. Conclusions: Despite availability of promising biomarker-based therapies, the lack of adequate testing in the community oncology setting means that not all eligible patients are receiving the most effective therapies upfront. Nearly 61% of patients had no DM test reported before 1L treatment in this mNSCLC cohort (all histologies), and some were determined to be DM positive at a later time, highlighting a missed opportunity to employ the most effective biomarker-directed front-line treatment. Next steps in this study will include assessing patterns by histology. READ ARTICLE

Journal of Clinical Oncology DOI:10.1200/JCO.2021.39.15_suppl.9079

Authors: Eric S. Nadler, Anupama Vasudevan, Kalatu Davies, Yunfei Wang, Ravindra Gupta, Sarika Ogale

Patient-derived lung cancer organoids for the selection of therapeutic options in an ALK-rearranged tumor

Background: ALK rearrangements are key targets in non-small-cell lung cancer (NSCLC). Unfortunately, the optimal sequential strategy of ALK-tyrosine kinase inhibitors (TKI) remains to be defined. Testing drug sensitivity in patient derived organoids (PDOs) could support a rational drug selection in this setting. Conclusions: We present clinical evidence that PDOs are an alternative tool in oncogenic addicted tumors helping to guide treatment decisions and increasing a more personalized sequential treatment approach. READ ARTICLE

Journal of Clinical Oncology DOI:10.1200/JCO.2021.39.15_suppl.e21014

Authors: Beatriz Jimenez Munarriz, Zahra Dantes, Javier De Castro, Paloma Navarro, Monica Yagüe, Arantzazu Barquin, Juan Francisco Rodriguez-Moreno, Elena Sevillano, Sergio Ruiz, Anabel del Barrio, Gema García Ledo, Miriam Dorta, Ana Collazo Lorduy, Emiliano Calvo, Jesús García-Donas, Sandra Serrano, Apoorva Manjunath, Luciana Ferreira, Barbara Hefel, Jordi Remon

Impact of rapid multigene assays with short turnaround time (TAT) on the development of precision medicine for non-small cell lung cancer (NSCLC)

Background: A variety of oncogene drivers have been identified in NSCLC and molecularly-stratified precision medicine has led to improved survival in advanced NSCLC. Next-generation sequencing (NGS)-based testing is utilized to detect actionable gene alterations; however, the TAT of NGS is often too long to translate into clinical decision making. Thus, rapid multi-gene testing alternatives are needed. Conclusions: Both the 9-in-1 test and Genexus/OPA had short TATs (3−4 days), high success rates (96−98%) and good concordance (95−98%) compared with another NGS assay (OCA). These rapid multi-gene assays highly contributed to enabling precision medicine and the development of targeted therapies for advanced NSCLC. READ ARTICLE

Journal of Clinical Oncology DOI:10.1200/JCO.2021.39.15_suppl.9094

Authors: Shingo Matsumoto, Takaya Ikeda, Kiyotaka Yoh, Akira Sugimoto, Terufumi Kato, Kei Kunimasa, Atsushi Nakamura, Ichiro Nakachi, Shoichi Kuyama, Jun Sakakibara-Konishi, Haruko Daga, Eiji Iwama, Kageaki Taima, Naoki Furuya, Kaname Nosaki, Hiroki Izumi, Yoshitaka Zenke, Koichi Goto

Biomarker tissue journey among patients (pts) with untreated metastatic non-small cell lung cancer (mNSCLC) in the U.S. Oncology Network community practices

Background: Given the importance of molecular testing and targeted therapy for mNSCLC, the MYLUNG (Molecularly Informed Lung Cancer Treatment in a Community Cancer Network) consortium pragmatic study assessed real-world biomarker testing rates and turnaround times (TAT) within The US Oncology Network of over 1,000 providers across the United States. Conclusions: This real-world study showed that most pts received at least one biomarker test prior to 1L, but <50% received all 5 tests. NGS testing occurred in <50% of pts but increased over the periods examined. Median time from dx to 1L therapy was about 5 weeks and TAT from orders to results about 2 weeks. Analyses by histology and other trends will be reported. These data will be compared to the next phase of the MYLUNG study, which will evaluate contemporary ordering practices and TATs prospectively. READ ARTICLE

Journal of Clinical Oncology DOI:10.1200/JCO.2021.39.15_suppl.9004

Authors: Nicholas J. Robert, Esmond D. Nwokeji, Janet L. Espirito, Liwei Chen, Mandar Karhade, Makenzi Colleen Evangelist, Alexander I. Spira, Marcus A. Neubauer, Susie A. Bullock, Robert L. Coleman, on behalf of MYLUNG Consortium Collaborators: The U.S. Oncology Network and sponsors

Outcomes of KRAS mutated, EGFR mutated, ALK mutated and wildtype patients in non-small cell lung cancer brain metastases

Background: Non-small cell lung cancer (NSCLC) is the most common primary tumor leading to brain metastases. Multiple genetic markers have been profiled in NSCLC patients for potential targeted therapies. EGFR is mutated in up 50% of NSCLCs, while ALK is mutated in around 4-7%. KRAS is the most commonly overexpressed marker, seen in up to 85% of all lung cancers. In this retrospective study, we evaluated the overall survival (OS) and progression-free survival (PFS) between NSCLCBM patients with KRAS mutations, ALK mutations, EGFR mutations, and wildtype. Conclusions: Molecular mutations serve as both prognostic predictors and alternative targeted therapies for NSCLCBM treatment. Our retrospective study showed improved mOS and mPFS in NSCLCBM patients with ALK rearrangements when compared to patients with EGFR mutations, KRAS mutations, and the wildtype. While these results looked at patient outcomes with specific tumor markers, further investigation needs to be done regarding outcomes..... READ ARTICLE

Journal of Clinical Oncology DOI:10.1200/JCO.2021.39.15_suppl.e21028

Authors: Yasmeen Rauf, Vineeth Tatineni, Patrick joseph Oshea, Xuefei Jia, David M. Peereboom, Manmeet Singh Ahluwalia

Conference PaperKirk SmithMay 28, 2021non-small cell lung cancer (NSCLC), mutations, PFS

Impact of prior ALK-tyrosine kinase inhibitor on pemetrexed-based chemotherapy in patients with advanced ALK positive non-small cell lung cancer

Background: In phase Ⅲ trial comparing crizotinib with chemotherapy in patients with ALK-positive non-small-cell lung cancer (NSCLC) patients, it suggests that pemetrexed is highly effective against ALK-positive NSCLC. However, it is unclear that pemetrexed-based chemotherapy is effective in patients previously treated with ALK-tyrosine kinase inhibitor (ALK-TKI) as well as ALK-TKI naïve patients. Therefore, we investigated the impact of prior ALK-TKI therapy on pemetrexed-based chemotherapy. Conclusions: Pemetrexed-based chemotherapy might be less effective in ALK-positive NSCLC patients previously treated with ALK-TKI. This retrospective study results suggested that ALK-TKI sequence can be a better treatment option in ALK-positive NSCLC patients. READ ARTICLE

Journal of Clinical Oncology DOI:10.1200/JCO.2021.39.15_suppl.e21113

Authors: Michitoshi Yabe, Hirotsugu Kenmotsu, Hiroaki Kodama, Naoya Nishioka, Eriko Miyawaki, Taichi Miyawaki, Nobuaki Mamesaya, Haruki Kobayashi, Shota Omori, Kazushige Wakuda, Akira Ono, Tateaki Naito, Haruyasu Murakami, Toshiaki Takahashi

Outcomes of first, second, and third-generation anaplastic lymphoma kinase (ALK) inhibitors in non-small cell lung cancer brain metastases (NSCLCBM)

Background: Non-small cell lung cancer (NSCLC) is the most common cause of brain metastases. ALK, which codes for tyrosine kinase receptors, is rearranged in 4-7% of NSCLC. First-generation ALK inhibitors have restricted efficacy due to poor blood-brain barrier (BBB) penetration and ALK-resistant tumor mutations. Second-generation ALK inhibitors have shown better BBB penetration, while third-generation ALK inhibitors were efficacious even against ALK-resistant mutations. In this retrospective study, we investigated the overall survival (OS) and progression-free survival (PFS) in NSCLCBM patients treated with first, second, and third-generation ALK inhibitors. Conclusions: Newer generations of targeted therapies in NSCLCBM have improved BBB penetration and effectiveness against resistant mutations. We determined that there was a significant 5-year OS benefit in patients who received second and third-generation ALK inhibitors compared to first-generation ALK inhibitors, and a respective..... READ ARTICLE

Journal of Clinical Oncology DOI:10.1200/JCO.2021.39.15_suppl.2034

Authors: Vineeth Tatineni, Patrick Joseph O'Shea, Yasmeen Rauf, Xuefei Jia, Erin Sennett Murphy, Samuel T. Chao, John H. Suh, David M. Peereboom, Manmeet Singh Ahluwalia

PROTACs: A novel strategy for cancer therapy

Chemotherapeutic strategy has been widely used for treating malignance by targeting irregular expressed or mutant proteins with small molecular inhibitors (SMIs) or monoclonal antibodies (mAbs). However, most intracellular proteins lack of active sites or antigens where SMIs or mAbs bind with, and are called as non-druggable targets for a long time. From the first year of this century, PROteolysis-TArgeting Chimeras (PROTACs) has emerged to be a promising approach for proteins, including those non-druggable ones, such as transcriptional factors and scaffold proteins. The first generation of peptide-based PROTACs adopts β-TrCP and VHL as E3 ligases, but the cellular permeability and chemical stability issues restrict their clinical application. The second generation of small molecule-based PROTACs adopts MDM2, VHL, IAPs and Cereblon as E3 ligases have been tensely studied. To date, the targets of PROTACs including those overexpressed oncogenic proteins such as ER, AR and BRDs, disease-r..... READ ARTICLE

Seminars in Cancer Biology DOI:10.1016/j.semcancer.2020.02.006

Authors: Jing Liu, Jia Ma, Yi Liua, Jun Xia, Yuyun Li, Z. Peter Wang, Wenyi Wei

Conference PaperKirk SmithDecember 1, 2020PROTACs, Cancer, Therapyopto-PROTAC, pcPROTAC, PHOTAC, Photo-PROTAC

Optimal Timing And Technique Of Local Therapy For Brain Metastases From Non-Small Cell Lung Cancer With Driver Mutations

Objective(s): Brain metastases (BM) are frequent in non-small cell lung cancer patients with driver mutations (dm-NSCLC). Since the availability of brain-penetrating tyrosine kinase inhibitors (TKI), the role of local therapy (LT) for BM from dm-NSCLC is frequently discussed. This analysis examines prognostic factors, particularly the effect of LT timing and technique, in patients with BM from dm-NSCLC. Conclusion: In this analysis, early LT improved icPFS but not OS in TKI-naive patients with BM from dm-NSCLC, compared to upfront TKI treatment. No benefit was shown for WBRT over SRS regarding either icPFS or OS. In light of the toxicities of WBRT, the choice of RT technique should be considered carefully in the context of overall prognosis and quality of life. Especially patients presenting initially with multiple BM may benefit from delaying RT or from individualized approaches like the SRS of multiple or only selected BM instead of WBRT. READ ARTICLE

International Journal of Radiation Oncology DOI:10.1016/j.ijrobp.2020.07.096

Authors: R. El Shafie, T. Eichkorn, D. Weber, F. Bozorgmehr, L. König, S. Rieken, M. Thomas, J. Debus, P. Christopoulos